P2X7 receptor inhibition modulates sulfate-reducing bacteria populations and attenuates inflammation in DSS-induced colitis

Objective This study investigated the association between P2X7 receptor (P2X7R) function and the mucosal expansion of sulfate-reducing bacteria (SRB) during experimental colitis. Methods Colitis was induced with 3% dextran sodium sulfate (DSS) in BALB/c mice treated with P2X7R antagonists (Brilliant blue G [BBG] or A740003) and in C57BL/6 wild-type (WT) versus P2X7−/− knockout mice. Colonoscopy, histology (H&E, PAS), mucosal cytokines, and oxidative markers (NOS2, NOX) were assessed. Desulfovibrio (DSV-DMB) mRNA was quantified in paired distal and proximal colon segments by RT-qPCR. In vitro, HCT-8 epithelial cells were treated with DSS, A740003, and Desulfovibrio to assess viability, reactive oxygen species (ROS), nitric oxide, and SRB recovery. Results Pharmacological P2X7R blockade (BBG or A740003) significantly reduced colonoscopic and histological injury scores, preserved goblet cells, and suppressed mucosal pro-inflammatory cytokines (IFN-γ, IL-1β) and oxidative stress. Crucially, P2X7−/− mice were virtually refractory to colitis and exhibited markedly reduced Desulfovibrio expansion compared with WT controls. Spatial analysis revealed comparable increases in Desulfovibrio across distal and proximal colon segments, which were uniformly suppressed by BBG. DSS promoted fecal SRB overgrowth and toxic H 2 S production, both of which were mitigated by P2X7R inhibition. In vitro, DSS enhanced SRB metabolic activity and compromised epithelial viability, whereas A740003 suppressed ROS/nitrite accumulation and preserved viability. Conclusion Host P2X7R signaling drives a self-sustaining inflammatory amplification loop that creates a mucosal niche favorable for Desulfovibrio overgrowth and toxic H 2 S production. Disrupting P2X7R activation breaks this loop, protecting barrier integrity and mitigating dysbiosis in colitis.