Gut Microbiome-Mediated Regulation of Neuroinflammation

John W. Bostick

a,1

Aubrey M. Schonhoff

a,1

Sarkis K. Mazmanian

Biology and Biological Engineering, California Institute of Technology, 1200 E. California Blvd.,

MC 140-18, Pasadena, CA, 91125, USA

Abstract

The intestinal microbiome influences neuroinflammatory disease in animal models, and recent

studies have identified multiple pathways of communication between the gut and brain. Microbes

are able to produce metabolites that enter circulation, can alter inflammatory tone in the intestines,

periphery, and central nervous system (CNS), and affect trafficking of immune cells into the

brain. Additionally, the vagus nerve that connects the enteric nervous system (ENS) to the

CNS is implicated in modulation of brain immune responses. As preclinical research findings

and concepts are applied to humans, the potential impacts of the gut microbiome-brain axis on

neuroinflammation represent exciting frontiers for further investigation.

Introduction

Neuroinflammation in the central nervous system (CNS) in response to injury, infection, or

disruption in neural tissue homeostasis is generally self-limiting and beneficial to the host,

mediating both the defense and repair of tissue. However, in some conditions, inflammatory

responses may become chronic or damaging and result in neuroinflammatory disease.

Growing evidence has defined a role for the microbiome in the regulation of several acute

and chronic diseases, including stroke [

–**

], multiple sclerosis [

–**

], Alzheimer’s

(AD) [

], and Parkinson’s disease (PD) [

]. These conditions are characterized by

neuronal damage, microglial activation, peripheral immune cell infiltration into the CNS,

and interestingly, often co-occur with gastrointestinal (GI) dysfunction [

–

]. The

fecal microbiome is altered compared to controls, showing enrichment of pro-inflammatory

microbes and depletion of anti-inflammatory species [

]. Since human research has been

largely observational and most mechanistic studies have been performed in animal models

to date, it remains unknown what (if any) contributions the gut microbiome has on disease-

associated pathology and symptoms. Translation of preclinical findings to interventional

These authors contributed equally to this work and are corresponding authors: John W. Bostick (jbostick@caltech.edu); Aubrey M.

Schonhoff (aschon@caltech.edu).

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to

influence the work reported in this paper.

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Curr Opin Immunol

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Published in final edited form as:

Curr Opin Immunol

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clinical studies will be critical in appreciating the impact of the gut microbiome on human

health.

The GI tract is home to commensal microbes and approximately 70% of the body’s

immune cells [

]. Immune development is intricately linked to the composition of the gut

microbiome in mice. For example, the lack of a microbiome can stunt immune development,

particularly T cell differentiation, whereas the presence of a complex microbiome induces

immune responses that resemble those of humans [

]. Furthermore, microbes can produce

signals affecting both the local enteric nervous system (ENS) and the more distal CNS

]. Gut dysbiosis and intestinal inflammation are consistent features of some

CNS diseases in humans, ranging from acute conditions such as stroke [

], to chronic

diseases such as neurodegeneration [

] and depression [

]. Microbiome-regulated

connections between the gut and brain are important in health and disease and occur

through several mechanisms, including transport of metabolites and other molecules to the

brain through the circulation, activation of immune cells at peripheral sites (e.g., gut and

lung) that migrate to the brain, and direct communication through the vagus nerve and

connected efferent and afferent neurons that innervate the gastrointestinal tract (Figure 1)

[

]. This Review will present and synthesize the state-of-the-art findings in gut microbiome

influences on neuroinflammation.

Metabolites and Other Microbe-Derived Molecules

Metabolites and other molecules, sourced from the host, diet, and/or microbiome, can be

transported from the gut to the brain through the circulation and have been shown to

influence neuroinflammatory diseases. These molecules can originate from the microbiome

or from host-microbial co-metabolism, and include microbial components and secreted

factors (e.g., hormones), metabolites, and host-induced hormones, cytokines, neuropeptides,

and neurotransmitters [

]. Altered metabolomes are implicated in numerous diseases

of the CNS, including stroke [

], multiple sclerosis (MS) [

], Parkinson’s disease

[

], Alzheimer’s disease [

], and depression [

]. Several microbiome-derived molecules

have been identified as regulators of inflammation and disease symptoms in experimental

autoimmune encephalomyelitis (EAE), including tryptophan metabolites signaling through

the aryl hydrocarbon receptor (Ahr) [*

], capsular carbohydrates [

], and peptide mimics

of myelin oligodendrocyte glycoprotein (MOG) [**

]. There is some overlap between the

metabolome in MS and PD patients, with alterations in metabolites related to oxidative

stress and mitochondrial function [

]. In PD, increased sulfur metabolism, p-cresol,

and phenylacetylglutamine, and decreased carbohydrate fermentation are factors in disease

[

]. Metabolite profiles can be drastically altered by dietary intake, and many of the

currently studied microbial metabolites are produced from dietary compounds as precursors,

highlighting the intertwined neuromodulatory potential of diet and gut metabolites. While

these findings are intriguing, their mechanism of action and how they affect disease remains

largely unknown. To date, most research has focused on short-chain fatty acids (SCFAs),

microbial surface structures, secreted metabolites, and bacterial mimics of mammalian

molecules.

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Short-chain fatty acids

SCFAs are metabolites produced by the microbiome from dietary fiber, the most abundant of

which include acetate, butyrate, and propionate [

]. Studies have revealed altered levels of

SCFAs, closely associated with microbial dysbiosis, in certain neuroinflammatory diseases

[

], though cause and effect have not been established.

In animals, SCFA treatments modulate immune responses in multiple disease models

but with differing outcomes. In the context of Alzheimer’s disease, mixed SCFA

supplementation in the 5xFAD mouse model attenuates the development of brain A

pathology and memory deficits, increases brain interleukin (IL)-10, and decreases brain IL-6

levels [

]. However, in the APPPS1 mouse model of AD, SCFA supplementation increases

brain A

pathology [*

]. Other studies have found that decreased levels of SCFAs in

the circulation are associated with increased severity of stroke [

]. In these studies,

young mouse microbiomes produced higher levels of SCFAs and lower levels of intestinal

and circulating pro-inflammatory cytokines (e.g., IL-17A, IL-6, Eotaxin, RANTES, and

tumor necrosis factor (TNF) compared to aged mouse microbiomes [

]. Furthermore,

fecal microbiome transfer (FMT) from young to aged mice decreased stroke severity

whereas FMT from aged to young mice resulted in worse outcomes [

]. However, a

causal role for SCFAs was not identified. Rather, these studies found that the microbiome

influenced inflammatory tone. In MS, compositional changes in the microbiome are

correlated with reduced propionic acid (PA) in humans, and supplementation with PA

changes inflammatory tone by modifying the microbiome and increasing the number and

suppressive capacity of regulatory T cells (Tregs) [

]. In an alpha-synuclein-overexpressing

(ASO) mouse model of Parkinson’s disease, feeding a mix of SCFAs to antibiotic-treated

mice induces alpha-synuclein (

Syn) aggregation, neuroinflammation, and motor deficits

[

]. However, in human PD, a meta-analysis of microbiome changes in PD across multiple

studies consistently find decreased abundance of the SCFA-producing bacterial family

Lachnospiraceae and genus

Faecalibacterium

[

]. These findings paint a complex picture in

which SCFA effects are disease dependent.

In particular, butyrate and acetate may have opposite effects on inflammatory processes

and disease pathology. Butyrate in the gut can induce Tregs and may be protective in

neuroinflammation [

]. Feeding sodium butyrate to 5xFAD mice decreases brain A

deposition and improves memory function [

]. In another model of AD, FMT from

butyrate-rich WT mice to butyrate-deficient APP/PS1 mice increases butyrate to WT levels,

improves memory function, and decreases both A

and tau pathology [

]. Restoration

of microbiota in antibiotic-treated APP/PS1 mice restores high levels of A

deposition

and microglial activation [

], suggesting that butyrate may promote anti-inflammatory

responses in the context of this AD model. Immune regulation may also be relevant in

humans, as higher A

reactivity on positron emission tomography (PET) scans negatively

correlates with levels of butyrate and anti-inflammatory cytokines [

]. Additionally, an

vitro

rotenone-based model of PD also demonstrated a protective effect of sodium butyrate

treatment [

]. However, in multiple sclerosis, butyrate is increased and positively correlates

with levels of pro-inflammatory cytokines interferon

(IFN

) and TNF [

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In contrast to butyrate, acetate supplementation of 5xFAD mice increased A

pathology,

decreased microglial uptake of A

, decreased mitochondrial ROS production, and led to

expression of disease-associated microglial genes such as

Trem2, Apoe,

and

Ldl

[**

although as a caveat, these experiments were performed in the artificial situation of a

germ-free mouse. In humans, higher A

reactivity on PET scans positively correlates with

levels of acetate, as well as lipopolysaccharide (LPS), and circulating pro-inflammatory

cytokines [

]. However, in multiple sclerosis patients, acetate negatively correlate with

IFN

levels [

]. It is likely that the effects are disease and SCFA-specific, potentially

acting through modulation of microglial states. SCFAs that increase microglial activation

and phagocytosis may be helpful in clearing A

plaques, but harmful in promoting further

inflammation in PD or MS. Results obtained from SCFA studies in mice are varied in their

manifestations and interpretations, and more work is needed to confidently assign SCFA

levels and profiles in humans. Further, SCFAs have functions outside the immune system,

such as an energy source of intestinal epithelial cells that interact with immune cells and

possible enteric neurons [

]. The ease and safety of a potential diet-based intervention is

offset by the widespread and context-dependent effects of SCFA, currently limiting their

development as treatments for human disease.

Other Microbial Products

Structural components and metabolites of microbes are also able to stimulate immune

responses and influence disease-related pathways. One such metabolite, trimethylamine

N-oxide (TMAO), is generated by metabolism and oxidation of dietary amines by microbes

in the gut and further processed by enzymatic reactions in the liver [

]. Several studies

have demonstrated an increased risk for thrombotic events (e.g., stroke and myocardial

infarction) correlated with higher circulating TMAO levels [

]. Mechanistically, TMAO

can enhance platelet activation and clot formation, among other features [

]. Indeed, in a

mouse model of ischemic stroke, animals with TMAO-high microbiomes were at greater

risk of poor outcomes than those with TMAO-low microbiomes [**

]. This effect was

mediated by the activity of the bacterial enzyme cutC [**

]. These findings suggest that

neutralizing microbial production of TMAO or limiting colonization of TMAO producers

may be a therapeutic avenue for stroke or other thrombotic events.

Lipopolysaccharide (LPS) is a well-known bacteria-derived immune activator, and systemic

levels can influence disease processes. Genes involved in LPS biosynthesis are increased in

the fecal metagenome of PD patients [

] and expression of its receptor toll-like receptor

4 (TLR4) is increased in PD colon samples [

]. TLR4 knock-out mice have less intestinal

inflammation, decreased microglial activation, less neurodegeneration in the substantia

nigra par compacta (SNpc), and less severe motor dysfunction upon administration of

the neurotoxin rotenone [

]. These findings directly connect gut-derived products to

neurodegenerative disease processes in mice through activation of the immune system. LPS

and other bacterial carbohydrates may play an opposite role in EAE, as increased LPS

levels in the lung microbiome can shift the inflammatory state of microglia and decrease

EAE severity [*

]. Additionally, polysaccharide A (PSA) from the capsule of

Bacteroides

fragilis

has been shown to reduce the severity of EAE after oral treatment by enhancing Treg

induction and suppressing T helper 17 cell (Th17) response [

]. These findings suggest

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the broader concept that disease context or nature of the bacterial molecule can determine

whether microbial components are positive or negative regulators of disease.

The microbiome can also produce molecules that mimic host proteins. Molecular mimicry

occurs when foreign (in this case, microbial) antigens share enough sequence similarity to

self-antigens to trigger adaptive immune activation. A study by Miyauchi and colleagues

identified a peptide produced by the

Lactobaccilus reuteri

gene

UvrA

that can stimulate

MOG-specific T cells in EAE [**

]. The presence of two ampicillin-sensitive bacteria,

L. reuteri

and

Allobaculum sp.

, is sufficient to induce IL-17A-producing CD4+ T cells

in the intestine and worsen EAE, whereas bacterial knockout of

UvrA

reduces T cell

proliferation [**

]. Intestinal T cells are thought to migrate to the CNS and contribute

to neuroinflammation [**

,**

], providing a link between bacterial products, auto-

reactive T cell activation, and CNS disease. Alternative hypotheses describe T cells with

dual T cell receptors responsive to both self and bacterial antigens, as demonstrated by

segmented filamentous bacteria induction of pathogenic Th17 cells [

Other bacterial products may also induce pathology. Curli are functional bacterial amyloid

proteins that can induce aggregation of

Syn in a prion-like manner. Production of curli

increases gut and brain synuclein pathology and enhances neuroinflammation in a mouse

model of PD [

]. It has been shown that curli can interact with

Syn

in vitro

and

promote its aggregation in biochemical reactions [

], suggesting a direct effect on

neuroinflammation mediated by

Syn aggregates that can travel from the gut to the brain.

This view has been supported by a recent study in nematodes that shows bacterial curli can

enhance aggregation of

Syn and other mammalian amyloids such as A

and huntingtin

[

]. It appears that several different classes of microbial molecules produced in the gut can

directly or indirectly lead to or modulate neuroinflammation in preclinical models. Caution

must be taken to not extrapolate these findings to humans without further research, though

intriguing associations appear to be emerging.

Peripheral Immunity

Immune cells rely on microbial signals for proper development, particularly the development

and differentiation of pathogenic and regulatory T cells, key adaptive immune subsets

implicated in CNS disease [

]. Recent findings have described direct trafficking of immune

cells between the gut and CNS [**

,**

]. Acute (e.g., infection) and chronic (e.g.,

autoimmune disease, diabetes, atherosclerosis) inflammation play roles in disease etiology

and progression, suggesting an intimate connection between the microbiome and the

immune system in the progression of CNS inflammation. Here we discuss how peripheral

immune activation may impact neuroinflammation.

Role of acute and chronic inflammatory conditions

Acute infection can affect the risk and development of CNS disease. Stroke is associated

with acute immune responses to infection and individuals with signatures of chronic

inflammation display elevated risk [

]. A recent study determined that the risk for MS

is greatly increased by a previous infection with peripheral Epstein-Barr virus (EBV), and

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antibodies that cross-react with an EBV transcription factor and CNS proteins have recently

been identified in patient cerebrospinal fluid (CSF) [

], supporting the role of viral

infections in the development of neuroinflammatory disease. Alzheimer’s disease has also

recently been linked to EBV, as Gate et al. (2020) identified clonally expanded CD8+ T cells

in the CSF of AD patients specific to EBV antigens [**

]. Although a direct link between

viral infections and PD has not been established, increased risk has been associated with

viral infections and viral pandemics [

]. It will be interesting to see how the current

coronavirus disease 2019 (COVID-19) pandemic affects rates of neuroinflammatory disease

in the future, as future increases in diagnoses of parkinsonian disorders similar to that which

occurred after the 1918 influenza pandemic have been hypothesized [

A chronic inflammatory state, whether induced by comorbid disease or altered baseline

inflammatory tone, can also influence CNS disease, and the microbiome can regulate

systemic inflammatory profiles. Circulating factors like C-reactive protein (CRP), IL-6,

TNF and IL-1

are signatures of systemic inflammation and are also elevated in

neuroinflammatory disease [

]. In mice, DSS colitis in an

Syn-overexpressing model

worsens motor symptoms [

]. In humans, chronic intestinal inflammation appears to be

associated with PD [

]. Inflammatory bowel disease (IBD), such as Crohn’s disease or

ulcerative colitis (UC), increases the risk of PD, and IBD patients that receive systemic anti-

TNF

therapy have a decreased risk for neurodegeneration [

]. Recurring gut infections

also increase the risk of developing dementia [

], indicating that gut inflammation

may trigger neurodegenerative processes, both in AD and PD. Mood disorders have also

recently been linked to inflammation and the gut. IBD patients are more likely to develop

depression or anxiety, and IBD patients with depression are at a higher risk for flare ups

and hospitalization [

]. Patients with UC and anxiety/depression have a less diverse gut

microbiome [

] and FMT from IBD patients with depression to mice enhances features

of colitis, increases circulating inflammatory cytokines, increases hippocampal IL-1

and

IBA1, and correlates with the appearance of depressive behaviors [*

]. These data indicate

a potential contribution by the microbiome and inflammation to depression.

Immune cell activation and trafficking

Immune cells can traffic from the periphery to the brain and meninges in health and

disease, and studies suggest that the gut may act as a reservoir for CNS-trafficking immune

cells in neuroinflammation [**

,**

]. Seminal work demonstrated that, in an

experimental stroke model, the recruitment of IL-17A-producing

γδ

T cells from the

small intestine to the meninges is regulated by the microbiome and positively correlates

with the severity of disease [**

]. In other neuroinflammatory conditions, Schnell and

colleagues demonstrated that a pathogenic clonotype of Th17 cells in EAE can derive from

a pool of homeostatic cells in the small intestine and traffic to the CNS [**

]. Mice

treated with antibiotics have fewer Th17 cells in the spleen and intestines, and increased

resistance to EAE induction, linking microbial regulation of Th17 cell development and/or

function in peripheral locations to disease outcomes [**

]. Other work has highlighted

the importance of the cytokine IL-17A in the recruitment of inflammatory neutrophils and

monocytes in early stages of EAE [

]. These findings suggest that the recruitment of

microbially-regulated IL-17A-producing cells from the gut may be a key event in either the

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initiation or development of several neuroinflammatory diseases, providing a clear paradigm

for gut-brain interactions that warrant further investigation.

Vagus nerve

The gut microbiome can also communicate with the brain through direct neuronal signaling

pathways. The vagus nerve connects the enteric and the central nervous systems, among

other organs in the periphery, and this direct connection may transmit a variety of signals

from the gut to the brain [

]. It was reported in humans that vagotomy, the surgical

cutting of one or more branches of the vagus nerve, reduces the risk for developing PD

later in life [

]. Additionally, appendectomy in early adulthood decreases risk of later

developing PD [

]. The mechanism proposed was prevention of the spread of

Syn from

the appendix to the brain via the vagus, which requires further validation [

]. Although

these studies have not been directly connected to microbes, studies have shown that multiple

genera of microbes can produce neurotransmitters such as

-aminobutyric acid (GABA)

[

], indicating neuromodulatory potential by the human microbiome.

Research in mice has made progress in identifying mechanisms of vagal contributions

to disease, particularly in models of PD, AD, and depression. In the inducible 6-

hydroxydopamine (6-OHDA) lesion model of PD, vagotomy blocks disease-related

increases of IL-1

and markers of oxidative stress in the SNpc [

]. Alternatively, acute

and chronic intestinal inflammation via DSS administration leads to increases in nigral

IL-1

and loss of TH+ neurons, which can be prevented by vagotomy [

]. Injection of

Syn fibrils into the aged mouse duodenum, which is heavily innervated by the vagus nerve,

increases

Syn pathology in the brain, slows gut motility, and increases duodenal cytokine

release [**

]. Vagotomy can prevent

Syn propagation to brain and the development of

motor symptoms [

]. Injecting either recombinant A

and tau or extracts from AD patient

brains into the colon in the 3xTg mouse model of AD led to increased pathology in the

vagus and brain, which was prevented with vagotomy [

]. It has also been reported that

non-invasive stimulation of the vagus nerve in aged APP/PS1 mice can decrease microglial

reactivity in the cortex [

]. In a corticosterone-based model of anxiety and depression in

mice, feeding

Lactobacillus rhamnosus

, a species that produces high amounts of GABA,

can increase brain GABA levels and reduced depressive behaviors [

]. Vagotomy prevented

these effects [

], providing striking evidence for microbial regulation of the brain via

the vagus nerve. Together, these studies implicate the vagus nerve as a bidirectional

highway for the brain and gut to affect immune responses related to neuroinflammation

and neurodegeneration, in addition to the many homeostatic functions of the vagus nerve.

Conclusions

The studies highlighted in this Review provide evidence that gut-immune-brain

communications appear to regulate CNS disease in animal models and correlate with

outcomes in humans. Acute and chronic inflammation in the GI tract and/or periphery can

change the risk of CNS inflammatory disease, affecting the baseline state of immune cells or

stimulating immune cell trafficking from the gut to the CNS [**

,**

]. Peripheral

immune cell infiltration into the CNS can have direct effects on brain pathology and

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behavior [

]. Finally, the nature of microbial molecules, their biodistribution, and

mechanisms-of-action in modulating neuroinflammation have received increasing attention

in recent years [

How, and in what contexts, metabolites and bacterial components directly affect neurons

is less well explored compared to the role of infiltrating or brain-resident immune cells.

Furthermore, the ways in which acute and chronic inflammation can influence CNS disease

requires further investigation, but could act through changes in the baseline state of immune

cells or stimulation of immune trafficking from the gut to the CNS. With a growing

knowledge base and new tools being developed or repurposed for gut-brain studies, research

in coming years will clarify the role of the microbiome in CNS inflammation and may

provide new insights into the treatment of diseases related to neuroinflammation.

Acknowledgements

Work in the authors’ laboratory is supported by grants from the Division of Biology & Biological Engineering (to

J.W.B.), and the Heritage Medical Research Institute, Aligning Science Across Parkinson’s (ASAP-000375), and

the NIH (MH100556 and AG063744) to S.K.M.

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