Microbiota metabolite butyrate alleviates intestinal inflammation associated with enhanced autophagy-related signaling in DSS-induced colitis

Background The incidence of inflammatory bowel disease (IBD) has been demonstrated to be increased over recent decades. Butyrate derived from the gut microbiota is known to be beneficial in alleviating inflammation, yet the underlying mechanisms remain undefined. Methods Human and mice fecal samples were analyzed using gas chromatography-mass spectrometry and 16S rRNA gene sequencing. Male wild-type C57BL/6J mice aged 6–8 weeks old were administered dextran sodium sulfate (DSS) to induce experimental colitis models. Mice were treated with sodium butyrate (SB) through oral gavage. 3-methyladenine (3MA) was administered intraperitoneally to suppress autophagy in mice. Results Our results showed that the butyric acid level in the feces of IBD patients was significantly lower than those in healthy controls (HCs) (134.5 vs. 605.9, p = 0.002), concomitant with a deficiency in butyrate-producing probiotics, such as Faecalibacterium . We found that oral SB changed the composition of the intestinal microbes (higher abundance of Barnesiella ), restored intestinal barrier function determined by enhanced tight junction protein expression (OCCLUDIN) in Western blotting and diminished the susceptibility of mice to DSS-induced colitis. Additionally, autophagy levels in the intestine were significantly increased in SB group with enhanced protein levels of ATG16L1 and LC3-II, and reduced level of p62/SQSTM1 protein. While the SB group showed changes consistent with enhanced autophagy-related signaling, 3MA-treated mice conversely displayed significantly attenuated autophagy activity. Meanwhile, the butyrate-mediated protection against colonic injury was considerably diminished in the 3MA-treated mice. Conclusion Our findings provide multi-line evidence that SB coordinates gut microbiota and is associated with enhanced autophagy-related signaling to alleviate inflammation in DSS-induced colitis, integrating human fecal metabolomic and microbiome analyses with in vivo pharmacological and transcriptomic data.