Healthy diet intervention reverses the progression of NASH through gut microbiota modulation

Abstract

ABSTRACT Diet and gut microbiota impact the progression of non-alcoholic steatohepatitis (NASH). An unhealthy diet, rich in fat and sugar, promotes gut microbiota dysbiosis, leading to the translocation of lipopolysaccharides (LPS) and other harmful pathogen-associated molecular patterns to the liver, triggering hepatic inflammation and aggravating NASH. Currently, there are no approved pharmacological treatments for NASH, although novel drugs, such as obeticholic acid (OCA), have demonstrated beneficial effects. Healthy dietary modifications have been proposed to prevent and treat NASH. However, the therapeutic effect of the combined implementation of a healthy dietary intervention with pharmaceutical agents or dietary supplements for NASH treatment and how it interplays with the gut microbiota and associated pathways remains poorly understood. This study aims to investigate the therapeutic efficacy of a healthy dietary modification, either alone or in combination with a dietary supplement [ginger essential oil (GEO)] or drug (OCA), in a Gubra-Amylin diet-induced NASH mouse model. NASH was induced for 12 weeks, after which the interventions were administered for a subsequent 3-week period. Our findings revealed that healthy dietary intervention primarily restores obesity, lipidemia, and NASH. In contrast, GEO and OCA have additional benefits by suppressing pro-inflammatory cytokines by partially modulating the NLRP3/ASC/caspase-1 pathways. Moreover, healthy dietary intervention restores gut microbiota composition and function from dysbiosis, while GEO and OCA partially mediate the gut-derived LPS/toll-like receptor 4/nuclear factor kappa B pathway. Therefore, adherence to healthy dietary patterns plays a primary role in NASH reversion, and additional supplementation of GEO or OCA could offer extra benefits in suppressing hepatic inflammation and preventing disease progression. IMPORTANCE The link between gut microbiota and diet is crucial in the development of non-alcoholic steatohepatitis (NASH). This study underscores the essential role of a healthy diet in preventing and treating NASH by reversing obesity, lipidemia, and gut microbiota dysbiosis. Moreover, the supplementation of functional food or drug to the diet can provide additional advantages by inhibiting hepatic inflammation through the modulation of the hepatic inflammasome signaling pathway and partially mediating the gut microbiota and lipopolysaccharide signaling pathway. This study highlights the importance of adopting healthy dietary habits in treating NASH and proposes that supplementing with ginger essential oil or obeticholic acid may offer additional benefits. Nonetheless, further clinical studies are necessary to validate these findings.