Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota

Abstract

<p class="first" id="P4">Multiple sclerosis (MS) is a central nervous system (CNS) inflammatory demyelinating disease impacted by the interplay of genetic and environmental factors. It is presumed to be autoimmune. MS is more common in western countries and differences in diet could contribute to its particular geographical distribution. Studies relating diet to MS have been inconclusive. A mechanism through which diet can influence immune responses is the gut microbiome, which is emerging as a critical contributor in numerous human diseases. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS animal model, experimental autoimmune encephalomyelitis (EAE), leading to less inflammation, demyelination and axonal damage. IF changed the gut microbiome resulting in increased bacteria richness and enrichment of the <i>Lactobacillaceae</i>, <i>Bacterioidaceae</i> and <i>Prevotellaceae</i> families. Gut microbiome richness was inversely correlated with leptin levels. Microbial metabolic pathway analysis revealed that IF-induced changes to the gut microbiome increased ketone formation and glutathione metabolism, enhancing anti-oxidative pathways. Furthermore, IF had direct effects on the composition of T cells in the gut lamina propria with a reduction of IL-17 producing T cells and an increase in the number of regulatory T cells. These effects might modulate systemic immune responses. Importantly, fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF immunomodulatory effects are at least partially mediated by the gut flora. We translated our findings to MS patients in a pilot clinical trial in MS patients undergoing relapse to test the safety, feasibility and effects of IF on clinical and laboratory measures. Potentially beneficial effects on levels of several immune inflammatory parameters as well as gut flora that resembled the protective changes observed in mice in EAE were observed. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome. </p><p id="P5">Intermittent fasting (IF) confers protection in the multiple sclerosis animal model through effects on the gut microbiota, with similar changes to gut microbiota observed in relapsing MS patients undergoing short-term IF. </p>