Dysbiosis‐induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice
Open accessAbstract
Intestinal barrier dysfunction is an important contributor to alcoholic liver disease (ALD). Translocated microbial products trigger an inflammatory response in the liver and contribute to steatohepatitis. Our aim was to investigate mechanisms of barrier disruption after chronic alcohol feeding. A Lieber‐DeCarli model was used to induce intestinal dysbiosis, increased intestinal permeability, and liver disease in mice. Alcohol feeding for 8 weeks induced intestinal inflammation in the jejunum, which is characterized by an increased number of tumor necrosis factor alpha (TNF‐α)‐producing monocytes and macrophages. These findings were confirmed in duodenal biopsies from patients with chronic alcohol abuse. Intestinal decontamination with nonabsorbable antibiotics restored eubiosis, decreased intestinal inflammation and permeability, and reduced ALD in mice. TNF‐receptor I (TNFRI) mutant mice were protected from intestinal barrier dysfunction and ALD. To investigate whether TNFRI on intestinal epithelial cells mediates intestinal barrier dysfunction and ALD, we used TNFRI mutant mice carrying a conditional gain‐of‐function allele for this receptor. Reactivation of TNFRI on intestinal epithelial cells resulted in increased intestinal permeability and liver disease that is similar to wild‐type mice after alcohol feeding, suggesting that enteric TNFRI promotes intestinal barrier dysfunction. Myosin light‐chain kinase (MLCK) is a downstream target of TNF‐α and was phosphorylated in intestinal epithelial cells after alcohol administration. Using MLCK‐deficient mice, we further demonstrate a partial contribution of MLCK to intestinal barrier dysfunction and liver disease after chronic alcohol feeding.Conclusion: Dysbiosis‐induced intestinal inflammation and TNFRI signaling in intestinal epithelial cells mediate a disruption of the intestinal barrier. Therefore, intestinal TNFRI is a crucial mediator of ALD. (H epatology 2015;61:883–894)
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Murine data show that nonabsorbable antibiotics and norfloxacin improve alcoholic liver disease and insulin resistance in NAFLD.
“As data from murine studies show that non-absorbable antibiotics and norfloxacin improve ALD48,116 and insulin resistance in NAFLD117, they might be particularly attractive for HCC prevention in these patient groups.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [116]
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- Authors
- Chen, P., Stärkel, P., Turner, J. R., Ho, S. B., & Schnabl, B.
- Affiliations
- University of California San Diego (US)
- UCLouvain (BE)
- University of Chicago (US)
- Corresponding author
- Schnabl, Bernd
- Venue
- Hepatology
- Published
- 2015-01-30
- Volume
- 61
- Issue
- 3
- Pages
- 883-894
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4340725
- OpenAlex
- W1969579498
- Cited by
- 312
- References
- 39
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 29 · 2023: 25 · 2022: 34 · 2021: 27 · 2020: 30 · 2019: 31 · 2018: 28 · 2017: 24 · 2016: 22 · 2015: 19 · 2014: 2
- FWCI
- 16.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Libraries (submittedVersion)
- Funders
- National Institutes of Health (DK081830, AA020703)
- ABMRF/The Foundation for Alcohol Research (research grant)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- alcoholic liver disease, gut dysbiosis, intestinal barrier dysfunction, intestinal permeability, TNF-α, intestinal inflammation, myosin light chain kinase, non-absorbable antibiotics, intestinal epithelial cells, steatohepatitis, chronic alcohol feeding
- MeSH terms
- Animals, Enteritis, Intestinal Mucosa, Jejunal Diseases, Liver Diseases, Alcoholic, Mice, Inbred C57BL, Myosin-Light-Chain Kinase, Permeability, Tumor Necrosis Factor-alpha, Receptors, Tumor Necrosis Factor, Type I, Mice, Dysbiosis
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