Parabacteroides distasonis regulates PPARɑ to alleviate colchicine-induced colonic injury through p-cresol sulfate

Colchicine has been extensively utilized for treating gouty arthritis over many years, yet its dose-limiting gastrointestinal toxicity remains a significant clinical challenge. While diarrhoea and nausea are well recognised, the extent of colchicine-induced occult colonic injury-including its impact on the gut microbiota and mucosal homeostasis-is poorly defined. This study investigates colchicine-induced colonic injury (e.g., oxidative stress, mitochondrial dysfunction) in vivo and in vitro and also the imbalance of gut microbiota composition in mice. It revealed a significant decreased content of Parabacteroides distasonis (p.d.) and various molecular signaling pathways were altered in colchicine-treated mice. Furthermore, our findings suggested that colchicine directly disrupted the colonization and reproduction processes of p.d. Interestingly, the level of p-cresol sulfate (PCS), a metabolite of the gut microbes, in mice colon tissue was significantly decreased upon colchicine administration, which was similar to the changed profile of p.d. Supplementation of PCS can alleviate colchicine-induced colonic injury. In vitro metabolic studies of microbiota demonstrated p.d. can produce PCS. Notably, we identified a pivotal role of peroxisome proliferators-activated receptor (PPARɑ) in colchicine-induced colonic injury, which suggested PPARɑ knockdown exacerbated the injury and it was the target of PCS or p.d. verified by PPARɑ knockout mice. In terms of mechanism, oxidative stress caused by mitochondrial dysfunction played an important role in colchicine-induced colon injury, and PCS supplementation effectively alleviated it by regulating mitochondrial function. In summary, our findings reveal a targetable gut microbiota-PPARɑ axis underlying colchicine toxicity and position P. distasonis or PCS supplementation as a plausible probiotic strategy to mitigate intestinal adverse effects, thereby offering valuable insights for its potential role as a probiotic candidate to address colchicine toxicity.