TY - JOUR
T1 - Longitudinal multi-omics analyses of the gut–liver axis reveals metabolic dysregulation in hepatitis C infection and cirrhosis
AU - Ali, Rabab O.
AU - Quinn, Gabriella M.
AU - Umarova, Regina
AU - Haddad, James A.
AU - Zhang, Grace Y.
AU - Townsend, Elizabeth C.
AU - Scheuing, Lisa
AU - Hill, Kareen L.
AU - Gewirtz, Meital
AU - Rampertaap, Shakuntala
AU - Rosenzweig, Sergio D.
AU - Remaley, Alan T.
AU - Han, Jung Min
AU - Periwal, Vipul
AU - Cai, Hongyi
AU - Walter, Peter J.
AU - Koh, Christopher
AU - Levy, Elliot B.
AU - Kleiner, David E.
AU - Etzion, Ohad
AU - Heller, Theo
N1 - Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut–liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been associated with an altered gut microbiome; however, how these changes impact metabolism across the gut–liver axis and how this varies with disease severity and time is unclear. Here we used multi-omics analysis of portal and peripheral blood, faeces and liver tissue to characterize the gut–liver axis of patients with HCV across a fibrosis severity gradient before (n = 29) and 6 months after (n = 23) sustained virologic response, that is, no detection of the virus. Fatty acids were the major metabolites perturbed across the liver, portal vein and gut microbiome in HCV, especially in patients with cirrhosis. Decreased fatty acid degradation by hepatic peroxisomes and mitochondria was coupled with increased free fatty acid (FFA) influx to the liver via the portal vein. Metatranscriptomics indicated that Anaerostipes hadrus-mediated fatty acid synthesis influences portal FFAs. Both microbial fatty acid synthesis and portal FFAs were associated with enhanced hepatic fibrosis. Bacteroides vulgatus-mediated intestinal glycan breakdown was linked to portal glycan products, which in turn correlated with enhanced portal inflammation in HCV. Paired comparison of patient samples at both timepoints showed that hepatic metabolism, especially in peroxisomes, is persistently dysregulated in cirrhosis independently of the virus. Sustained virologic response was associated with a potential beneficial role for Methanobrevibacter smithii, which correlated with liver disease severity markers. These results develop our understanding of the gut–liver axis in HCV and non-HCV liver disease aetiologies and provide a foundation for future therapies.
AB - The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut–liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been associated with an altered gut microbiome; however, how these changes impact metabolism across the gut–liver axis and how this varies with disease severity and time is unclear. Here we used multi-omics analysis of portal and peripheral blood, faeces and liver tissue to characterize the gut–liver axis of patients with HCV across a fibrosis severity gradient before (n = 29) and 6 months after (n = 23) sustained virologic response, that is, no detection of the virus. Fatty acids were the major metabolites perturbed across the liver, portal vein and gut microbiome in HCV, especially in patients with cirrhosis. Decreased fatty acid degradation by hepatic peroxisomes and mitochondria was coupled with increased free fatty acid (FFA) influx to the liver via the portal vein. Metatranscriptomics indicated that Anaerostipes hadrus-mediated fatty acid synthesis influences portal FFAs. Both microbial fatty acid synthesis and portal FFAs were associated with enhanced hepatic fibrosis. Bacteroides vulgatus-mediated intestinal glycan breakdown was linked to portal glycan products, which in turn correlated with enhanced portal inflammation in HCV. Paired comparison of patient samples at both timepoints showed that hepatic metabolism, especially in peroxisomes, is persistently dysregulated in cirrhosis independently of the virus. Sustained virologic response was associated with a potential beneficial role for Methanobrevibacter smithii, which correlated with liver disease severity markers. These results develop our understanding of the gut–liver axis in HCV and non-HCV liver disease aetiologies and provide a foundation for future therapies.
UR - http://www.scopus.com/inward/record.url?scp=85144091944&partnerID=8YFLogxK
U2 - 10.1038/s41564-022-01273-y
DO - 10.1038/s41564-022-01273-y
M3 - Article
C2 - 36522461
AN - SCOPUS:85144091944
SN - 2058-5276
VL - 8
SP - 12
EP - 27
JO - Nature Microbiology
JF - Nature Microbiology
IS - 1
ER -