<i>Peptostreptococcus Anaerobius</i> enhances dextran sulfate sodium-induced colitis by promoting nf-κB-NLRP3-Dependent macrophage pyroptosis

Evidence indicates that gut microbiota is crucial in ulcerative colitis (UC) development. Increased <i>Peptostreptococcus</i> species abundance is linked to UC, but its role and mechanisms in intestinal inflammation are not well understood. This study used a dextran sulfate sodium (DSS)-induced colitis model in mice, and different bacterial strains were administered via gavage. We assessed clinical manifestations, colonic barrier function, gut microbiota composition, and levels of inflammatory cytokines, NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling molecules, and pyroptosis-related proteins. Mouse bone marrow-derived macrophages (BMDMs) were infected with <i>Peptostreptococcus anaerobius</i> at different time points and multiplicities of infection (MOI). Cell viability and the expression of NLRP3 signaling molecules and pyroptosis-associated proteins were assessed. The inhibitors C29, TAK-242, and MCC950 were employed for Toll-like receptor (TLR) and NLRP3 signaling pathways. It was observed that <i>P. anaerobius</i> exacerbated intestinal inflammation and barrier injury in DSS-induced colitis in mice. Additionally, <i>P. anaerobius</i> contributed to gut microbiota dysbiosis during colitis progression. <i>P. anaerobius</i> induced the expression of NLRP3 signaling molecules and pyroptosis-associated proteins in mouse colitis tissues. <i>In vitro</i> assays demonstrated that <i>P. anaerobius</i> activated NLRP3 inflammasome and evoked gasdermin D-mediated pyroptosis and interleukin (IL)-1β secretion in macrophages. Furthermore, TLR2 and TLR4 were identified as key mediators of <i>P. anaerobius</i>-induced macrophage pyroptosis via activation of the Nuclear Factor-kappa B (NF-κB)-NLRP3 pathway. In conclusion, <i>P. anaerobius</i> promotes macrophage pyroptosis and IL-1β secretion through the TLR2/4-NF-κB-NLRP3 signaling axis, thereby aggravating colitis. <i>P. anaerobius</i> may represent a potential risk factor for UC development.