Gut microbe-derived milnacipran enhances tolerance to gut ischemia/reperfusion injury

There are significant differences in the susceptibility of populations to intestinal ischemia/reperfusion (I/R), but the underlying mechanisms remain elusive. Here, we show that mice exhibit significant differences in susceptibility to I/R-induced enterogenic sepsis. Notably, the milnacipran (MC) content in the enterogenic-sepsis-tolerant mice is significantly higher. We also reveal that the pre-operative fecal MC content in cardiopulmonary bypass patients, including those with intestinal I/R injury, is associated with susceptibility to post-operative gastrointestinal injury. We reveal that MC attenuates mouse I/R injury in wild-type mice but not in intestinal epithelial aryl hydrocarbon receptor (AHR) gene conditional knockout mice (AHRflox/flox) or IL-22 gene deletion mice (IL-22−/−). Collectively, our results suggest that gut microbiota affects susceptibility to I/R-induced enterogenic sepsis and that gut microbiota-derived MC plays a pivotal role in tolerance to intestinal I/R in an AHR/ILC3/IL-22 signaling-dependent manner, revealing the pathological mechanism, potential prevention and treatment drugs, and treatment strategies for intestinal I/R. [Display omitted] •Gut microbiota differences affect susceptibility to intestinal I/R•Fecal milnacipran content correlate with post-operative gastrointestinal injury•Milnacipran alleviates intestinal I/R-induced enterogenic sepsis injury•AHR/ILC3/IL-22 signaling is a potential therapeutic strategy for intestinal I/R Deng et al. reveal that the gut microbiota affects susceptibility to I/R-induced enterogenic sepsis and gut microbiota-derived milnacipran plays a pivotal role in tolerance to intestinal I/R in an AHR/ILC3/IL-22 signaling-dependent manner, revealing the pathological mechanism, potential prevention and treatment drugs, and treatment strategies for intestinal I/R injury.