Intestinal fungi contribute to development of alcoholic liver disease

An-Ming Yang, Tatsuo Inamine, Katrin Hochrath, Peng Chen, Lirui Wang, Cristina Llorente, Sena Bluemel, Phillipp Hartmann, Jun Xu, Yukinori Koyama, Tatiana Kisseleva, Manolito G. Torralba, Kelvin Moncera, Karen Beeri, Chien-Sheng Chen, Kim Freese, Claus Hellerbrand, Serene M.L. Lee, Hal M. Hoffman, Wajahat Z. Mehal & 9 others Guadalupe Garcia-Tsao, Ece A. Mutlu, Ali Keshavarzian, Gordon D. Brown, Samuel B Ho, Ramon Bataller, Peter Stärkel, Derrick E. Fouts, Bernd Schnabl

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Abstract

Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin–like receptor CLEC7A on Kupffer cells and possibly other bone marrow–derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non–alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.
Original languageEnglish
Pages (from-to)2829-2841
Number of pages13
JournalThe Journal of Clinical Investigation
Volume127
Issue number7
Early online date22 May 2017
DOIs
Publication statusPublished - 1 Jul 2017

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Alcoholic Liver Diseases
Glucans
Liver Diseases
Fungi
Fibrosis
Alcohols
Alcohol Drinking
Ethanol
Dysbiosis
Alcoholic Liver Cirrhosis
Kupffer Cells
Antifungal Agents
Interleukin-1
Candida
Cause of Death
Hepatocytes
Chronic Disease
Bone Marrow
Inflammation
Bone and Bones

Cite this

Yang, A-M., Inamine, T., Hochrath, K., Chen, P., Wang, L., Llorente, C., ... Schnabl, B. (2017). Intestinal fungi contribute to development of alcoholic liver disease. The Journal of Clinical Investigation, 127(7), 2829-2841. https://doi.org/10.1172/JCI90562

Intestinal fungi contribute to development of alcoholic liver disease. / Yang, An-Ming; Inamine, Tatsuo ; Hochrath, Katrin ; Chen, Peng; Wang, Lirui ; Llorente, Cristina; Bluemel, Sena ; Hartmann, Phillipp ; Xu, Jun; Koyama, Yukinori ; Kisseleva, Tatiana ; Torralba, Manolito G. ; Moncera, Kelvin ; Beeri, Karen ; Chen, Chien-Sheng ; Freese, Kim ; Hellerbrand, Claus ; Lee, Serene M.L. ; Hoffman, Hal M. ; Mehal, Wajahat Z. ; Garcia-Tsao, Guadalupe ; Mutlu, Ece A.; Keshavarzian, Ali ; Brown, Gordon D.; Ho, Samuel B; Bataller, Ramon ; Stärkel, Peter ; Fouts, Derrick E. ; Schnabl, Bernd .

In: The Journal of Clinical Investigation, Vol. 127, No. 7, 01.07.2017, p. 2829-2841.

Research output: Contribution to journalArticle

Yang, A-M, Inamine, T, Hochrath, K, Chen, P, Wang, L, Llorente, C, Bluemel, S, Hartmann, P, Xu, J, Koyama, Y, Kisseleva, T, Torralba, MG, Moncera, K, Beeri, K, Chen, C-S, Freese, K, Hellerbrand, C, Lee, SML, Hoffman, HM, Mehal, WZ, Garcia-Tsao, G, Mutlu, EA, Keshavarzian, A, Brown, GD, Ho, SB, Bataller, R, Stärkel, P, Fouts, DE & Schnabl, B 2017, 'Intestinal fungi contribute to development of alcoholic liver disease', The Journal of Clinical Investigation, vol. 127, no. 7, pp. 2829-2841. https://doi.org/10.1172/JCI90562
Yang A-M, Inamine T, Hochrath K, Chen P, Wang L, Llorente C et al. Intestinal fungi contribute to development of alcoholic liver disease. The Journal of Clinical Investigation. 2017 Jul 1;127(7):2829-2841. https://doi.org/10.1172/JCI90562
Yang, An-Ming ; Inamine, Tatsuo ; Hochrath, Katrin ; Chen, Peng ; Wang, Lirui ; Llorente, Cristina ; Bluemel, Sena ; Hartmann, Phillipp ; Xu, Jun ; Koyama, Yukinori ; Kisseleva, Tatiana ; Torralba, Manolito G. ; Moncera, Kelvin ; Beeri, Karen ; Chen, Chien-Sheng ; Freese, Kim ; Hellerbrand, Claus ; Lee, Serene M.L. ; Hoffman, Hal M. ; Mehal, Wajahat Z. ; Garcia-Tsao, Guadalupe ; Mutlu, Ece A. ; Keshavarzian, Ali ; Brown, Gordon D. ; Ho, Samuel B ; Bataller, Ramon ; Stärkel, Peter ; Fouts, Derrick E. ; Schnabl, Bernd . / Intestinal fungi contribute to development of alcoholic liver disease. In: The Journal of Clinical Investigation. 2017 ; Vol. 127, No. 7. pp. 2829-2841.
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abstract = "Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin–like receptor CLEC7A on Kupffer cells and possibly other bone marrow–derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non–alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.",
author = "An-Ming Yang and Tatsuo Inamine and Katrin Hochrath and Peng Chen and Lirui Wang and Cristina Llorente and Sena Bluemel and Phillipp Hartmann and Jun Xu and Yukinori Koyama and Tatiana Kisseleva and Torralba, {Manolito G.} and Kelvin Moncera and Karen Beeri and Chien-Sheng Chen and Kim Freese and Claus Hellerbrand and Lee, {Serene M.L.} and Hoffman, {Hal M.} and Mehal, {Wajahat Z.} and Guadalupe Garcia-Tsao and Mutlu, {Ece A.} and Ali Keshavarzian and Brown, {Gordon D.} and Ho, {Samuel B} and Ramon Bataller and Peter St{\"a}rkel and Fouts, {Derrick E.} and Bernd Schnabl",
note = "This study was supported in part by NIH grants R01 AA020703, U01 AA021856 and by Award Number I01BX002213 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.). K.H. was supported by a DFG (Deutsche Forschungsgemeinschaft) fellowship (HO/ 5690/1-1). S.B. was supported by a grant from the Swiss National Science Foundation (P2SKP3_158649). G.G. received funding from the Yale Liver Center NIH P30 DK34989 and R.B. from NIAAA grant U01 AA021908. A.K. received support from NIH grants RC2 AA019405, R01 AA020216 and R01 AA023417. G.D.B. is supported by funds from the Wellcome Trust. We acknowledge the Human Tissue and Cell Research (HTCR) Foundation for making human tissue available for research and Hepacult GmbH (Munich, Germany) for providing primary human hepatocytes for in vitro analyses. We thank Dr. Chien-Yu Lin Department of Medicine, Fu-Jen Catholic University, Taiwan for statistical analysis.",
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T1 - Intestinal fungi contribute to development of alcoholic liver disease

AU - Yang, An-Ming

AU - Inamine, Tatsuo

AU - Hochrath, Katrin

AU - Chen, Peng

AU - Wang, Lirui

AU - Llorente, Cristina

AU - Bluemel, Sena

AU - Hartmann, Phillipp

AU - Xu, Jun

AU - Koyama, Yukinori

AU - Kisseleva, Tatiana

AU - Torralba, Manolito G.

AU - Moncera, Kelvin

AU - Beeri, Karen

AU - Chen, Chien-Sheng

AU - Freese, Kim

AU - Hellerbrand, Claus

AU - Lee, Serene M.L.

AU - Hoffman, Hal M.

AU - Mehal, Wajahat Z.

AU - Garcia-Tsao, Guadalupe

AU - Mutlu, Ece A.

AU - Keshavarzian, Ali

AU - Brown, Gordon D.

AU - Ho, Samuel B

AU - Bataller, Ramon

AU - Stärkel, Peter

AU - Fouts, Derrick E.

AU - Schnabl, Bernd

N1 - This study was supported in part by NIH grants R01 AA020703, U01 AA021856 and by Award Number I01BX002213 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.). K.H. was supported by a DFG (Deutsche Forschungsgemeinschaft) fellowship (HO/ 5690/1-1). S.B. was supported by a grant from the Swiss National Science Foundation (P2SKP3_158649). G.G. received funding from the Yale Liver Center NIH P30 DK34989 and R.B. from NIAAA grant U01 AA021908. A.K. received support from NIH grants RC2 AA019405, R01 AA020216 and R01 AA023417. G.D.B. is supported by funds from the Wellcome Trust. We acknowledge the Human Tissue and Cell Research (HTCR) Foundation for making human tissue available for research and Hepacult GmbH (Munich, Germany) for providing primary human hepatocytes for in vitro analyses. We thank Dr. Chien-Yu Lin Department of Medicine, Fu-Jen Catholic University, Taiwan for statistical analysis.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin–like receptor CLEC7A on Kupffer cells and possibly other bone marrow–derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non–alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.

AB - Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin–like receptor CLEC7A on Kupffer cells and possibly other bone marrow–derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non–alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.

U2 - 10.1172/JCI90562

DO - 10.1172/JCI90562

M3 - Article

VL - 127

SP - 2829

EP - 2841

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

SN - 0021-9738

IS - 7

ER -