Dual Effects of Fasting on Gut Microbiota and Metabolism: Protective Adaptation versus Barrier Dysfunction Risks

ABSTRACT: Fasting is increasingly recognized as a metabolic intervention that reshapes gut microbiota and host metabolism, but its duration-dependent effects on intestinal epithelial integrity remain incompletely understood. In this study, we compared ad libitum feeding, 12 h fasting, and 24 h fasting in male C57BL/6J mice using 16S rRNA gene sequencing, untargeted metabolomics, histological assessment, Occludin immunofluorescence, and a cecal ligation and puncture inflammatory challenge model. Fasting induced time-dependent microbial and metabolic remodeling. The 12 h fasting condition was characterized by enrichment of Akkermansia muciniphila and fasting-responsive metabolites associated with mucosal homeostasis and immune modulation. However, early epithelial structural changes, including reduced crypt/gland depth and decreased Occludin signal, were already detectable after fasting and became more evident after 24 h. In the CLP model, 24 h fasting was associated with increased mortality, suggesting reduced resilience to severe polymicrobial inflammatory stress. Correlation analyses further linked fasting-responsive microbial taxa with metabolites involved in inflammatory and metabolic pathways, although these associations do not establish causality. Collectively, our findings suggest that acute fasting induces concurrent microbial-metabolic adaptation and epithelial vulnerability, with prolonged fasting shifting the balance toward impaired stress resilience. These results highlight the importance of defining fasting duration carefully and warrant future studies using direct permeability assays and mechanistic microbiota-intervention models.

INSTRUMENT(S): Liquid Chromatography MS - alternating - normal-phase

PROVIDER: MTBLS15098 | MetaboLights | 2026-07-20

REPOSITORIES: MetaboLights