Functional Interactions between Gut Microbiota Transplantation, Quercetin, and High‐Fat Diet Determine Non‐Alcoholic Fatty Liver Disease Development in Germ‐Free Mice

Scope Modulation of intestinal microbiota has emerged as a new therapeutic approach for non‐alcoholic fatty liver disease (NAFLD). Herein, it is addressed whether gut microbiota modulation by quercetin and intestinal microbiota transplantation can influence NAFLD development. Methods and results Gut microbiota donor mice are selected according to their response to high‐fat diet (HFD) and quercetin in terms of obesity and NAFLD‐related biomarkers. Germ‐free recipients displayed metabolic phenotypic differences derived from interactions between microbiota transplanted, diets, and quercetin. Based on the evaluation of hallmark characteristics of NAFLD, it is found that gut microbiota transplantation from the HFD‐non‐responder donor and the HFD‐fed donor with the highest response to quercetin results in a protective phenotype against HFD‐induced NAFLD, in a mechanism that involves gut–liver axis alteration blockage in these receivers. Gut microbiota from the HFD‐responder donor predisposed transplanted germ‐free mice to NAFLD. Divergent protective and deleterious metabolic phenotypes exhibited are related to definite microbial profiles in recipients, highlighting the predominant role of Akkermansia genus in the protection from obesity‐associated NAFLD development. Conclusions The results provide scientific support for the prebiotic capacity of quercetin and the transfer of established metabolic profiles through gut microbiota transplantation as a protective strategy against the development of obesity‐related NAFLD. A potential preventive strategy of quercetin intake and intestinal microbiota transplantation on obesity‐associated non‐alcoholic fatty liver disease (NAFLD) is reported. Hight‐fat diet and quercetin administration result in different metabolic phenotypes, which are transmissible through gut microbiota transplantation to germ‐free mice. The interplay between intestinal microbiota profiles transplanted, diet, and quercetin results in metabolic phenotype transfer associated with protection or predisposition to develop obesity and NAFLD.