Bacteroides vulgatusattenuates colitis by inhibiting CD82 and increasing activation of the NLRP3 inflammasome

Abstract

Abstract Inflammatory bowel disease (IBD), involving Crohn’s disease (CD) and ulcerative colitis (UC), is a worldwide disease. IBD is known as a chronic immune-mediated intestinal inflammation caused by a variety of causes, such as genetic, microbial and environmental factors, but the exact etiology and treatment are unclear and undiscovered. Although the correlation between IBD and gut microbiota dysbiosis has not been fully demonstrated, it has long been hypothesized that changes in the microbiome are responsible for IBD. Thus, we analyzed each microbiome using pyrosequencing of the colon of normal mice and DSS-induced colitis mice, and found that the relative abundance of Bacteroides vulgatus(B. vulgatus) was increased in the colon of DSS-induced colitis mice. Next, we confirmed that B. vulgatusregulates CD82 expression and promotes activation of NLRP3 inflammasome. CD82 binds to NLRP3 and BRCC3, with a higher affinity for BRCC3. This binding mediated degradation of NLRP3 by inhibition BRCC3-dependent K63-specific deubiquitination. Therefore, we verified the difference between DSS-induced colitis in CD82 KO mice and normal mice, and the effect of B. vulgatus on DSS-induced colitis in CD82 KO mice and normal mice. Deficiency of CD82 decreased the severity of colitis in mice with enhancing the level of IL-1β and IL-18. Also, administration of B. vulgatus increased the survival through mediating CD82 expression and activating BRCC-dependent deubiquitination of NLRP3 in mice. Taken together, suppression of CD82 reduced the pathogenesis of colitis with elevating the activation of NLRP3 inflammasome by BRCC-dependent K63 deubiquitination. Additionally, B. vulgatusmay be a novel therapeutic candidate for colitis. This work was supported by the NRF grant funded by the Korea government (MSIP) (2019R1I1A2A01064237).