Sonja Lang1, Yi Duan1,2, Jinyuan Liu3, Manolito G Torralba4, Claire Kuelbs4, Meritxell Ventura-Cots5, Juan G Abraldes6, Francisco Bosques-Padilla7, Elizabeth C Verna8, Robert S Brown9, Victor Vargas10,11, Jose Altamirano10, Juan Caballería11,12, Debbie Shawcross13, Michael R Lucey14, Alexandre Louvet15, Philippe Mathurin15, Guadalupe Garcia-Tsao16,17, Samuel B Ho1,2, Xin M Tu3, Ramon Bataller5, Peter Stärkel18, Derrick E Fouts19, Bernd Schnabl1,2. 1. Department of Medicine, University of California San Diego, La Jolla, CA. 2. Department of Medicine, VA San Diego Healthcare System, San Diego, CA. 3. Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA. 4. J. Craig Venter Institute, La Jolla, CA. 5. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA. 6. Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Canada. 7. Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, México. 8. Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, New York, NY. 9. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY. 10. Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 11. Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain. 12. Liver Unit, Hospital Clinic, Barcelona, Spain. 13. Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, London, United Kingdom. 14. Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, School of Medicine and Public Health, WI. 15. Service des Maladies de L'appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France. 16. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT. 17. Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT. 18. St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. 19. J. Craig Venter Institute, Rockville, MD.
Abstract
Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.
Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion:Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.
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