MiR-29a deficiency disrupts gut microbiota-bile acid homeostasis and impairs the anti-inflammatory effects of lithocholic acid in colitis.

BACKGROUND

Gut microbiota, bile acid metabolism, and their derived metabolites are critical regulators of intestinal inflammation in inflammatory bowel disease (IBD). While microRNA-29a (miR-29a) is a recognized epigenetic regulator of intestinal inflammation, its role in shaping microbiota-driven bile acid metabolism, particularly secondary bile acid production, remains unclear. This study aimed to investigate how miR-29a regulates microbiota-bile acid axis, with an emphasis on lithocholic acid (LCA) and its anti-inflammatory effects in colitis.

METHODS

Colitis was induced in wild-type and Mir29a/Mir29b-1 locus-deficient mice using dextran sulfate sodium (DSS), and disease severity, colonic injury, and inflammatory responses were assessed. Fecal microbiota composition and bile acid profiles were characterized using 16S rRNA gene sequencing and targeted metabolomics. Alterations in bile acids were further examined in relation to disease severity. In vitro, Caco-2 cells were used to evaluate the anti-inflammatory effects of LCA under modulation of miR-29a expression.

RESULTS

MiR-29a/b1 deficiency significantly exacerbated DSS-induced disease severity, colonic injury, inflammatory responses, and epithelial ultrastructural damage. KO-DSS mice exhibited gut microbiota dysbiosis, with reduced microbial diversity and altered community structure. Targeted metabolomics revealed impaired primary-to-secondary BA biotransformation, characterized by chenodeoxycholic acid (CDCA) accumulation and a reduced LCA/CDCA ratio. In vitro, LCA supplementation attenuated DSS-induced pro-inflammatory gene expression, whereas this protective effect was partially diminished by miR-29a inhibition.

CONCLUSIONS

These results support a role for miR-29a in maintaining gut microbial bile acid homeostasis during colitis and contributing to the epithelial anti-inflammatory response to LCA. Together, these findings link host microRNA regulation to microbiota-derived BA function and may inform future precision strategies for IBD.