The Gut–CNS Axis in Multiple Sclerosis

doi:10.1016/j.tins.2020.06.002

Trends in Neurosciences

Volume 43, Issue 8, August 2020, Pages 622-634

https://doi.org/10.1016/j.tins.2020.06.002 Get rights and content

Highlights

MS is an autoimmune inflammatory disease characterized by CNS inflammation and damage to myelin.
T cells, B cells, and CNS-resident cells including astrocytes and microglia contribute to MS pathogenesis.
MS pathogenesis has been linked to genetic and environmental factors, as well as to the gut microbiome.
The microbiome modulates the differentiation and function of peripheral immune cells that control CNS inflammation.
Microbial metabolites that reach the CNS can modulate the activity of resident glial cells such as astrocytes and microglia.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS driven by the inflammatory activity of peripheral immune cells recruited to the CNS and by CNS-resident glial cells. MS pathogenesis has been linked to both genetic and environmental factors. In addition, the commensal flora have been shown to modulate immune processes relevant to MS pathogenesis. We discuss the effects of the gut microbiota on T cells and glial cells, and their relevance for the control of inflammation and neurodegeneration in MS. A better understanding of the gut–CNS axis will shed new light on the mechanisms of disease pathogenesis, and may help to guide the development of efficacious therapies for MS.

Section snippets

The Gut–CNS Axis in Multiple Sclerosis

The concept of a ’gut–CNS axis’ linking the gut and the CNS was put forward more than 200 years ago when physicians acknowledged that the gastrointestinal and mental status were somehow connected [1]. Recent advances in neuroimmunology, gastroenterology, and microbiology support this concept and have provided several mechanistic insights, which we discuss below in the context of MS.

MS is an autoimmune disease which targets the CNS [2]. Genetic and environmental factors, as well as the

Autoimmune Pathogenesis of MS: Role of T Cells and Glia

Genetic and immunologic studies in MS and its animal model experimental autoimmune encephalomyelitis (EAE, see Glossary), as well as the clinical success of therapies targeting the immune system, have established T cell autoimmunity as an important contributor to MS pathogenesis.

Approximately 100 billion nonregenerative neurons form complex circuits in the CNS, and these are difficult to repair following damage. Consequently, inflammatory responses that could potentially trigger

The Gut Microbiota in MS and EAE

Mammals coevolved with a vast number of commensal gut microbiota. It is estimated that, in humans, the internal surface area of the gastrointestinal tract harbors >100 trillion microbial cells belonging to >1000 bacterial species [48]. Thus, it is not surprising that the microbiome plays important roles in multiple aspects of physiology, including the regulation of immune system development and function [49]. Indeed, perturbations in commensal communities (referred to as dysbiosis) have been

Cells Participating in the Gut–CNS Axis in MS

To investigate the Gut–CNS axis in MS, it is central to identify the mechanisms that link the gut microenvironment to CNS inflammation. Based on the important roles of CD4⁺ T cells in MS, the effects of the gut microbiome on T cells are likely to play major roles in MS pathogenesis [99]. Indeed, the gut microbiota and the diet provide multiple antigens and small molecules which can mimic self-antigens [84,100,101] and stimulate innate immunity [85], potentially promoting the activation of

Effects of the Microbiome on CNS-Resident Cells

Alterations in the gut microbiome have been described in a variety of neurologic disorders, including disorders in which peripheral immune cells are not generally thought to play a central role in disease pathogenesis. These include social behavior disorders [117], Parkinson’s disease (PD) [118], and amyotrophic lateral sclerosis (ALS) [119]. It seems likely that the involvement of the gut microbiome in these disorders is via direct effects of the microbiome on CNS-resident cells, rather than

Concluding Remarks and Future Perspectives

The multiple mechanisms by which the gut–CNS axis controls CNS inflammation identify gut-targeting approaches as novel avenues for therapeutic intervention in MS and other neurologic diseases. The targeting of ‘oral tolerance’ [130], the phenomenon by which oral administration of myelin antigens suppresses CNS inflammation, was one of the first attempts to therapeutically target the gut–CNS axis (Box 2). Several clinical studies have investigated the therapeutic potential of probiotics (Box 2),

Acknowledgments

A.K. was supported by a Uehara Memorial Foundation Overseas Research Fellowship and by the Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship. F.J.Q. is supported by grants NS102807, ES02530, ES029136, and AI126880 from the National Institutes of Health, RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society, and PA-1604-08459 from the International Progressive MS Alliance.

Glossary

Adaptive immunity: immune response mediated by antigen-specific receptors in T cells and B cells.
Amyotrophic lateral sclerosis (ALS): a progressive neurodegenerative disease which usually affects upper and lower motor neurons, causing muscle weakness and eventually loss of muscle control.
Antigen: a molecule capable of inducing a specific immune response.
Chemokines: a family of cytokines which induce chemotaxis towards producing cells.
Co-stimulatory molecules: cell-surface molecules expressed by

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Trends in Neurosciences

ReviewThe Gut–CNS Axis in Multiple Sclerosis

Highlights

Section snippets

The Gut–CNS Axis in Multiple Sclerosis

Autoimmune Pathogenesis of MS: Role of T Cells and Glia

The Gut Microbiota in MS and EAE

Cells Participating in the Gut–CNS Axis in MS

Effects of the Microbiome on CNS-Resident Cells

Concluding Remarks and Future Perspectives

Acknowledgments

Glossary

Cell

Trends Immunol.

J. Neuroimmunol.

Cell

Trends Mol. Med.

Trends Neurosci.

Neuron

Neurotherapeutics

Am. J. Pathol.

Immunity

Cell

Cell

FEBS Lett.

Cell

Mucosal Immunol.

Immunity

Neurochem. Int.

J. Neuroimmunol.

Immunity

Front. Microbiol.

Cell Host Microbe

Lancet Neurol.

The gut–brain axis: historical reflections

Microb. Ecol. Health Dis.

Multiple sclerosis

N. Engl. J. Med.

T cell responses in the central nervous system

Nat. Rev. Immunol.

Myeloid cells in the central nervous system: so similar, yet so different

Sci. Immunol.

The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27

Nat. Immunol.

Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells

Nat. Immunol.

Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha

Nat. Med.

IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation

Brain

An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis

Proc. Natl. Acad. Sci. U. S. A.

In vivo induction of Tr1 cells via mucosal dendritic cells and AHR signaling

PLoS One

Opposing T cell responses in experimental autoimmune encephalomyelitis

Nature

The emerging roles of gamma-delta T cells in tissue inflammation in experimental autoimmune encephalomyelitis

Front. Immunol.

Mucosal-associated invariant T cells in autoimmune diseases

Front. Immunol.

Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS

Cell

Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE

Nat. Immunol.

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

Nat. Med.

Microglial control of astrocytes in response to microbial metabolites

Nature

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

Proc. Natl. Acad. Sci. U. S. A.

Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor

Nat. Med.

MAFG-driven astrocytes promote CNS inflammation

Nature

Environmental control of astrocyte pathogenic activities in CNS inflammation

Cell

Loss of 'homeostatic' microglia and patterns of their activation in active multiple sclerosis

Brain

Astrocytes: biology and pathology

Acta Neuropathol.

Review
The Gut–CNS Axis in Multiple Sclerosis

Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3⁺ regulatory T cells