TY - JOUR
T1 - Development of Alcohol-Associated Hepatitis Is Associated With Specific Changes in Gut-Modified Bile Acids
AU - Muthiah, Mark D.
AU - Smirnova, Ekaterina
AU - Puri, Puneet
AU - Chalasani, Naga
AU - Shah, Vijay H.
AU - Kiani, Calvin
AU - Taylor, Stephanie
AU - Mirshahi, Faridoddin
AU - Sanyal, Arun J.
N1 - Funding Information:
Supported by the National Institutes of Health (NIH) (grants UO1 AA021891‐01 and T32 DK07150‐40 to A.J.S.), NIH through Virginia Commonwealth University (VCU) BERD Core (Clinical and Translational Science Award [CTSA] UL1TR002649 to E.S.), National Center for Advancing Translational Sciences through VCU Institutional Career Development Core (CTSA 5KL2TR002648 to E.S.), National Medical Research Council Singapore (Research Training Fellowship MOH‐000193 to M.D.M.), and National Institute on Alcohol Abuse and Alcoholism (UO1 grant to A.J.S.).
Funding Information:
Potential conflict of interest: Dr. Mirshahi owns stock in Sanyal Biotechnology. Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Tiziana, Durect, Indalo, and Inversago. He has served as a consultant to Medimmune, Astra Zeneca, Nitto Denko, Nimbus, Salix, Tobira, Takeda, Terns, Conatus, Lilly, Poxel, Blade, Surrozen, Birdrock, Siemens, Madrigal, Novartis, Pfizer, Hemoshear, Novo Nordisk, Gilead, Exhalenz, Bristol Myers Squibb, Glympse, and Genfit. He has been an unpaid consultant to Intercept, Zafgen, Prosciento, Iquvia, NGM Bio, Echosens, Immuron, Syntlogic, Zafgen, Zydus, and Nordic Bioscience. His institution has received grant support from Gilead, Salix, Tobira, Intercept, Merck, Astra Zeneca, Zydus, and Novartis. Dr. Chalasani has ongoing paid consulting activities (or had in the preceding 12 months) with Abbvie, Madrigal, Foresite labs, Altimmune, Zydus, Galectin, and Boehringer‐Ingelheim. Dr. Chalasani receives research grant support from Exact Sciences and DSM where his institution receives the funding. Dr. Chalasani has equity ownership in RestUp, Inc. The other authors have nothing to report.
Publisher Copyright:
© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
PY - 2022/5
Y1 - 2022/5
N2 - The perturbations in bile acids (BAs) in alcohol-associated hepatitis (AH) and its relationship to disease severity is not well defined. The aims of this study were to define (1) the effects of heavy alcohol consumption on BAs and related microbiome, (2) the additional changes with AH, and (3) the relationship of these changes to disease severity. In this multicenter study, plasma and fecal BAs and related microbiome were interrogated in healthy individuals, heavy drinking controls (HDCs) without overt liver disease, and AH. Compared to healthy controls, HDCs had increased glycine-conjugated 7α and 27α primary BAs and increased secondary BA glycocholenic sulfate (multiple-comparison adjusted P < 0.05 for all). Plasma-conjugated cholic and chenodeoxycholic acid increased in AH along with the secondary BAs ursodeoxycholic and lithocholic acid (P < 0.001 for all), whereas deoxycholic acid decreased; however fecal concentrations of both deoxycholic acid and lithocholic acid were decreased. Glycocholenic acid further increased significantly from HDCs to AH. HDCs and AH had distinct plasma and fecal BA profiles (area under the curve, 0.99 and 0.93, respectively). Plasma taurochenodeoxycholic acid and tauroursodeoxycholic acid were directly related to disease severity, whereas fecal ursodeoxycholic acid was inversely related. The fecal abundance of multiple taxa involved in formation of secondary BAs, especially deoxycholic acid (Clostridium cluster XIVa) was decreased in AH. Multiple genera containing taxa expressing 3α, 3β, 7α, and 7β epimerases were decreased with concordant changes in fecal BAs that required these functions for formation. Conclusion: There are distinct changes in BA-transforming microbiota and corresponding BAs in AH that are related to disease severity.
AB - The perturbations in bile acids (BAs) in alcohol-associated hepatitis (AH) and its relationship to disease severity is not well defined. The aims of this study were to define (1) the effects of heavy alcohol consumption on BAs and related microbiome, (2) the additional changes with AH, and (3) the relationship of these changes to disease severity. In this multicenter study, plasma and fecal BAs and related microbiome were interrogated in healthy individuals, heavy drinking controls (HDCs) without overt liver disease, and AH. Compared to healthy controls, HDCs had increased glycine-conjugated 7α and 27α primary BAs and increased secondary BA glycocholenic sulfate (multiple-comparison adjusted P < 0.05 for all). Plasma-conjugated cholic and chenodeoxycholic acid increased in AH along with the secondary BAs ursodeoxycholic and lithocholic acid (P < 0.001 for all), whereas deoxycholic acid decreased; however fecal concentrations of both deoxycholic acid and lithocholic acid were decreased. Glycocholenic acid further increased significantly from HDCs to AH. HDCs and AH had distinct plasma and fecal BA profiles (area under the curve, 0.99 and 0.93, respectively). Plasma taurochenodeoxycholic acid and tauroursodeoxycholic acid were directly related to disease severity, whereas fecal ursodeoxycholic acid was inversely related. The fecal abundance of multiple taxa involved in formation of secondary BAs, especially deoxycholic acid (Clostridium cluster XIVa) was decreased in AH. Multiple genera containing taxa expressing 3α, 3β, 7α, and 7β epimerases were decreased with concordant changes in fecal BAs that required these functions for formation. Conclusion: There are distinct changes in BA-transforming microbiota and corresponding BAs in AH that are related to disease severity.
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U2 - 10.1002/hep4.1885
DO - 10.1002/hep4.1885
M3 - Article
C2 - 34984859
AN - SCOPUS:85122284394
VL - 6
SP - 1073
EP - 1089
JO - Hepatology Communications
JF - Hepatology Communications
SN - 2471-254X
IS - 5
ER -