Astragaloside IV alleviates ulcerative colitis via gut microbiota - butyrate metabolism axis to reshape Th17/Treg balance

Gut microbiota dysbiosis and Th17/Treg cell imbalance play critical roles in the pathogenesis of ulcerative colitis (UC). Astragaloside IV (AS-IV) exhibits extensive anti-inflammatory and immunomodulatory activities; however, the crosstalk between gut microbiota and Th17/Treg cells modulated by AS-IV remains unreported. Here, chronic colitis was induced in mice by free access to 2.5 % dextran sulfate sodium (DSS) solution over three 7-day cycles, with concurrent AS-IV administration. AS-IV effectively alleviated DSS-induced chronic colitis in mice, as evidenced by increased body weight and colon length, decreased disease activity index (DAI), colon weight, colon weight/colon length, and colon weight index, and enhanced the gene and protein expression of tight junction molecules Claudin-1, Occludin, ZO-1. Notably, AS-IV not only effectively regulated the differentiation balance of Th17/Treg cells, but also significantly improved the composition of gut microbiota and butyric acid metabolism in chronic colitis mice. Intriguingly, Th17/Treg cells and butyric acid were significantly correlated with α/β diversity, as well as the genera Enterorhabdus, Mucispirillum, and Helicobacter. However, AS-IV lost its therapeutic efficacy against colitis and its regulatory effects on Th17/Treg cell balance and butyric acid metabolism following gut microbiota depletion. Critically, FMT from AS-IV-treated mice restored the protective effects against colitis and the regulation of Th17/Treg cell balance and butyric acid metabolism. Collectively, AS-IV inhibits chronic colitis by regulating gut microbiota composition, butyric acid metabolism, and Th17/Treg cell differentiation balance, whose protective effects are dependent on the regulatory mechanism of Th17/Treg cell differentiation balance mediated by gut microbiota-derived butyrate metabolism.

Astragaloside IV; Chronic colitis; Fecal microbiota transplantation; Gut microbiota; Th17/Treg cells.