Dual effects of fasting on gut microbiota and metabolism: protective adaptation versus barrier dysfunction risks

Fasting reshapes gut microbiota and metabolism, but its time-dependent dual impacts on intestinal barrier remain unclear. This study explored how 12 h and 24 h acute fasting modulate gut microbes, metabolites, epithelial structure and inflammatory resilience in mice.

C57BL/6 J mice were assigned to ad libitum feeding, 12 h fasting and 24 h fasting groups. We integrated PacBio 16S rRNA sequencing, untargeted LC-MS metabolomics, colon/cecum histology, Occludin immunofluorescence and CLP sepsis model, with LEfSe, multivariate statistics and correlation analysis for data interpretation. Data are available via MetaboLights with identifier MTBLS15098.

Fasting induced time-dependent microbial and metabolic remodeling: Akkermansia muciniphila peaked at 12 h fasting, while prolonged fasting elevated microbial richness and inflammation-associated taxa. Shared fasting-responsive metabolites altered pathways of immunity and energy metabolism. Both fasting durations reduced crypt depth and Occludin expression, with 24 h fasting triggering worse epithelial damage and higher post-CLP mortality. Correlations linked mucosal-protective microbes to beneficial metabolites and pro-inflammatory taxa to lipid mediators.

Short-term fasting generates favorable microbial-metabolic adaptation yet initiates mild epithelial injury, while 24 h fasting aggravates barrier defects and weakens anti-inflammatory resilience. Beneficial microbiota signatures are decoupled from intact mucosa, indicating fasting duration determines the balance between gut adaptation and epithelial vulnerability.