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Gut microbial β-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome
Open accessAbstract
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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“Similar to IBD, studies in mice and humans have provided evidence that host- and bacterial-derived proteases may contribute to pathogenesis and symptom generation.7,13,57,58”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [57]
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“The authors also showed that β-glucuronidases released by commensal microbes suppressed host PA, thereby protecting the intestinal epithelium and suggest that a decrease in microbial β-glucuronidase activity may contribute to IBS pathogenesis.57”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [57]
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“In a recent study, metagenomic analysis of faecal samples from patients with post-infectious IBS revealed an altered gut microbiota composition and high gut proteolytic activity driven by specific host serine proteases compared with controls.”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [57]
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“suggest that a decrease in microbial β-glucuronidase activity may contribute to IBS pathogenesis.57”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [57]
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Self-citation
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
- 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
- Published
- 2022-04-28
- Volume
- 7
- Issue
- 5
- Pages
- 680-694
- ISSN
- 2058-5276 (ISSN-L)
- 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
- 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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