Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic γδ T-Cell Receptor–Positive Cells and Pathogenesis of Cholestatic Liver Disease
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Background & aims Variants at the ABCB4 or MDR2 locus, which encodes a biliary transport protein, are associated with a spectrum of cholestatic liver diseases. Exacerbation of liver disease has been linked to increased hepatic levels of interleukin (IL) 17, yet the mechanisms of this increase are not understood. We studied mice with disruption of Mdr2 to determine how defects in liver and alteration in the microbiota contribute to production of IL17 by intrahepatic γδ T cells.Methods We performed studies with Mdr2-/- and littermate FVB/NJ (control) mice. IL17 was measured in serum samples by an enzyme-linked immunosorbent assay. Mice were injected with neutralizing antibodies against the γδ T-cell receptor (TCR; anti-γδ TCR) or mouse IL17A (anti-IL17A). Livers were collected and bacteria were identified in homogenates by culture procedures; TCRγδ+ cells were isolated by flow cytometry. Fecal samples were collected from mice and analyzed by 16S ribosomal DNA sequencing. Cells were stimulated with antibodies or bacteria, and cytokine production was measured. We obtained tissues from 10 patients undergoing liver transplantation for primary sclerosing cholangitis or chronic hepatitis C virus infection. Tissues were analyzed for cytokine production by γδ TCR+ cells.Results Mdr2-/- mice had collagen deposition around hepatic bile ducts and periportal-bridging fibrosis with influx of inflammatory cells and increased serum levels of IL17 compared with control mice. Administration of anti-IL17A reduced hepatic fibrosis. Livers from Mdr2-/- mice had increased numbers of IL17A+ γδTCR+ cells-particularly of IL17A+ Vγ6Jγ1 γδ TCR+ cells. Fecal samples from Mdr2-/- mice were enriched in Lactobacillus, and liver tissues were enriched in Lactobacillus gasseri compared with control mice. Mdr2-/- mice also had increased intestinal permeability. The γδ TCR+ cells isolated from Mdr2-/- livers produced IL17 in response to heat-killed L gasseri. Intraperitoneal injection of control mice with L gasseri led to increased serum levels of IL17 and liver infiltration by inflammatory cells; injection of these mice with anti-γδ TCR reduced serum level of IL17. Intravenous injections of Mdr2-/- mice with anti-γδ TCR reduced fibrosis; liver levels of IL17, and inflammatory cells; and serum levels of IL17. γδTCR+ cells isolated from livers of patients with primary sclerosing cholangitis, but not hepatitis C virus infection, produced IL17.Conclusions In Mdr2-/- mice, we found development of liver fibrosis and inflammation to require hepatic activation of γδ TCR+ cells and production of IL17 mediated by exposure to L gasseri. This pathway appears to contribute to development of cholestatic liver disease in patients.
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Our results are in line with those found in other models of cholestatic disease like the genetically modified Mdr2−/− mice, which show certain similarities in bacterial composition to mice undergoing BDL, including enrichment of Lactobacillus, Prevotella and Clostridiaceae.
“Interestingly, our results are in line with those found in other models of cholestatic disease like the genetically modified Mdr2−/− mice27, which show certain similarities in bacterial composition to mice undergoing BDL, including enrichment of Lactobacillus, Prevotella and Clostridiaceae as we show in the present study.”
From Cholestasis induced by bile duct ligation promotes changes in the intestinal microbiome in mice (2019) · cites this paper as [27]
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- Authors
- Tedesco, D., Thapa, M., Chin, C. Y., Ge, Y., Gong, M., Li, J., Gumber, S., Speck, P., Elrod, E. J., Burd, E. M., Kitchens, W. H., Magliocca, J. F., Adams, A. B., Weiss, D. S., Mohamadzadeh, M., & Grakoui, A.
- Affiliations
- Emory University (US)
- University of Florida (US)
- Corresponding author
- Grakoui, Arash
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 154
- Issue
- 8
- Pages
- 2178-2193
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC5985208
- OpenAlex
- W2788255593
- Cited by
- 137
- References
- 53
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 21 · 2023: 17 · 2022: 19 · 2021: 14 · 2020: 18 · 2019: 17 · 2018: 5
- FWCI
- 8.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Gastroenterology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (ORIP/OD P51OD011132, P51RR000165, R01AI070101, R01AI124680, R01AI126890, R01AI136533)
- Yerkes National Primate Research Center, Emory University
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- gut microbiota, IL-17, γδ T cells, MDR2, cholestatic liver disease, primary sclerosing cholangitis, chronic hepatitis C, Lactobacillus gasseri, intestinal permeability, liver fibrosis, ABCB4
- MeSH terms
- Gastrointestinal Microbiome, Lactobacillus gasseri, Intraepithelial Lymphocytes, ATP-Binding Cassette Sub-Family B Member 4, Adult, Aged, Animals, Bile Ducts, Cells, Cultured, Cholestasis, Disease Models, Animal, Female, Humans, Liver, Liver Cirrhosis, Male, Middle Aged, Cholangitis, Sclerosing, Liver Transplantation, Receptors, Antigen, T-Cell, gamma-delta, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Hepatitis C, Chronic, Interleukin-17, Mice, Young Adult, End Stage Liver Disease
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