Intermittent fasting promotes cyclic changes of innate immune response and gut microbiome in a mouse model of multiple sclerosis

Intermittent fasting (IF) is a dietary regimen consisting of cycles of fasting and refeeding. IF ameliorates autoimmune response in animal model of MS through suppression immune responses and modulation of the gut microbiome. However, the distinct effects of fasting and refeeding periods of IF on immune response in the central nervous system and the gut microbiome, and their role in MS, have not been thoroughly explored. Here, we demonstrate that acute fasting for 24 hours reduced the number of microglia in a brain-region specific manner, with refeeding reversing these changes. Chronic fasting-refeeding cycles resulted in a persistent reduction of microglia numbers, although changes in microglia gene expression associated with neuroprotection during fasting are transient. The diversity and composition of the gut microbiome fluctuated with fasting and refeeding periods, converging by the end of the 4-week of chronic IF. Both fasting- and refeeding-derived microbiota improved the clinical course of the MS model. Chronic IF significantly increased the production of microbiome-derived metabolites in the gut, with spermidine, a fasting mimetic, showing the most significant increase. Oral spermidine supplementation suppressed neuroinflammation in MS models , revealing another novel mechanism by which IF protects against autoimmunity. For the first time, we demonstrated significantly higher levels of spermidine in patients with MS compared to healthy controls, particularly in patients with active disease, likely reflecting a complementary mechanism of action in the body