Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease

Abstract

Abstract Background: Due to the global increase in alcoholic liver disease (ALD) rates, interest in gut-derived bacterial products is growing in targeted therapies. Identifying microbiome-derived metabolite signatures is challenging due to the complex patterns that have long-term effects on the development of ALD. We evaluated a feature of the gut-microbiota-derived metabolite signatures in patients with ALD. Methods: A prospective cohort study was carried out between April 2017 and March 2022. Stool samples (healthy control [HC, n = 62], alcoholic fatty liver [AFL, n = 25], alcoholic hepatitis [AH, n = 80], and alcoholic cirrhosis [AC, n = 80]) were collected for the microbiota analysis by 16S rRNA sequencing and metabolite profiles by using GC-MS and LC-MS methods. Results: Proteobacteria relative abundance increased in ALD, while Bacteroides decreased (p = 0.001). Fusobacteria levels were found to be higher in AH (p = 0.0001). A total of 103 metabolites were quantified and screened. 3-Indole propionic acid levels are significantly lower in AH and AC (p = 0.001). Surprisingly, AC increases indole-3-lactic acid (p = 0.04). AC had significantly lower levels of short-chain fatty acids (SCFAs) and bile acids (BAs). The levels of stercobilin, hexadecanedioic acid, and 3-methyladipic acid were significantly decreased in ALD. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely related to ALD metabolism. Conclusions: Short-chain fatty acids, bile acids, and indole metabolites were depleted according to the ALD progression. Microbial dysbiosis is associated with a shift in metabolite changes in ALD. Clinicaltrials.gov, number NCT04339725.