CME Article

An Update on the Relationship Between

the Gut Microbiome and Obsessive-
Compulsive Disorder
Jasmine Turna, BSc, PhD(C); Beth Patterson, BScN, MSc; and Michael Van Ameringen, MD, FRCPC

ABSTRACT
The gut microbiome, the collection of
microbes and their genetic material in the
human gastrointestinal tract, has recently
become a topic of interest in psychiatry. To
date, animal studies have repeatedly shown
behavior to be affected by alterations in the
gut microbiota. Furthermore, studies in
clinical psychiatric populations have also
illustrated that microbial dysbiosis may
play a role in these conditions, but results
have been inconsistent. Given the exist-
ing animal and human literature provid-
ing evidence for a role of the microbiome
in anxiety and depressive disorders, this
review explores and develops similar lines
of evidence in obsessive-compulsive disor-
der. Theoretical treatment options target-

© Shutterstock
ing the gut microbiome are also discussed.
[Psychiatr Ann. 2017;47(11):542-551.]

O
bsessive-compulsive disorder
Jasmine Turna, BSc, PhD(C), is a Research Assistant, MacAnxiety Research Centre, McMaster (OCD) is a psychiatric condition
University; and a Graduate Student, MiNDS Neuroscience Graduate Program, McMaster Univer- marked by recurrent intrusive
sity. Beth Patterson, BScN, MSc, is a Research Nurse, Department of Psychiatry and Behavioural thoughts and ritualistic behaviors aimed
Neurosciences, McMaster University; and a Research Research Manager, MacAnxiety Research at reducing the associated distress. The
Centre, McMaster University. Michael Van Ameringen, MD, FRCPC, is a Professor, Department of etiology of OCD is complex and involves
Psychiatry and Behavioural Neurosciences, McMaster University; the Director, MacAnxiety Re- multiple pathways, with imbalances in
search Centre, McMaster University; and a Psychiatrist, Hamilton Health Sciences. central serotonin, glutamate, and dopa-
Address correspondence to Jasmine Turna, BSc, PhD(C), MacAnxiety Research Centre, McMas- mine systems thought to play a causative
ter University, 1057 Main Street W, L02, Hamilton, ON, L8S 1B7; email: turnaj@mcmaster.ca. role. This etiological basis remains large-
Grant: M. V. A. has received grants from the Hamilton Academic Health Sciences Organization ly theoretical and has received mixed
and the Canadian Foundation for Innovation. scientific support. The current theories
Disclosure: Beth Patterson reports that her spouse is on the speakers bureau for Lundbeck, are premised on the observed benefit
Purdue, and Allergen; her spouse is a consultant for Purdue and Allergen; and her spouse has of pharmacological interventions such
performed contracted research for Shire, Janssen-Ortho, and Pfizer. Michael Van Ameringen is as serotonin reuptake inhibitors (SRIs).
on the speakers bureau for Lundbeck, Purdue, and Allergen; is a consultant for Purdue and Aller- Given that 40% to 60% of patients with
gen; and has performed contracted research for Shire, Janssen-Ortho, and Pfizer. The remaining OCD do not respond to first-line treat-
author reports no relevant financial relationships. ments such as SRIs or cognitive-behav-
doi: 10.3928/00485713-20171013-01 ioral therapy (CBT),1 it is important that

542 Copyright © SLACK Incorporated


researchers examine alternative putative
pathophysiological mechanisms that
may be involved in OCD. The connection
between the gut microbiome and brain is
a novel pathway, and its role in mental
health is currently being explored. There
is some evidence to suggest that it may
play a role in the neurobiological under-
pinnings of OCD.
WHAT IS THE GUT MICROBIOME?
The human gut microbiome refers
to the collection of microbes and their
genetic material in the human gastroin-
testinal (GI) tract.2 These microorgan-
isms populate the human distal gut and
outnumber all remaining human cells by
more than 10-fold.3 They serve numer-
ous structural, metabolic, and protective
functions, and it is believed that a deli-
cate balance of these bacteria may con-
tribute to overall health.
The composition of the core bacteria
is established in early life and begins
to resemble the fully formed adult gut
microbiome by age 3 years.4 The adult
gut microbiome is predominantly stable
and dominated by the Firmicutes (spe-
cies such as Lactobacillus, Clostridium,
and Enterococcus) and Bacteroidetes
(species like Bacteroides) phyla.4 Other
phyla such as Actinobacteria (Bifidobac-
teria), Proteobacteria (Escherichia coli),
Fusobacteria, Verrucomicrobia, and
Cyanobacteria are also present.5 Many
factors affect the relative proportions
of the bacteria comprising the microbi-
ome. For instance, whether a person was
born vaginally or via cesarean delivery,
whether they were breast-fed or bottle-
fed, his or her diet, medications, and
stress have all been shown to alter the
presenting gut microbial profile.4
HOW DOES THE GUT MICROBIOME
RELATE TO MENTAL HEALTH?
Research has shown that the gut and
brain are connected through a system
termed the “gut-brain axis,” and the mi-
crobiota are thought to modulate this
PSYCHIATRIC ANNALS • Vol. 47, No. 11, 2017
CME Article
bi-directional pathway.5-8 Because of
the ability of the gut microbiota to alter
behavior,5-8 researchers have begun ex-
ploring its involvement in neuropsychi-
atric conditions. The existing scientific
literature strongly supports the theory
Animal studies have repeatedly
shown that rodent behavioral
responses change when the gut
microbiome is modified.
that the behavioral influence of the gut
microbiota may be regulated by the im-
mune system via cytokine release, lead-
ing to an inflammatory response.9 Other
proposed mechanisms of action include
release of gut hormones activating the
enteric nervous system and signaling the
brain via ascending neural pathways (ie,
vagus nerve).10 The final proposed mech-
anism involves the inherent ability of
these bacteria to produce neurotransmit-
ters such serotonin, dopamine, gamma-
aminobutyric acid, norepinephrine, and
acetylcholine,11 as dysregulation of
many of these neurotransmitter systems
has been implicated in numerous psy-
chiatric conditions.
Animal Studies
To date, animal studies have repeat-
edly shown that rodent behavioral re-
sponses change when the gut microbi-
ome is modified. For example, germ-free
(GF) mice (those with no commensal in-
testinal bacteria) exhibit altered anxiety
behaviors compared to conventionally
reared mice.5-8 This theory has been fur-
thered by exploiting the inherent behav-
ioral differences in BALB/c (generally
more anxious) and National Institutes
of Health (NIH) Swiss mice (gener-
ally more exploratory). When GF mice
of both breeds are colonized with the
microbiomes of each respective breed,
the recipient’s exploratory behaviors
become representative of the donor.12
Furthermore, re-establishment of the gut
microbiota in GF mice during the early
part of life also alters their behavior such
that they begin to act similarly to non-
GF mice.6,7 This normalization, howev-
er, does not apply if the microbiota are
reconstituted in adulthood, suggesting
that the anxiety response may be pro-
grammed during a critical period early in
life. Studies using probiotic treatments
have also shown reduced anxiety13,14 and
depression-like14,15 symptoms in healthy
mice, effects that are lost when part of
the vagus nerve is removed, suggesting
a role for vagal response in the gut-brain
axis. Similarly, top-down modulation of
the gut-brain axis has also been observed
with external stressors (eg, maternal
separation, prolonged stressors) affect-
ing the composition of the gut micro-
biome.16-18 This indicates a role for the
hypothalamic-pituitary-adrenal (HPA)
axis in the gut microbiome, which is
enhanced in GF mice.19 Taken together,
these findings suggest a role of the gut
microbiome in mental health.
Human Studies
The existing dogma surrounding mi-
crobiome research suggests that “dys-
biosis” is associated with a diseased
state. The extant literature has linked al-
terations in the gut microbiota to several
physical conditions, including celiac
disease,20 obesity,21 inflammatory bowel
disease (IBD; ie, ulcerative colitis and
Crohn’s disease),22 and irritable bowel
syndrome (IBS).23 Interestingly, high
levels of comorbid psychiatric symp-
toms, particularly depression and anxi-
ety, have also been documented in these
populations.24 As such, the attention of
microbiome research has shifted to psy-
chiatric populations.
Presently, the gut microbiome has
only been evaluated in clinical popula-
tions of patients with autism spectrum
543

disorder (ASD), major depressive disor-
der (MDD), and bipolar disorder (BD).
Typically, these studies use 16s ribo-
somal RNA pyrosequencing to analyze
fecal samples and determine micro-
bial profiles, with differences reported
in terms of species diversity, alpha-
diversity (richness), beta-diversity (dis-
similarity measure), and relative abun-
dance of operational taxonomic units
(OTUs; groups of microorganisms
clustered by DNA sequence similar-
ity). Compared to healthy children,
children with autism have been found
to have 10 times more Clostridium
type microbes,25-28 in addition to a va-
riety of other microbial compositional
differences (Figure 1).
Case-control studies have consistent-
ly observed microbiota compositional
changes in patients with MDD com-
pared to healthy controls (HC), notwith-
standing the fact that these differences
have varied across studies (Table 1).35-38
A recent study also evaluated the
gut microbiome in people with BD
(n = 116, most taking more than one
psychotropic medication) and HCs
(n = 64).39 The OTU analysis revealed
significantly decreased levels of Fae-
calibacterium (phylum Firmicutes,
family Ruminoccocae), independent
of age, sex, body mass index, and false
discovery rate.39
WHY OBSESSIVE-COMPULSIVE
DISORDER?
Although no longer classified as an
anxiety disorder, anxiety remains a pre-
dominant feature of OCD. As a result,
much of the aforementioned animal
literature regarding anxiety and the gut
microbiome may also be applicable to
OCD. For instance, our early neurobio-
logical understanding of OCD posited
that balancing certain neurotransmitters
(ie, serotonin, dopamine, and glutamate)
accounts for the treatment effects of
traditional therapies (ie, SRIs and aug-
mentative antipsychotic agents).40 The
544
CME Article
gut bacteria may be able to alter levels
of neurotransmitters, as they are known
to produce them. There is also extensive
evidence linking the HPA axis and gut
microbiome.2 Interestingly, elevated
basal activity of the HPA axis has also
been noted in OCD, as demonstrated by
increased urinary free cortisol,41 and ce-
rebrospinal fluid levels of corticotropin-
releasing hormone and adrenocortico-
tropic hormone,42,43 suggesting a role in
OCD. Although preclinical data suggest
a role for the gut microbiome in anxiety
disorders, the literature specific to OCD
is limited. One study revealed that 2 and
4 weeks of pretreatment with a probiotic
(Lactobacillus rahmnosus GG) attenu-
ated OCD symptoms to the same degree
as fluoxetine in an RU24969 (also known
as 5-HT1A/1B receptor agonist) mouse
model of OCD.44 In healthy people
(n = 66), 30 days of daily intake of a
probiotic formulation containing Lacto-
bacillus helveticus and Bifidobacterium
longum has been shown reduce a variety
of subscores on the Hopkins Symptom
Checklist (HSCL-90), including “obses-
sive-compulsive” (P < .05) and global
Hospital Anxiety and Depression Scale
score (P < .05) compared to placebo.45
Additional lines of evidence that have
typically been used to link anxiety and
mood disorders and the gut microbiome
may also be relevant to OCD. This in-
cludes comorbidity with GI conditions
and inflammation.
Overlap with Gastrointestinal
Illness
As mentioned previously, gut micro-
bial dysregulation has been demonstrat-
ed in numerous GI conditions. These
illnesses are also often paired with high
rates of comorbid anxiety and mood dis-
orders. However, the prevalence of OCD
in these populations may also be signifi-
cant.46,47 Whereas one study reported
the lifetime prevalence of OCD was no
different in their IBS proband versus
controls or in relatives of these people,48
another indicated that 74.2% of their IBS
sample had an anxiety or depressive dis-
order, including OCD.49 A more recent
study examining psychiatric disorders
in patients with functional bowel dis-
orders reported that 85% of the sample
was diagnosed with a psychiatric dis-
order, the most prevalent being dysthy-
mia (25%) and OCD (20%).50 Some lit-
erature also suggests that IBS and other
functional bowel disorders may also be
more prevalent in OCD populations. For
instance, one study reported increased
prevalence of IBS in their OCD sample
(n = 37) (35.1%) compared to age- and
sex-matched nonpsychiatric controls
(n = 40, 2.5%, P = .00002).51 Similar
rates have also been reported in a sample
from India in which 26.2% of patients
with OCD and 3.5% of the control group
had IBS;52 however, rates of IBS in OCD
populations may be similar to that of
community samples.53 In a sample of
children with ASD, children with mixed
bowel issues (constipation and diarrhea)
were more likely to have parent reports
of repetitive or compulsive behaviors
and a previous OCD diagnosis as per
parental report.54
There may also be overlap between
symptoms of OCD and GI conditions,
further promoting the involvement of
the gut-brain axis in OCD. Patients
with IBD have been frequently de-
scribed as obsessive, rigid, and com-
pulsive.55 “Bowel obsession syndrome”
(BOS) has also been used to describe
people with an overwhelming fear of
bowel incontinence when in public,
paired with ritualistic behaviors sur-
rounding prevention of such occur-
rences. Although not considered a
functional gastrointestinal disorder,
the clinical characteristics of BOS sig-
nificantly overlap with the diagnostic
criteria of OCD. Interestingly, these
symptoms have also been successfully
treated with imipramine or doxepin,56
clomipramine,57 and psychotherapy58-60
in a number of case reports. A single
Copyright © SLACK Incorporated

Figure 1. Microbial differences observed in people with autism spectrum disorder per varying taxonomic levels.
case report also revealed abrupt onset
of OCD in a child with Crohn’s disease
without a familial or personal history of
OCD.55 No previous exposure to group
A beta-hemolytic streptococcal infec-
tion was noted, reducing the probability
of pediatric autoimmune neuropsychi-
atric disorder associated with strep-
tococcal (PANDAS) infection. The
only determined temporal association
to the onset of OCD symptoms was a
change in medication from infliximab
to adalimumab (two immunomodulat-
ing medications) after exacerbation
of IBD symptoms. Although the OCD
symptoms resolved after 10 days with-
out any intervention,55 this highlights
the overlap between OCD and GI ill-
ness while furthering the suggestion of
OCD potentially being immunomodu-
lated. Overall, the data suggest that
there may be a more substantial link
between OCD and GI conditions than
PSYCHIATRIC ANNALS • Vol. 47, No. 11, 2017
CME Article
previously thought, promoting the link
between OCD and the gut microbiome.
Immune Dysregulation
There is much support for the role
of inflammation in neuropsychiatric
conditions, including OCD. Some evi-
dence draws from PANDAS, a condi-
tion where antibodies produced against
the streptococcal proteins find targets
in the brain leading to inflammation of
the basal ganglia and bilateral lentiform
nuclei.61 Given the sudden onset, it is
thought that the repetitive behaviors
may be a result of this neuroinflamma-
tion. Increased levels of systemic pro-
inflammatory markers (tumor necro-
sis factor [TNF]-alpha and eotaxin-3,
P < .05) and decreased anti-inflam-
matory (interleukin [IL]-8, interferon
gamma-induced protein-10, IL-17a,
interferon-gamma, IL-10, and IL-12;
P < .05) markers have been reported
in patients with PANDAS when com-
pared to children who experienced a
group A streptococcal infection but did
not subsequently develop PANDAS.62
Human leukocyte antigen analysis has
also revealed positive association in
patients with a diagnosis of pediatric
acute-onset neuropsychiatric syndrome
(PANS) versus controls, and prevalence
rates for arthritis and autoimmune dis-
ease (ie, Hashimoto’s thyroiditis, celiac
disease, and psoriasis) were 25% and
18%, respectively.63 The average length
of PANS flare-up is significantly shorter
when treated with nonsteroidal anti-in-
flammatory drugs (NSAIDs) or predni-
sone.63 Past infection has also been re-
lated to future onset of OCD in adults.
For example, a large prospective cohort
study revealed that intestinal infection
(odds ratio [OR] = 1.34, P < .01) was
associated with subsequent onset of an
anxiety disorder (including OCD).64
545
 CME Article

TABLE 1.

Summary of Microbial Differences Observed in

Major Depressive Disorder Case-Control Studies

Study Bacterial Difference Significance of Bacterial Changes

35
Naseribafrouei et al. General underrepresentation of Bacteroidetes phylum Congruent to obese microbiota that, like MDD, have been
MDD (n = 37) (decreased Bacteroidales [order] associated with MDD) associated with low-grade inflammation (no difference in
(P = .05) MDD and HC BMI)
HC (n = 18)
Increased Alistipes (P = .007) and Oscillibacter (P = .03) Alistipes increased in CFS and IBS; associated with inflam-
(genus) mation and indole-positive so may influence tryptophan
availability
Oscillibacter produces valeric as final metabolic product,
which structurally resembles GABA and binds GABA
receptors
Jiang et al.36 A-MDD vs. HC: species diversity increased in A-MDD Increased diversity usually associated with nondiseased
MDD (n = 46) (Shannon index) state, finding unclear
A-MDD (n = 29) Increased RA Bacteroidetes (primarily Parabacteroides Bacteroidetes: Alistipes (refer to Naseribafrouei et al.35)
and Alistipes), Fusobacteria, and Proteobacteria (P < .05) Proteobacteria: Increased gut permeability allows for such
R-MDD (n = 17)
Decreased RA Firmicutes and Actinobacteria (P < .05). invasive gram-negative bacteria into systemic circulation
HC (n = 30)
and presence of these bacteria in gut have been linked to
behavioral changes in mice previously
Firmicutes (Lachnospiraceae family): decreases SCFA pro-
duction, causing intestinal barrier dysfunction
R-MDD vs. HC: Increased RA Firmicutes, Fusobacteria, and Atypical antipsychotic use was widespread among patients;
Actinobacteria (P < .05) a previous animal study demonstrated similar results where
Increased RA Bacteroidetes and Proteobacteria (P < .05) chronic antipsychotic administration increased Firmicutes
and decreased Bacteroidetes (Davey et al.95)
Negative correlation between RA Faecalibacterium and
MDD symptoms (P < .05)
Zheng et al.37 Increased RA Actinobacteria and decreased Bacteroidetes Findings conflict with Jiang et al.,36 and appear to be driven
MDD (n = 58) (P < .01) by disturbances of microbial genes and host metabolites
involved in carbohydrate and amino acid metabolism;
HC (n = 63)
however, FMT of MDD samples into GF-mice revealed onset
of depression-like behaviors 2 weeks post-FMT
Aizawa et al.38 Significantly increased Bifidobacterium counts Bifidobacterium and Lactobacillus thought to have benefi-
MDD (n = 43) (P < .012) and decreased Lactobacillus counts (P < .067) cial effect on stress response and MDD
than controls
HC (n = 57)

Abbreviations: A-MDD, active MDD; BMI, body mass index; CFS, chronic fatigue syndrome; FMT, fecal microbiota transplant; GABA, gamma-aminobutyric acid; GR, germ free; HC, healthy controls;
IBS, irritable bowel syndrome; MDD, major depressive disorder; RA, relative abundance; R-MDD, responding MDD; SCFA, short chain fatty acid.

Toxoplasma gondii infection has also
been associated with OCD (OR = 3.4,
P = .0004).65
Numerous studies have also re-
ported an altered inflammatory cy-
tokine profile in adult patients with
OCD.66,67 The only study evalu-
ating primary pediatric OCD re-
ported increased levels of IL-17A
(P = .03), TNF-alpha (P = .01), and
IL-2 (P = 0.02) in patients with OCD
than in controls; symptom severity
and illness duration were not signifi-
cantly correlated with cytokine lev-
els.68 This may be further supported
by the finding in patients with early-
onset OCD revealing increased pro-
duction of inflammatory cytokines by
monocytes when stimulated with lipo-
polysaccharide (LPS) or dexametha-
sone and LPS.69 As such, patients with
OCD may possess an intrinsic vulner-
ability to monocyte activation, which
may generate an increased inflam-
matory response.69 In adult popula-
tions, results of studies investigating
cytokines are inconsistent; however,
many believe that this may be con-
sequent to the confounding effects of
medications and comorbid conditions
(specifically mood disorders, which
have been associated with low-grade
inflammation) in study populations.
For example, a meta-analysis revealed
decreased levels of IL-1 beta while
showing no differences in levels of

546 Copyright © SLACK Incorporated


IL-6 and TNF-alpha between cases
and controls, suggesting a noninflam-
matory profile.70 However, a stratified
subgroup analysis revealed moder-
ating effects of age and inclusion of
patients on pharmacological treatment
and with comorbid mood disorders.70
A recent study in drug-naïve, comor-
bidity-free patients with OCD revealed
increased plasma levels of IL-2, IL-4,
IL-6, IL-10, and TNF-alpha compared
to age- and sex-matched controls,
suggesting immune dysregulation as
increased levels of the anti-inflam-
matory cytokine IL-10 may have been
in response to an overall proinflam-
matory cytokine profile.71 A positive
association between some autoim-
mune conditions (systemic lupus ery-
thematosus, thyroid dysfunction, and
multiple sclerosis) and OCD has also
been suggested.72 Although circulat-
ing cytokines do not provide a clear
picture of increased inflammation in
OCD, these bodies of evidence further
the role of immune dysregulation, and
as an extension, the inflammatory re-
sponse in OCD.
Beyond this, the role of inflam-
mation in OCD may also be support-
ed by treatment response observed
in trials using immunomodulating
compounds. In a 28-week crossover,
randomized controlled trial (RCT),
intake of Trichuris suis ova (stud-
ied in autoimmune disorders) in pa-
tients with ASD was shown to reduce
scores on the Yale-Brown Obsessive-
Compulsive Scale (Y-BOCS) compul-
sion subscale (d = 0.52).73 Adjuvant
celecoxib (200 mg twice daily), a
NSAID, has also been shown as su-
perior to fluvoxamine monotherapy
(200 mg/day) after 10 weeks of
treatment while also having an ear-
lier response.74 Similarly, an ear-
lier study had shown adjunctive ce-
lecoxib (200 mg twice daily) was
superior to 8 weeks of fluoxetine
(20 mg/day) monotherapy.75
PSYCHIATRIC ANNALS • Vol. 47, No. 11, 2017
CME Article
WHAT DOES THIS MEAN FOR
TREATMENT?
At the present time, there are no
published studies evaluating the gut
microbiome in OCD. As such, we can
only consider theoretical treatments
that either alter the gut microbiota
or have shown promise in conditions
in which microbial disruption has
Probiotics are live
microorganisms that, when
administered in adequate
amounts, confer a health
benefit on the host.
occurred. Potential therapies include
antibiotics, probiotics, and fecal bio-
therapy.
Antibiotics
With the ability to eliminate micro-
bial pathogens, antibiotic treatment
can dramatically alter the gut microbi-
al landscape both in the short and long
term, in part by reducing bacterial den-
sities.76 Given that microbiome dysbio-
sis does not preclude the overgrowth
of certain microbial components at the
root of any observed dysbiosis, antibi-
otics targeting a given class of bacte-
ria could theoretically offer benefit by
“normalizing” the microbial profile.
The extant literature supports the
use of antibiotics in ASD, MDD, and
BD, conditions in which microbial
dysregulation has been identified. In
one study, 8 weeks of open-label treat-
ment with vancomycin (500 mg/d) in
children with regressive-onset autism
(n = 11) revealed short-term improve-
ments in communication and behavior.34
Like imipramine, the tetracycline anti-
biotic doxycycline was shown to reverse
LPS-induced behavioral effects (ie,
depressive behavior) in mice.77 Similar-
ly, minocycline is known to alter gluta-
mate transmission and has a regulatory
effect on proinflammatory cytokines. It
has also been evaluated in psychiatric
conditions revealing antidepressant ef-
fects when used as a monotherapy in
patients with HIV with mild-to-mod-
erate depression,78 as an adjunctive
therapy in patients with unipolar psy-
chotic depression,79 and in rats based
on the forced swim test.80 Eight weeks
of open-label adjunctive treatment with
minocycline also revealed significant
changes in the Montgomery-Asberg
Depression Rating Scale in bipolar I or
II disorder patients in the midst a major
depressive episode.81
When considering antibiotics as
a treatment for OCD, much support
stems from PANDAS, where system-
atic evidence alludes to their ben-
efit in acute episodes.82 However,
open-label83 and RCT84 data suggest
that the therapeutic benefits of mi-
nocycline may also translate to non-
PANDAS OCD. In a 10-week RCT,
minocycline adjunctive to fluvox-
amine in moderate-to-severe OCD
(n = 51) revealed significant-
ly higher rates of remission, par-
tial (≥25% reduction in Y-BOCS
score) and complete response
(≥35% reduction in Y-BOCS score)
(P < .001) than placebo (n = 51).84 With
antibiotics eliciting anti-inflammatory
effects and symptomatic relief achieved
in psychiatric conditions in which mi-
crobial dysbiosis has been suggested,
it is possible that these effects may be
regulated by the microbiome.
Probiotics
Probiotics are live microorganisms
that, when administered in adequate
amounts, confer a health benefit on the
host.85 To date, they have been an ef-
fective treatment for a wide range of GI
conditions, including IBS and IBD.85
547

There is much animal data illus-
trating the behavioral effects of probiot-
ics,13-15,19,86 and some evidence suggest-
ing probiotics may ameliorate anxiety
and depressive symptoms in primarily
healthy populations.87 A 3-week RCT
(n = 124) involving daily intake of a pro-
biotic milk (containing Lactobacillus
casei) or placebo did not demonstrate
an overall change in mood or cogni-
tion.88 However, lower baseline mood, as
per the profile of mood states, revealed
greater improvements in the group re-
ceiving the probiotic drink than the pla-
cebo group (P < .025).88 In addition
to improved “obsessive-compulsive”
subscores on the HSCL-90, Messaoudi
et al.45 also noted improvements in de-
pression, anxiety, and paranoid-ideation
subscores and urinary free cortisol lev-
els in healthy adults randomized to a
probiotic formulation containing Lacto-
bacillus helveticus and Bifidobacterium
longum or placebo. Steenbergen et al.89
had 20 healthy participants consume ei-
ther a multispecies probiotic or placebo
for 4 weeks and found that the probiotic
group had reduced cognitive reactivity to
sad mood. Significant pre- to post reduc-
tions in anxiety and depressive symp-
toms were also reported in a sample of
petrochemical workers after intake of a
probiotic capsule or yogurt; however, no
significant between-group differences
were seen post-intervention, as all three
groups had reductions in the mean scores
on the General Health Questionnaire and
the Depression Anxiety Stress Scale.90
Presently there is only one RCT show-
ing benefit of a probiotic in patients with
MDD.91 In this study, 40 patients with
MDD (who met Diagnostic and Statisti-
cal Manual of Mental Disorders, fourth
edition criteria,92 and had a 17-item Ham-
ilton Depression Rating Scale score ≥15)
and were randomized to receive a pro-
biotic capsule (Lactobacillus acidophi-
lus, L. casei, and B. bifidum) or placebo
(n = 20) for 8 weeks. At endpoint, those
receiving probiotics reported signifi-
548
CME Article
cantly lower scores on the Beck Depres-
sion Inventory total scores (-5.7 ± 6.4 vs
-1.5 ± 4.8, P = .001) compared to place-
bo. Significant decreases in serum insu-
lin levels (-2.3 ± 4.1 vs 2.6 ± 9.3 μIU/mL,
P = .03) and serum high-sensitivity
The interest in the gut-brain
axis and potential role of the
gut microbiome in psychiatry
has gained much traction in
recent years.
C-reactive protein concentra-
tions (-1138.7 ± 2274.9 vs 188.4 ±
1455.5 ng/mL, P = 0.03) were noted,
in addition to an increase in total plas-
ma glutathione levels (1.8 ± 83.1 vs
-106.8 ± 190.7 μmol/L, P = 0.02).
There are a variety of mechanisms
by which probiotics may elicit these ef-
fects, many which involve the gut mi-
crobiota. Although the exact mechanism
of action remains unknown, strains
of lactobacilli and bifidobacterium
have been shown to produce gamma-
aminobutyric acid,24 the primary inhibito-
ry neurotransmitter in the central nervous
system, and oral administration of Bifi-
dobacterium infantis has been shown to
increase levels of tryptophan, a precursor
to serotonin.15 Based on such evidence,
probiotics may act as a direct delivery
vehicle for neuroactive compounds. They
may also inhibit proinflammatory cyto-
kines such TNF-alpha and IL-6, some of
which have been implicated in psychiat-
ric conditions, including OCD.
Fecal Microbiota Transplant
Fecal microbiota transplant (FMT),
also known as bacteriotherapy, involves
the transfer of fecal microbes from a
healthy person to an ailing person.93
Although many patients view this treat-
ment negatively, it is has proven to be
a reliable an inexpensive option with a
low side-effect profile.93 It has been used
to mainly treat recurrent Clostridium
difficile infections.93 Although there are
no existing clinical trials evaluating the
effects of FMT in neuropsychiatric con-
ditions, this may change as the body of
microbiome research in psychiatric con-
ditions continues to grow. This notion is
supported by the wealth of rodent data
suggesting significant changes in im-
mune response and behavior after FMT.
More interestingly, FMT of pooled fecal
samples from five nonmedicated patients
with MDD and five healthy controls into
GF-mice revealed behavioral differenc-
es 2 weeks post-FMT.37,94 Recipients of
the MDD fecal samples illustrated more
depression-like symptoms compared to
recipients of “healthy” microbiota, and
the initially observed microbial differ-
ences in the stool samples were main-
tained.37 This finding promotes the pos-
sible involvement of the gut microbiome
in neuropsychiatric illness and suggests
FMT as a viable treatment option as the
relationship between psychiatry and the
gut microbiome continues to develop.
CONCLUSION
The interest in the gut-brain axis and
potential role of the gut microbiome in
psychiatry has gained much traction in
recent years, as evidenced by the grow-
ing scientific literature suggesting dys-
biosis in conditions such as ASD, MDD,
and BD. Although promising, it should
be noted that many of these studies (in
particular those for MDD and BD) are
accompanied by several limitations. In
addition to small sample sizes, much of
the existing literature fails to evaluate
many factors known to alter the gut mi-
crobiome, such as diet and medications,
leaving the results muddled with con-
founding effects of such variables.
Although the state of the gut microbi-
ome in OCD has not yet been evaluated,
Copyright © SLACK Incorporated

the substantial preclinical and clinical
evidence outlined here suggests that
there may be a role for this theoretical
relationship. Similar to mood and anxi-
ety disorders, rates of comorbid OCD
in patients with GI disorders may also
be significant. Immune dysregulation
has also been demonstrated in OCD and
may serve as a potential route of com-
munication between the gut microbiota
and the brain, as it has also been noted
in many illnesses in which microbial
alterations have been observed. Over-
all, the multifactorial nature of OCD
pathophysiology and a lack of putative
mechanisms beyond those involving
neurotransmitters highlights the dearth
of knowledge available to guide new
therapeutic advances. As such, there is
a need to explore mechanisms beyond
these current theories. Although treat-
ments targeting the gut microbiome are
currently available, the existing state of
the literature does not support their use
in treating OCD, anxiety, or mood disor-
ders. It does, however, shed light on the
need to explore the potential role of the
gut microbiome in OCD, as this could
shape the future of novel therapies for
a condition that is highly refractory in
nature.
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