<i>Parasutterella excrementihominis</i> exacerbates experimental colitis and colitis-associated colorectal cancer via pathogenic NETosis activation.

Abstract

<i>Parasutterella excrementihominis (P. excrementihominis),</i> a <i>Betaproteobacteria</i> 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. This study investigates the pathogenic role of <i>P. excrementihominis</i> in UC and CAC, focusing on its induction of neutrophil extracellular traps (NETs) and underlying mechanisms. Clinical stool samples from UC patients and healthy controls were analysed for <i>P. excrementihominis</i> 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. <i>P. excrementihominis</i> was significantly enriched in UC patients and exacerbated colitis and CAC in mice by expanding colonic neutrophils and NETs formation. Metabolomic profiling revealed that <i>P. excrementihominis</i> 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. Our findings identify <i>P. excrementihominis</i> 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.