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

Abstract

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 Network Involving Gut Microbiota, Circulating Bile Acids, and Hepatic Metabolism Genes That Protects Against Non‐Alcoholic Fatty Liver Disease

“…Moreover, the secondary BA lithocholic acid, despite representing only a 1–2% of the total BAs in feces, was also increased (Figure S5, Supporting Information). Finally, and in agreement with previous results, ethanol and LPS levels were found reduced in the plasma of protected mice (Figure S3, Supporting Information).…”

“…We have previously shown that dC ‐receiver mice fed with HFD ( dC /HFD) display increased body weight gain and impaired insulin sensitivity (+373%, +530%, respectively) versus dC ‐receiver mice fed with control diet ( dC/ C). Conversely, dHFD −/HFD and dHFDQ /HFD mice show reduced body weight gain (−48% and −49%, respectively) and insulin resistance (HOMA‐IR: −82% and −76%, respectively) in comparison with dHFD+ /HFD mice …”

“…In the present study, GFm were colonized with cecal microbiota from control ( dC ), HFD‐fed ( dHFD+ and dHFD − as responder and non‐responder to diet, respectively), and HFD‐fed supplemented with quercetin ( dHFDQ ) donors. In a previous study, we investigated whether gut microbiota transplantation can modulate NAFLD and provided evidence for the prebiotic properties of quercetin and the transfer of healthier metabolic phenotypes by means of microbiota transplantation as a strategy for protection against NAFLD . However, mechanistic insights remained to be elucidated.…”

“…After 16 weeks of treatment, animals were sacrificed under anesthesia. Plasma, cecal, and fecal contents and liver tissue were collected as previously indicated …”

“…Thus, quercetin, a flavonoid with high antioxidant capacity and strong anti‐inflammatory properties, has shown a potential prebiotic effect modulating gut microbiota composition in animal models of obesity and NAFLD . In addition, recently it was demonstrated that transplanting cecal microbiota from both non‐responder to high‐fat diet (HFD) and quercetin‐treated donors triggered a protected metabolic phenotype that strongly determined susceptibility to NAFLD development, by mechanisms not yet completely understood . The aim of this work is to examine the impact of protective and non‐protective microbiota transfer from different donor mice into germ‐free mice (GFm) on gut microbiota, circulating BAs, and liver BA‐ and lipid‐metabolism genes to characterize the key players in the gut–liver axis that promote protection against NAFLD.…”