Intermittent fasting alleviates ulcerative colitis via lithocholic acid-mediated macrophage reprogramming

Ulcerative colitis (UC) is a relapsing inflammatory disorder, in which nutritional intervention has emerged as a modifiable factor for influencing disease onset and severity. This study aimed to investigate whether intermittent fasting (IF) alleviates UC and identify the underlying mechanisms, focusing on bile acid metabolism-immune system crosstalk.

The study employed a 5:2 IF intervention (5 days ad libitum eating, 2 days low-calorie intake) in a chronic colitis model. Bile acid metabolic flux and lithocholic acid (LCA) levels were measured via metabolomics profiling, while gut microbiota composition was analyzed via 16S rRNA sequencing. Mechanistic studies explored the effect of LCA on macrophage polarization and metabolic reprogramming. UC patient samples were integrated to validate correlations between LCA levels, disease severity, erythrocyte sedimentation rate (ESR) and calprotectin.

5:2 IF promoted remission of chronic colitis. Mechanistically, IF reshaped gut microbiota composition, enhanced bile acid metabolic flux and elevated LCA levels. LCA directly inhibited pro-inflammatory macrophage polarization via inducing metabolic reprogramming and enhancing mitochondrial oxidative respiration. Analysis of human UC samples revealed that higher LCA levels correlated with milder UC, lower ESR, and reduced calprotectin.

IF alleviated chronic experimental colitis by enhancing bile acid metabolism and elevating LCA, which exerted anti-inflammatory effects via regulating macrophage mitochondrial oxidative respiration. This identifies LCA as a key mediating metabolite and provides a mechanistic basis for understanding how IF may affect intestinal inflammation in preclinical models.