Gut microbiota remodelling alleviates elderly sepsis by microbiota-derived acetic acid via FFAR2/NLRP3 pathway

BACKGROUND: Elderly patients with sepsis have higher morbidity, mortality, and susceptibility than adults. Young-donor faecal microbiota transplantation (FMT) can remodel and improve intestinal dysbiosis to alleviate age-related diseases via microbiota-derived acetic acid and may be a treatment option for elderly sepsis. This study aimed to elucidate the influence of remodelling of the elderly gut microbiota on sepsis via acetic acid and explore the underlying mechanism. We analyzed the gut microbiota and plasma acetic acid in elderly patients with sepsis, performed young-donor FMT, and acetic acid supplementation in a caecum ligation and puncture-induced aged septic model mice, and assessed the effects of acetic acid on the septic myocardium by examining NLRP3 inflammasome in FFAR2 knockdown mice. RESULTS: Elderly sepsis had higher mortality, reduced gut microbiota diversity, increased Escherichia-Shigella abundance, and reduced plasma acetic acid levels. Young-donor FMT improved the gut microbiota, increased the abundance of the probiotic genus Akkermansia and faecal acetic acid levels in the gut, and improved colon barrier function and outcomes. Intestinal acetic acid intervention improved age-related intestinal dysbiosis, organ dysfunction, and adverse effects in aged septic mice. These beneficial effects on the myocardium were mediated by activation of the FFAR2/NLRP3 axis, as evidenced by the finding that FFAR2 knockdown abrogated the amelioration of acetic acid. The elderly gut microbiota is fragile, which is related to the severity and poor prognosis of elderly sepsis. CONCLUSION: Gut microbiota remodelling improves elderly sepsis via acetic acid, which can inhibit inflammatory reactions to alleviate myocardial damage by FFAR2/NLRP3 inflammasome inactivation.