Microbial Metabolites in Multiple Sclerosis: Implications for Pathogenesis and Treatment

Abstract

Metabolites produced by the gut microbiota have been shown to play an important role in numerous inflammatory, neuropsychiatric, and neurodegenerative diseases. Specifically, microbial metabolites have been implicated in the modulation of innate and adaptive immunity, especially in the generation of regulatory T cells (Tregs), which are key regulators of multiple sclerosis (MS) pathogenesis. Furthermore, they affect processes relevant to MS pathophysiology, such as inflammation and demyelination, which makes them attractive molecules to be explored as therapeutics in MS. In this review, we discuss the importance of these metabolites as factors contributing to disease pathogenesis and as therapeutic targets in MS. Establishing an improved understanding of these gut-microbiota derived metabolites may provide new avenues for the treatment of MS.

Keywords: experimental autoimmune encephalomyelitis (EAE); gut microbiota-derived metabolites; multiple sclerosis (MS); polyamines; short-chain fatty acids; urolithins.

FIGURE 1

Schematic summarizing the role of microbial metabolites in the pathogenesis of MS. MS patients have reduced levels of SCFAs and SCFAs producers, which is associated with a more severe pathology. However, levels of acetate are increased in MS patients, which is linked with more disability. Acetate can both have detrimental and beneficial effects. For instance, acetate leads to more IL-10 secretion and thus alleviates EAE. On the other hand, acetate is also able to increase the frequency of Th17 cells and thus aggravate EAE. Propionate increases axonal density recovery and inhibits demyelination, the latter also being mediated by butyrate. Furthermore, propionate augments the frequency of Tregs (for instance, in the blood, spinal cord, and spleen) and their suppressive capacity while also upregulating IL-10, TGF-β, and FOXP3 levels in the gut. Polyamines, specifically spermidine, inhibit pro-inflammatory cytokines, and nitric oxide (NO) secreted by microglia likely via suppression of the NF-κB pathway. Moreover, spermidine inhibits macrophage and T cell migration to spinal cord and downregulates the levels of CD80 and CD86 on macrophages. Furthermore, spermidine shifts macrophages to the alternative or M2 profile, increases FOXP3⁺ Tregs differentiation, decreases chemokine secretion by astrocytes and the levels of LFA-1 on T cells and decreases the number of GFAP⁺ and Iba-1⁺ cells. Urolithins, specifically urolithin A (UA), increase tight junction protein levels and gut barrier function, which decreases intestinal permeability. Furthermore, UA inhibits inflammation, reduces cognitive deficits, diminishes Th17 differentiation, IL-17 secretion, MHC-II, CD80, and CD86 expression on DCs. Moreover, UA increases ceramide levels and blocks CD4⁺ T cell activation and proliferation. Altogether, these molecules, alone or synergistically, act to promote host homeostasis, but disease states and changes in diet can severely alter the gut microbiota composition and thus the gut microbial metabolites and favor disease initiation and progression.