Introduction Microbial dysbiosis plays a pivotal role in the pathogenesis of ulcerative colitis (UC) and inflammation-associated colorectal cancer. Among emerging pathobionts, Parasutterella excrementihominis has recently gained attention because of its enrichment in patients with UC, although its direct mechanistic contribution to intestinal inflammation and tumorigenesis has remained uncertain.
Introduction
Microbial dysbiosis plays a pivotal role in the pathogenesis of ulcerative colitis (UC) and inflammation-associated colorectal cancer. Among emerging pathobionts, Parasutterella excrementihominis has recently gained attention because of its enrichment in patients with UC, although its direct mechanistic contribution to intestinal inflammation and tumorigenesis has remained uncertain.
Problem Statement
The pathways through which specific gut bacteria promote chronic mucosal inflammation and colitis-associated colorectal cancer (CAC) are incompletely understood. In particular, the role of bacterial metabolites in triggering pathogenic neutrophil extracellular trap formation (NETosis) and inflammation-driven carcinogenesis has not been clearly defined.
Summary
This study identified P. excrementihominis as a potent microbial driver of experimental colitis and CAC progression. Stool analyses confirmed significant enrichment of the bacterium in patients with UC. In murine dextran sulphate sodium colitis and azoxymethane/DSS CAC models, colonisation with P. excrementihominis markedly aggravated intestinal inflammation, enhanced tumour burden and promoted colonic neutrophil infiltration with excessive NET formation. Mechanistic investigations demonstrated that the bacterium altered host carbohydrate metabolism, resulting in increased production of succinic acid and 6-hydroxyhexanoic acid. These metabolites triggered pathogenic NETosis through activation of succinate receptor-1 and GPR84 signalling pathways in lipopolysaccharide-primed neutrophils. Importantly, this process was dependent on Gasdermin D-mediated NETosis, linking microbial metabolic activity directly to inflammatory tissue injury and tumorigenesis. Neutrophil-specific deletion of gasdermin D significantly attenuated metabolite-induced tumour progression, confirming the central pathogenic role of NETosis. The study provides compelling evidence that microbial metabolites can orchestrate immune-mediated colorectal carcinogenesis through neutrophil activation pathways. These findings position P. excrementihominis and its metabolite–NETosis axis as promising therapeutic targets for UC and CAC, with potential implications for microbiome-directed interventions in inflammation-driven colorectal cancer.
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