Parasutterella excrementihominis exacerbates experimental colitis and colitis-associated colorectal cancer via pathogenic NETosis activation

Abstract

Background: Parasutterella excrementihominis (P. excrementihominis), a Betaproteobacteria species enriched in ulcerative colitis (UC) patients, is implicated in chronic inflammation. However, its mechanistic role in UC progression and colitis-associated colorectal cancer (CAC) remains unclear.

Objective: This study investigates the pathogenic role of P. excrementihominis in UC and CAC, focusing on its induction of neutrophil extracellular traps (NETs) and underlying mechanisms.

Design: Clinical stool samples from UC patients and healthy controls were analysed for P. excrementihominis abundance. Murine models of dextran sulphate sodium (DSS)-induced colitis and azoxymethane/DSS-induced CAC were used to evaluate bacterial pathogenicity. RNA sequencing and metabolomic analyses were conducted on germ-free mice with monocolonisation, and in vitro cell experiments were carried out to elucidate the role of bacterial metabolites in NETosis.

Results: P. excrementihominis was significantly enriched in UC patients and exacerbated colitis and CAC in mice by expanding colonic neutrophils and NETs formation. Metabolomic profiling revealed that P. excrementihominis enhances the host's carbohydrate metabolic capacity, leading to increased production of succinic acid (Suc) and 6-hydroxyhexanoic acid (6-HHA). These metabolites activated gasdermin D (GSDMD)-dependent NETosis in lipopolysaccharide-primed neutrophils through the succinate receptor 1/G protein-coupled receptor 84 signalling pathway. Conversely, neutrophil-specific GSDMD deletion attenuated metabolite-driven tumourigenesis.

Conclusion: Our findings identify P. excrementihominis as a critical microbial driver of UC and CAC pathogenesis. This bacterium significantly accelerates disease progression by producing specific metabolites (Suc and 6-HHA) that induce pathogenic NETosis. Targeting this bacterium or its metabolic axis offers novel therapeutic strategies for inflammation-driven colorectal carcinogenesis.

Keywords: BACTERIAL PATHOGENESIS; IBD BASIC RESEARCH; ULCERATIVE COLITIS.