GPR15 differentially regulates the effects of cigarette smoke exposure on Crohn's disease and ulcerative colitis

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder characterized by gastrointestinal inflammation. Cigarette smoke is a well-established risk factor for the development and exacerbation of CD while exerting a paradoxical protective effect against the onset of UC. The exact mechanisms by which cigarette smoke influences IBD, as well as the opposite effects in UC and CD, have long remained unexplained. Here, we demonstrated the detrimental impact of cigarette smoke on CD progression while highlighting its beneficial effects on UC, as evidenced by analyses of human sample data. Mouse models of CD and UC exposed to cigarette smoke presented phenotypes consistent with those observed in human disease. GPR15, previously reported to direct regulatory T (Treg) cell colon homing, was upregulated in the colon tissues of both chemically induced colitis models after smoke exposure. Importantly, Gpr15 deletion ameliorated smoke-induced CD while increasing UC severity in mice. Furthermore, our study revealed that cigarette smoke mediated GPR15 to amplify colonic T helper type 17 (Th17) cell populations, thereby worsening the adverse effects of smoking on CD in mouse models. Moreover, cigarette smoke induced an increase in Treg cells through GPR15, which contributed to mitigating its impact on UC in mouse models. Moreover, in cigarette smoke-exposed CD and UC model mice, C57BL/6JGpt-Tg (human GPR15) transgenic mice presented phenotypes opposite those of Gpr15-deficient mice. Overall, our study offers mechanistic insights into the role of cigarette smoke-induced GPR15⁺ T cells in mediating the divergent effects of smoking on UC and CD.