Functional Microbiomics Reveals Alterations of the Gut Microbiome and Host Co‐Metabolism in Patients With Alcoholic Hepatitis

Abstract

Alcohol-related liver disease is a major public health burden, and the gut microbiota is an important contributor to disease pathogenesis. The aim of the present study is to characterize functional alterations of the gut microbiota and test their performance for short-term mortality prediction in patients with alcoholic hepatitis. We integrated shotgun metagenomics with untargeted metabolomics to investigate functional alterations of the gut microbiota and host cometabolism in a multicenter cohort of patients with alcoholic hepatitis. Profound changes were found in the gut microbial composition, functional metagenome, serum, and fecal metabolomes in patients with alcoholic hepatitis compared with nonalcoholic controls. We demonstrate that in comparison with single omics alone, the performance to predict 30-day mortality was improved when combining microbial pathways with respective serum metabolites in patients with alcoholic hepatitis. The area under the receiver operating curve was higher than 0.85 for the tryptophan, isoleucine, and methionine pathways as predictors for 30-day mortality, but achieved 0.989 for using the urea cycle pathway in combination with serum urea, with a bias-corrected prediction error of 0.083 when using leave-one-out cross validation. Conclusion: Our study reveals changes in key microbial metabolic pathways associated with disease severity that predict short-term mortality in our cohort of patients with alcoholic hepatitis. (Hepatology Communications 2020;4:1168-1182). A lcohol-related liver disease is a major health care burden and a leading cause of morbidity and mortality worldwide. (1) The individual susceptibility of patients with alcohol use disorder to liver disease is highly variable. Some patients develop alcoholic hepatitis, a severe manifestation of alcoholrelated liver disease with a short-term mortality of about 40%-50% (2) Pharmacologic treatment options Abbreviations: AUC, area under the curve; AUROC, area under the receiver operating characteristic curve; AH_c, patients with alcoholic hepatitis with cirrhosis; AUD_nc, patients with alcohol use disorder without cirrhosis; AUD_c, patients with alcohol use disorder with cirrhosis; Ctrl, control; FIB-4, Fibrosis-4 index; G1, controls; G2, patients with alcohol use disorder without cirrhosis; G3, patients with alcohol use disorder with cirrhosis; G4, patients with alcoholic hepatitis without cirrhosis; G5, patients with alcoholic hepatitis with cirrhosis;

From intestinal dysbiosis to alcohol-associated liver disease

“…61 Metabolomic analysis revealed that fecal and serum levels of tryptophan were decreased in alcoholic hepatitis patients when compared with controls. 62 In line with the decrease of fecal levels of tryptophan-derived metabolites, indole-3-acetic acid, indole-3-propionic acid, and indole-3-lactic acid were also significantly reduced in alcoholic hepatitis patients. 22,62 The metabolic syndrome is associated with reduced capacity of the microbiota to metabolize tryptophan into derivatives that can activate AhR.…”

“…62 In line with the decrease of fecal levels of tryptophan-derived metabolites, indole-3-acetic acid, indole-3-propionic acid, and indole-3-lactic acid were also significantly reduced in alcoholic hepatitis patients. 22,62 The metabolic syndrome is associated with reduced capacity of the microbiota to metabolize tryptophan into derivatives that can activate AhR. Fecal samples of individuals with metabolic syndrome contain low levels of tryptophan-based metabolites and have reduced AhR activity.…”

CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease

“…Chronic alcohol consumption leads to intestinal microbial dysbiosis [12][13][14] , which contributes to the development and progression of alcohol-associated liver disease [15][16][17][18] . Gut dysbiosis induces gut barrier dysfunction and allows viable bacteria to translocate from the gut to the liver 19,20 .…”

The Role of Gut Bacteria and Fungi in Alcohol-Associated Liver Disease

“…Aromatic amino acids are important factors to maintain the homeostasis of intestinal flora, among which tryptophan is fully studied in ALD. Tryptophan and tryptophan-derived metabolites are reduced in the fecal and serum of alcoholic hepatitis patients with cirrhosis when compared with nonalcoholic controls, despite that the ability of microorganisms to synthesize tryptophan has improved ( 72 ). In ALD animal experiment, Lactobacillus rhamnosus GG derived exosome enriched with bacterial metabolites of tryptophan can improve intestinal barrier function through AhR signaling that promotes IL22 production by intestinal immune cells ( 73 ).…”