Chronic Exposure to Fluxapyroxad Exacerbated Susceptibility to Colitis in Mice via a Gut Microbiota–Indole Derivatives–Th17/Treg Cell Balance Axis

Fluxapyroxad is the most commonly used succinate dehydrogenase inhibitor fungicide. This work investigated its adverse effects on colitis susceptibility and explored the underlying mechanisms based on a mouse model. After 13 weeks of exposure at the acceptable daily intake (ADI) level, fluxapyroxad exacerbated the susceptibility to colitis, impaired the intestinal barrier, and elevated proinflammatory cytokines and chemokines of the colon in mice. It was found that this toxic effect was caused by the disruption of the gut microbiome. Specifically, the abundance of <i>Lachnospiraceae</i> and <i>Muribaculaceae</i> decreased, while <i>Desulfovibrionaceae</i> and <i>Eggerthellaceae</i> increased. Altered microbiota reduced fecal indole derivatives, including indole-3-lactic acid (ILA), indole-3-acetic acid (IAA), and indole-3-acrylic acid (IArA), inhibiting aryl hydrocarbon receptor (AHR) activation, disrupting immune homeostasis by overactivating Th17 cells and insufficient Treg cell differentiation, and causing mild colonic inflammation. Oral antibiotic-treated mice and fecal transfer experiments validated the pathway. Susceptibility to colitis induced by fluxapyroxad was not detected in the oral antibiotic-treated mice. Fecal transfer of the disordered gut microbiota caused by fluxapyroxad could aggravate the severity of colitis in recipient oral antibiotic-treated mice that did not receive fluxapyroxad exposure. In conclusion, chronic fluxapyroxad exposure at the ADI level exacerbated colitis via a gut microbiota-indole derivatives-Treg/Th17 cell balance axis, offering a new risk assessment perspective of fluxapyroxad.