Intermittent fasting exacerbates colon inflammation by promoting Th17 cell differentiation through inhibition of gut microbiota-derived Indoleacrylic acid

Background Intermittent fasting (IF), particularly time-restricted feeding (TRF), is increasingly popular for weight loss, yet its effects on gut health remain unclear. This study explores how TRF affects intestinal health and underlying mechanisms. Methods Mice were assigned to normal control (NC) and intermittent fasting (IF) groups. IF mice underwent TRF, while NC mice fed ad libitum. Body weight, fecal characteristics, and intestinal morphology were assessed. Colon tissues, serum, and feces were collected for histological staining, ELISA, flow cytometry, 16S rRNA sequencing, and metabolomics analysis. Results IF significantly altered body weight and intestinal morphology, damaged the intestinal barrier, increased pro-inflammatory cytokines, and enhanced gut immune activation (P < 0.05). IF also disrupted gut microbiota balance, increasing pro-inflammatory bacteria and reducing anti-inflammatory metabolites while elevating pro-inflammatory metabolites (P < 0.05). Furthermore, Indoleacrylic acid (IAA) supplementation significantly alleviated intestinal inflammation and reversed immune dysfunction induced by IF (P < 0.05). Conclusion Long-term intermittent fasting damages intestinal barrier function, disrupts gut microbiota, and exacerbates intestinal inflammation. However, supplementation with IAA effectively ameliorates fasting-induced intestinal inflammation and immune imbalance, suggesting its therapeutic potential.