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Current Topics in Medicinal Chemistry, 2020, 20, 1353-1397

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eISSN: 1873-4294

Periodontal Pathogens and Neuropsychiatric Health Impact

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Abhishek Wadhawan1,2, Mark A. Reynolds3, Hina Makkar1, Alison J. Scott4, Eileen Potocki5,
Current Topics in Medicinal Chemistry

Andrew J. Hoisington6, Lisa A. Brenner7,8,9, Aline Dagdag1, Christopher A. Lowry7,9,8,10,11,

Yogesh Dwivedi12 and Teodor T. Postolache1,8,9,13,*

1
Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, USA;
2
Department of Psychiatry, Saint Elizabeths Hospital, Washington, D.C. 20032, USA; 3Department of Advanced Oral
Sciences & Therapeutics, University of Maryland School of Dentistry, Baltimore 21201, USA; 4Department of Microbial
Pathogenesis, University of Maryland School of Dentistry, Baltimore, USA; 5VA Maryland Healthcare System, Balti-
more VA Medical Center, Baltimore, USA; 6Air Force Institute of Technology, Wright-Patterson Air Force Base, USA;
7
Departments of Psychiatry, Neurology, and Physical Medicine & Rehabilitation, University of Colorado Anschutz
Medical Campus, Aurora, USA; 8Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC),
Veterans Integrated Service Network (VISN) 19, Aurora, USA; 9Military and Veteran Microbiome: Consortium for Re-
search and Education (MVM-CoRE), Aurora, USA; 10Department of Integrative Physiology, Center for Neuroscience
and Center for Microbial Exploration, University of Colorado Boulder, Boulder, USA; 11Rocky Mountain Mental Illness
Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center
(RMRVAMC), Aurora, USA; 12Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Bir-
mingham, Alabama, USA; 13Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Integrated
Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, USA

Abstract: Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic dis-

ARTICLE HISTORY
Received: September 01, 2019
Revised: December 04, 2019
Accepted: December 04, 2019
DOI:
10.2174/1568026620666200110161105
eases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of
the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a
polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the dis-
ease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and
neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation
as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the
pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vascula-
ture has important pathophysiological consequences. Distant effects via translocation rely on virulence
factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its
capability to manipulate the immune system via several mechanisms, including its capacity to induce
production of immune-downregulating micro-RNAs. Possible targets for intervention and drug devel-
opment to manage distal consequences of infection with P. gingivalis are also reviewed.

Keywords: Chronic periodontitis, Porphyromonas gingivalis, Dementia, Cardiovascular disease, Metabolic syndrome, Suicidal
behavior, Mood disorders, micro-RNAs.

1. INTRODUCTION of periodontal diseases. Gingivitis is characterized by gingi-

1.1. Periodontal Diseases
Periodontal diseases are infections of the supporting tis-
sue(s) of the teeth. Oral bacterial biofilms are the primary
etiology of periodontal diseases, which are often chronic in
nature. Gingivitis and periodontitis are the two major types
*Address correspondence to this author at 685 W. Baltimore Street, Suite #
930, Baltimore, MD 21201, USA; Tel: +1-(301) 996-9040;
E-mail: tpostola@som.umaryland.edu
val inflammation without the destruction of the supporting
periodontal ligament and bone. Gingivitis can generally be
resolved by effective oral hygiene [1-8], although other risk
factors may also lead to inflammation of the gums (reviewed
in [9]), which can then advance to periodontitis, if not treated
appropriately [10]. In periodontitis, the inflammatory condi-
tion results in the breakdown of the periodontal ligament and
resorption of alveolar bone, resulting in loss of tooth support
[3]. This destructive process, which results in apical migra-
tion of the gingival epithelium, is characterized clinically by

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1354 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 Wadhawan et al.

formation of periodontal pockets. With advancing destruc-
tion of the periodontal tissues, an increase in tooth mobility
and masticatory impairment occurs. Tooth loss can eventu-
ally occur if periodontitis is not treated [11]. Based on a
combination of clinical measures, i.e., clinical Attachment
Loss (CAL) and Periodontal Probing Depth (PPD), used to
diagnose and characterize periodontal disease, a frequently
used composite case definition of periodontitis was intro-
duced by the American Academy of Periodontology (AAP)
and the Centers for Disease Control and Prevention (CDC).
“Severe periodontitis” is defined as “≥ 1 interproximal site
with PPD ≥ 5 mm and ≥ 2 interproximal sites with CAL ≥ 6
mm (not on the same tooth).” “Moderate periodontitis” is
defined as “≥ 2 interproximal sites with PPD ≥ 5 mm (not on
same tooth), or ≥ 2 interproximal sites with CAL ≥ 4 mm
(not on same tooth)” “Mild periodontitis” is defined as “≥ 2
interproximal sites with CAL ≥ 3 mm, and one site with PPD
≥ 5 mm or ≥ 2 interproximal sites with PPD ≥ 4 mm (not on
the same tooth)” “No periodontitis” is defined as “No evi-
dence of mild, moderate, or severe periodontitis” [12].
Periodontitis is a major public health issue and its preva-
lence is high in the adult population of the United States
[13]. Estimates of the prevalence of periodontitis across
populations vary substantially because no sets of thresholds
have been consistently used in epidemiological studies. De-
spite these shortcomings, based on the definitions provided
by AAP and CDC, the data obtained from the National
Health and Nutrition Examination Survey (NHANES) 2009-
2012 indicated that 46% of the adult population of the
United States (≥ 30 years) consisting of approximately 65
million adults, had periodontitis, and 8.9% among those had
severe periodontitis [14]. Additionally, 44.7% of the adults
aged ≥ 30 years had periodontitis between the years 2011 to
2012 [14]. Prevalence of periodontitis has been reported to
be higher in older adults (≥ 65 years old), with almost two-
thirds of that subpopulation being affected throughout the
United States [15], likely due to lack of access to dental care,
in addition to other factors [16].
1.2. Associations of Periodontal Disease with Cardiovas-
cular, Metabolic and Neuropsychiatric Disorders
Increasing evidence has demonstrated that periodontitis
is associated with conditions that pose a significant risk of
morbidity and mortality (Fig. 1), such as cardiovascular dis-
eases (e.g., heart attack, coronary artery disease, and stroke)
and type 2 diabetes mellitus [17, 18]. Moreover, periodontal
disease and systemic conditions, such as cardiovascular dis-
ease, often share common risk factors, including obesity,
smoking, and aging [19]. Accumulating data indicate that
patients with other systemic diseases, such as Acquired Im-
munodeficiency Syndrome (AIDS), Down’s syndrome, and
leukemia, are at increased risk of developing periodontitis
[20, 21]. Periodontitis appears to be a risk indicator or factor
for major chronic systemic conditions and health-related
outcomes, including in pregnant women [22].

Barrier Systemic
Periodontium breach Circulation spread Distal sites

Atherosclerosis Alzheimer’s
Viable
Ginglval disease
bacteria
Tooth epithelium
enamel
Periodontal Stroke
pocket

Obesity Pulmonary
Leukocytes infections
Bacterial
Bacteria products
LPS Rheumatoid Inflammatory
arthritis bowel
disease
Acute-
Alveolar phase Colon
Pro-inflammatory response
bone cancer
mediators

IL-17 TNF-a Diabetes

Vasculature
Junctional IL-1b IL-6 Pregnancy
epithelium Osteoclast complications

Fig. (1). Periodontitis and systemic diseases. Ulceration of the gingival epithelium initiates periodontitis, which is followed by influx of im-
mune cells and bacterial invasion that eventually leads to destruction of the supporting alveolar bone and inflammatory damage of the perio-
dontal tissues. These processes mediated by chronic inflammation allow leakage of host inflammatory factors, pathogenic oral bacteria, and
bacterial products into the systemic circulation, from where they are translocated to distal tissue sites and organs. When periodontally-
derived products reach the bloodstream, a multitude of systemic diseases are potentially adversely affected by them, either indirectly via
amplification of the systemic inflammatory response, or directly in situ. IL: interleukin; TNF-α: tumor necrosis factor-alpha; LPS: lipopoly-
saccharide. (Reproduced from: Konkel JE, O’Boyle C and Krishnan S (2019) Distal Consequences of Oral Inflammation. Front. Immunol.
10:1403. doi: 10.3389/fimmu.2019.01403.
Periodontal Pathogens and Neuropsychiatric Health
Previous research has reported an association between
periodontitis and cardiovascular diseases, including ischemic
heart disease [23], cerebrovascular disease [24], atheroscle-
rotic cardiovascular disease [25], and peripheral arterial dis-
ease [26, 27]. Specifically, several systematic reviews, co-
hort, cross-sectional, and case-control studies have also dem-
onstrated a statistically significant relationship between pe-
riodontitis and myocardial infarction [28-41]; however, this
association has not been observed in all studies [42-48].
Many candidate mechanisms have been postulated to explain
the positive association between periodontal and cardiovas-
cular diseases. An individual may be at a higher risk for de-
veloping both periodontal disease and atherosclerosis in the
presence of an underlying inflammatory response trait [49].
Once periodontal disease occurs, it may serve to initiate and
exacerbate atherogenesis and thromboembolic events by
providing a biological burden of inflammatory molecular
mediators [thromboxane A2, interleukin (IL)-1 beta, prosta-
glandin E2 and tumor necrosis factor-alpha (TNF-α)] and
immune triggers such as endotoxin [49]. Additionally, the
presence of bacteria in the bloodstream has been associated
with elevation of biomarkers for inflammation [50, 51]. Oral
bacteria can pass into the bloodstream due to disruptions in
the integrity of gingival sulcular/pocket epithelium (barrier),
which is characteristic of periodontitis [52, 53]. Periodontitis
has been reported to be associated with ischemic stroke as
well. Based on five case-control studies (pooled Relative
Risk [RR] = 3.04, 95% CI: 1.10–8.43) [54-58] and three co-
hort studies (pooled RR = 2.52, 95% CI: 1.77–3.58) [49, 59,
60], a statistically significant association was reported in a
meta-analytical study [61].
A relationship between periodontitis and metabolic dis-
eases has also been reported. As shown by several studies,
chronic periodontitis has been associated with obesity [62-
64], and this relationship even exists in adolescents [65].
Cross-sectional evidence exists for a negative correlation
between periodontitis and good physical fitness after adjust-
ing for a number of confounders, including higher fasting
plasma glucose, old age, and smoking habits [66]. Prospec-
tive studies also indicate an increased risk of periodontitis
being associated with a sedentary lifestyle, as well as a linear
and inverse association between periodontitis and sustained
physical activity [67-69]. When compared with non-
diabetics, diabetic patients have been reported to have higher
plaque deposits and poorer oral hygiene [70]. Bad periodon-
tal health has been reported in individuals with metabolic
syndrome as compared to healthy controls [71-72]. Moreo-
ver, clinical measures of periodontitis have been reported to
have a relationship with various components of metabolic
syndrome in a dose-dependent manner [73]. Specifically, an
association has been exhibited between periodontitis and
components of metabolic syndrome, including hypertension,
obesity, dyslipidemia, and hyperglycemia [74-79].
Periodontal disease has been reported to be positively as-
sociated with dementia as well [80]; however, the data are
inconsistent. Although one systematic review reported a
positive association between periodontal disease and Alz-
heimer’s disease (AD) [Odds ratio (OR): 1.69, 95% confi-
dence intervals (CI): 1.21-2.35] [81], another review failed to
provide conclusive evidence for either periodontitis or mul-
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1355
tiple tooth loss as significant risk factors for dementia [82].
However, when compared to healthy individuals, under-
standably demented patients have been shown to exhibit sig-
nificantly poorer measures of periodontal health [83]. Simi-
larly, a prospective cohort study from Japan reported an in-
crease in the risk of all-cause dementia and AD with tooth
loss [84]. Specifically, an increase in multivariable-adjusted
hazard ratio of all-cause dementia was reported with decreas-
ing number of remaining teeth (p for trend = .04), after ad-
justing for potential confounders [84]. Another prospective
cohort study also confirmed an increased risk of developing
dementia in patients with complete tooth loss [hazard ratio
(HR) = 1.10, 95% CI = 1.04-1.16] and those not undergoing
periodontal treatment [HR = 1.14, 95% CI = 1.04-1.24],
when compared with individuals who received dental pro-
phylaxis, following adjustment for confounders [85]. Addi-
tionally, as compared to AD patients without periodontitis,
AD patients with periodontitis have been reported to have a
sixfold increase in cognitive decline over a period of 6-
months in a prospective observational study [86].
Patients with AD have been reported to have altered cy-
tokine profiles, microglial activation, inflammasome activa-
tion, and complement activation, features that are consistent
with infectious pathologies [87, 88]. Interest in identifying a
potential infectious cause of AD has grown with the recent
characterization of amyloid-β (Aβ) as an antimicrobial pep-
tide [89-91]. Porphyromas gingivalis (P. gingivalis) infec-
tion, as well as periodontitis, have been reported to be risk
factors for the development of AD, Aβ plaques, and demen-
tia [92-96]. Data from a study on Apoe−/− mice indicated
that brain infection and activation of the complement path-
way occurred only upon oral infection with P. gingivalis,
which was not seen upon infection of these mice with other
two oral bacteria used in this study [97]. As compared to
control mice, infection of the oral cavity with P. gingivalis
resulted in alveolar bone loss, impaired cognitive function,
and increased deposition of AD-like plaques in transgenic
mice overexpressing mutated hAPP-J20 [98]. Detection of P.
gingivalis lipopolysaccharide (LPS) in the postmortem hu-
man brain tissue of AD patients [99] supports the hypothesis
that infection of the brain by P. gingivalis may affect the
pathophysiology of AD [100]. More recently, Dominy et al.
identified P. gingivalis DNA in the cerebrospinal fluid (CSF)
of living subjects with probable AD and the postmortem
brain tissue of AD patients, but not in patients with other
neurodegenerative diseases. These results suggest a certain
pathophysiological specificity and that DNA of P. gingivalis
could be used as a potential diagnostic marker in AD [101].
Moreover, evidence from a recent animal study points to-
wards neuroinflammatory mechanisms potentially mediating
the associations between ischemic stroke and periodontitis
[102], which perhaps, could also have a role in the patho-
physiology of vascular dementia.
Psychiatric patients have also been shown to have an ele-
vated risk of periodontal disease. In a study of institutional-
ized psychiatric patients, the majority had periodontal bleed-
ing on probing and periodontal pockets; moreover, older
patients were more likely to be edentulous (i.e., lacking
teeth) [103]. Moderately deep pockets have been reported in
about 59% of psychiatric outpatients [104] and 15-28% of
1356 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15
psychiatric inpatients [103, 105, 106]. A meta-analysis re-
ported that patients with severe mental illness had a signifi-
cantly more likelihood of losing all their teeth, as compared
to the general community (OR: 2.8, 95% CI: 1.7-4.6) [107].
More recently, patients with schizophrenia have been re-
ported to have a higher evidence of periodontal disease,
higher unmet dental prosthetic needs, and greater dental car-
ies [108]. Moreover, the severity of schizophrenia and ex-
trapyramidal side-effects were associated with poor oral
health [108]. Likewise, in a separate study, poorer oral hy-
giene and periodontal health, as evidenced by plaque index,
gingival index, and probing pocket depths, were reported in
patients who had a diagnosis of schizophrenia for a duration
of ≥ 11 years (p < 0.001) [109]. In a case-control study, bi-
polar disorder was associated with an increased risk for pe-
riodontitis (OR = 2.13; 95% CI: 1.39-3.27), and periodontitis
was also strongly associated with the depressive phase of
bipolar disorder (OR = 28.94; 95% CI: 4.44-177.27;
p<0.001) and the total bacterial load (OR = 1.91; 95% CI:
1.0-1.99; p < 0.001) [110]. Similar associations were found
in a separate study, which reported higher caries prevalence,
poorer periodontal health, and poorer oral hygiene in bipolar
patients as compared to healthy controls [111]. A recent
cross-sectional study indicated that depression was signifi-
cantly associated with alcohol use (OR = 1.47; 95% CI: 1.38,
1.57) and periodontal disease during pregnancy (OR = 1.76;
95% CI: 1.73, 1.80), and that depression during pregnancy
was positively associated with having a preterm delivery
(OR = 1.18; 95% CI: 1.15, 1.21 and having low birth weight
(OR = 1.21; 95% CI: 1.17, 1.21], with depression possibly
serving as a mediator in the association between adverse
birth outcomes and periodontal disease [112]. A prospective
cohort study also revealed a positive association between
depressive symptoms and moderate/severe periodontitis
[RR: 1.18], as well as higher risk of periodontitis (RR: 1.19)
[113]. Moreover, in the Old Order Amish, tooth loss has
been associated with cardinal symptoms of depression, such
as anhedonia and dysphoria/hopelessness. These effects were
reported to be mediated by inflammation [114].
The associations between psychiatric disorders and
periodontal disease and its manifestations have been related
to poor compliance of dental treatments, negative outlook
towards the physician, dental phobia, poor oral hygiene,
trouble accessing health care services, lack of self-care, poor
nutrition, and medication side-effects (dry mouth) in patients
with schizophrenia, depression, and anxiety disorders [115-
124]. Negative thought patterns may be precipitated or wors-
ened in patients with periodontitis due to the social stigma
associated with halitosis, as well as their altered appearance
resulting from pathologic tooth migration, tooth loss, or both
[125, 126]. In contrast to bipolar disorder patients experienc-
ing depressive and mixed states when self-neglect may be
the most distinctive feature requiring motivating and educa-
tional efforts, those patients experiencing mania may have
mucosal or gingival lacerations or dental abrasions resulting
from overenthusiastic flossing and tooth brushing [118], re-
quiring supervision of dental hygiene. In subjects with psy-
chiatric illnesses, co-morbid substance use disorders (psy-
chostimulants, alcohol, tobacco) may also increase the risk
of oral health problems [127-129]. An extensive review by
Makkar et al. lists the bidirectional associations of periodon-
Wadhawan et al.
tal disease with cardiovascular, metabolic and psychiatric
disorders, with inflammation being proposed as the mediator
for these associations [9]. Moreover, comorbidities exist
between metabolic and psychiatric disorders/symptoms
[130] that may be explained by genes of the prolactin-
pathway and the shared inherited predisposition to psycho-
neuro-endocrine dysfunction [131].
2. PERIODONTAL PATHOGENS
The oral cavity is continuously bathed in saliva and char-
acterized by a pH close to neutrality and in a narrow range of
temperature (34 to 36 ⁰C) creating a distinct habitat for a
variety of microorganisms [132]. In addition to bacteria, the
oral cavity harbors other types of microflora as well, includ-
ing protozoa, fungi, viruses, and mycoplasma [133]. While
there are over 700 species of bacteria that can colonize the
oral cavity [134], only a relatively small number of bacterial
species are closely associated with periodontitis [135]. Bac-
teria in the oral cavity are classified broadly in two ways: a)
according to Gram-staining-Gram-positive and Gram-
negative; and b) according to their oxygen requirements-
aerobic or anaerobic. The anaerobic bacteria are further sub-
divided into facultative and obligate anaerobic subsets (Ta-
ble 1). Nevertheless, the oral cavity has a stable community
of microbes that coexist symbiotically, despite the presence
of such diversity in the oral microbiome. Hence, periodontal
disease may result from microbial dysbiosis, leading to the
emergence of pathogenic microorganisms. In fact, a shift in
the predominant species of microbes in the gingival sulcus to
Gram-negative, proteolytic, anaerobic and chemoorganotro-
phic organisms from an initial preponderance of Gram-
positive, fermentative and facultative microorganisms has
been associated with damage to the periodontal tissues [136].
Seminal work by Socransky and colleagues utilized
whole genomic DNA probes and checkerboard DNA–DNA
hybridization to characterize periodontal microbial commu-
nities based on a color-coded system that reflected associated
disease severity, community ordination, and cluster analysis
[137]. These investigators reported that a total of five major
complexes were observed consistently, using their analytical
methods, which were initially color-coded as red, orange,
green, yellow, and purple complexes [137]. Amongst these
groups, the foremost complex was the “red complex” that
consisted of three species, i.e., Tannerella forsythia (T. for-
sythia), Treponema denticola (T. denticola) and P. gin-
givalis, and their detection was associated with diseased
sites, as well as with each other [137]. Whereas orange com-
plex [consisting of Parvimonas micra (P. micra), Prevotella
intermedia (P. intermedia), Fusobacterium nucleatum (F.
nucleatum), Eubacterium nodatum (E. nodatum), Prevotella
nigrescens (P. nigrescens), and Campylobacter rectus (C.
rectus)] is also correlated with diseased periodontal tissues,
yellow, green, and purple complexes have been associated
with healthy periodontal status [137, 138].
Additionally, these complexes likely reflect early to late
colonizers in developing dental biofilms as part of microbial
succession [139]. Members of the purple (e.g., Veillonella
parvula and Actinomyces odontolyticus), yellow (some
Streptococcus species, e.g., Streptococcus mitis) and green
Periodontal Pathogens and Neuropsychiatric Health
Table 1. More frequently isolated microorganisms from human oral cavity (Reproduced from How KY, Song KP, and Chan KG
(2016) Porphyromonas gingivalis: An Overview of Periodontopathic Pathogen below the Gum Line. Front. Microbiol. 7:53.
doi: 10.3389/fmicb.2016.00053).
Microbial group
Aerobic or facultative
Gram-positive
Obligate anaerobes
Aerobic or facultative
Gram-negative
Obligate anaerobes
[e.g., Aggregatibacter actinomycetemcomitans (A. actinomy-
cetemcomitans), Eikenella corrodens, Capnocytophaga spu-
tigena, Capnocytophaga ochracea, and Campylobacter con-
cisus] complexes constitute most of the early colonizing mi-
crobial species. Generally, after establishment of the early
colonizers, the orange complex bacteria (i.e., F. nucleatum,
P. micra, P. intermedia, P. nigrescens, E. nodatum, and C.
rectus) appear, which are putative periodontal pathogens. All
three members of the red complex (i.e., P. gingivalis, T. for-
sythia and T. denticola) are also on the list of putative perio-
dontal pathogens and are considered as the climax commu-
nity [137]. Follow-up studies placed early colonizers, includ-
ing Actinomyces species, in a sixth group, i.e., the blue com-
plex [138, 140]. Notably, putative periodontal pathogens are
present in all groups of colonizers, i.e., early to late [137,
138, 140]. These bacteria could contribute significantly to
the initiation and progression of periodontal infections under
appropriate conditions. Despite the presence of other oral
pathogens of interest, we have narrowed our discussion in
this review to P. gingivalis, because of the recent emergence
of data that has implicated this bacterium in AD [97-101]
and due to the ongoing development of drugs against this
pathogen, as described in later parts of this review.
2.1. Porphyromonas gingivalis
The bacterial species that is highly implicated with both
chronic and aggressive periodontitis is the Gram-negative,
asaccharolytic, P. gingivalis, which can be found in almost
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1357
Microbial genus/species
Streptococcus (S. gordonii, S. mitis, S. auralis, S. salivarius)
Staphylococcus (S. aureus, S. epidermidis)
Enterococcus (E. faecalis)
Lactobacillus (L. casei, L. fermentum)
Corynebacterium (C. matruchotii)
Actinomyces (A. naeslundii, A. israelli, A. viscosus)
Arachnia (A. propionica)
Rothia (R. dentocariosa)
Bacillus (B. cereus)
Propionibacterium (P. acnes)
Peptostreptococcus (P. micros, P. anaerobius)
Campylobacter (C. rectus, C. concisus, C. gracilis)
Actinobacillus (A. actinomycetemcomitans)
Fusobacterium (F. nucleatum)
Porphyromonas (P. gingivalis)
Prevotella (P. melaninogenica, P. oralis, P. intermedia)
85% of the sites with periodontal destruction [141, 142].
Also, in healthy sites, P. gingivalis, is found rarely or in low
counts. It forms black-pigmented colonies on blood agar
plates after 6 to 10 days due to heme accumulation, and iron
is an absolute requirement for the growth of this bacterium
[143]. Within the human oral cavity, the major habitat of P.
gingivalis is the subgingival pocket where availability of
sugar is low. Hence, the survival of this bacterium in the
deep periodontal pocket is dependent upon the fermentation
of amino acids for energy production [144]. As P. gingivalis
is an obligate anaerobe, it often attaches to the primary colo-
nizers of dental plaque, including P. intermedia and Strepto-
coccus gordonii, and therefore, it is referred to as the secon-
dary colonizer of dental plaque. In advanced periodontal
lesions, it has been demonstrated that P. gingivalis associates
with T. denticola and T. forsythia to establish the red com-
plex [145]. Evidence from immunological studies also indi-
cates that patients diagnosed with adult periodontitis have
higher serum levels of antibodies to P. gingivalis [146-149].
Based on their capacity to develop abscesses in experi-
mental animal models, strains of P. gingivalis have been
divided into two types: invasive and non-invasive. Under
both in vivo and in vitro conditions, the invasive strain of P.
gingivalis has been reported to demonstrate greater patho-
genicity than the non-invasive strain [150, 151]. The process
of periodontal tissue destruction is complex, and its induc-
tion and progression depend on the release of bacterial sub-
1358 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15
stances, host inflammatory response, and plaque accumula-
tion. Constituents or metabolites of a pathogen that cause
damage to the host and are essential in various stages of the
pathogen’s life cycle are referred to as virulence factors. P.
gingivalis possesses virulence factors that can penetrate the
gingivae and cause tissue destruction directly or indirectly by
induction of inflammation; these virulence factors include
LPS, fimbriae, capsule, gingipains or cysteine proteinases,
outer membrane proteins, outer membrane vesicles, and
haemagglutinins [152-155]. Changes in the external envi-
ronment of the periodontopathogen often determine the ex-
pression of virulence factors. If these virulence factors are
activated, induction of host immune responses via cytokine
production, inhibition of host protective mechanisms, bone
resorption, as well as rapid and significant destruction of
periodontal tissues can occur in hosts. A paucity of informa-
tion is available on the mechanisms and the expression of
these virulence determinants during various stages of perio-
dontal disease. Below, we summarize the virulence factors
(Fig. 2) possessed by P. gingivalis:
Capsule
OM and Gingipains
LPS
Fimbriae
Fig. (2). Virulence factors of Porphyromonas gingivalis.
2.1.1. Gingipains
A virulence factor that allows most P. gingivalis strains
to colonize the oral cavity is their ability to secrete toxic me-
tabolites together with numerous lipolytic, proteolytic and
hydrolytic enzymes. Some of the enzymes are transported
from the outer membrane into outer membrane vesicles dur-
ing bacterial growth, while others are found within the perip-
lasmic space. Usually, these bacterial enzymes are present
adjacent to the host cells. Of these enzymes, the progression
of periodontal disease mainly involves proteolytic enzymes,
including peptidases, as well as caseinolytic-, trysin- and
thiol-proteinases [156, 157]. Generally, P. gingivalis pro-
duces proteases that belong to two distinct families: a) serine
proteinase family, and b) cysteine proteinase family (also
known as “trypsin-like” enzyme) [144]. Cleavage of poly-
peptides at the C-terminal after the lysine or arginine residue
is carried out by the “trypsin-like” enzymes, which are usu-
ally referred to as gingipains. Depending on whether gingi-
pains cleave after the lysine or arginine residue, they are
called gingipain K or R, respectively. Of the total extracellu-
lar proteolytic activity that occurs at the sites infected by P.
gingivalis, these enzymes responsible for about 85% of the
Wadhawan et al.
proteolysis [158]. While gingipain K has one sub-type, i.e.,
Kgp; gingipain R has two sub-types, RgpA and RgpB. The
extracellular matrix components, such as collagen, immuno-
globulins, complement factors, cytokines and the integrin–
fibronectin-binding are degraded by gingipain R [156, 159].
Additionally, maturation and processing of the major fim-
briae (FimA) are also carried out by this enzyme [160].
Available evidence suggests a direct role of P. gingivalis
proteases in the colonization and destruction of supporting
periodontal tissues [161, 162]. Furthermore, high resistance
to host defense mechanisms is conferred to the microorgan-
isms by these enzymes. P. gingivalis proteases also disrupt
inflammatory response of the host, activate the matrix metal-
loproteinases in the host, inactivate inhibitors of plasma pro-
teinases, and cleave the receptors on the surface of host cells
[159, 163]. Within biofilms consisting of mixed-species in-
cluding P. gingivalis, these enzymes mediate detachment
and reduction of A. actinomycetemcomitans aggregation
[164], as well as reduction in the numbers of T. forsythia
[165]. Furthermore, gingipains contribute to inhibition of
blood coagulation and, consequently, increased bleeding by
degrading fibrinogen and host heme proteins, hence promot-
ing bacterial growth by enhancing the availability of hemin
[166]. Since erythrocytes are found in abundance in perio-
dontal pockets, it is not surprising to find a high proliferation
of P. gingivalis within them. Gingipains also have a role in
the breakdown of complement factors (e.g., C4 and C3), T-
cell receptors (e.g., CD8 and CD4), and antibacterial pep-
tides (e.g., neutrophil-derived α -defensins) [165, 167]. P.
gingivalis and its gingipains have been reported to proac-
tively manipulate host molecules and prevent bacterial clear-
ance by interfering with the crosstalk between toll-like re-
ceptor (TLR) and C5a receptor signaling [168]. Evidence
from in vitro studies indicates that inflammatory mediators
from various host cells are also regulated by gingipains, such
as soluble triggering receptor expressed on myeloid cells-1
[169], protease-activated receptor-2 [170], and various inter-
leukins (IL-1α, IL-1β, IL-18) [171]. However, it remains
unclear whether periodontitis progresses due to the concur-
rent effects of gingipains on the abovementioned inflamma-
tory mediators. Toxicity of P. gingivalis has been reported to
be mediated by gingipains within the epithelial cells, endo-
thelial cells and fibroblasts [172-174]. Furthermore, gingi-
pains are implicated as narrow-spectrum virulence targets
because eradication of P. gingivalis rarely occurs on treat-
ment with broad-spectrum antibiotics and may result in resis-
tance [175-179]. P. gingivalis virulence can be reduced by
using short peptide analogs that block the proteolytic activity
of gingipains [180]. In a recent study, it was reported that as
compared to the non-AD control individuals, AD brains had
significantly higher gingipain immunoreactivity [101]. These
researchers performed further testing in vivo of the potent,
selective, brain-penetrant, small-molecule gingipain inhibi-
tors developed by them and reported that a disease-
modifying effect in AD could be achieved by small-molecule
inhibition of gingipains [101].
2.1.2. Lipopolysaccharide
LPS composes the outer membrane of Gram-negative
bacteria and is an important factor for innate immune recog-
nition by TLR 4 [181, 182]. Three structurally distinct re-
gions characterize LPS – O-antigen polysaccharide, core
Periodontal Pathogens and Neuropsychiatric Health
oligosaccharide, and lipid A – with structural diversity de-
creasing proximally [183]. LPS serves as an essential immu-
nomodulatory tool for P. gingivalis, with modifications to
the canonical structure resulting in altered innate recognition
and adaptive functions [184]. Lipid A, commonly known as
endotoxin, is the predominantly hydrophobic moiety of LPS
that forms the outer leaflet of the asymmetric outer mem-
brane bilayer [185]. TLR4 recognition of lipid A is based on
the positioning, length, and quantity of acyl chains along
with the presence and modification of terminal phosphates
on the diglucosamine framework [186, 187]. The most po-
tent TLR4 agonists are the hexaacylated bis-phosphorylated
enteric lipid A structures, but subtle modifications to this
structure can lead to a range of potency from partial or weak
agonists to full antagonists [188]. P gingivalis LPS (LPSPg),
specifically lipid A, is unique in structure and activity, and
both are important considerations to understand innate in-
flammation stemming from infection [184]. The heteroge-
nous lipid A structures of LPSPg range from tetra- and penta-
acylated forms with mono- and bis-phosphorylation; how-
ever, none elicits robust TLR4 signaling [189, 190]. Struc-
tures of the tetra-acylated forms are condition dependent,
including non-phopshorylated (TLR4 silent) and monophos-
phorylated forms (TLR4 antagonist) [191, 192]. Whereas
most Gram-negative organisms found in the body (commen-
sals and pathogens) have lipid A structures with acyl chain
lengths of even carbon numbers, lipid A of P. gingivalis has
branched odd carbon length primary acyl chains that drasti-
cally reduce recognition by the MD2/TLR4 signaling com-
plex [184]. Importantly, TLR4 is the only recognized recep-
tor for LPSPg, a point that has been clarified after numerous
early reports of TLR2 activity; this was later attributed to
lipoprotein contamination in LPSPg biological extracts [184,
193-198]. Exclusivity of TLR4 activation by LPSPg, though
it is a weak agonist, has been definitively demonstrated using
both ultra-purified biological and synthetic lipid A prepara-
tions, thoroughly discussed elsewhere [194, 199-202]. Struc-
tural modification of P. gingivalis lipid A is influenced by
environmental (niche) and host factors, notably hemin (oxi-
dized heme) [203, 204]. Hemin levels initiate a lipid A modi-
fication cascade that switches between weakly agonistic to
antagonistic structures, directly manipulating the host innate
immune response in turn [203, 205].
P. gingivalis can subvert detection by the innate host sur-
veillance via LPS hypoacylation and phosphate cleavage,
which possibly interferes with the distribution of leukocytes
in the area surrounding the bacterial colonies. Additionally,
activation of neutrophils, eosinophils, and basophils is af-
fected due to a reduction in the ability of gingival epithelial
cells to secrete IL-8 (a chemokine) after being stimulated
with LPSPg, a phenomenon that is referred to as chemokine
paralysis [206, 207]. Thus, P. gingivalis may become resis-
tant to damage mediated by the oxidative burst from the po-
lymorphonuclear neutrophils. Within the periodontal liga-
ment stem cells that participate in periodontal tissue regen-
eration, mineralization and osteoblastic differentiation are
also inhibited by LPSPg [208]. It has been demonstrated that
in mice, cardiac dysfunction occurs after being exposed to a
low dose of LPSPg, which was mediated by the induction of
an inflammatory response in the left ventricle [209]. Fur-
thermore, a significant increase in matrix metalloproteinase-
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1359
9 was seen in exposed mice versus mice that received saline
[209]. Additionally, LPS Pg also stimulates the expression of
thrombospondin-1 [210] and plasminogen activator inhibitor
type I (PAI-1) [211], both of which also play a role in the
cardiovascular disease pathophysiology [212, 213].
2.1.3. Outer Membrane Proteins
P. gingivalis consists of two cell membranes, the inner
membrane (IM) and the outer membrane (OM) as part of its
cell envelope, which are separated by the periplasm that con-
tains an additional layer of peptidoglycan. Within the asym-
metrical bilayer of OM, the outer and inner leaflets consist of
LPS and phospholipids, respectively. The cell membrane
offers protection and acts as a selective barrier permitting
exchange of several materials via the porin proteins in the
OM [214]. There are two categories of OM proteins, one that
consists of integral proteins containing membrane-spanning
regions, and the other that consists of proteins anchored to
the OM by an N-terminal lipid tail [215]. The proteins in the
OM are considered to mediate the interaction among perio-
dontal microflora, which in turn, is postulated to be associ-
ated with the formation and maintenance of periodontal
biofilms [215]. Additionally, data suggest that when acti-
vated with P. gingivalis OM proteins, T-helper cells of ag-
gressive periodontitis patients, as compared with T-helper
cells of healthy controls, produced higher levels of proin-
flammatory cytokines such as IL-1β and IL-6 [216]. A major
OM protein (75-kDa) from P. gingivalis has been reported to
stimulate production of IL-1 in mouse peritoneal macro-
phages, as well as activation of polyclonal B-cells [217].
Another OM protein (40-kDa) from P. gingivalis has been
reported to act as an aggregation factor and the aggregation
activity of P. gingivalis cells for A. viscosus (an early colo-
nizer of tooth surfaces) is inhibited by the antibody against
this protein [218]. Yet another P. gingivalis OM protein
named LptO (PG0027) is considered to be essential to pro-
vide attachment to host cells, as it is also required for the O-
deacylation of LPS of this bacterium that further confers this
property to P. gingivalis [219]. Moreover, production of ac-
tive gingipains involves the role of another OM protein re-
ferred to as PG534 [220]. In fact, upon comparison with the
wild-type strain of P. gingivalis, the strain with defective
PG534 protein has been reported to have reduced activities
of gingipains R (RgpA and RgpB) and gingipain K (Kgp)
[220].
2.1.4. Fimbriae
Bacterial cells can have surface appendages extending
from their outer membrane, referred to as fimbriae, which
are characteristically thin and proteinaceous. Most P. gin-
givalis strains harbor these structures, which are about 3-25
μm long [221, 222]. On the cell surface of P. gingivalis, two
different types of fimbriae are expressed: a) major or long
fimbriae (consists of a subunit protein named FimA or fim-
brillin that is encoded by the fimA gene), and b) Mfa1 or
minor or short fimbriae (consists of a subunit Mfa protein
that is encoded by the mfa1 gene). Despite differing in their
amino acid composition and being antigenically distinct,
these two types of fimbriae play a role in the development of
inflammatory reactions associated with periodontal disease
[223]. For instance, macrophage-mediated production of IL-
1α, IL-1β, IL-6 and TNF-α has been reported to be induced
1360 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 Wadhawan et al.

by minor fimbriae [224]. Additionally, fimbriae play an es-
sential role in binding to and subsequent invasion of P. gin-
givalis into the host cells [225], as well as in adherence to
several molecules and oral substrates, including the oral epi-
thelium and commensal bacteria (streptococci and Actinomy-
ces viscosus) and the extracellular matrix proteins [226,
227]. Specifically, due to their ability to attach to cellular
α5β1-integrin, type II fimbriae lead to rearrangement of the
actin cytoskeleton and facilitate the phagocytosis of bacteria
by the host dendritic cells and phagocytes [223]. The host
cellular function is eventually impaired by the virulence fac-
tors of these intracellular bacteria [228]. Moreover, progres-
sion of atherosclerosis may involve P. gingivalis fimbriae.
Reduction in regulatory T cells (Tregs) has been reported in
atherosclerotic patients with P. gingivalis infection as com-
pared with healthy, non-atherosclerotic patients, and P. gin-
givalis FimA genotype II has been reported to be the domi-
nant type associated with reduced Treg population in patients
with atherosclerosis [229].
2.2. Interactions between Periodontal Pathogens
Whether periodontal tissue breakdown would occur or
not is determined by the balance between host protection and
bacterial aggression, factors that are further influenced by the
complex interactions between bacterial flora and the host
defense mechanisms [152]. Several experimental studies
have indicated that Gram-negative rods, including P. gin-
givalis, F. nucleatum, P. intermedia, P. nigrescens, A.
actinomycetemcomitans and T. forsythia (previously desig-
nated Bacteroides forsythus), are the primary etiological
agents of periodontal diseases. However, a concerted interac-
tion amongst these microbes is required to cause the destruc-
tive events involved in periodontal disease progression,
which cannot be precipitated by only one of these microbial
species in isolation [132, 135, 230].
Hajishengallis and Lamont have proposed “a polymicro-
bial synergy and dysbiosis (PSD) model” of periodontal dis-
ease [231]. According to this model, even though diverse
microbiota colonize the gingival crevicular space, hetero-
typic communities are assembled only between compatible
microorganisms [231]. Despite the fact that these heterotypic
communities can produce toxic products such as proteases
and promote inflammation, the host controls their over-
growth and overt pathogenicity. Moreover, there can be a
person-to-person and site-to-site variation of the microbial
constituents of these communities over time. The virulence
of the entire community can be elevated after colonization by
keystone pathogens (e.g., P. gingivalis) and their interactive
communication with other pathogens (e.g., Streptococcus
mitis). Furthermore, tissue homeostasis is disrupted, and de-
struction of periodontal tissues occurs upon impairment of
the host immune surveillance and an increase in the number
of dysbiotic communities [231].
In agreement with this model, evidence from animal
studies suggests that tissue damage during periodontitis can
be significantly enhanced by co-infection with P. gingivalis,
T. denticola, and F. nucleatum, when compared to infection
with these species in isolation [232-234] (Fig. 3). More re-
cently, Deng et al. [235] reported a synergistic interaction
between these three microbes that enhances their pathogenic-
ity, a finding that was based on their in vivo transcriptional

P. gingivalis
Pr
ote min
a
oly o a
ity
bil

sis cid
Mo

fre
s
e

T. denticola F. nucleatum
Hemolysis free iron
from heme

Free amino acids

Fig. (3). Synergistic pathogenicity of Treponema denticola (T. denticola), Porphyromas gingivalis (P. gingivalis), Fusobacterium nucleatum
(F. nucleatum) in chronic periodontitis, as demonstrated by an interaction model. Free amino acids, which could be contributed by other
members of the periodontal microbiota, are indicated by the dashed line. (Adapted from Deng Z-L, Sztajer H, Jarek M, Bhuju S and Wagner-
Döbler I (2018) Worlds Apart – Transcriptome Profiles of Key Oral Microbes in the Periodontal Pocket Compared to Single Laboratory
Culture Reflect Synergistic Interactions. Front. Microbiol. 9:124. doi: 10.3389/fmicb.2018.00124).
Periodontal Pathogens and Neuropsychiatric Health
profiles. Two-way synergistic interactions, where each spe-
cies gives and takes, were proposed in this study via a sche-
matic interaction model [235]. Enhanced adhesion in the
periodontal niche was indicated by the upregulation of many
surface proteins in vivo [236], and the authors reported that
mobility of P. gingivalis was enhanced by attaching to T.
denticola via upregulation of hemagglutinin and fimbriae
[235]. Since P. gingivalis has strong proteolytic activities, a
bacterial species like F. nucleatum that exhibits no or weak
intrinsic proteolytic activity, would benefit from coexisting
with P. gingivalis [237]. Deng and colleagues also reported
that F. nucleatum up-regulates peptide transporters and uses
the proteolytic activity of other species to its advantage, par-
ticularly of P. gingivalis and T. denticola that have an in-
creased cysteine protease activity [235]. Shared labor be-
tween periodontal pathogens has been observed in terms of
iron as well, which is an important pathogenic element
[238]. Whereas T. denticola has been reported to have down-
regulation in hemolysins, F. nucleatum has been shown to
engage in lysing erythrocytes by upregulating hemolysins
[235]. Thus, the hemolytic activity of F. nucleatum profits P.
gingivalis and T. denticola, both of which can uptake free
iron or bind heme to acquire iron for themselves [235].
3. IMMUNE RESPONSE TO PERIDONTAL PATHO-
GENS
Various innate immune mechanisms operate via some
acute-phase reactants in periodontitis (mainly a chronic con-
dition), which is indicative that systemic inflammation exists
in periodontitis [239, 240]. The acute-phase reactants pos-
sess proinflammatory properties such as neutralizing invad-
ing pathogens, activating complement factors, and regenerat-
ing and repairing different tissues. Plasminogen activator
inhibitor-1 (PAI-1) and C-reactive protein (CRP) are the
acute-phase reactants that have received the most focus in
research. A number of meta-analyses have noted that in-
flammation is the chief mediator of the association between
periodontal and cardiovascular disease [241-246].
Inflammation plays a central role in both periodontitis
and coronary artery disease. Indeed, acute coronary syn-
drome has been linked to periodontitis, with the recognition
of immunological burden as an important mediator between
these conditions [34, 247]. Although no causal relationship
has been identified between chronic periodontitis and a
higher risk for cardiovascular diseases, an association be-
tween them has been confirmed in several studies, even after
adjusting for known confounding variables, including obe-
sity, smoking and diabetes mellitus [29]. An inflammatory
reaction and periodontal bone loss has been reported to be
induced after implantation of P. gingivalis in an animal study
[248]. A critical role in osteoclast development and innate
immunity against invading pathogens is played by tumor
necrosis factor receptor-associated factor 6 (TRAF6) [249].
It has been shown that in the IL‐1 receptor/TLR
(IL‐1R/TLR) signaling pathway that mediates inflammation,
TRAF6 expression is increased by P. gingivalis and bacterial
pathogen‐associated molecular patterns (PAMPs), which
eventually activates the secretion of proinflammatory cyto-
kines in human periodontal ligament fibroblasts (HPDLFs);
thereby suggesting that TRAF6 might have an important role
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1361
in regulating the production of proinflammatory cytokines
[250, 251].
To understand periodontal disease and its association
with coronary artery disease, P. gingivalis serves as a model
pathogen and has been researched more extensively at the
molecular level. It expresses cysteine proteases (Arg-specific
gingipains), which release biologically active C5a by cleav-
ing C5. This process occurs independent of the complement
cascade activation and an interaction between the TLR2 and
C5a receptor (C5aR, also known as CD88) can be induced
by P. gingivalis [228].
IL-6 has been identified as an independent risk factor for
rupture of atherosclerotic plaque and coronary artery disease
[252]. This cytokine also has a well-documented role in
chronic periodontitis. IL-6 mediates periodontal tissue de-
struction and is elevated in periodontal tissues after being
stimulated by other cytokines (TNF-α and IL-1β) or by LPS.
A recent study reported that as compared to healthy subjects,
a significantly higher level of IL-6 was observed in patients
with chronic periodontitis [253], a finding that was consis-
tent with a previous study [254].
Another recognized risk factor for acute coronary syn-
drome is increased white blood cell count [255, 256], which
is increased in infections, including chronic periodontitis
[253]. However, a shared risk factor for chronic periodontitis
as well as acute coronary syndrome is smoking, which can
also increase the white blood cell count [257]. Besides, as
compared to non-smokers with periodontitis, smokers with
periodontitis have been reported to have significantly higher
white blood cell counts [258].
Heat-shock proteins (HSPs) protect human cells in the
state of stress, for instance, during inflammation, and can
result in the production of HSP-specific antibodies as well as
T-cells by interacting with the innate and adaptive immune
responses [259]. In the same way, the antigens that are ex-
pressed by the bacteria under stress could simulate/mimic
human HSPs, which could further stimulate the production
of antibodies and autoreactive T-cells against human cells
[260]. Additionally, evidence suggests that increased levels
of these HSPs occur in patients with periodontitis, which
could stimulate atherosclerosis by promoting inflammation
[261]. Several studies have stated that periodontal pathogens,
like P. gingivalis, express HSPs that have been involved in
atherosclerosis [262-264]. Furthermore, the presence of
cross-reactivity between periodontal bacterial HSPs and en-
dothelial cell-HSPs has been reported by numerous studies
[265-268], which further suggests that HSP-induced immune
responses might promote atherosclerosis.
One of the markers for activated cell-mediated immunity
includes neopterin [269]. The production of neopterin results
from the interaction between T-helper (Th)1 lymphocytes
and phagocytic cells, which include granulocytes, macro-
phages, monocytes and dendritic cells [269-271]. Interferon-
gamma (IFN-γ) is the main stimulating factor leading to the
formation of neopterin [270]. On the other hand, increased
neopterin levels can also result from additional proinflamma-
tory markers like LPS and TNF-α [272]. Also, neopterin
concentration in the bodily fluids marks the immune-related
oxidative stress [273]. Additionally, there exists an associa-
1362 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15
tion between neopterin concentration and reactive oxygen
species (ROS), which in turn is stimulated by IFN-γ [274].
Ozmeriç et al. [275] reported that a significantly higher total
amount of neopterin in gingival crevicular fluid (GCF) was
present in individuals with aggressive periodontitis com-
pared to that of healthy controls. They further reported that
systemically healthy individuals with aggressive periodonti-
tis had significantly higher salivary neopterin levels than the
systemically and periodontally healthy individuals [275]. In
another study, salivary neopterin levels increased signifi-
cantly with the number of affected teeth in periodontitis pa-
tients, with higher salivary neopterin levels reported in sub-
jects with ≥ 20 diseased teeth when compared to subjects
with < 20 teeth affected by periodontitis [276]. A positive
association has been reported between CAL and GCF neop-
terin concentrations in a different study, with lowest GCF
neopterin concentrations seen in the healthy group of indi-
viduals (mean = 1.36 nmol/l) and the highest concentrations
seen in individuals with moderate to severe periodontitis
(mean = 51 nmol/l) [277].
3.1. Role of Micro-RNAs
MicroRNAs (miRs) belong to a family of 19-24 nucleo-
tide-long RNAs that are post-transcriptional regulators of
gene expression (they do so by destabilizing the mRNA
translation) and have important physiological functions [278,
279]. Since the discovery of miRNAs in 1993 [280], they
have emerged as a critical player in almost all key cellular
processes, including development of diseases [281-283].
Several studies have shown that miRs have a role in inflam-
mation and immune response [284-287]. The role of miR-
NAs has been well established in various psychiatric ill-
nesses, such as major depression, schizophrenia, and bipolar
disorder [288-293]. More recently, the role of miRNAs has
been studied in various immune functions [294]. In the CNS,
selective activation of microglia and astrocyte are critical in
triggering cascades of events associated with neuroinflam-
mation [295]. Interestingly, miRNAs modulate both innate
and adaptive immunity in the CNS [296-298]. Accumulating
reports suggest that a set of miRNAs can generate proin-
flammatory response by inhibiting translation of many anti-
inflammatory cytokines. On the contrary, an anti-
inflammatory response can be triggered via a set of miRNAs
by altering the expression and functions of proinflammatory
modulators [299]. Both clinical and preclinical studies sug-
gest a significant involvement of miR-155, miR-124, miR-
146a, miR-21, miR-27b, miR-223 and let-7 in this process
[300]. Depending on the types of inflammatory molecules
released by microglia at their different maturation states, the
target response of different miRNAs or different sets of
miRNAs can be unique. M1 microglia, which represent the
proinflammatory state, produce inflammatory mediators such
as proinflammatory cytokines (IL-6, IL-1β and TNF-α), ROS
and matrix metalloproteinase-9. Whereas, microglia in their
anti-inflammatory state or M2, release anti-inflammatory
cytokines including IL-10, transforming growth factor beta
(TGF-β), IL-4, and IL-13 [298]. This dynamic is signifi-
cantly modified by participating miRNAs.
The role of miR-155 has been well-documented in sev-
eral inflammatory disorders. Increased level of miR-155 has
been associated with increased level of TNF-α. Since miR-
Wadhawan et al.
NAs inhibit gene expression, upregulation of TNF-α by miR-
155 could be an indirect regulation via several other inter-
mediates. Thus, being pleotropic in nature, miR-155 demon-
strates both inhibiting and enhancing properties to achieve a
specific goal. On the other hand, miR-155 can be upregu-
lated by various TLR ligands. For instance, in the early
phase of TLR4 signaling, miR-155 was found to be upregu-
lated [301]. Conversely, miR-146 expression can dysregulate
a set of TLRs with an immediate effect on cytokine produc-
tion. This innate immune effect functions as a negative feed-
back loop. miR-146 in knock-out mice show widespread
immune suppressive ability, primarily via IL-1 receptor-
associated kinase-1 (IRAK1) and TRAF6 [302]. It is upregu-
lated in the monocytes in response to bacterial components
(e.g., LPS) and inflammatory cytokines [303]. In turn, miR-
146a leads to downregulation of the adaptor proteins that
operate downstream of cytokine receptors and TLRs, includ-
ing TRAF6 and IRAK1 [303]. Consequently, this abolishes
the activation of a key transcription factor, nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-κB),
which has a role in the transcription of several genes in-
volved in inflammation, including adhesion molecules, pros-
taglandins, chemokines, TNF-α, IL-1β, IL-6, and IL-8 [304].
Eventually, miR-146a leads to inhibition of the inflammatory
response in keratinocytes, macrophages, and monocytes
[305, 306].
Wang et al. have shown the inability of miR19a-3p in
suppressing TNF-α expression in the brain of suicide sub-
jects [293]. It appears that RNA binding protein human anti-
gen R (HuR) competitively inhibits miR-19a-3p binding to
TNF-α 3’UTR region, thus blocking the action of this
miRNA in regulating TNF-α expression [293]. Another anti-
inflammatory miRNA is miR-124, which prevents activation
of microglia, and hence, has a protective role in neurodegen-
erative diseases and CNS. Elevated levels of miR-124 can
negatively regulate TLR signaling by targeting TLR6 and
TNF-α. Part of the adaptive immune response can also be
targeted by miR-124. Data show that miR-124 can induce T
cell activity with a marked increase in effector response.
This increased activity was found to be associated with
upregulated expression of IL-2, IFN-γ, and TNF-α [307].
Role of miR-181 family members, including miR-181a,
miR-181b, miR-181c, and miR-181d, have been implicated
in immune cell homeostasis with proinflammatory response.
Both vesicular and neurological changes have been associ-
ated with miR-181 expression causing altered expression of
TNF-α, IL-6, IL-1β, and IL-8 in the proinflammatory arm.
The overproduction of these proinflammatory cytokines also
resulted in an elevated level of anti-inflammatory cytokine
IL-10 [308]. Some other prominent miRNAs with immuno-
modulatory roles include miR-223, miR-34, and miR-21.
miR-223 has anti-inflammatory properties in peripheral im-
mune cells. In T cells, miR-223 was upregulated in patients
with rheumatoid arthritis and miR-223 impaired activation of
a protective IGF-1/IL-10 axis. Exacerbation of traumatic
brain injury mediated via inflammation and apoptosis has
been linked with increased expression of miR-34. miR-21 is
upregulated in activated immune cells, including neutrophils,
dendritic cells, monocytes/macrophages, and T cells. miR-21
also affects differentiation of other immune cells, including
T cells and dendritic cells. Dendritic cells, that are deficient
Periodontal Pathogens and Neuropsychiatric Health
in miR-21, express higher IL-12 level. On the other hand,
miR-21 deficiency enhances Th1 and Th17 cell responses.
Let-7 miRNAs modulate inflammation. Increasing let-7 ex-
pression in macrophages promotes differentiation likely by
reducing expression of the transcription factor
CCAAT/enhancer-binding protein alpha (CEBP-α) [295,
298-299, 302].
Several studies suggest that inflammatory response asso-
ciated with diabetes mellitus may be critical factor in depres-
sion development in diabetes mellitus patients and that
miRNAs may be playing crucial role in such development.
Interestingly, diabetes mellitus, when associated with sys-
temic inflammation (whether it is related to autoimmune or
metabolic disease), is associated with differential miRNA
expression. For example, the autoimmune process in type 1
diabetes mellitus has been linked to the islet-specific miR-
326 [309], as well as other miRNAs known to be involved in
islet cell function (miR-24, 26, 127-3p, 148, 182, 184, 195,
375, and 493) [281]. Alterations in expression of miRNAs
have also been linked to system metabolic inflammatory
disease and diabetes mellitus complications (e.g., miR-16,
21, 29, 93, 98, 133, 192, 200a, 200b, 200c, 216, 320, 429,
and 503) [281, 283]. It has recently been shown that tran-
scriptional regulation of miR-146b is involved in TNF-α and
IL-6 induced inflammatory response in obesity [310].
Recently, extracellular vesicular miRNAs have been
studied for their role in regulating distal targets besides their
autocrine role in the CNS. Depending on the pathogenicity,
the microvesicles can be uploaded with a selective set of
miRNAs to deliver distantly in peripheral circulation. For
example, let-7b can travel in vesicle and modulates inflam-
matory response by selectively binding and masking TLR7
[311]. Let-7, miR-124 and miR-21 have been found in
exosomes, which are released from neurons. These miRNAs
regulate microglia functions [298]. Altogether, it appears
that miRNAs are actively involved in regulating immune
response associated with various disorders. This also opens
the possibility to use miRNAs for diagnostic and therapeutic
purposes.
As reviewed earlier in the manuscript, P. gingivalis has
several virulence factors. Production of a variety of miRs is
stimulated by P. gingivalis, including immunoinflammatory
miR-146a that orchestrates the innate host immune response
[4, 312], miR-203 production that inhibits SOCS3 and
SOCS6, and miR-105 that suppresses TLR2 production
[153]. MiR-146a has been reported to have a critical regula-
tory role in periodontal disease [313, 314]. In an in vitro
study, Tang et al. reported that HPDLFs had a significantly
increased expression of miR-146a after being stimulated
with P. gingivalis and its LPS [315]. Additionally, signifi-
cant suppression of TRAF6 expression, p38 phosphorylation,
and of IL-6, IL-8, and IL-1β secretion was reported with
overexpression of miR-146a [315]. Moreover, P. gingivalis-
stimulated HPDLFs, but not P. gingivalis-LPS stimulated
HPDLFs, had direct binding of miR-146a to the 3’-UTR of
TRAF6 [315]. Phosphorylation of p38 could be inhibited by
the suppression of TRAF6. Lastly, P. gingivalis-induced
miR-146a upregulation in HPDLFs was significantly abol-
ished by inhibition of p38 and TRAF6 [315]. Similarly, pre-
vious studies had also reported that in HPDLFs and human
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1363
fibroblasts, miR-146a regulated the proinflammatory cyto-
kine expression by negatively regulating the inflammatory
response via NF-κB and IRAK1, post-stimulation with LPS
of P. gingivalis [7, 8].
Human studies have also reported similar observations.
As compared to healthy controls, individuals with chronic
periodontitis have been reported to have an upregulation of
miR-146a, suggesting that this miR may facilitate the sur-
vival of the periodontopathic bacteria [4]. These findings
corroborate the hypothesis that bacterial components of
plaque (e.g., LPS) in aggressive periodontitis, might increase
the miR-146a via stimulation of TLRs, which, via a negative
feedback loop, may subsequently control the level of proin-
flammatory cytokines [5]. Ghotloo et al. reported that, as
compared to healthy controls, individuals with aggressive
periodontitis had significantly increased levels of miR-146a
(p<0.001), and the severity of the disease was directly asso-
ciated with the increases in these levels [5]. Moreover, a re-
duction in the levels of proinflammatory cytokines was ac-
companied with an overexpression of miR-146a [5]. Given
that inflammation plays a central role in the pathophysiology
of periodontitis, the unexpected finding of reduced expres-
sion of major proinflammatory cytokines (IL-6, TNF-α and
IL-1β) in this study suggests that either a nonimmunologic-
dependent mechanism operates in the progression of perio-
dontal disease, and/or other inflammatory mediators are in-
volved in the disease process [5]. However, in a study by
Bagavad Gita et al., in response to the negative regulatory
role of miR-146a, the expected downregulation of its poten-
tial targets (TNF-α and IL-1β) was not seen in individuals
with chronic periodontitis and acute coronary syndrome, and
an upregulation of these cytokines (TNF-α, IL-6 and IL-1β)
was reported instead [253]. Alternatively, many genes are
regulated by miR-146a, including downregulation of TGF-β
and epidermal growth factor receptor [355-357]; hence, it is
possible that the periodontal tissue repair and regeneration
that is stimulated by both TGF-β and epidermal growth fac-
tor receptor are disrupted by miR-146a [355, 357].
Many factors, including miRs, strictly and finely regulate
the balance of TLR4 signaling pathways [358, 359]. Asso-
ciations have been reported between response to antidepres-
sants and miR-146a from whole blood [360, 361]. In a recent
study by Hung et al., associations between major depressive
disorder and the expression of intracellular miRs that regu-
late TLR4 signaling in monocytes and peripheral blood
mononuclear cells (PBMCs) were investigated [6]. Authors
reported that miR-146a levels in PBMCs were significantly
lower before treatment with antidepressants in individuals
with a diagnosis of major depressive disorder than in healthy
controls, and after antidepressant treatment, miR-146a levels
increased significantly [6]. A similar pattern was observed
for miR-146a in monocytes. Moreover, a negative associa-
tion was found between 17-item Hamilton Depression Rat-
ing Scale scores and the levels of miR-146a [6]. Together,
these results suggest that an aberrant expression of intracel-
lular regulatory miRs that regulate TLR4 signaling may play
a role in those with a diagnosis of major depressive disorder
and that treatment with antidepressants can ameliorate these
impairments [6].
1364 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15
Another miR of interest is miR-21 which is expressed
universally in mammalian organs, including the spleen,
heart, colon, and the small intestine [362]. Significant atten-
tion has been given to the roles of miR-21 in cardiovascular
biology and disease [363]. Specifically, miR-21 is greatly
expressed by the major types of cardiovascular cells that
include cardiac fibroblast [364], vascular smooth muscle cell
[365], endothelial cell [366] and cardiomyocyte [367]. Re-
cently, miR-21 was reported to be overexpressed in patients
having a combination of heart failure and diabetes mellitus,
in patients with a combination of coronary artery disease and
diabetes mellitus, as well as in patients having diabetes mel-
litus alone [368]. When compared to that of healthy control
subjects, the expression of miR-21 in these groups of pa-
tients was elevated 2.21, 1.79 and 1.30 times, respectively
[368]. The authors further reported that in asymptomatic
type-2 diabetes mellitus patients, miR-21 expression could
be useful in predicting the onset of heart failure [368]. An-
other recent study reported that in elderly patients with acute
myocardial infarction, serum levels of miR-21 were posi-
tively correlated with both serum levels of cardiac troponin I
(r = 0.5128, p = 0.009) and serum levels of creatine kinase
MB isoenzyme (r = 0.3683, p = 0.0229) [329]. The authors
also reported that the upregulation of miR-21 expression was
present in the serum of elderly patients with acute myocar-
dial infarction, which further, via activation of the c-Jun N-
terminal kinases/p38/caspase-3 signaling pathway, inhibited
the TNF-α-induced apoptosis in human cardiac myocytes
[329]. Similarly, other studies have also reported a higher
miR-21 expression in human hearts from patients with heart
failure, when compared with that of healthy controls [369,
370].
Upregulation of miR-21 also has been reported in re-
sponse to stimulation by periodontal pathogen [330]. Moreo-
ver, miR-21 has also been demonstrated to be involved in the
development of gingival mesenchymal stem cells and perio-
dontal ligament cells [371-374]. P. gingivalis virulence fac-
tors signal via TLRs, inducing inflammation by activating
the NF-κB pathway, which further leads to miR-21 upregula-
tion [198, 375]. LPSPg has also been reported to induce
upregulation of miR-21 [330-332], thereby suggesting that
periodontal pathogen-induced inflammation is closely asso-
ciated with miR-21. Furthermore, during pathogenesis of
periodontitis, NF-κB was predicted to be regulated by miR-
21 and other miRs [330, 332]. More recently, Zhou et al.
reported a greater expression of miR-21 in LPSPg-challenged
cells, ligated mice, as well as in periodontitis patients. The
authors also concluded that the absence of miR-21 increased
NF-κB activation, proinflammatory cytokine production, and
programmed cell death protein 4 (PDCD4) expression [333].
Additionally, miR-21 down-regulated LPSPg-induced in-
flammation [333]. Together, these results point towards
miR-21's negative regulatory functions on proinflammatory
responses induced by the periodontal pathogens, and protec-
tion offered by this miR in terms of progression of periodon-
titis, which was shown in an in vivo periodontitis animal
model [333].
Psychiatric disorders, including schizophrenia, alcohol-
ism, and depression, have been reported to have miRNA
alterations in particular brain regions, reflecting the patho-
physiological roles of these non-coding type of mRNAs
Wadhawan et al.
[292, 376-379]. Dwivedi (2018) recently presented a thor-
ough review of the role of miRs in suicidal behavior and
depression and commented that miRs that were particularly
involved in stress response, synaptic plasticity, and neu-
rotrophic activity were the ones that were highly associated
with depressive symptoms [380]. Specifically, miR-21 has
also been reported to have a role in schizophrenia, alcohol-
ism, and major depressive disorder [334]. Miguel-Hidalgo et
al. reported that, as compared to non-psychiatric controls,
human subjects with depression and alcoholism had signifi-
cantly low levels of miR-21 in the white matter adjacent to
the orbitofrontal cortex [334]. Another study was done by
performing miR microarray analysis in PBMCs obtained
from healthy controls and from patients with schizophrenia,
who were not on antipsychotic medication [381]. It was ob-
served that after antipsychotic treatment, serum miR-21 ex-
pression decreased in patients with schizophrenia. Moreover,
there was a negative correlation observed between improve-
ment of positive, general psychopathology and aggressive-
ness symptoms of schizophrenia and the change in miR-21
expression [381]. In a different study by Beech et al., it was
reported that, following psychological stress, expression of
miR-21 was upregulated in non-smoking heavy alcohol
drinkers but not in non-smoking moderate drinkers [382].
Even though the differences were not statistically significant
between the two groups, the expression levels of miR-21
were correlated [miR-21; R2 = 0.57] with the amount of al-
cohol drunk in the heavy drinkers group, but not in the mod-
erate drinkers group [382]. Thus, alteration in miRs, espe-
cially the elevation of miR-21 expression, could be a part of
the shared molecular inflammatory mechanisms that link the
pathophysiology of periodontal, cardiovascular, and psychi-
atric disorders. In addition, other miRs that are implicated in
periodontal and cardiovascular disease are listed in Table 2.
3.2. Kynurenine Pathway
The kynurenine pathway is a critical pathway involved in
immunoregulation, by limiting very intense or prolonged
inflammation, and in the containment of infection, by depriv-
ing microorganisms of critical supply of tryptophan. Moreo-
ver, the kynurenine pathway is a central pathway connecting
inflammation with brain function and behavior, in principal
contributing to both adaptive and maladaptive reactions to
local and systemic infections and low-grade inflammation.
One of the essential amino acids, tryptophan, is found in
many foods that are rich in protein [383]. It is transported
across the blood-brain barrier by a transporter for large neu-
tral amino acids. Two pathways are involved in the metabo-
lism of this essential amino acid in the brain. The less preva-
lent metabolic pathway involves tryptophan acting as the
precursor for the neurotransmitter, serotonin, both centrally
and peripherally [384-385]. On the other hand, almost 90%
of tryptophan metabolism occurs via synthesis of kynurenine
[386] and the rate-limiting enzymes of this pathway include
tryptophan-2, 3-dioxygenase and indoleamine-2, 3-
dioxygenase (IDO). Expression of IDO can be induced by
inflammation in the brain, which further increases the syn-
thesis of downstream metabolites of this pathway, such as
quinolinic acid (QA) and kynurenic acid (KYNA) [387].
Whereas quinolinic acid produces free radicals and is an
Periodontal Pathogens and Neuropsychiatric Health Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1365

Table 2. Micro-RNAs involved in periodontitis, cardiovascular diseases, and depression.

Micro-RNA Upregulation (↑) or Upregulation (↑) or Upregulation (↑) or Reported function References
(miR) downregulation (↓) in downregulation (↓) in downregulation (↓) in
periodontitis cardiovascular disease depression

miR-16 ↑ ↑ ↓ Facilitates cell-cycle [316-322]

arrest and apoptosis,
activated by p53

miR-19a ↑ ↑ ↓ Targets TNF-α, protects [313, 323-326]

cardiomyocytes by
inhibiting apoptosis or
activating autophagy,
negatively regulates
neurogenin 1 to inhibit
the differentiation of
neural stem cells into
neurons

miR-21 ↑ ↑ ↓ Promotes the post- [327-334]

translational degradation
of a transporter that
regulates cholesterol
efflux (ABCG1) in
macrophages and en-
hances macrophage
apoptosis; increased
expression of Col-1, α-
SMA and F-actin, pro-
motes the effects of
TGF-β1-induced activa-
tion of cardiac fibro-
blasts; absence of miR-
21 increased NF-κB
activation, proinflamma-
tory cytokine produc-
tion, and programmed
cell death protein 4
(PDCD4) expression

miR-29a ↑ ↑ - Mediates osteoblast [335-338]

differentiation; targets
IL-12p19 and p40 and
downregulates IL-23;
inhibits both intrinsic
and extrinsic apoptosis;
induces angiogenesis in
hypoxia, hypoxamir

miR-30e ↓ ↓ ↑ Inhibiting cytotoxicity [339-342]

of natural killer cells

miR-146a ↑ ↑ ↓ Regulates the proin- [5, 6, 315, 343, 344]

flammatory cytokine
expression by negatively
regulating the inflamma-
tory response via NF-κB
and IRAK1; regulate
TLR4 signaling
(Table 2) contd….
1366 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 Wadhawan et al.

Micro-RNA Upregulation (↑) or Upregulation (↑) or Upregulation (↑) or Reported function References
(miR) downregulation (↓) in downregulation (↓) in downregulation (↓) in
periodontitis cardiovascular disease depression

miR-155 ↑ ↑ ↑ Activation by nuclear [344-347]

factor-kappaB, fos/jun,
targeting nuclear factor-
kappaB signaling; medi-
ating type 1 interferon
response to infection;
critical for dendritic cell
function and maturation;
inducing activation of
natural killer cells; es-
sential for T-cell devel-
opment and T-helper 17
response; inhibits DNA
damage-induced apopto-
sis

miR-210 ↓ ↑ - Impairs immune- [314, 343, 348]

suppressive functions of
regulatory T-cells by
targeting forkhead box
P3; hypoxamir, controls
host responses in hy-
poxia by induction of
autophagy and targeting
of hypoxia-inducible
factor-1a (pro-survival)

miR-223 ↑ ↑ ↑ Modulates differentia- [313, 314, 349-352]

tion and activation of
myeloid cells, enhances
granulopoiesis, inhibits
macrophage differentia-
tion, controls excessive
innate immune re-
sponses

miR-486 ↑ ↑ - Leads to stronger activa- [314, 337, 353, 354]

tion of NF-κB by dis-
rupting NF-κB negative-
feedback loops

agonist at (N-methyl-D-aspartate receptor (NMDA) recep-
tors that eventually results in neurotoxicity, KYNA antago-
nizes glutamate to confer neuroprotection and acts as a free
radical scavenger. QA is primarily produced by the brain
microglia and the peripheral macrophages invading the
brain. Thus, activation of the kynurenine pathway may ex-
plain the association between inflammation in the brain and
degeneration of neurons [387]. Another neurotoxic metabo-
lite of the kynurenine pathway of tryptophan metabolism
includes 3-hydroxykynurenine (3-HK), which like QA acts
as an NMDA receptor agonist and generates oxidative free
radicals. 3-HK is a product of enzymatic action by
kynurenine-3-monooxygenase on kynurenine and it is con-
verted into QA after a few more enzymatic steps [388]. Also,
a neuroprotective metabolite of kynurenine pathway called
picolinic acid (PIC) is produced competitively by the amino-
β-carboxymuconate-semialdehyde-decarboxylase (ACMSD)
to limit the formation of QA [389]. Together with activation
of IDO, metabolites of kynurenine pathway - including tryp-
tophan, kynurenine, KYNA, and others are involved in the
pathophysiology of psychiatric disorders and suicidal behav-
ior [390]. Individuals with both treatment-resistant depres-
sion and suicidal behavior reportedly have kynurenine path-
way dysregulation, which is associated with neuroinflamma-
tion [391]. It has been hypothesized that NMDA receptors
and alteration in glutamate neurotransmission may mediate
the pathogenesis of depression [392-396].
Increasing evidence points towards an association be-
tween dysregulation of the kynurenine pathway as a conse-
quence of inflammation, which eventually leads to an imbal-
ance of neuroactive metabolites in suicidal patients [397,
398]. Sublette et al. [399] analyzed group differences in
KYN levels between three groups of individuals, i.e., pa-
tients with major depressive disorder with a history of sui-
Periodontal Pathogens and Neuropsychiatric Health
cide attempt, patients with major depressive disorder without
history of suicide attempt, and healthy volunteers. The
authors reported that, as compared to the patients with major
depressive disorder without a history of suicide attempt, pa-
tients with major depressive disorder with a history of sui-
cide attempt had a higher level of kynurenine in their plasma
(t = 2.105, df = 58, p = 0.040) [399]. Dysfunction of gluta-
mate receptors may also be implicated in the pathophysiol-
ogy of suicide, as evidenced by a post-mortem study assess-
ing the differences in glutamate receptors in the frontal corti-
ces of human suicide victims versus those of controls who
died of sudden death due to causes other than suicide [394].
Additionally, as compared to healthy controls, suicide at-
tempters have been reported to have a decreased PIC/QA
ratio and reduced PIC levels in both plasma and CSF [400].
Alterations in the kynurenine pathway have also been re-
ported in bipolar disorder [401-404] and schizophrenia, and
it is hypothesized that KYNA may play a major role in the
pathophysiology of these disorders [405], as it is a naturally
occurring astrocyte-derived NMDA and alpha-7 nicotinic
acetylcholine (a7nACh) receptor antagonist [406, 407].
Higher levels of KYNA have been reported in the postmor-
tem prefrontal cortex (2.9 pmol/mg protein vs. 1.9 pmol/mg
protein in controls) [408] and the CSF (approximately 1.7
nM vs. 1.0 nM in healthy volunteers) [409] of patients with
schizophrenia. These findings were confirmed in later stud-
ies that demonstrated increased KYNA levels in both drug-
naïve [410] and drug-treated [411, 412] schizophrenia pa-
tients. More recently, a meta-analysis on 13 studies revealed
that specifically within the central nervous system, KYNA
levels were moderately increased in patients with schizo-
phrenia, when compared to healthy controls [standardized
mean differences (SMDs) = 0.66, 95% CI = 0.25-1.06, p =
.001] [413]. Alterations in glutamatergic and cholinergic
signaling, and indirectly, in dopaminergic signaling, may be
caused by increased concentration of KYNA, which may
eventually lead to schizophrenia symptoms [405].
Moreover, disturbances in the kynurenine pathway have
also been reported in AD [414], cardiovascular disorders,
and metabolic disorders. As compared to cognitively
screened controls, older patients with histopathologically
confirmed AD were reported to have an association between
poor cognition and elevated QA levels in the plasma [414].
Furthermore, peripheral monocytes from patients with AD
have been reported to have increased expression of the exci-
totoxic metabolite of the kynurenine pathway of tryptophan
metabolism, i.e., QA [415].
To the best of our knowledge, there are no studies avail-
able that have directly examined the levels of kynurenine
metabolites in periodontal disease. However, Buczko et al.
[416] reported that, in comparison with healthy volunteers
and patients with hypertension or diabetes alone, patients
with both diabetes and hypertension had significantly higher
concentrations of kynurenine and KYNA in their saliva,
which could eventually contribute to the local and distant
effects of periodontal pathogens, downregulation of antimi-
crobial immune pressure, and thus facilitation of transloca-
tion. Additionally, the onset and development of periodontal
disease may involve the kynurenine derivatives in the human
saliva [417]. IDO expression has also been confirmed in hu-
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1367
man gingival tissues [418]. As compared to healthy gingiva,
chronic periodontitis has been reported to have an upregula-
tion in the expression of this enzyme, which may occur, in
part, due to the inflammatory cytokines- and bacterial prod-
ucts-induced activation of human gingival fibroblasts [418].
LPS treatment of primary human periodontal ligament cells
has been reported to induce IDO mRNA expression as well,
in a dose-dependent manner, peaking at 8 hours post-
treatment. Moreover, LPS treatment also increased the pro-
duction of kynurenine after 72 hours of treatment [419].
Obese individuals may have activation of IDO, which is
suggested by an increased kynurenine:tryptophan ratio and
lower levels of tryptophan in their adipose tissue [420, 421].
Kynurenine pathway metabolites may also mediate the asso-
ciations between metabolic and psychiatric disorders [401].
For instance, in a study of individuals with bipolar disorder,
serum kynurenine and the kynurenine:tryptophan ratio were
reported to be positively correlated with high levels of car-
bohydrate craving [422]. Authors also reported that serum
kynurenine:tryptophan ratio was increased in patients with
bipolar disorder, who were also overweight/obese [422].
Moreover, increased tryptophan breakdown in individuals
with cardiovascular disease often results in increased serum
kynurenine:tryptophan ratios and are also linked to greater
risk for fatal outcomes of cardiovascular pathologies [423].
Cardiovascular disease mortality has been reported to be
associated with tryptophan catabolites, including kynurenine
and 3-HK [424]. Macrophage-rich cores of human advanced
atherosclerotic plaques have been reported to have an in-
creased expression of IDO [425]. Furthermore, in both gen-
ders, more advanced atherosclerosis has been positively as-
sociated with IDO activity in the blood [426]. In patients
with suspected stable angina pectoris, increased risk of acute
myocardial infarction can be predicted by elevated levels of
plasma kynurenines, including, among others, KYNA and 3-
HK [427]. Post-stroke patients have also been reported to
have higher concentration of several kynurenine metabolites
(such as KYNA) and activation of IDO [428], factors that
have also been associated with development of post-stroke
cognitive impairment and increased mortality [429]. Thus,
kynurenine pathway metabolites are involved in neuropsy-
chiatric, cardiovascular, and metabolic conditions, and might
have a role in periodontal disease and the pathogens contrib-
uting to the local and systemic progression of infection, in-
cluding P. gingivalis.
4. INFLAMMATION AND MENTAL HEALTH
It has been reported that activation of microglial cells as
part of a chronic inflammatory process in the brain (neuroin-
flammation) can be stimulated by periodontitis, which is
well-known to induce systemic inflammation as well [9,
430-432]. In fact, several neurodegenerative disorders, in-
cluding AD, amyotrophic lateral sclerosis, multiple sclerosis
and Parkinson’s disease, have been reported to have neuroin-
flammation as one of their major features [433-435]. Psychi-
atric disorders have received attention over the past 20 years,
in terms of the possible role that neuroinflammation might
play in their pathogenesis. Specifically, the brains of major
depression [436, 437] and schizophrenia [438-440] patients
have been reported to have activation of the microglia, as
evidenced by studies utilizing positron emission tomography
1368 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 Wadhawan et al.

and immunohistochemistry. Hence, neuroinflammation croglia [460]. Elevation of excitotoxic kynurenine metabolite
likely has a significant role in the overall neuropsychiatric QA may lead to neurodegenerative changes that could be
health of an individual. linked to the reduction of astrocytes [461]. Neuronal repair
and neuroregeneration are also suppressed by chronic stress.
Psychological stress is defined as the emotional and
physiological sequelae experienced by individuals faced with A decrease in the synthesis of brain-derived neurotrophic
factor (BDNF) has been associated with a stress-induced
adverse life events that exceed perceived coping skills. Both
increase in proinflammatory cytokines, and chronic admini-
physiologic and emotional reactions are evoked by stress,
stration of antidepressant medications can reverse these al-
although modifiable, which serves as an important risk factor
terations [462]. Depending upon their concentrations, gluco-
for both physical and mental illnesses. Stressful life events
corticoids may have either pro- or anti-inflammatory effects.
are robustly, and presumably causally, associated with major
depressive disorder [441, 442]. Both molecular and cellular Studies have demonstrated that, while higher concentrations
of cortisol equivalent to those seen following a major physi-
abnormalities are thought to play a role in the neurobiology
cal stress increase the inflammatory response triggered by
of stress and depression, and these abnormalities also have
LPS, basal cortisol concentrations exert an anti-
interactions with environmental and genetic determinants
inflammatory effect [463]. Activation of the NF-κB pathway
[443]. The role of psychological stress as a potential cofactor
and mitogen-activated protein kinase signaling, which are
in the pathogenesis of infectious disease is exemplified by an
association between dose-dependent stress and an increased essential for the synthesis of proinflammatory cytokines and
chemokines, results in this proinflammatory effect [464].
risk of acute infectious respiratory illness [444]. The immune
Depression is also accompanied by neurodegeneration, par-
system may be impacted directly by stress. For instance,
ticularly in the hippocampus, frontal cortex, and amygdala,
after adjustment for age, gender, and cigarette smoking,
and the frequency and severity of depressive episodes are
Genco et al. reported a higher risk of more severe periodon-
positively associated with the amount of neurodegeneration
tal CAL (OR = 2.24) and alveolar bone loss (OR = 1.91)
among individuals with financial strain and an inadequate [465, 466]. These neurotoxic effects are mediated by the
proinflammatory cytokines, hypercortisolemia, and the syn-
coping style, as opposed to those with low levels of financial
thesis of QA, an NMDA agonist, together with xanthurenic
strain within the same coping group [445]. Data also support
acid and other intermediates via the kynurenine pathway,
a higher risk of infection and immune reaction in the care-
which leads to the production of ROS. The kynurenine
givers of those with chronic illnesses [446-448]. Further-
pathway is further activated via the induction of IDO by the
more, clinical wound healing may be altered by stress [449],
with reports of slow wound healing in individuals with proinflammatory cytokines (particularly IFN-γ) in response
to infections [467-468]. Moreover, infectious agents, includ-
higher psychological stress levels that were independent of
ing Toxoplasma gondii, have also been associated with
the duration of stressors [449-451]. Stress has also been re-
symptoms of depression [469, 470], suggesting the possible
ported to impede oral mucosal wound healing [452]. An
role of periodontal pathogens, especially P. gingivalis, as
overview of the mechanisms that link chronic stress, perio-
well as periodontal disease/tooth loss, in depression as well
dontal disease, and depression can be found in an extensive
review by Warren et al. [115]. [114, 471].
Major psychiatric disorders, including depression [472-
A part of the adaptive mechanism in the ‘fight or flight’
475], schizophrenia [476-479], and bipolar disorder [480-
response is the stress-induced hypercortisolemia. However,
483], have been reported to manifest a proinflammatory
the stress response can have detrimental effects on the brain
state. Neuroinflammation has been reported to be involved in
and the peripheral organs if it is prolonged and dissociated
from the initiating stimulus. For instance, hypercortisolemia, the pathophysiology of AD as well [484, 485]. Moreover,
onset of AD may be delayed, and its progression may be
which indicates the hyperactivity of the hypothalamic-
slowed by conventional non-steroidal anti-inflammatory
pituitary-adrenal axis, is present in about 80% of severely
drugs (NSAIDs) [486, 487]. Increased risk for all-cause de-
depressed patients but in only about 50% of depressed pa-
mentia has been reported in subjects treated for chronic in-
tients overall [453]. Counterintuitively, major depression is
flammatory disorders, including inflammatory arthritis (OR:
frequently associated with an increase in proinflammatory
cytokines, chemokines, and prostaglandins, despite the pres- 1.33, 95% CI: 1.06-1.63), bullous skin diseases (OR: 1.55,
95% CI: 1.11-2.18), systemic vasculitis (OR: 1.64, 95% CI:
ence of increased glucocorticoids that are usually associated
1.24-2.18) and Crohn's disease (OR: 2.08, 95% CI: 1.16-
with a reduction in proinflammatory mediators [454, 455].
3.74) [488]. The authors also reported that a reduced risk
Although glucocorticoids suppress expression of inflamma-
for dementia across most conditions, especially for systemic
tion after an acute stress response, glucocorticoid receptor
autoimmune disorders (OR: 0.41, 95% CI: 0.18-0.95), was
desensitization after chronic stress ultimately leads to a
proinflammatory state [456]. Following chronic stress, mi- associated with combined glucocorticoids and NSAIDs ther-
apy [488].
croglia change from the resting to the active state in several
regions of the brain [457]. Depressed patients may also evi- Neuroinflammation has been reported to play a role in
dence these changes [458]. Indirect evidence in support of suicidal behavior [489]. Meta-analytical evidence exists for
stress-induced microglial activation in depression is provided the presence of immune activation in the blood and CSF of
by clinical studies reporting enhancement of peripheral suicide attempters as well as in the postmortem brain sam-
macrophage activity following chronic social stress [459]. ples of individuals who died by suicide [490-492]. Victims
Furthermore, reduction in the oligodendroglia and astrocytes who died by suicide have been demonstrated to have pro-
in certain regions of the brain, such as the sub-genual pre- nounced microgliosis [458], as well as mRNA transcripts of
frontal cortex and amygdala, accompany the changes in mi- inflammatory cytokines in their orbitofrontal cortex [493].
Periodontal Pathogens and Neuropsychiatric Health
Exacerbation of aggression, an endophenotype associated
with suicidal behavior [494], can be precipitated, at least
partially, by the effects of individual proinflammatory cyto-
kines [495-497]. At both the mRNA and protein levels, in-
creased levels of proinflammatory cytokines like IL-1β, IL-
6, and TNF-α, have been reported in the anterior prefrontal
cortex of teenagers who died by suicide [498]. The signifi-
cantly elevated levels of IL-6 in the CSF of suicide attempt-
ers further supports the role of neuroinflammation in suicidal
behavior [499]. Other inflammatory triggers, such as trau-
matic brain injury, have also been implicated in suicidal be-
havior [500].
Peripheral inflammatory changes are also associated with
what we consider to be primary depression [501-504]. Both
central and peripheral innate immune systems have been
linked to depression [505]. In fact, more data are surfacing
that confirm the presence of pronounced inflammatory
changes in both the CSF and blood of patients with suicidal
ideations and behavior [490, 499, 506, 507]. In the past, only
a limited number of inflammatory factors have been studied
in association with suicide risk and depressive symptoms
[499, 508, 509]. However, a complex interaction exists
among the inflammatory factors with specific inflammatory
factors and groups of inflammatory factors yet to be defined
etiologically in suicidal and depressive symptoms.
Neopterin has also been implicated in psychiatric disor-
ders, including bipolar disorder [510], schizophrenia [511,
512], and major depression [513]. As compared to those of
healthy controls, significantly higher plasma neopterin levels
[475, 514], as well as urinary neopterin levels [515, 516]
have been reported in individuals with depression. In fact,
neopterin can serve as an independent predictor for the de-
velopment of major depression 6-months post-acute
ischemic stroke [517]. Moreover, as compared to healthy
controls, antipsychotic-naive patients with schizophrenia had
significantly higher serum neopterin levels before treatment.
Neopterin levels declined significantly within this cohort of
schizophrenic patients after three months of treatment with
antipsychotic medications. [518].
Elevated levels of CRP have also been reported to be as-
sociated with an increased risk for suicidal ideation, with
suicidal ideation being significantly more prevalent in the
highest compared with the lowest serum CRP quartile (OR:
1.79; 95% CI: 1.11–2.89), even after adjustment for multiple
confounders [519]. Many studies have reported that patients
with depression have higher levels of IL-1β, IL-6, TNF-α
and CRP [498, 520-522]. Studies have reported a correlation
between increased white blood cell counts and suicidality
(ideation and behavior) in depressive patients [523]. Moreo-
ver, increased white blood cell counts have been associated
with impulsivity as well [524], which in turn, has been
linked to suicide [525]. For example, Batty et al. evaluated
over 300,000 women and reported that in about 1,000 who
eventually died by suicide, suicide-related mortality was
predicted by higher levels of white blood cell counts [526].
In a recent study by Keaton et al., a distinct inflammatory
profile in women patients who were at an increased risk for
suicide was reported [527]. It was found that the strongest
influence on suicide risk was conferred by the increased lev-
els of white blood cell count and polymorphonuclear leuko-
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1369
cyte count. In addition, a biological cluster containing these
two factors together with increased levels of IL-6, lympho-
cytes and monocytes, significantly impacted suicide risk
[527]. An independent and negative association was uncov-
ered between the cytokine IL-8 and higher risk for suicide.
Moreover, even after adjusting for confounders, these results
remained significant [527]. IL-6 is a proinflammatory cyto-
kine and has been previously associated with suicidality as
well, and may be a part of the immunobiological network
that plays a role in increasing the risk for suicide [499, 507,
528, 529]. Many cells of the immune system, including
monocytes and granulocytes of the innate immune system,
can secrete IL-6, which is both a regulatory and a proin-
flammatory cytokine [530-532]. Moreover, this cytokine can
also be secreted in response to exercise and by adipose tissue
[533-536].
TLRs mediate the recognition of PAMPs from endoge-
nous and infectious pathogens, and hence, play an important
role in early innate immune response. Once the pathogens
are recognized, production of large amounts of inflammatory
cytokines is induced, such as IL-1β, TNF-α and IL-6, via
activation of NF-κB and other transcription factors [537].
Protein expressions of TLR2, TLR3, TLR4, TLR6 and
TLR10, and mRNA expression of TLR2 and TLR3 have
been recently reported to be significantly increased in the
postmortem brain of depressed and suicide subjects [538].
Additionally, peripheral blood mRNA levels of TLR3,
TLR4, TLR5, and TLR7 in depressed patients have been
reported to be significantly increased as well [539].
5. OTHER MECHANISMS POTENTIALLY CON-
TRIBUTING TO CARDIOVASCULAR AND NEURO-
PSYCHIATRIC DISORDERS
5.1. Translocation of Bacteria
While frequently found in individuals with periodontal
infections, P. gingivalis is also found in a significant propor-
tion of individuals without any evidence of local periodontal
conditions [540]. This suggests that translocation of this bac-
terium into other organs and tissues may contribute to its
presence in distal sites. Besides dental procedures, common
and less traumatic activities including chewing, brushing,
and flossing, can also lead to transient bacteremia of P. gin-
givalis [53], which results in translocation of this bacterium
to several distant tissues, such as liver [541], coronary arter-
ies [542], and placenta [543], thereby contributing to the
development of diabetes mellitus (by influencing hepatic
glycogenesis), atherosclerosis, and pre-term delivery, respec-
tively (Figs. 1 and 4). In fact, P. gingivalis arterial coloniza-
tion was recently reported in 100% of patients with cardio-
vascular disease [544].
Periodontopathic bacteria can gain access to the systemic
circulation due to breakdown of tissues in the oral cavity, a
characteristic of periodontitis [52, 53]. Animal models of
oral infection with P. gingivalis have described stimulation
of inflammatory reactions in distal sites, such as atheroma-
tous plaques [545-547]. Other common oral pathogens in-
cluding Streptococcus sanguis, Chlamydia pneumoniae, and
Streptococcus mutans (S. mutans) have been isolated in hu-
man atherosclerotic plaques as well [548-551]. Several spe-
cies of oral bacteria have also been detected in human
1370 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15
Mfa1
Escape to
cytosol?
Fig. (4). Dendritic cell entry can be manipulated by P. gingivalis using its accessory proteins and minor fimbriae Mfa1 that interact with host
cell α5β1-integrin, an adhesion molecule. (Reproduced from How KY, Song KP and Chan KG (2016) Porphyromonas gingivalis: An Over-
view of Periodontopathic Pathogen below the Gum Line. Front. Microbiol. 7:53. doi: 10.3389/fmicb.2016.00053).
cardiac valve samples, including S. mutans, P. intermedia, P.
gingivalis, and T. denticola [552]. Hence, systemic as well as
local systemic inflammatory reactions could be promoted by
the periodontal bacteria residing within the atheromas and
the cardiac valves, or by the proinflammatory components
produced by these bacteria [553]. Moreover, murine models
have reported induction of platelet aggregation by P. gin-
givalis and S. mutans inoculation, presumably leading to
formation of thrombi and accelerating the process of athero-
genic plaque formation [554, 555].
Yet, treatment for periodontitis may in itself be a trigger
for a transient rise in systemic inflammation [556]. In fact,
periodontal treatment has been associated with a temporary
increase in systemic pro-thrombotic/inflammatory mediators
lasting for at least one week [556], as well as with endothe-
lial dysfunction 24 hours post-treatment [557]. These asso-
ciations can be explained by the trauma, and bacteremia fol-
lowing periodontal treatment [558]. However, the eventual
reduction in inflammation after treatment for periodontitis is
lasting and prolonged, which outweighs the transient initial
rise in inflammation post treatment. For example, in a self-
controlled case-series study, it was reported that after exclud-
ing subjects with hypertension, diabetes and coronary artery
disease, as well as the individuals with prescriptions for sali-
cylate or antiplatelet drugs before dental treatment, the inci-
dence rate ratio for rate of vascular events in the first 4
weeks after invasive dental treatment was significantly
higher (1.50; 95% CI: 1.09-2.06) [559]. On follow-up of
these individuals, authors further found that within 6 months
of receiving the invasive dental treatment, the increased rate
of vascular events normalized to baseline values [559].
Metabolic diseases are characterized by chronic low-
grade inflammation [560] in which innate and adaptive im-
Wadhawan et al.
Dendritic Cell
Internalization Membrane
?
Vacuole
mune responses may promote inflammatory reactions driven
by gut microbiota [561, 562], ultimately resulting in insulin
resistance [563]. Commensal bacteria that exist under
physiological conditions in the gut prevent pathogens from
invading tissues and organs, mediate food digestion, and
strengthen the immune system. However, when detrimental
bacteria become predominant resulting in dysbiosis, the gut
epithelial wall may be damaged by noxious agents, including
bacterial metabolites and toxins, which could result in im-
pairment of various tissue and organs after being absorbed
into the systemic circulation via the disrupted gut epithelium
[564]. In fact, P. gingivalis has been reported to be associ-
ated with non-alcoholic steatohepatitis (NASH) in mice, was
found to aggravate NASH via promoting inflammation, and
was present in injured liver as well [565]. Moreover, massive
invasions of the gut by oral bacterial species have been im-
plicated in the major changes observed in gut microbiota of
the patients with liver cirrhosis [566].
Periodontopathic bacteria may also have effects on insu-
lin action [567] and glycogenesis in liver [541], and could
lead to systemic inflammation and metabolic alterations by
inducing a change in gut microbiome [568]. In particular,
increased systemic inflammation and insulin resistance have
been reported in mice after P. gingivalis was administered
via oral route to them [568]. In another study by this group
of researchers, it was reported that upon comparison with
sham-inoculated mice, C57BL/6 mice that received P. gin-
givalis (strain W83) orally had increased serum endotoxin
levels and significantly altered gut microbiota [569]. Down-
regulation of the expression of occludin and tjp-1, genes that
play a role in intestinal permeability, was also observed
[569]. These findings coincided with the dissemination of
enterobacteria to the liver, and the alterations in gut microbi-
Periodontal Pathogens and Neuropsychiatric Health
ota occurred prior to the changes in systemic inflammation
[569]. Hence, periodontal pathogens may induce alterations
in the gut microbiota [153, 568, 570] and altered nutrition
associated with periodontal disease [571] may affect the gut
microbiota as well [572]. Psychiatric symptomatology can
also be affected by changes induced in the gut microbiome
[573], through the gut-brain connection. This is evident from
a number of clinical studies [574], imaging studies [575],
and animal [576-582] studies. Additionally, microbes in the
gut may have immuno-modulatory effects on the brain [583-
585], and have implications for mental illness. For example,
more recently, Painold et al. [586] performed a cross-
sectional study by performing 16S rRNA gene sequencing of
stool samples in 10 healthy controls and 32 individuals with
bipolar disorder. Authors reported that microbial alpha di-
versity was negatively correlated with bipolar disorder ill-
ness duration (R = −0.408, p = 0.021) and that bacterial
clades in patients with bipolar disorder were associated with
several highly relevant variables, including metabolic syn-
drome, inflammatory status, depressive symptoms, trypto-
phan levels, serum lipids, and oxidative stress [586] (Fig. 5).
After establishing infection in the mouth, P. gingivalis
may spread via several routes and eventually can access the
brain. For example, it may: a) infect and spread via cranial
nerves [i.e., olfactory [587] or trigeminal] to the brain; b)
infect the monocytes that may then undergo recruitment to
the brain [588, 589]; and/or c) directly infect and damage the
endothelial cells that protect the blood-brain barrier [172]. If
it gains entry into the brain, P. gingivalis may slowly spread
along anatomically connected pathways from neuron to neu-
ron over many years, a phenomenon that has been described
for vascular cell-to-cell transmission of this bacterium as
well [590]. Moreover, neuron-to-neuron spread, a pattern
that mimics the course of an infection, has been suggested
for tau pathology as well [591]. Dominy et al. [101] pro-
posed that transneuronal spread of P. gingivalis may be re-
sponsible for the tau pathology seen in AD brains. Gingi-
pains of this bacterium activate the human proteases operat-
ing on tau, and since tau is a target of gingipain proteolysis,
they can directly damage the tau themselves. Blood-brain
barrier can be damaged by bacterial LPS via aberrant activa-
tion of matrix metalloproteinase, thereby increasing its per-
meability [592], and eventually, allowing the penetration of
brain by the periodontal bacteria in the blood stream. Detec-
tion of LPS derived from P. gingivalis has been reported in
AD patients’ brains [99] and DNA of this periodontal patho-
gen has also been found in the brain of mice that were in-
fected with P. gingivalis orally via quantitative polymerase
chain reaction [101]. Additionally, areas of the brain which
are deficient of a contiguous blood-brain barrier, such as the
choroid plexuses and circumventricular organs, could allow
the periodontal pathogens that are circulating in the blood-
stream to gain access into the brain.
Thus, periodontal pathogens or their virulence factors
could infiltrate the brain through any of the pathways (as
described above) and may eventually lead to microglial acti-
vation, as evidenced by the reports that have implicated LPS
of P. gingivalis or the P. gingivalis bacterium itself in in
vitro production of proinflammatory cytokines (IL-6, IL-1
and TNF-α) via activation of microglial cells [593, 594].
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1371
5.2. Neuroinflammation
Proinflammatory cytokines that are produced peripher-
ally from systemic inflammation, which in turn is generated
by periodontitis, may lead to neuroinflammation even with-
out the periodontal pathogens or virulence factors directly
coming in contact with the neural tissues. Potentially, these
neuroinflammatory effects of the peripherally produced
proinflammatory cytokines can be mediated through three
pathways (cellular, neural and humoral). Periodontal patho-
gens may communicate with microglia in the brain at the
meningeal interface. Meninges function as a physical barrier
between the bloodstream and the CSF and cover the paren-
chymal surface of the brain. Receptors for LPS of P. gin-
givalis, such as TLR 2 and 4, are also expressed on the men-
ingeal cells. P. gingivalis LPS circulating in the bloodstream
can lead to activation of the meningeal cells, which eventu-
ally form proinflammatory cytokines inside the neural tis-
sues lined by these cells [595, 596]. Thus, neuroinflamma-
tion may ultimately ensue via microglial activation resulting
from the proinflammatory cytokines that were originally
produced by the meningeal cells. Also, systemic inflamma-
tion manifested by a greater number of monocytes circulat-
ing in the bloodstream together with activated endothelial
cells is involved in the cellular pathway [597]. Endothelial
cells that express receptors for IL-1 and TNF-α can be acti-
vated by these proinflammatory cytokines in the bloodstream
[598]. Upon activation, these endothelial cells interact with
the macrophages located in the perivascular space [598].
Eventually, activation of the microglia occurs due to the in-
teraction between these perivascular macrophages and the
microglia. Besides producing proinflammatory cytokines,
upon activation, microglia release chemokines (including
monocyte chemoattractant protein-1) and proteases as well.
In fact, recruitment of monocytes in the brain regions that
are implicated in behavioral control, such as basal ganglia,
motor cortex and hippocampus, is likely mediated by mono-
cyte chemoattractant protein-1 [599]. Neural pathway in-
volves the direct activation of the vagus nerve or other pri-
mary afferent nerves by the cytokines in the systemic circu-
lation. The nucleus of tractus solitarius serves as the primary
projection of the neural pathway and receives the incoming
signal, which is then relayed onto hypothalamic nuclei in the
brain that act as the secondary projection of this pathway
[600]. Although, peripheral production of proinflammatory
cytokines induced by LPS is not affected by subdiaphrag-
matic vagotomy, it does lead to the impeding of the sickness
behavior induced by LPS in rats [601]. Circumventricular
organs and choroid plexus that are devoid of the blood-brain
barrier are implicated in the humoral pathway. Through vol-
ume diffusion via these permeable areas, the proinflamma-
tory cytokines circulating in the bloodstream can gain access
to the brain tissue and may modify the functioning of the
brain by inducing signaling events downstream [597].
6. UPCOMING CONCEPTS AND POSSIBLE INTER-
VENTIONAL STRATEGIES
Dominy et al. reported multiple lines of evidence sug-
gesting a causal role of P. gingivalis in AD [101]. For exam-
ple: 1) both P. gingivalis RgpB and Kgp gingipain loads in
human brains were correlated with AD diagnosis, ubiquitin
load, and tau load; 2) co-localization of RgpB was observed
1372 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 Wadhawan et al.

Depression
Dementia
Myocardial Coronary Carotid Schizophrenia
Endothelial Bipolar disorder
infarction artery artery
cells Suicidal behavior
Atherosclerosis domain domain
Stroke

Translocation

Liver Gut
P. gingivalis

Micro-RNAs
(miR-21,
miR-146a)

Inflammation

Metabolic dysregulation
Gut dysbiosis
Diabetes
Gut permeability
Dyslipidemia
Immune dysregulation
Metabolic syndrome

Fig. (5). Schematic showing possible mechanisms by which periodontal infection with Porphyromas gingivalis (P. gingivalis) may result in
neuropsychiatric and cardiovascular disorders. Infection with P. gingivalis is associated with an increase in inflammation that helps in sup-
pressing this pathogen. However, anti-inflammatory micro-RNAs (miRs), i.e., miR-21 and miR-146a are induced by P. gingivalis infection
that inhibit inflammation, thereby facilitating the survival of this pathogen in the host and giving it an opportunity to translocate to distant
sites via blood vessels. Then, P. gingivalis localizes in the endothelial cells of the carotid and coronary artery domains, and gains access to
vital organs. This advance of P. gingivalis could further lead to multiple neuropsychiatric and cardiovascular disorders. Additionally, when
present in the gut, it may induce dysbiosis of host gut microbiome that leads to immune dysregulation and an increase in inflammation.

with human hippocampal astrocytes, neurons, and pathology TNF-α levels in mice brain tissue with established P. gin-
in AD (i.e., intraneuronal Aβ and tau tangles); 3) P. gin- givalis infection [101].
givalis 16S rRNA gene, hmuY genes, and Kgp gingipain Based on the above detailed commentary in our manu-
were all detected in the cerebral cortex of AD brains; 4) P.
script so far, it becomes essential to consider future direc-
gingivalis DNA was identified in the CSF of individuals
tions for developing novel treatments for reducing the load
clinically diagnosed with probable AD; 5) observation of
of periodontal pathogens and their associated systemic and
fragmentation of tau by gingipains; 6) P. gingivalis gingi-
psychological manifestations. Dominy et al. [101] have
pains were found to have toxic effects on neurons in vitro
shown that twice-daily oral administration of COR271, a
and these effects could be reversed by administering small- Kgp inhibitor capable of bypassing the blood brain barrier,
molecule gingipain inhibitors in mouse models; 7) brain in-
results in significantly reduced brain bacterial load at 5
fection with P. gingivalis and induction of Aβ1-42 occurred in
weeks in P. gingivalis-infected BALB/c mice as compared to
mice infected orally with this bacterium; 8) antibacterial ef-
control mice. Even though prevention of the increasing colo-
fects of Aβ1-42 on P. gingivalis were uncovered; 9) effective
nization of the brain by P. gingivalis between day 35 and day
treatment of P. gingivalis brain infection and prevention of
70 was achieved by the broad-spectrum antibiotic moxiflox-
loss of hippocampal glutamic acid decarboxylase-67+ in- acin, it was not effective in decreasing the load of P. gin-
terneurons in vivo were achieved by oral administration of a
givalis below the baseline levels seen (i.e., 5-weeks prior)
Kgp inhibitor; and 10) dose-dependent efficacy of COR388
[101]. Besides, efficacy was not improved with combina-
(a selective irreversible small-molecule inhibitor of Kgp)
tions of COR271 with moxifloxacin or COR286 versus that
treatment in reducing P. gingivalis load, host A β1-42, and
achieved with COR271 administration in isolation. Another
highly potent and selective irreversible small-molecule in-
Periodontal Pathogens and Neuropsychiatric Health
hibitor of Kgp is COR388 which has significant CNS pene-
tration and superior oral pharmacokinetic properties.
Dominy et al. [101] reported that this compound was effec-
tive in treating an in vivo brain infection with P. gingivalis in
a mouse model. Dose-dependent efficacy to treat P. gin-
givalis brain infection that had already been established was
reported for twice daily dosing with COR388. For instance, a
3 mg/kg dosage of COR388 showed some decrease in the
load of brain P. gingivalis, but there was no drop in the lev-
els of TNF-α or Aβ1-42 in the brain. On the other hand, in
comparison with infected animals treated with vehicle,
higher doses of 10 mg/kg and 30 mg/kg of this compound
reduced P. gingivalis load, TNF-α, and Aβ1-42 levels in the
brain tissue of infected mice. In fact, COR388 is currently
under clinical trials (GAIN Trial) [602].
Additionally, neuroprotective effects of the small-
molecule gingipain inhibitors have been demonstrated in
mice. After a single administration of gingipain inhibitors by
combining COR286 (given subcutaneously) and COR271
(given by oral gavage), or both vehicles in eight-week-old
BALB/c mice, stereotactic injection was performed 1.5
hours later with a combination of RgpB and Kgp into the
hippocampus of these mice [101]. After 7 days, neurodegen-
eration was assessed in the brains of these mice. It was re-
ported that, as compared to those of the saline-injected mice,
significantly greater numbers of degenerating neurons were
present in the mice that were injected with gingipains [101].
Moreover, the pre-treatment with gingipain inhibitors such
as COR286 and COR271, blocked the neurodegeneration
[101], indicating the need for more research on these agents
to be developed into potential novel treatments for infection
with P. gingivalis and prophylactic prevention or reduction
of the subsequent burden of AD.
Dominy et al. [92] identified gingipain antigens in the
brains of individuals with both diagnosed and probable AD.
This finding suggests that poor dental care following the
onset of dementia does not result in the brain infection with
P. gingivalis; rather, infection seems to be primary and oc-
curs at a much earlier age, thereby explaining why AD pa-
thology can appear in middle-aged individuals prior to a de-
cline in cognitive functioning [603]. Reasonably, P. gin-
givalis strains may exhibit differences in virulence. Studies
are necessary to identify and characterize different strains
[603]. Also, more research needs to be done to determine
which strains present in the CSF and in the brain. Moreover,
it needs to be ruled out whether other Porphyromonas spe-
cies possessing gingipains such as Porphyromonas gulae,
which inhabits the oral cavity of pets including dogs, can be
transmitted to their owners’ oral cavity, and could result in
an infection of their brain [604].
It has been demonstrated that protection against in vitro
P. gingivalis-induced cell death can be achieved by gingipain
inhibitors but not by broad-spectrum antibiotics [101]. Also,
to help achieve in vivo eradication of P. gingivalis from the
brain, a high-dose subcutaneous broad-spectrum antibiotic
was less efficacious than an orally administered Kgp inhibi-
tor [101]. Resistance is not developed by P. gingivalis to the
Kgp inhibitor COR388, but it develops rapidly to moxiflox-
acin (a broad-spectrum antibiotic) [101]. Together, these
findings indicate that treatment with a selective and potent
Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1373
Kgp inhibitor may result in the prevention or slowing of fur-
ther neurodegeneration and accumulation of pathology in
AD patients, in the reduction in brain infection with P. gin-
givalis, and in the possible modification of the neuropsy-
chiatric and systemic manifestations of P. gingivalis infec-
tion in the brain, cardiovascular system, and metabolic or-
gans which may positively impact the overall health of its
human host.
Notable too is that, activity of P. gingivalis can also be
inhibited by several plant-derived compounds. Murakami et
al. performed a study on anti-inflammatory activity of res-
veratrol, quercetin, and their related compounds (4-
allylphenol, catechin, epicatechin and orcinol) [605, 606].
The authors reported inhibitory effects of these natural com-
pounds on the activity of fimbriae of P. gingivalis, although
more research is needed on the various strains of this perio-
dontal pathogen, which may have differing pathogenicity
and virulence. Inhibition of the proinflammatory effects of P.
gingivalis LPS by several natural compounds has also been
reported. For instance, a reduction in IL-8 and IL-6 expres-
sion has been demonstrated in human gingival fibroblasts
stimulated by P. gingivalis LPS by using alpha-mangostin
[607]. The roles of α-tocopherol in mitigating the harmful
effects of LPS have been reported to be mediated by elevat-
ing β-defensins (an antimicrobial peptide), stimulating the
migration and growth of gingival fibroblasts, and by decreas-
ing the inflammatory cytokines [608]. P. gingivalis LPS-
induced inflammatory response in human gingival fibro-
blasts has been reported to be inhibited by tormentic acid,
which can be a possible therapeutic agent for periodontal
disease as it possesses anti-inflammatory effects by inhibit-
ing IL-6 and IL-8 production [609]. P. gingivalis LPS has
also been reported to be inhibited by grape seed proantho-
cyanidin extracts [610]. Downregulation of two protease
genes that are associated with inactivation of host defense
mechanisms and tissue destruction, i.e., RgpA and Kgp, can
be achieved by rhein, an anthraquinone from rhubarb roots
that exhibits antibacterial synergistic effects with other poly-
phenols [611]. Additionally, marked inhibition of the prote-
inase activities of P. gingivalis gingipains occurs in a dose-
dependent manner via theaflavins, the main polyphenols in
black tea [612]. Moreover, a synthetic dual protease inhibitor
of Rgp and Kgp proteases, named KYT-41, is known to pos-
sess anti-inflammatory and anti-bacterial properties against
P. gingivalis and could be promising in treating and prevent-
ing periodontitis [613]. Studies on diminishing the effects of
OM proteins of P. gingivalis are also available. P. gingivalis
adhesion and invasion have been shown to be reduced by
about 50% with natural plant extracts that interact with bac-
terial OM proteins, such as polyphenols of Myrothamnus
flabellifolia [614]. Cytoprotective effects relating to cytokine
secretion also accompany these anti-adhesive effects [614].
Although, it is important to note that testing of this plant
extract was not done on other virulence factors of P. gin-
givalis and was only carried out on OM proteins.
6.1. Caution
The capability of P. gingivalis of translocation and ma-
nipulation of the immune system locally and systemically
may lead to different interpretations of the microbe having a
causal effect on a number of periodontal and distant patholo-
1374 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15
gies, such as AD. Yet, the causality may be spurious, and the
criterion of “necessary and sufficient” is likely to not be met
by P. gingivalis infection.
It is possible that unmeasured confounders or upstream
factors (such as genetic and epigenetic) may contribute to a
spurious association. The presence of the pathogen in the
brain or arterial wall could be an epiphenomenon and could
be, non-consequential. Furthermore, and even more impor-
tantly, strong enthusiasm for periodontal treatment in the
clinical domain may overlook the fact that the dental proce-
dures, and especially procedures targeting periodontal dis-
ease, are acutely linked to an increase in cardiovascular
events, and only longer term with improvement. Thus, if one
would conceptualize that acute inflammation secondary to P.
gingivalis infection and/or induction of bacteremia may con-
tribute to exacerbation of mood disorders and suicidal behav-
ior (previously associated with inflammation-elevating
events), one would have to consider, theoretically and clini-
cally, the exacerbation of mental illness and mortality after
periodontal procedures and their potential longer-term bene-
fits.
CONCLUSION, FUTURE DIRECTIONS AND RE-
SEARCH IMPLICATIONS
P. gingivalis is a highly successful and intriguing patho-
gen, in part because of its multiple unique capabilities. First,
to manipulate the immune system and hijacking phagocytes
for traveling to distant sites, as well as for evading detection
by other immune cells. Second, to simultaneously lead to a
proinflammatory state, and at the same time, to induce pro-
duction of miRNAs that have immunomodulatory effects.
The activation of these miRNAs may induce escape from
immune surveillance and immune pressure, resulting in the
capability of P. gingivalis to migrate to other distant sites.
Third, the impressive capability of the microbe to localize in
the wall of blood vessels, and also in the atheroma lesions
and thrombi. Fourth, although naturally a microbe tends to
compete with other pathogens, P. gingivalis does not show
evidence of competition between its serotypes and with other
bacteria, and it appears that it mostly provides synergistic
interactions with a number of other pathogens. The capacity
of P. gingivalis to build a biofilm is a formidable defense
mechanism, and its biofilm includes other pathogens con-
tributing to their co-evading of the immune system. Finally,
when translocated to the arterial wall, P. gingivalis can in-
duce local downregulation of inflammation employing cer-
tain miRNAs as well as elevation of anti-inflammatory cyto-
kines such as IL-10 and downregulation of proinflammatory
cytokines. Yet, when the microorganism dies, release of its
LPS induces inflammation, locally and systemically, elevat-
ing proinflammatory cytokine production. The immune ma-
nipulation and, especially, the anti-inflammatory induction
by P. gingivalis are factors that could be studied for potential
large applications in metabolic disease, cancer, autoimmune
disease, and neuropsychiatric illness.
Mental health symptoms contribute to periodontal dis-
ease (either through self-neglect, or other factors leading to
reduced resilience of the mucosa; e.g., medications, reduced
dental hygiene, eating night snacks), but could also be a con-
sequence of them through a number of factors (such as pain,
Wadhawan et al.
insomnia) of which inflammation is a compelling mechanis-
tic hypothesis. Inflammation has been implicated in mood
disorders, anxiety disorders, schizophrenia and cognitive
disorders such as dementia, and behavioral abnormalities
such as suicidal behavior and aggression. As a proximate
modifiable cause of inflammation of demonstrated clinical
relevance, P. gingivalis infection stands apart, both in terms
of robustness of its pathophysiological effects, as well as in
the availability of multiple preventative interventions known
to affect chronic periodontitis prospectively (flossing, rins-
ing, tooth brushing, dental checkups, and routine preventa-
tive periodontal interventions). Presumably, therefore, teach-
ing oral hygiene to patients and mental health providers, as
well as increasing access to preventative dental care and
treatment, coupled with motivation to attend dental appoint-
ments, should have a positive effect in reducing the intensity
and frequency of exacerbation of mood and anxiety disor-
ders, and in reducing the slope of deterioration in cognitive
disorders and schizophrenia, as well as in lowering the
prevalence of metabolic disease, cardiovascular symptoms,
and mortality in patients with mental illness.
Presuming that the connection between P. gingivalis
translocation, immune activation, mental symptoms and be-
havioral dysregulation will be confirmed by future studies,
one particularly relevant aspect is the temporality of the phe-
nomena. The initial consequence of periodontal treatment is
increased translocation and immune activation, and thus, an
initial worsening of symptoms, functioning, and cardiovas-
cular and suicide mortality is expected. This might be met
with the recommendation of increased efforts for mental
health professional visits scheduled during the intervals of
increased risk, and with prophylactic visits and pharmacol-
ogical and psychotherapeutic approaches.
Large population studies need to test the effect of perio-
dontal intervention on mental health and mental health mor-
tality, including cardiovascular mortality in patients with
mental illness. The intervention could be analyzed through
marginal structural modeling, reducing the risk of bias, and
potentially, by contributing to a model of a “quasi-clinical
trial” nested in a population study.
One way to start the investigation of P. gingivalis con-
tributing to mood disorders and increased suicide risk factors
is to investigate the role of translocated P. gingivalis in ani-
mal models of anxiety-like and depressive-like behaviors, as
well as decision making and aggression modeling, testing
various psychotropic interventions, and in particular, gingi-
pain-targeting pharmacological agents, followed by human
experiments and clinical trials.
The capability to identify translocated P. gingivalis using
positron-emission tomography imaging, correspondence
between oral microbiome identification of P. gingivalis,
identification of serotypes with particularly high pathogenic-
ity in terms of effects at a distance (via immune activation or
translocation) are important efforts. A special focus is repre-
sented by the pregnant woman, when identifying and ad-
dressing infection with P. gingivalis, as periodontal inflam-
mation may contribute to placental health, fetal outcome, and
peripartum depression in the mother. Moreover, immuno-
suppression tends to occur early in the phase of pregnancy
(to favor immunotolerance of the fetus) [615], thereby giving
Periodontal Pathogens and Neuropsychiatric Health Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15 1375

more opportunities to oral pathogens to infect, disseminate IDO = Indoleamine-2,3-

and manifest diverse symptomatology. However, immune Dioxygenase
activation may occur in the later phases of pregnancy and
IFN = Interferon-γ
contribute to depressive symptomatology [616, 617]. Hence,
it becomes essential to clarify the risks vs. benefits of perio- IL = Interleukin
dontal interventions in pregnancy, demonstrate windows of IRAK1 = Interleukin-1 Receptor-
vulnerability for negative effects of translocation on placen- Associated Kinase-1
tal circulation and fetal outcomes, and windows of opportu-
nity when periodontal interventions are expected to result in IM = Inner Membrane
strong benefits. Finally, studies on family aggregation (with KYNA = Kynurenic Acid
differential effects of heritability and household, such as
possible in the Old Order Amish of Lancaster, Pennsylvania) LPS = Lipopolysaccharide
– may compare potential infectious transmission between miR = Micro-RNA
spouses and between siblings and parents and offspring. This
may change the way we think about prevention of putative NASH = Non-Alcoholic Steatohepa-
infectious causes of AD, and by extension, brain involve- titis
ment in neuropsychiatric illness, and may have a consider- NF-κB = Nuclear Factor Kappa-
able prophylactic impact. Light-Chain-Enhancer Of
Activated B Cells
LIST OF ABBREVIATIONS NHANES = National Health and Nutri-
3-HK = 3-Hydroxykynurenine tion Examination Survey
a7nACh receptor = Alpha7 Nicotinic Acetyl- NMDA = N-Methyl-D-Aspartate
choline Receptor NSAIDs = Non-Steroidal Anti-
AAP = American Academy of Pe- Inflammatory Drugs
riodontology OM = Outer Membrane
A. actinomycetemcomitans = Aggregatibacter actinomy- OR = Odds Ratio
cetemcomitans
PAI-1 = Plasminogen Activator In-
ACMSD = Amino-β- hibitor-1
Carboxymuconate-
Semialdehyde- PAMPs = Pathogen‐Associated Mo-
Decarboxylase lecular Patterns
AD = Alzheimer’s Disease PBMCs = Peripheral Blood Mononu-
clear Cells
BDNF = Brain-Derived Neurotrophic
Factor PDCD4 = Programmed Cell Death
Protein 4
CAL = Clinical Attachment Loss
P. gingivalis = Porphyromas gingivalis
CEBPA = CCAAT/Enhancer-Binding
Protein Alpha PIC = Picolinic Acid
CDC = Centers for Disease Control P. intermedia = Prevotella intermedia
and Prevention PPD = Periodontal Probing Depth
CI = Confidence Intervals PSD = Polymicrobial Synergy and
CRP = C-reactive Protein Dysbiosis
CSF = Cerebrospinal Fluid QA = Quinolinic Acid
F. nucleatum = Fusobacterium nucleatum ROS = Reactive Oxygen Species
GCF = Gingival Crevicular Fluid RR = Relative Risk
hAPP-J20 = Human Amyloid Precursor T. forsythia = Tannerella forsythia
Protein T. denticola = Treponema denticola
HPDLFs = Human Periodontal Liga- TGF-β = Transforming Growth Fac-
ment Fibroblasts tor Beta
HR = Hazard Ratio TNF-α = Tumor Necrosis Factor-
HSPs = Heat-Shock Proteins Alpha
HuR = Human Antigen R TLR = Toll-Like Receptor
1376 Current Topics in Medicinal Chemistry, 2020, Vol. 20, No. 15
TRAF6 = Tumor Necrosis Factor Re-
ceptor-Associated Factor 6
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
The project was supported by intramural funds from the
University of Maryland Baltimore, MD. Dr. Dwivedi’s con-
tribution was supported by intramural funding from the De-
partment of Psychiatry and Behavioral Neurobiology/ Uni-
versity of Alabama at Birmingham, Birmingham, AL and, by
the grant number R01MH082802 from the National Institute
of Mental Health (NIMH / National Institutes of Health
(NIH), Bethesda, MD. Rocky Mountain MIRECC for Sui-
cide Prevention, Aurora, CO and Military and Veteran Mi-
crobiome Consortium for Research and Education (MVM-
CoRE), Aurora, CO supported Drs. Brenner, Postolache,
Lowry and Hoisington. The Department of Veterans Affairs
Office of Research and Development (VA-ORD) RR&D
Small Projects in Rehabilitation Research (SPiRE: grant
number 1 I21 RX002232-01) supported in part Drs. Brenner,
Lowry, Hoisington and Postolache. The Capitol MIRECC,
VISN 5, Baltimore, MD, supported, in part, the input of Drs.
Potocki and Postolache. The NIMH/ NIH, Bethesda, MD
(grant number 1R21MH116263), and the Department of the
Navy, Office of Naval Research Multidisciplinary University
Research Initiative (MURI) Award (grant number N00014-
15-1-2809) partially supported the writing contribution of
Dr. Lowry. The DC Department of Behavioral Health,
Washington, DC, supported, in part, contributions of Drs.
Wadhawan and Postolache. No funding agency was involved
in article conception, writing, and finalizing the manuscript.
The views expressed here belong to the authors, and do not
necessarily represent the views of National Institutes of
Health, Veterans Health Administration, the Department of
Defense, or the DC Department of Behavioral Health.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Support for the writing of this manuscript was provided
by the Rocky Mountain MIRECC, Aurora, CO and the Mili-
tary and Veteran Microbiome: Consortium for Research and
Education (MVM-CoRE), Aurora, CO, and in part, by Tun-
ing, Inc, Silver Spring, MD, the CS-MAP Washington, DC,
and by the DC Department of Behavioral Health. The views,
opinions and findings contained in this article belong to the
authors.
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