Protection against fibrosis by a bacterial consortium in metabolic dysfunction-associated steatohepatitis and the role of amino acid metabolism
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
Affiliations
Suet-Ying Kwan
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Kristyn A. Gonzales
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Mohamed A. Jamal
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Heather L. Stevenson
Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
Lin Tan
Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Philip L. Lorenzi
Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
P. Andrew Futreal
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ernest T. Hawk
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Joseph B. McCormick
School of Public Health, University of Texas Health Science Center at Houston, Brownsville, TX, USA
Susan P. Fisher-Hoch
School of Public Health, University of Texas Health Science Center at Houston, Brownsville, TX, USA
Robert R. Jenq
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Laura Beretta
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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.
