Background: Lizhong decoction (LZD), a Traditional Chinese Medicine formula, is widely utilized to treat gastrointestinal diseases, including ulcerative colitis in China for thousands of years.

Objective: To investigate whether the protective effect of LZD on ulcerative colitis is dependent on gut microbiota and T-cell immune homeostasis.

Methods: The preventive effects of LZD on dextran sodium sulfate (DSS)-induced colitis mice were evaluated through the measurement of body weight, disease activity index, colon length and hematoxylin-eosin staining. Flow cytometry was used to detect the ratio of Th17/Treg cells. Pseudo sterile mice and fecal transplantation experiments were used to investigate whether the preventive effect of LZD was dependent on the gut microbiota. The alterations of gut microbiota were identified by the 16S rDNA sequencing. The content of intestinal short-chain fatty acids (SCFAs) was detected by LC-MS/MS analysis. The downstream signal pathways of SCFAs were detected by the immunoblotting.

Results: LZD administration significantly alleviated weight loss and intestinal injury in DSS-induced colitis mice. LZD administration also promotes the balance of Th17/Treg cells. Moreover, LZD administration relies on gut microbiota to alleviate ulcerative colitis and regulate Th17/Treg cell balance. LZD administration significantly improves gut microbial composition in colitis mice, elevating the abundance of SCFAs producing bacterium such as lachnospiraceae_nk4a136_group and Akkermansia. LZD treatment further increases the abundance of SCFAs and promotes activation of free fatty acid activated receptor 2 (FFAR2).

Conclusions: LZD administration promotes Th17/Treg cell balance in a gut microbiota-SCFAs dependent manner, which in turn ameliorates ulcerative colitis.