Modulation of gut microbiota and its metabolites with probiotic bacteria Lactobacillus rhamnosus GG and prebiotics oat and rye bran fibers as the management for non-alcoholic fatty liver disease in young mice

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an obesity related comorbidity which results from energy imbalance through overnutrition and inadequate physical activity. Starting from a benign form steatosis, it can progress to a more severe form of non-alcoholic steatohepatitis (NASH) which predisposes to fibrosis, cirrhosis and eventually hepatocellular carcinoma and liver failure. The aetiology of the progression from NAFLD to NASH is largely unknown. Over the last two decades, increasing amount of research has focused on gut microbiota as the potential mediator of “gut liver axis” pointing towards the commensals as a significant factor in NAFLD development and progression. Modulation of gut microbiota with probiotics and prebiotics has delivered encouraging outcomes although the molecular mechanisms behind their protective properties are incompletely understood. This study hypothesised that microbiota modulation with either probiotic Lactobacillus rhamnosus GG (LGG) or prebiotic from oat and from rye bran fibers will help to ameliorate NAFLD disease in young mice fed Western diet (WD) through microbial activities and their metabolites namely short chain fatty acids (SCFA), bile acids (BA) and products of tryptophan (TRP) metabolism. Firstly it was shown that fiber deprived WD evoked yet unknown shift in the intestinal metabolism resulting in an exacerbation of metabolic complication upon LGG supplementation. Proposed mechanism behind those unexpected changes was microbial dysbiosis driven impairment of gut barrier function and enhanced abundance of H2S producing bacterial species with subsequent H2S translocation and obesogenic downstream signalling. Secondly, it was shown that when the intestinal and microbial environments are allowed to mature with the presence of fiber post weaning, these detrimental changes can be reversed and LGG can contribute to improving NAFLD condition and glucose responses. This study is the first to propose that LGG driven reduction of hepatic steatosis and inflammation as well as glucose intolerance might be mediated through enhanced synthesis of SCFA and downstream signalling leading to the inhibition of lipogenic pathways. Lastly, two different fibers, from oat and rye brans were shown to modulate microbial metabolites and ameliorate NAFLD outcomes. It was found that both fibers created specific microbial environment resulting in the generation of FXR antagonistic bile acids by oat and conjugated bile acids with their increased faecal excretion by rye, which consequently improved BA and cholesterol metabolism. Furthermore, both fibers enhanced production of SCFA leading to improved gut integrity, reduced liver inflammation and possibly determining the path of tryptophan metabolism, in particular TPH-1 activity and indole production. These studies collectively confirm the pivotal role of gut microbiota and its metabolites in the pathology of NAFLD and the opportunities for the use of probiotics and prebiotics in the management of fatty liver, with LGG and oat and rye bran fibers as the proposed choices for supplementation.