The Synbiotic Combination of Akkermansia muciniphila and Quercetin Ameliorates Early Obesity and NAFLD through Gut Microbiota Reshaping and Bile Acid Metabolism Modulation

María Juárez-Fernández,Susana Martínez-Flórez,Esther Nistal,Ramiro Jover,María Victoria García-Mediavilla,Javier González-Gallego,Polina Soluyanova,Sonia Sánchez-Campos,Sara Román-Sagüillo,David Porras,Petar Petrov

doi:10.3390/antiox10122001

Abstract

Gut microbiota plays a key role in obesity and non-alcoholic fatty liver disease (NAFLD), so synbiotics could be a therapeutic alternative. We aim to evaluate a nutritional intervention together with the administration of the bacteria Akkermansia muciniphila and the antioxidant quercetin in an in vivo model of early obesity and NAFLD. 21-day-old rats were fed with control or high-fat diet for six weeks. Then, all animals received control diet supplemented with/without quercetin and/or A. muciniphila for three weeks. Gut microbiota, NAFLD-related parameters, circulating bile acids (BAs) and liver gene expression were analyzed. The colonization with A. muciniphila was associated with less body fat, while synbiotic treatment caused a steatosis remission, linked to hepatic lipogenesis modulation. The synbiotic promoted higher abundance of Cyanobacteria and Oscillospira, and lower levels of Actinobacteria, Lactococcus, Lactobacillus and Roseburia. Moreover, it favored elevated unconjugated hydrophilic BAs plasma levels and enhanced hepatic expression of BA synthesis and transport genes. A. muciniphila correlated with circulating BAs and liver lipid and BA metabolism genes, suggesting a role of this bacterium in BA signaling. Beneficial effects of A. muciniphila and quercetin combination are driven by gut microbiota modulation, the shift in BAs and the gut-liver bile flow enhancement.

Highlights

Obesity is nowadays one of the major public health concerns worldwide and it is considered an international epidemic
The aim of this study is to evaluate the combinatory effect of a nutritional intervention together with quercetin supplementation and A. muciniphila administration on gut microbiota composition, hepatic lipid and bile acids (BAs) metabolism genes, circulating BAs, and non-alcoholic fatty liver disease (NAFLD) severity in an in vivo model of early obesity and NAFLD
No significant differences in the total bacterial concentration and α-diversity were found between all the experimental groups at the end of the study, the group supplemented with the synbiotic showed the highest total bacteria counts and a slightly decreased Shannon index (Figure 4B,C)

Summary

Introduction

Obesity is nowadays one of the major public health concerns worldwide and it is considered an international epidemic. This disease is continuously rising in children and adolescents, reaching numbers of 124 million worldwide in 2016 [1]. Obesity is associated with many comorbidities, including metabolic syndrome and its hepatic manifestation, non-alcoholic fatty liver disease (NAFLD) [2]. NAFLD is one of the commonest manifestations of chronic hepatic disease and it affects around 20–30% of worldwide population. This prevalence is much higher when obesity is considered, reaching numbers around 90% in adults and 40% in children [3]. According to the multiple-hit hypothesis [4], the pathogenesis of NAFLD is Antioxidants 2021, 10, 2001.

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