Quorum-Sensing Molecules are Elevated in Long-standing Ulcerative Colitis and are Linked to the Development of Colitis-Associated Cancer.

Abstract

Chronic colonic inflammation can lead to colitis-associated cancer (CAC) in ulcerative colitis (UC) patients. The host-microbiome interface plays a critical role in CAC development. Quorum-sensing molecules (QSMs) are bacterial products that regulate bacterial processes. We investigated whether QSMs are related to risk factors for CAC in UC patients and drive CAC development in mouse models. Blood samples from UC patients and mouse models of CAC (azoxymethane-dextran sodium sulfate) were analyzed for 3 bacterial QSM classes: short-chain n-acyl homoserine lactones (scAHLs) and long-chain n-acyl homoserine lactones and autoinducer-2. CAC mouse models (specific pathogen-free and germ-free) were challenged with C6-scAHL. QSM levels, colitis-associated tumor development, microbiome composition, and metabolome profiles were examined. Murine and human colonic organoid cultures were used to examine C6-scAHL-driven cytokine production. Serum scAHL levels were higher in UC patients than in healthy controls. UC patients with inflammation and ≥10 years of disease had elevated autoinducer-2 levels. Systemic C6-scAHL administration to a CAC mouse model increased tumor number and size and was associated with microbiome and metabolome changes similar to those in inflammatory settings. C6-scAHL administration also promoted tumor development in germ-free mice. In colonoids derived from mice and UC patients, C6-scAHL increased tumorigenic and proinflammatory cytokine production. The bacterial QSM C6-scAHL is elevated in UC patients with CAC risk factors. C6-scAHL promotes colon tumor development in mice and drives proinflammatory and protumorigenic cytokine production in vitro. Our findings highlight a previously unexplored pathogenetic pathway linking the microbiome to CAC development and suggest targets to modify CAC risk.