Molecular Neurobiology

https://doi.org/10.1007/s12035-018-0983-2

Neuroinflammation, Gut Microbiome, and Alzheimer’s Disease

Li Lin 1 & Li Juan Zheng 1 & Long Jiang Zhang 1

Received: 28 July 2017 / Accepted: 28 February 2018

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that develops insidiously and causes dementia finally.
There are also clinical complications in advanced dementia, such as eating problems, infections, which will lead to the decline of
patients’ life quality, and the rising cost of care for AD to our society. AD will be important public health challenge. Early
detection of AD may be a key issue to prevent, delay, and stop the disease. Gut microbiome and neuroinflammation are closely
related with nervous system diseases, although the specific mechanism is not clear. This review introduces the relationship
between neuroinflammation, gut microbiome, and AD.

Keywords Alzheimer’s disease . Gut microbiome . Neuroinflammation

Introduction resulting from AD will reach 700,000 in 2016, and many of

Alzheimer’s disease (AD) is a neurodegenerative disease. It is
the most common cause of dementia and develops insidiously.
Extracellular plaques containing amyloid beta (Aβ) and intra-
cellular neurofibrillary tangles containing hyperphosphorylated
tau protein, along with synaptic and neuronal losses are the
main features of AD [1]. Patients with AD often suffer from a
decline in memory, aphasia, performance disorders, and per-
sonality and behavior changes. There are also clinical compli-
cations in advanced dementia, such as eating problems and
infections [2]. These clinical complications will lead to the
decline of patients’ life quality and the rising cost of care for
AD, which will be important public health challenges.
The surveys showed that there are about 35 million people
suffering from dementia, and the number is increasing in the
elderly people in the world [3]. Recent report showed that
from 2000 to 2013, deaths from stroke reduced 23%, heart
disease declined 14%, and prostate cancer dropped 11%; how-
ever, deaths caused by AD increased 71% [3, 4]. In 2013,
official report showed that 84,767 persons died from AD,
and it becomes the sixth main reason of death and the fifth
main reason of death in individuals age ≥ 65 years in the USA
[3, 4]. It is speculated that deaths of Americans age ≥ 65 years
* Long Jiang Zhang
kevinzhlj@163.com
1
Department of Medical Imaging, Jinling Hospital, Medical School of
Nanjing University, Nanjing, Jiangsu 210002, China
them die from the complications caused by AD [4].
Thus, early detection of AD may be a key issue to prevent,
delay, and stop the disease. However, the pathogenesis of AD
is still unclear, and it is still difficult to diagnose AD before the
symptoms appear. There are great challenges in finding mea-
sures to prevent AD. Recent studies indicated the close corre-
lation between neuroinflammation, gut microbiome, and AD,
which shed the light on the better understanding the pathogen-
esis of AD. In this review, we will discuss the pathogenesis of
AD and the possibility of early diagnosis, effective preven-
tion, and treatment based on existing knowledge.
Neuroinflammation and AD
Mechanism of Neuroinflammation
So far, the exact mechanism of AD remains uncovered. The
current mainstream doctrine is the amyloid cascade hypothe-
sis that Aβ deposition is the main reason of neurofibrillary
tangles (NFTs), synaptic dysfunction, and dementia [5].
Honig et al. found that Solanezumab (designed to increase
the clearance from the brain of soluble Aβ) at a dose of
400 mg administered every 4 weeks in patients with mild
Alzheimer’s disease did not significantly affect cognitive de-
cline, which challenges the theory of amyloid protein in
Alzheimer’s disease; however, the results may be subject to
some factors, such as the small bioavailability caused by the
blood-brain barrier (BBB) [1]. Recently, an increasing number

of evidences show that neuroinflammation plays an important
role in the pathogenesis of AD. Experimental evidence dem-
onstrates that neuroinflammation is an active player in the
development and progression of AD [6, 7]. In the inflamma-
tory response, microglia and astroglia are the essential
members.
Microglia originate from myeloid and account for about
15% of the nonneuronal cells in the brain [8] and are important
players in the development and progression of neuroinflam-
mation. Researchers categorized activated microglia as a clas-
sic, proinflammatory (M1) phenotype and others as a nonin-
flammatory, alternative activation (M2) phenotype [9].
Increased concentrations of proinflammatory cytokines are
the features of classic M1 activation, which include tumor
necrosis factor-α (TNF-α), interleukin 1, interleukin 6, inter-
leukin 12, and interleukin 18, with impaired phagocytic ca-
pacity accompanied [10]. Secretion of the anti-inflammatory
cytokines is the character of the M2 state, including interleu-
kin 4, interleukin 10, interleukin 13, and transforming growth
factor-β (TGF-β), with phagocytic capacity increased, where-
as toxic nitric oxide produced not [11, 12].
In AD, by the way of cell-surface receptors, microglia bind
to soluble Aβ oligomers and Aβ fibrils [13, 14]. Through
sequential cleavages by two membrane-bound proteases, amy-
loid precursor protein (APP) produces the Aβ peptide.
Microglia begin to clean up Aβ fibrils via phagocytosis after
the receptor. As a consequence, these fibrils enter the
endolysosomal pathway [14]. Compared to fibrillar Aβ, solu-
ble Aβ can be degraded by various proteases outside the cell,
which is mostly resistant to enzymatic degradation [14, 15].
However, in AD, several mechanisms compromise cessation
of inflammation, such as progressing formation of Aβ and
positive feedback loops between inflammation and APP pro-
cessing. On the contrary, further accumulation of Aβ, neuronal
debris, and, most probably, further activating factors establish
chronic, nonresolving inflammation [14]. Chronic neuroin-
flammation can damage the BBB, causing activated microglia
to release proinflammatory cytokines [16]. The classical pro-
inflammatory cytokine TNF-α produced by microglia, which
are early cellular markers of AD pathology, was shown to in-
duce neuronal cell cycle events [17]. In addition, in sporadic
cases of AD, inefficient clearance of Aβ has been confirmed as
a major pathogenic pathway [14, 18]. By the way of downreg-
ulating the expression of Aβ phagocytosis receptors to increase
cytokine concentrations, which is considered to be the reason
of insufficient microglial phagocytic capacity [14, 19] (Fig. 1).
Except for microglia, astrocytes are major participants in
neuroinflammation, and which is closely related to AD. It is
estimated that astrocytes represent between 30 and 50% of
human neural cells, and they have long been acknowledged
to provide crucial trophic and metabolic support for neurons
[20]. In AD brain, there are alterations in astrocyte morphol-
ogy, gene expression, protein composition, and activity that
Mol Neurobiol
are linked to changes in astrocyte function [21]. Altered astro-
cyte morphology in aging and diseased brain is complex and
region-specific [22]; however, the accumulation of activated
astrocytes, often in clusters around amyloid plaques [23], cor-
relates strongly with Braak staging in AD [24]. Importantly,
astrocyte activation, together with the presence of phosphory-
lated tau in synapses, is one of the best biological correlates of
cognitive decline in AD [25]. In many transgenic mouse
models of AD, before the appearance of plaque and/or tangle
pathology, researchers found activated astrocytes accumulated
in affected brain regions as well [26], suggesting that astrocyte
activation is involved in disease pathogenesis. One research
suggested that astrocytes played a role in disease progression
in AD, probably due to the interaction of Aβ with astrocytes
inducing a pro-inflammatory profile [27].
Astrocytes, which far more than microglia in the brain, is
considered to play a more significant and continuous role than
microglia in the enduring neuroinflammatory [28, 29], and
compared to microglia, astrocytes can eliminate and degrade
Aβ without mediators or stimuli [30]. Astrocytes induce cen-
tral nervous system (CNS) inflammation of AD via acting as
immune cells, releasing cytokines and chemokines to affect
effector cells, regulating the blood-brain barrier and shaping
glial scars [31]. Astrocytes play a role in the occurrence and
development of AD mainly through elevating the expression
of proinflammatory cytokines and chemokines and modulat-
ing the generation, internalization, and degradation of Aβ
[30]. Besides, Aβ could upregulate the expression of cyto-
kines and chemokines in astrocytes, as a result that astrocytes
reactivated [30]. Furthermore, astrocytes are closely related to
the oxidative stress response in AD, and it has been confirmed
that activation of astrocytes are associated with intracellular
neurofibrillary tangles [32, 33].
Neuroinflammatory Imaging
Recently, the developed positron emission tomography (PET)
imaging agents targeting neuroinflammatory processes offer
the possibility to in vivo track diverse brain inflammatory
events. Specifically, neuroinflammatory events such as
microglial activation, reactive astrocytosis, and increased
phospholipase activity can be quantified by using PET radio-
tracers [34–36].
Currently, molecular agents targeting the 18 kDa
translocator protein (TSPO), the formerly name of the periph-
eral benzodiazepine receptor (PBR), can be used for PET im-
aging of microglial activation [37]. A lot of studies showed
that TSPO is a sensitive marker of reactive microglia and
inflammation secondary to neurodegeneration, including of
the AD type [38, 39].
[11C] PK11195 and [18F] DPA-714 are currently used as
radiotracers for PET, both based on TSPO as ligand [39].
However, [11C]PK11195 imaging agent itself has some
Mol Neurobiol

Fig. 1 Pathological mechanism

of microglia activation. Microglia
has the function of surveillance
and synaptic remodeling. In the
acute inflammatory response,
microglia bind TLR to help clear
and restore tissue homoeostasis.
However, microglia activated by
amyloid beta deposits and
persistently exposed to
proinflammatory cytokines,
which result in chronic
neuroinflammation. As a result,
synaptic remodeling was reduced
and caused neuronal death. TLR
Toll-like receptor. With
permission, from [14]

drawbacks, such as low permeability in the brain, nonspecific
binding and nuclide [11C] shorter half-life (20 min), being
difficult to prepare, etc., affecting its wide clinical application.
Wiley et al. [40] found that [11C]PK11195 imaging agent on
the detection of mild to moderate AD patients with microglia
activation level is not sensitive. Compared to the first genera-
tion of ligand [11C]PK11195 imaging agent, [18F] DPA-714
imaging agent as a new generation of TSPO specific ligand
showed a great potential [14]. Recent studies have found that
[18F] DPA-714 PET can accurately assess neuritis in early and
preclinical AD (Fig. 2) [41]. In general, PET has been used to
assess neuroinflammation of early and preclinical AD, al-
though there are still some shortcomings.
Neuroinflammation as a Therapeutic Target in AD
very high doses directly bind to Aβ, but Szekely et al. showed
they were no more effective than other NSAIDs in reducing
the risk of AD [44, 47]. A systematic review pointed that it
requires NSAID use lasting over 2 years to reduce risk esti-
mates [48], while the obvious protective effects of NSAIDs
are reduced among elderly people, even disappeared [45, 49].
Whether NSAIDs are effective and which is the best for AD is
still unclear. However, a recent study found that IL-33 ame-
liorated AD-like pathology and cognitive decline [50]. By the
way of promoting the recruitment and phagocytic activity of
microglia, IL-33 decreased soluble Aβ and amyloid plaque
load. In addition, IL-33 injection regulated the immune re-
sponse of amyloid precursor protein/presenilin 1 (APP/PS1)
mice and polarized microglia/macrophages toward an anti-
inflammatory phenotype. Collectively, these results suggest
that IL-33 may be a potential treatment of AD.

Lots of epidemiological studies have pointed that the inci-

dence of AD reduced after patients use nonsteroidal anti-
inflammatory drugs (NSAIDs) [42]. Four large epidemiolog-
ical studies have investigated how NSAID affects individuals
with AD. The Baltimore longitudinal study [43, 44] showed
that people who use NSAID greater than 2-year duration
spared approximately 60% [44, 45]; the Rotterdam study
showed a sparing of 80% in AD patients using NSAID was
confirmed via prescription records [44]; and the MIRAGE
study showed a sparing of 36% [44, 46]. Some NSAIDs at
Gut Microbiome and Central Nervous System
The microbiome of the human gastrointestinal tract is the larg-
est reservoir of microbes in humans, containing approximately
1014 microorganisms from at least 1000 distinct microbial
species that vary in diversity and stability between individuals
and outnumber human host cells by about 100 to 1. The bac-
terial density of human gut microbiota is up to 1012/mL,

Fig. 2 Image of 18F-DPA-714 PET (SUVr) in AD. a Patients with
prodromal Alzheimer’s disease (p-AD) and controls. b Alzheimer’s
disease dementia (d-AD) and controls. (i and iii) BGlass brain^
which is the highest density in any known microbial ecosys-
tem [51, 52]. The latest researches showed that changes in
gut microbiota could affect the brain’s physiological, be-
havioral, and cognitive function [53–57]. Pinto-Sanchez
et al. found that the probiotic BL (Bifidobacterium
longum NCC3001) reduces depression in patients with
irritable bowel syndrome, which were associated with
changes in brain activation patterns that indicate that this
probiotic reduces limbic reactivity [58]. Another func-
tional MR imaging study found less hippocampal activity
viewing negative valences images in participants with
high Prevotella and greater prominence for gray matter
(cerebellum, frontal regions, and the hippocampus) in
participants with high Bacteroides [59].
Gut Microbiome Affects Neurodevelopment
Neurogenesis is influenced by the presence of microorgan-
isms. Specifically, neurogenesis in the dorsal hippocampus
of adult germ-free (GF) mice is increased compared to con-
ventional mice [60, 61]. Interestingly, colonization of GF mice
at weaning could not reverse this phenotype, indicating that
microbial signals very early in life reduce rates of
neurogenesis in the hippocampus. Moreover, adult GF mice
exhibited increased volume of the amygdala and hippocampus
(specifically CA2/3) and differed in dendrite morphology,
while no differences in total brain volume were recorded be-
tween GF and specific pathogen-free (SPF) animals [60, 62].
By tapping into pathways that govern neuronal differentiation
and survival, via neurotrophins and their receptors, gut mi-
crobes can influence the fate of neurons in various regions
of the brain and subsequently neurodevelopment and health.
A central role for the microbiota in the development and mat-
uration of the microglia has recently emerged [63, 64]. In the
Mol Neurobiol
representations and (ii and iv) sagittal, coronal, and axial views (x = 65,
y = 44, and z = 37) with corresponding z-values. With permission, from [41]
absence of the microbiota, mice harbor microglia with signif-
icantly altered developmental states. These microglia display
morphological characteristics and a gene expression profile
that indicate an arrest in their developmental maturation and
subsequently are maintained in an immature status [63, 64].
Notably, microglia derived from GF mice display limited re-
sponses toward viral infection and microbially associated mo-
lecular patterns. Such defective responses can be rescued by
administration of short-chain fatty acids [63, 64].
In addition, the importance of gut microbiome and mi-
crobial metabolites in the formation of the BBB has been
exemplified in GF mice [60, 65]. In the absence of gut
microorganisms, the BBB is more permeable to macro-
molecules compared to conventionally raised animals,
mediated by decreased expression of key tight-junction
proteins in the brain endothelium. Furthermore, perme-
ability decreased upon colonization of GF animals or, al-
ternatively, upon administration of the short-chain fatty
acid butyrate that is produced as a result of bacterial fer-
mentation in the gut [60, 65]. Correspondingly, the BBB
in the sterile fetus is permeable, compared to the adult
BBB [60].
Gut Microbiome and Mental Illness
Microbes which resident in our gastrointestinal tract play an
important role in nervous system, and the disruption of the
microbes may cause the development or exacerbation of men-
tal disorders. For example, major depressive disorder is typi-
cally influenced by the microbiome [66]. In schizophrenia,
dysbiosis and psychopathogenesis are similar [67, 68]. More
than half of all patients with irritable bowel syndrome are
affected by mood disorders [69], and antidepressants are often
used to treat irritable bowel syndrome [69, 70]. As we know,
Mol Neurobiol
gut–brain axis is the most popular hypothesis, which includes
a bidirectional communication network that monitors and in-
tegrates gut functions and links them to cognitive and emo-
tional centers of the brain. It consists of the central, autonomic
and enteric nervous systems, the neuroendocrine,
enteroendocrine and neuroimmune systems [69, 71, 72].
Although the exact mechanism of gut-brain axis has not yet
been fully clarified, the evidences from animals and human
studies have shown that gut microbiota can play an important
role in brain behavior and cognitive development by produc-
ing hormones, immune factors, and metabolites, which also
indicated that altering the gut microbiota may improve or even
cure brain diseases [53].
Increasing evidences point toward a role for beneficial ef-
fects of probiotics that extend beyond the modification of the
composition of the microbiota, including a beneficial impact
on behavior, mood, and cognition [73]. Gareau et al. found
that probiotics could not only dampen the hypothalamic-
pituitary-adrenal axis (HPA-axis) but they could also restore
neuronal activation indicated by nuclear c-Fos and brain-
derived neurotrophic factor (BDNF) expression in the CA1
region of the hippocampus which were decreased following
exposure to acute stress in infected mice [74]. This study sug-
gested that probiotics could influence expression of key me-
diators of cognitive behavior within structures of the limbic
system. Follow-up studies revealed a role for the adaptive
immune system in modulating the microbiota–gut–brain axis.
In healthy Balb/c mice, administration of Bifidobacterium
(B. longum but not B. breve) could improve cognitive function
as measured using the NOR task and the Barnes maze com-
pared to vehicle, highlighting a strain-specific beneficial effect
[75]. Feeding mice a Western-style diet can also induce weight
gain and cognitive deficits, which can be ameliorated by ad-
ministration of L. helveticus R0052 [76]. The beneficial im-
pact of probiotic administration on cognitive function in
humans is also being investigated. These studies, although
small in size, suggest that consumption of probiotic-
containing products may have a beneficial impact on overall
cognitive function in healthy adult populations [77, 78].
Gut Microbiome, Neuroinflammation,
and Alzheimer’s Disease
For a long time, researchers have studied possible infectious
reasons of neurodegenerative diseases. In AD, it has reported
the connections to Herpes simplex virus 1, spirochetal, and
Chlamydophila pneumoniae infections [79, 80]. Recently, one
research found fungal infection in the brains of AD and amyo-
trophic lateral sclerosis (ALS) patients [81, 82]. Preliminary
observations in the APP/PS1 mouse model of AD indicated
that these animals had decreased Allobaculum and
Akkermansia, with an increase in Rikenellaceae compared to
wild-type controls [83]. It is presumed that neuroinflammation
is one of the major reasons in the pathology of neurodegener-
ative diseases [84, 85]. Proinflammatory cytokines produced
both in the brain and periphery nervous system modulate neu-
ronal function and can initiate pathologic cell death [86, 87].
Given the importance of microglia functions in both the pre-
vention and promotion of neurodegenerative processes, it is
tempting to speculate that the gut microbiota may influence
these inflammatory diseases of the aging brain.
It is possible that changes of the gut microbiota facilitate
inflammatory processes that may contribute to the neuroin-
flammation in AD. Bacteria populating the gut microbiome
can excrete large quantities of lipopolysaccharides (LPSs) and
amyloids. These LPSs and amyloids may lead to the patho-
genesis of AD during aging, when both the gastrointestinal
tract epithelium and blood–brain barrier become more perme-
able. It has been proposed that LPS and amyloids may directly
pass through a compromised gastrointestinal tract or blood–
brain barrier and/or indirectly pass through these protective
physiological barriers via LPS/amyloid triggered cytokines
or other small proinflammatory molecules that are normally
transited [88–90]. A recent study reported that Bacteroides
fragilis lipopolysaccharide (BF-LPS) exposure to human pri-
mary brain cells was extremely potent inducer of the pro-
inflammatory transcription factor NFκB (p50/p65) complex,
a known trigger involved in inflammatory neurodegeneration
in the AD brain [91].
In addition to LPS, a significant quantity of functional am-
yloid can be generated by many bacterial strains, including
Escherichia coli, Bacillus subtilis, Salmonella typhimurium,
Salmonella enterica, Mycobacterium tuberculosis, and
Staphylococcus aureus, through the accumulation of protein-
aceous misfolded Aβ oligomers and fibrils, which may con-
tribute to the pathology of AD [92, 93]. It has been hypothe-
sized that functional amyloids produced by gut bacteria may
be the source of misfolding of neuronal proteins such as alpha-
synuclein, Aβ via cross-seeding, priming of the innate im-
mune system, and activation of neuroinflammation [94, 95].
Future Directions
Gut microbiome and neuroinflammation are closely related
with nervous system diseases, although the specific mecha-
nism remains unclear. Researches showed that the amyloid
plaques, neurofibrillary tangles, gut microbiome, and neuro-
inflammation play important roles in AD. Nowadays, imaging
biomarkers of brain structure and function have been applied
to diagnose AD. However, it is greatly significant to find
whether gut microbiome has influences on neuroinflammation
in aging and AD. Thus, in future, we hypothesized whether
we could diagnose AD early in combination with the imaging
findings of neuroinflammation and the inflammatory markers

caused by intestinal microbes, and whether we could find new
methods of treating AD basing on AD-related neuroinflam-
mation and intestinal microbial changes, such as NSAIDs for
the treatment of neuroinflammatories and probiotics that im-
prove intestinal microbes. The recognition of the potential
contribution of microbiome-generated LPS and signaling
pathways implicated in neuroinflammation, brain Aβ deposi-
tion, and AD pathogenesis regulated by amyloids are relative-
ly recent discoveries. As a result, scientists might find the
biomarkers according to these advances, making the early
diagnosis of AD, novel therapeutics, and preventive strategies
possible.
In general, gut microbiome may initiate AD with the com-
bination of the amyloid plaques, neurofibrillary tangles, and
neuroinflammation. To study the relationship between gut
microbiome, neuroinflammation, and AD, new methods need
to be developed to assist in the clinical diagnosis of AD. For
the effects of gut microbiome, it may be able to find a new
way to help clinicians make the early diagnosis, prevention
and treatment of AD. However, these assumptions are also
lack of experimental verification; we expect that there will
be more studies to verify this conjecture.
Acknowledgements Supported by grants from the National Natural
Science Foundation of China (grant nos. 81322020 and 81230032 to
L.J.Z.).
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
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