Intermittent Fasting Alleviates Risk Markers in a Murine Model of Ulcerative Colitis by Modulating the Gut Microbiome and Metabolome

Abstract

Clinical trials have demonstrated the health benefits of intermittent fasting (IF). However, the potential mechanism of IF in alleviating dextran sulfate sodium (DSS)-induced colitis is not fully understood. The present study was mainly designed to explore the dynamic changes in the gut microbiota and metabolome after short-term (2 weeks) or long-term (20 weeks) IF and therefore clarify the potential mechanisms by which IF ameliorates DSS-induced colitis in a murine model. Thirty-two C57BL/6 male mice were equally divided into four groups and underwent IF intervention for 2 weeks (SIF group, n = 8), 20 weeks (LIF group, n = 8), or were allowed free access to food for 2 weeks (SAL group, n = 8) or 20 weeks (LAL group, n = 8). The thirty-two C57BL/6 male mice were accepted for the diet intervention of 2 weeks of IF or fed ad libitum. Colitis was induced by drinking 2% DSS for 7 days. Our findings showed that short-term IF prominently elevates the abundance of Bacteroides, Muibaculum and Akkermansia (p < 0.001, p < 0.001, p < 0.001, respectively), and decreased the abundance of Ruminiclostridium (p < 0.05). Long-term IF, however, decreased the abundance of Akkermansia and obviously increased the abundance of Lactobacillus (p < 0.05, p < 0.001, respectively). Metabolites mainly associated with nucleoside, carbohydrate, amino acid, bile acid, fatty acid, polyol, steroid and amine metabolism were identified in the faeces using untargeted GC/MS. In particular, inosine was extremely enriched after short-term IF and long-term IF (p < 0.01, p < 0.01, respectively); butyrate, 2-methyl butyric acid and valeric acid were significantly decreased after short-term IF (p < 0.001, p < 0.001, p < 0.01, respectively); and 2-methyl butyric acid was significantly increased after long-term IF (p < 0.001). The abundance of lithocholic acid (LCA), one of the secondary bile acids, increased significantly after short-term and long-term IF based on UPLC–MS/MS (p < 0.001, p < 0.5, respectively). Of note, IF markedly mitigated DSS-induced acute colitis symptoms and down-regulated pro-inflammatory cytokines IL-1α, IL-6, keratinocyte-derived chemokine (KC) and G-CSF levels in the serum (p < 0.01, p < 0.001, p < 0.05, p < 0.001, respectively). Furthermore, a correlation analysis indicated that the disease activity index (DAI) score and serum levels of IL-1α, IL-6, KC, and G-CSF were negatively correlated with the relative abundance of Akkermansia and the faecal metabolites LCA and inosine. This study confirmed that IF altered microbiota and reprogramed metabolism, which was a promising development in the attempt to prevent DSS-induced colitis. Moreover, our findings provide new insights regarding the correlations among the mucosal barrier dysfunction, metabolome, and microbiome.