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

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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)680-694
Number of pages15
JournalNature Microbiology
Volume7
Issue number5
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
We thank L. Anderson and K. Zodrow for administrative support; the Center for Mass Spectrometry and Proteomics at the University of Minnesota for resources used to generate and analyse faecal metaproteomics data. Funds for data collection, analysis and personnel support were provided to M.G. by: the National Institutes of Health (DK 103911, DK 120745, DK 127998); the Mayo Clinic Research Pipeline K2R Program Award; the Pilot & Feasibility Award from Mayo Clinic Cell Signalling in Gastroenterology via P30DK084567 through the National Institutes of Health.

Funding Information:
We thank L. Anderson and K. Zodrow for administrative support; the Center for Mass Spectrometry and Proteomics at the University of Minnesota for resources used to generate and analyse faecal metaproteomics data. Funds for data collection, analysis and personnel support were provided to M.G. by: the National Institutes of Health (DK 103911, DK 120745, DK 127998); the Mayo Clinic Research Pipeline K2R Program Award; the Pilot & Feasibility Award from Mayo Clinic Cell Signalling in Gastroenterology via P30DK084567 through the National Institutes of Health.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Gut microbial β-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome'. Together they form a unique fingerprint.

Cite this