Protection Against Fibrosis by a Bacterial Consortium in Metabolic Dysfunction-Associated Steatohepatitis and the Role of Amino Acid Metabolism

Authors

Suet-Ying Kwan
Kristyn A Gonzales
Mohamed A Jamal
Heather L Stevenson
Lin Tan
Philip L Lorenzi
P Andrew Futreal
Ernest T Hawk
Joseph B McCormick
Susan P Fisher-Hoch
Robert R Jenq
Laura Beretta

Publication Date

1-1-2024

Journal

Gut Microbes

Abstract

The gut microbiota drives progression to liver fibrosis, the main determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH). In this study, we aimed to identify bacterial species associated with protection against liver fibrosis in a high-risk population, and test their potential to protect against liver fibrosis in vivo. Based on stool shotgun metagenomic sequencing of 340 subjects from a population cohort disproportionally affected by MASH, we identified bacterial species from the Bacteroidales and Clostridiales orders associated with reduced risk of liver fibrosis. A bacterial consortium was subsequently tested in a mouse model of MASH, which demonstrated protective effects against liver fibrosis. Six of the eight inoculated bacteria were detected in mouse stool and liver. Intrahepatic presence of bacteria was further confirmed by bacterial culture of mouse liver tissue. Changes in liver histological parameters, gut functional profiles, and amino acid profiles were additionally assessed. Comparison between fibrosis-associated human metagenome and bacteria-induced metagenome changes in mice identified microbial functions likely to mediate the protective effect against liver fibrosis. Amino acid profiling confirmed an increase in cysteine synthase activity, associated with reduced fibrosis. Other microbiota-induced changes in amino acids associated with reduced fibrosis included increased gut asparaginase activity and decreased hepatic tryptophan-to-kynurenine conversion. This human-to-mouse study identified bacterial species and their effects on amino acid metabolism as innovative strategies to protect against liver fibrosis in MASH.

Keywords

Animals, Gastrointestinal Microbiome, Humans, Liver Cirrhosis, Mice, Amino Acids, Bacteria, Male, Liver, Female, Feces, Mice, Inbred C57BL, Middle Aged, Fatty Liver, Disease Models, Animal, Metagenome, Adult

DOI

10.1080/19490976.2024.2399260

PMID

39239875

PMCID

PMC11382720

PubMedCentral® Posted Date

9-6-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes