Intestinal microbiota
dysbiosis and metabolic disruption are well-known as the primary triggers of
ulcerative colitis (UC). However, their role in regulating the group 3 innate lymphoid cells (ILC3s), which are essential for intestinal health, remains unexplored during the development of disease severity. Here, our results showed that the microbiota structure of patients with severe UC (SUCs) differed from those with mild UC (MiUCs), moderate UC (MoUCs), and healthy controls (HCs). Microbes producing secondary
bile acids (SBAs) and SBAs decreased with the aggravation of UC, and a strong positive correlation existed between them. Next,
fecal microbiota transfer was used to reproduce the human-derived microbiota in mice and decipher the microbiota-mediated inflammatory modulation during an increase in disease severity. Mice receiving SUC-derived microbiota exhibited enhancive
inflammation, a lowered percentage of ILC3s, and the down-regulated expressions of
bile acid receptors, including
vitamin D receptor (VDR) and
pregnane X receptor (PXR), in the colon. Similar to clinical results, SBA-producing microbes, deoxycholic
acids (DCA), and 12-ketolithocholic
acids (12-KLCA) were diminished in the intestine of these recipients. Finally, we compared the therapeutic potential of DCA and 12-KLCA in preventing
colitis and the regulatory mechanisms mediated by ILC3s. 12-KLCA but not DCA represented a strong anti-inflammatory effect associated with the higher expression of VDR and the lower secretion of
IL-17A from colonic ILC3s. Collectively, these findings provide new signatures for monitoring the acute deterioration of UC by targeting gut microbiota and
bile acid metabolism and demonstrate the therapeutic and preventive potential of a novel microbiota-derived metabolite, 12-KLCA.