Cited by 124Gut microbiota and healthGastrointestinal motility and disordersInflammatory Bowel Disease

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Gut microbial β-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome

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Edwinson, Adam L., Yang, Lu, Peters, Stephanie, Hanning, Nikita, Jeraldo, Patricio, Jagtap, Pratik, Simpson, Joshua B., Yang, Tzu-Yi, Kumar, Praveen, Mehta, Subina, Nair, Asha, Breen-Lyles, Margaret, Chikkamenahalli, Lakshmikanth, Graham, Rondell P., De Winter, Benedicte, Patel, Robin, Dasari, Surendra, Kashyap, Purna, Griffin, Timothy, Chen, Jun, Farrugia, Gianrico, Redinbo, Matthew R., Grover, Madhusudan·2022·Nature Microbiology

DOI 10.1038/s41564-022-01103-1PMC PMC9081267

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Abstract

Intestinal proteases mediate digestion and immune signalling, while increased gut proteolytic activity disrupts the intestinal barrier and generates visceral hypersensitivity, which is common in irritable bowel syndrome (IBS). However, the mechanisms controlling protease function are unclear. Here we show that members of the gut microbiota suppress intestinal proteolytic activity through production of unconjugated bilirubin. This occurs via microbial β-glucuronidase-mediated conversion of bilirubin conjugates. Metagenomic analysis of faecal samples from patients with post-infection IBS (n = 52) revealed an altered gut microbiota composition, in particular a reduction in Alistipes taxa, and high gut proteolytic activity driven by specific host serine proteases compared with controls. Germ-free mice showed 10-fold higher proteolytic activity compared with conventional mice. Colonization with microbiota samples from high proteolytic activity IBS patients failed to suppress proteolytic activity in germ-free mice, but suppression of proteolytic activity was achieved with colonization using microbiota from healthy donors. High proteolytic activity mice had higher intestinal permeability, a higher relative abundance of Bacteroides and a reduction in Alistipes taxa compared with low proteolytic activity mice. High proteolytic activity IBS patients had lower fecal β-glucuronidase activity and end-products of bilirubin deconjugation. Mice treated with unconjugated bilirubin and β-glucuronidase-overexpressing E. coli significantly reduced proteolytic activity, while inhibitors of microbial β-glucuronidases increased proteolytic activity. Together, these data define a disease-relevant mechanism of host-microbial interaction that maintains protease homoeostasis in the gut.

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Authors: Edwinson, A. L., Yang, L., Peters, S., Hanning, N., Jeraldo, P., Jagtap, P., Simpson, J. B., Yang, T.-Y., Kumar, P., Mehta, S., Nair, A., Breen-Lyles, M., Chikkamenahalli, L., Graham, R. P., De Winter, B., Patel, R., Dasari, S., Kashyap, P., Griffin, T., Chen, J., Farrugia, G., Redinbo, M. R., & Grover, M.
Affiliations: Mayo Clinic (US)
University of Minnesota (US)
University of North Carolina at Chapel Hill (US)
Corresponding author: Grover, Madhusudan
ORCID: Edwinson, Adam L.
Yang, Lu
Peters, Stephanie
Hanning, Nikita
Jeraldo, Patricio
Jagtap, Pratik
Simpson, Joshua B.
Yang, Tzu-Yi
Kumar, Praveen
Mehta, Subina
Graham, Rondell P.
De Winter, Benedicte
Patel, Robin
Dasari, Surendra
Kashyap, Purna
Griffin, Timothy
Chen, Jun
Farrugia, Gianrico
Redinbo, Matthew R.
Grover, Madhusudan
Venue: Nature Microbiology
Publisher: Springer Science and Business Media LLC
Published: 2022-04-28
Volume: 7
Issue: 5
Pages: 680-694
ISSN: 2058-5276 (ISSN-L)
DOI: 10.1038/s41564-022-01103-1
PMC: PMC9081267
OpenAlex: W4225117821
Cited by: 105
References: 80
Citations by year: 2026: 30 · 2025: 25 · 2024: 28 · 2023: 18 · 2022: 4
FWCI: 7.67
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Microbiology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (DK127998, DK120745, DK103911)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Keywords: irritable bowel syndrome, gut microbiota, beta-glucuronidase, intestinal proteases, serine protease, unconjugated bilirubin, Alistipes, Bacteroides, intestinal permeability, host-microbe interactions, post-infectious IBS, germ-free mice, microbial colonization, intestinal barrier
MeSH terms: Gastrointestinal Microbiome, Animals, Bilirubin, Escherichia coli, Glucuronidase, Humans, Endopeptidases, Irritable Bowel Syndrome, Mice, Serine Proteases

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Gut microbial β-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome

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