Interleukin-17 Weakens the NAFLD/NASH Process by Facilitating Intestinal Barrier Restoration Depending on the Gut Microbiota

Interleukin-17 (IL-17) is associated with nonalcoholic fatty liver disease (NAFLD) and gut microbiota, and how IL-17 mediates the NAFLD/nonalcoholic steatohepatitis (NASH) process depending on the gut microbiota is unclear. We found that T helper 17 (T(H)17) cells were decreased in the small intestine in a methionine choline-deficient (MCD) diet-induced NASH model. IL-17-deficient (Il17(−/−)) mice showed alterations in intestinal microbiota, including the inhibition of probiotic growth and the overgrowth of certain pathogenic bacteria, and were prone to higher endotoxemia levels and more severe gastrointestinal barrier defects than wild-type (WT) mice. Furthermore, T(H)17 cells were responsible for restoring the intestinal barrier after administration of recombinant IL-17 to Il17(−/−) mice or injection of CD4(+) T cells into a Rag1(−/−) mouse model. Additionally, transplantation of the microbiota from WT mice to Il17(−/−) mice restored the intestinal barrier. Notably, microbiota-depleted Il17(−/−) mice were resistant to MCD diet-induced intestinal barrier impairment. Fecal microbiota transplantation from Il17(−/−) mice to microbiota-depleted mice aggravated intestinal barrier impairment and then promoted the development of NASH. Collectively, this study showed that host IL-17 could strengthen intestinal mucosal barrier integrity and reduce dysbiosis-induced intestinal injury and secondary extraintestinal organ injury induced by a special diet.