The Gut-CNS Axis in Multiple Sclerosis

Abstract

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.

Keywords: T cells; astrocytes; glial cells; gut microbiota; gut–CNS axis; microglia; multiple sclerosis.

Figure 1.

In MS, naive CD4⁺ T cells are polarized into proinflammatory phenotypes (Th1 and Th17 T helper cells) in peripheral lymphoid organs (bottom right). Proinflammatory CD4⁺ T cells, which overcome regulatory mechanisms such as regulatory T cell (Treg) suppression, traffic to the CNS and initiate inflammation. Antigen-presenting cells (APCs) in gut-associated lymphoid tissue (GALT) present gut-derived antigens and promote the differentiation of CCR9⁺ memory CD4⁺ T (CCR9⁺ Tm) cells. CCR9⁺ Tm cells circulate systemically (bottom left), and reach the CNS (top right) to suppress inflammation; they also recirculate to the gut to become CD4⁺ intraepithelial lymphocytes (IELs) and CD4⁺ lamina propria lymphocytes (LPLs). Small intestine CD4⁺ IEL cells migrate to the CNS and suppress inflammation, and their differentiation depends on the AHR agonist indole-3-carbinol (I3C) and the gut microbiota. The terminal differentiation of CCR9⁺ Tm cells into IEL and LPL cells depends on the microbiota. Some bacteria preferentially induce specific Th subtypes. For example, segmented filamentous bacteria (SFB) induce Th17 cell differentiation in the ileum, and Clostridia strains and Bacteroides fragilis favor Treg differentiation in the colon. In the figure, gut T cells (CD4⁺ IELs and LPLs) and CCR9⁺ Tm cells are depicted as ‘gut-induced T cells’. Metabolites controlled by the commensal flora such as short-chain fatty acids or tryptophan derivatives may reach the CNS directly or after further processing in other organs. For example, bacterially produced indole is further metabolized to indoxyl-3-sulfate (I3S) in the liver. Once in the CNS, microbe-controlled metabolites can modulate the activity of astrocytes and microglia.