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Cell Host Microbe, Available online 30 August 2023 | https://doi.org/10.1016/j.chom.2023.08.002 Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization

Kyung Ku Jang ¹, Thomas Heaney ¹, Mariya London¹, Yi Ding², Gregory Putzel^1,3, Frank Yeung ¹, Defne Ercelen ¹, Ying-Han Chen¹, Jordan Axelrad ⁴, Sakteesh Gurunathan ⁴, Chaoting Zhou^5,6, Magdalena Podkowik ^3,7, Natalia Arguelles ^1,3, Anusha Srivastava ^1,3, Bo Shopsin ^1,3,7, Victor J. Torres ^1,3, A. Marijke Keestra-Gounder ⁸, Alejandro Pironti ^1,3, Matthew E. Griffin ^9,13, Howard C. Hang ^9,10, Ken Cadwell ^6,11,12,14

¹Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
²Department of Laboratory Medicine, Geisinger Health, Danville, PA 17822, USA
³Antimicrobial-Resistant Pathogens Program, New York University Grossman School of Medicine, New York, NY 10016, USA
⁴Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
⁵Cell and Molecular Biology Graduate Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
⁶Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
⁷Division of Infectious Diseases and Immunology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
⁸Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
⁹Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
¹⁰Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
¹¹Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
¹²Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
¹³Present address: Department of Chemistry, University of California, Irvine, Irvine, CA 92617, USA
¹⁴Lead contact

Corresponding author : Ken Cadwell

Abstract

Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1β (IL-1β) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.

논문정보

형식Research article
게재일2023년 08월 (BRIC 등록일 2023-08-31)
연구진국외 연구진
분야 생명과학 > 면역학

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