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

The DOI matches its Crossref record; 80 of the 80 references it cites were found in a registry or an index.

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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  1. Ripley, B. et al. Package ‘MASS’. Cran R 538, 113–120 (2013).

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Metadata

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
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
Licence
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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