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Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice
  1. Tim Hendrikx1,
  2. Yi Duan1,2,
  3. Yanhan Wang1,2,
  4. Jee-Hwan Oh3,
  5. Laura M Alexander3,
  6. Wendy Huang4,
  7. Peter Stärkel5,
  8. Samuel B Ho1,2,
  9. Bei Gao6,
  10. Oliver Fiehn6,
  11. Patrick Emond7,8,
  12. Harry Sokol9,10,11,
  13. Jan-Peter van Pijkeren3,
  14. Bernd Schnabl1,2
  1. 1 Department of Medicine, University of California San Diego, La Jolla, California, USA
  2. 2 Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
  3. 3 Department of Food Science, University of Wisconsin-Madison, Madison, Wisconsin, USA
  4. 4 Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA
  5. 5 Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
  6. 6 West Coast Metabolomics Center, University of California, Davis, California, USA
  7. 7 UMR 1253, iBrain, Université de Tours, Inserm, France
  8. 8 CHRU de Tours, Service de Médecine Nucléaire In Vitro, Tours, France
  9. 9 École normale supérieure, CNRS, INSERM, APHP Laboratoire des Biomolécules (LBM), Sorbonne Universités, UPMC Univ. Paris 06, Paris, France
  10. 10 Micalis Institute, Institut National de la Recherche Agronomique (INRA), AgroParisTech, Université Paris–Saclay, Jouy-en-Josas, France
  11. 11 Department of Gastroenterology, Saint Antoine Hospital, Assistance Publique – Hopitaux de Paris, Paris, France
  1. Correspondence to Professor Bernd Schnabl, Department of Medicine, University of California San Diego, La Jolla CA 92093, USA; beschnabl{at}


Objective Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease.

Design Interleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model).

Results In a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g–/– mice.

Conclusion Ethanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.

  • ILC
  • microbiome
  • metabolome
  • immune response

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  • Contributors TH designed and performed the experiments, analysed and interpreted the data and wrote the manuscript; YD and YW provided technical support and critically revised the manuscript. J-HO, LMA, PS, SBH, BG, OF, HS and J-PvP provided technical and material support and critically revised the manuscript. BS conceived, designed and supervised the study, wrote and critically revised the manuscript.

  • Funding This work was supported by an Erwin Schrodinger Fellowship (J4063-B30) from the Austrian Science Fund (to TH), by NIH grants R01 AA020703, R01 AA24726, U01 AA021856 and U01 AA026939 (to BS), R01 GM124494 (to WH) and by Award Number I01BX002213 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to BS). HS received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (ERC-2016-StG-71577). J-PvP was supported by Award Number 233PRJ75PW from the UW-Madison Food Research Institute and by funds from the UW-Madison Institute of Clinical and Translational Research funded by the National Center for Advancing Translational Science award UL1TR000427.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of the University of California, San Diego. For human samples, the protocol was approved by the Ethics Committee of each participating center and patients were enrolled after written informed consent was obtained from each patient.

  • Provenance and peer review Not commissioned; externally peer reviewed.