Abstract
Nonalcoholic fatty liver disease (NAFLD) is a liver disease characterized by hepatic steatosis, inflammation, and fibrosis, as well as gut dysbiosis. No approved effective therapeutic medicine is available to date for NAFLD. Helminth therapy is believed to be a novel direction and therapeutic strategy for NAFLD. Our previous study showed that Trichinella spiralis-derived antigens (TsAg) had the potential for partially alleviating obesity via regulating gut microbiota. However, the effect of TsAg on NAFLD remains unclear. In this study, high-fat diet (HFD)-induced model mice were treated with TsAg and microbiota transplantation experiments, and alterations in the pathogenesis of nonalcoholic liver disease were assessed. The results showed that TsAg markedly reduced hepatic steatosis, improved insulin resistance, and regulated the abnormal expression of hepatic lipid-related genes. Of note, TsAg ameliorated hepatic inflammation by decreasing pro-inflammatory TNF-α and IL-1β, suppressing hepatic macrophage infiltration, as well as promoting M2 macrophage polarization. Moreover, TsAg reversed gut dysbiosis, as especially indicated by an increase in beneficial bacteria (e.g., Akkermansiaceae and Rikenellaceae). Furthermore, our study found that TsAg reduced LPS hepatic translocation and hepatic TLR4/NF-κB signaling, which further contributed to inhibiting hepatic inflammation. In addition, TsAg inhibited hepatic oxidative stress involving Nrf2/NQO-1 signaling. Microbiota transplantation showed that TsAg-altered microbiota is sufficient to confer protection against NAFLD in HFD-induced mice. Overall, these findings suggest that TsAg involving gut-liver axis and Nrf2/NQO-1 signaling is a novel promising candidate for NAFLD treatment. TsAg restores intestinal microbiota and intestinal barrier to inhibit bacteria and LPS translocation into the liver, contributing to reduce inflammation, oxidative stress, and hepatic steatosis in the liver of NAFLD mice. The effects were attributed to, at least in part, the inactivation of NF-κB pathway and the activation of Nrf-2/NQO-1 pathway. This study provides new insights for understanding immune modulation by T. spiralis-derived products as well as the potential application of TsAg as a modality for NAFLD.