Corynebacterium glutamicum alleviated colitis by downregulating the TNF signaling pathway mediated by cIAP1/2 in mice

Abstract

The gut microbiota and its associated micro-ecosystem were closely related to the onset and development of ulcerative colitis (UC). We found that Corynebacterium glutamicum (C. glutamicum) helps rebuild gut eubiosis from diabetes dysbiosis, while its effects on UC remain unknown. This study aims to investigate the therapeutic effects and mechanisms of C. glutamicum on UC. In this study, C. glutamicum was encapsulated with thiolated hyaluronic acid (HA-SH) to form a hydrogel termed as CG-HA-SH. The adhesion and distribution of CG-HA-SH in the intestine were evaluated, along with its therapeutic effects on UC mice, including its impact on the gut microbiota. Additionally, changes in short-chain fatty acids (SCFAs) in the intestines of UC mice were analyzed, and RNA sequencing (RNA-Seq) was employed to investigate the mechanisms by which C. glutamicum alleviated inflammation. HA-SH enhanced the resistance of C. glutamicum in gastric and intestinal fluids, providing approximately 12 hours of adhesion at colitis inflammation sites. C. glutamicum reduced the levels of pro-inflammatory factors like IL-1β (by 97.31%) and TNF-α (by 90.10%) while increasing anti-inflammatory IL-10 (by 197.59%) in the colon. It also increased the abundance of E. fissicatena, Muribaculum, and butyrate, enhanced intestinal tight junctions (OCC, by 318.93%) and mucus barrier (MUC2, by 515.93%). The mRNA levels of cIAP1/2 decreased by 4.33 folds, their protein expression levels were reduced by 36.97% correspondingly. The enrichment of TNF pathway was the most significant. Therefore, C. glutamicum exhibited remarkable efficacy in alleviating inflammation and reshaping dysbiotic gut microbiota by downregulating the cIAP1/2-mediated TNF signaling pathway and NF-κB signaling pathway. cIAP1 and cIAP2 might serve as effective therapeutic targets.