Alterations of the gut microbiome and metabolome in alcoholic liver disease

Alcohol consumption is one of the leading causes of liver diseases and liver-related death worldwide. The gut is a habitat for billions of microorganisms which promotes metabolism and digestion in their symbiotic relationship with the host. Alterations of gut microbiome by alcohol consumption are referred to bacterial overgrowth, release of bacteria-derived products, and/or changed microbiota equilibrium. Alcohol consumption also perturbs the function of gastrointestinal mucosa and elicits a pathophysiological condition. These adverse effects caused by alcohol may ultimately result in a broad change of gastrointestinal luminal metabolites such as bile acids, short chain fatty acids, and branched chain amino acids. Gut microbiota alterations, metabolic changes produced in a dysbiotic intestinal environment, and the host factors are all critical contributors to the development and progression of alcoholic liver disease. This review summarizes recent findings of how alcohol-induced alterations of gut microbiota and metabolome, and discusses the mecha-nistic link between gastrointestinal dyshomeostasis and alcoholic liver injury.

Adipose tissue-liver axis in alcoholic liver disease

Alcoholic liver disease(ALD) remains an important health problem worldwide. The disease spectrum is featured by early steatosis, steatohepatitis(steatosis with inflammatory cells infiltration and necrosis), with some individuals ultimately progressing to fibrosis/cirrhosis. Although the disease progression is well characterized, no effective therapies are currently available for the treatment in humans. The mechanisms underlying the initiation and progression of ALD are multifactorial and complex. Emerging evidence supports that adipose tissue dysfunction contributes to the pathogenesis of ALD. In the first part of this review, we discuss the mechanisms whereby chronic alcohol exposure contributed to adipose tissue dysfunction, including cell death, inflammation and insulin resistance. It has been long known that aberrant hepatic methionine metabolism is a major metabolic abnormality induced by chronic alcohol exposure and plays an etiological role in the pathogenesis of ALD. The recent studies in our group documented the similar metabolic effect of chronic alcohol drinking on methionine in adipose tissue. In the second part of this review, we also briefly discuss the recent research progress in the field with a focus on how abnormal methionine metabolism in adipose tissue contributes to adipose tissue dysfunction and liver damage.

Targeting the gut barrier for the treatment of alcoholic liver disease

Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide.Intriguingly,dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease(ALD).A functional gut barrier,which consists of a mucus layer,an intact epithelial monolayer and mucosal immune cells,supports nutrient absorption and prevents bacterial penetration.Compromised gut barrier function is associated with the progression of ALD.Indeed,alcohol consumption disrupts the gut barrier,increases gut permeability,and induces bacterial translocation both in ALD patients and in experimental models with ALD.Moreover,alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations.Here,we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD.Unfortunately,there is no effectual Food and Drug Administration-approved treatment for any stage of ALD.Therefore,we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD.The principle behind antibiotics,prebiotics,probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function.Nutrientbased treatments,such as dietary supplementation with zinc,niacin or fatty acids,have been shown to regulate tight junction expression,reduce intestinal inflammation,and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings.Interestingly,saturated fatty acids may also directly control the gut microbiome.In summary,clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD.

Metabolomics in human type 2 diabetes research

The high prevalence of diabetes and diabetic complications has caused a huge burden on the modern society.Although scientific advances have led to effective strategies for preventing and treating diabetes over the past several decades,little progress has been made toward curing the disease or even getting it under control,from a public health and overall societal standpoint.There is still a lack of reliable biomarkers indicative of metabolic alterations associated with diabetes and different drug responses,highlighting the need for the development of early diagnostic and prognostic markers for diabetes and diabetic complications.The emergence of metabolomics has allowed researchers to systemically measure the small molecule metabolites,which are sensitive to the changes of both environmental and genetic factors and therefore,could be regarded as the link between genotypes and phenotypes.During the last decade,the progression made in metabolomics has provided insightful information on disease development and disease onset prediction.Recent studies using metabolomics approach coupled with statistical tools to predict incident diabetes revealed a number of metabolites that are significantly altered,including branched-chain and aromatic amino acids,such as isoleucine,leucine,valine,tyrosine and phenylalanine,as diagnostic or highly-significant predictors of future diabetes.This review summarizes the current findings of metabolomic studies in human investigations with the most common form of diabetes,type 2 diabetes.

Insulin resistance and the metabolism of branched-chain amino acids

Insulin resistance(IR)is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders.IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network.Branched-chain amino acids(BCAAs),namely valine,leucine and isoleucine,are among the nine essential amino acids,accounting for 35%of the essential amino acids in muscle proteins and 40%of the preformed amino acids required by mammals.The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency.Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight,it is only recently that BCAAs are found to be closely associated with IR.This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.