Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice
Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested...
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.812882/full |
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| author | Jeffrey B. Warner Jeffrey B. Warner Ida S. Larsen Josiah E. Hardesty Ying L. Song Dennis R. Warner Craig J. McClain Craig J. McClain Craig J. McClain Craig J. McClain Craig J. McClain Rui Sun Zhongbin Deng Zhongbin Deng Zhongbin Deng Zhongbin Deng Benjamin A. H. Jensen Benjamin A. H. Jensen Irina A. Kirpich Irina A. Kirpich Irina A. Kirpich Irina A. Kirpich |
| author_facet | Jeffrey B. Warner Jeffrey B. Warner Ida S. Larsen Josiah E. Hardesty Ying L. Song Dennis R. Warner Craig J. McClain Craig J. McClain Craig J. McClain Craig J. McClain Craig J. McClain Rui Sun Zhongbin Deng Zhongbin Deng Zhongbin Deng Zhongbin Deng Benjamin A. H. Jensen Benjamin A. H. Jensen Irina A. Kirpich Irina A. Kirpich Irina A. Kirpich Irina A. Kirpich |
| author_sort | Jeffrey B. Warner |
| collection | DOAJ |
| description | Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD. Male C57Bl/6J mice were fed an ethanol (EtOH)-containing diet for 6 weeks with daily administration of hBD-2 (1.2 mg/kg) by oral gavage during the final week. Two independent cohorts of mice with distinct baseline gut microbiota were used. Oral hBD-2 administration attenuated liver injury in both cohorts as determined by decreased plasma ALT activity. Notably, the degree of hBD-2-mediated reduction of EtOH-associated liver steatosis, hepatocellular death, and inflammation was different between cohorts, suggesting microbiota-specific mechanisms underlying the beneficial effects of hBD-2. Indeed, we observed differential mechanisms of hBD-2 between cohorts, which included an induction of hepatic and small intestinal IL-17A and IL-22, as well as an increase in T regulatory cell abundance in the gut and mesenteric lymph nodes. Lastly, hBD-2 modulated the gut microbiota composition in EtOH-fed mice in both cohorts, with significant decreases in multiple genera including Barnesiella, Parabacteroides, Akkermansia, and Alistipes, as well as altered abundance of several bacteria within the family Ruminococcaceae. Collectively, our results demonstrated a protective effect of hBD-2 in experimental ALD associated with immunomodulation and microbiota alteration. These data suggest that while the beneficial effects of hBD-2 on liver injury are uniform, the specific mechanisms of action are associated with baseline microbiota. |
| first_indexed | 2024-12-20T11:11:48Z |
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| language | English |
| last_indexed | 2024-12-20T11:11:48Z |
| publishDate | 2022-01-01 |
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| series | Frontiers in Physiology |
| spelling | doaj.art-1ccda6c98f434d308c98fe4bfddef7ab2022-12-21T19:42:43ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-01-011210.3389/fphys.2021.812882812882Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in MiceJeffrey B. Warner0Jeffrey B. Warner1Ida S. Larsen2Josiah E. Hardesty3Ying L. Song4Dennis R. Warner5Craig J. McClain6Craig J. McClain7Craig J. McClain8Craig J. McClain9Craig J. McClain10Rui Sun11Zhongbin Deng12Zhongbin Deng13Zhongbin Deng14Zhongbin Deng15Benjamin A. H. Jensen16Benjamin A. H. Jensen17Irina A. Kirpich18Irina A. Kirpich19Irina A. Kirpich20Irina A. Kirpich21Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United StatesDepartment of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United StatesQuébec Heart and Lung Institute (IUCPQ), Faculty of Medicine, Laval University, Québec city, QC, CanadaDivision of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United StatesDivision of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United StatesDivision of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United StatesDivision of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United StatesDepartment of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United StatesUniversity of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, United StatesUniversity of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United StatesRobley Rex Veterans Medical Center, Louisville, KY, United StatesJames Graham Brown Cancer Center, University of Louisville, Louisville, KY, United StatesUniversity of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, United StatesUniversity of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United StatesJames Graham Brown Cancer Center, University of Louisville, Louisville, KY, United StatesDepartment of Surgery, University of Louisville, Louisville, KY, United StatesQuébec Heart and Lung Institute (IUCPQ), Faculty of Medicine, Laval University, Québec city, QC, CanadaDepartment of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDivision of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, United StatesDepartment of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, United StatesUniversity of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, United StatesUniversity of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, United StatesAlcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD. Male C57Bl/6J mice were fed an ethanol (EtOH)-containing diet for 6 weeks with daily administration of hBD-2 (1.2 mg/kg) by oral gavage during the final week. Two independent cohorts of mice with distinct baseline gut microbiota were used. Oral hBD-2 administration attenuated liver injury in both cohorts as determined by decreased plasma ALT activity. Notably, the degree of hBD-2-mediated reduction of EtOH-associated liver steatosis, hepatocellular death, and inflammation was different between cohorts, suggesting microbiota-specific mechanisms underlying the beneficial effects of hBD-2. Indeed, we observed differential mechanisms of hBD-2 between cohorts, which included an induction of hepatic and small intestinal IL-17A and IL-22, as well as an increase in T regulatory cell abundance in the gut and mesenteric lymph nodes. Lastly, hBD-2 modulated the gut microbiota composition in EtOH-fed mice in both cohorts, with significant decreases in multiple genera including Barnesiella, Parabacteroides, Akkermansia, and Alistipes, as well as altered abundance of several bacteria within the family Ruminococcaceae. Collectively, our results demonstrated a protective effect of hBD-2 in experimental ALD associated with immunomodulation and microbiota alteration. These data suggest that while the beneficial effects of hBD-2 on liver injury are uniform, the specific mechanisms of action are associated with baseline microbiota.https://www.frontiersin.org/articles/10.3389/fphys.2021.812882/fullalcoholdefensingut-liver axisintestineALDimmunomodulation |
| spellingShingle | Jeffrey B. Warner Jeffrey B. Warner Ida S. Larsen Josiah E. Hardesty Ying L. Song Dennis R. Warner Craig J. McClain Craig J. McClain Craig J. McClain Craig J. McClain Craig J. McClain Rui Sun Zhongbin Deng Zhongbin Deng Zhongbin Deng Zhongbin Deng Benjamin A. H. Jensen Benjamin A. H. Jensen Irina A. Kirpich Irina A. Kirpich Irina A. Kirpich Irina A. Kirpich Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice Frontiers in Physiology alcohol defensin gut-liver axis intestine ALD immunomodulation |
| title | Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice |
| title_full | Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice |
| title_fullStr | Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice |
| title_full_unstemmed | Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice |
| title_short | Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice |
| title_sort | human beta defensin 2 ameliorated alcohol associated liver disease in mice |
| topic | alcohol defensin gut-liver axis intestine ALD immunomodulation |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.812882/full |
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