# Unraveling the enzymatic pathway of gut bacterial mucus degradation to treat inflammation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $567,962

## Abstract

Summary
The composition and physiology of the microbial community (microbiota) in the human colon has been linked
to a number of diseases. Mechanistic details for most of these interactions are still badly needed. The shared
focus of the four investigators assembled to conduct the proposed project is to understand how gut microbes
interact with and metabolize complex carbohydrates—especially the glycans attached to secreted host mucus.
Mucus is the first barrier that separates intestinal bacteria from host tissue and is a complex mixture of
secreted mucin glycoprotein and other molecules. Some bacteria have evolved to forage on mucus as a
source of nutrients. We have previously shown that this mucus foraging activity increases when exogenous
dietary fiber polysaccharides are absent. Using a gnotobiotic model of fully sequenced human gut bacteria, we
have shown that during fiber deficiency the gut microbiota resorts to degrading mucus for nutrients, leading to
erosion of its integrity. In wild-type mice, a reduced mucus barrier increases epithelial access and lethal colitis
by the mucosal pathogen, Citrobacter rodentium. More strikingly, when this same synthetic microbiota is
assembled in mice deficient in interleukin 10, a cytokine for which loss of function is associated with human
pediatric inflammatory bowel disease (IBD), animals develop lethal inflammation in the absence of pathogen,
but only on a low fiber diet. Our work has therefore revealed functional connections between mucus integrity,
diet and gut microbes in precipitating IBD. The complete deconstruction of mucin glycoproteins requires a
consortium of enzymes: peptidases to hydrolyze the protein backbone and sulfatases and glycoside
hydrolases that recognize sulfated or unsulfated oligo- and monosaccharides within discrete glycosidic linkage
contexts. Our central hypothesis is that mucin is degraded in a series of sequential steps by individual activities
in this enzyme consortium and that essential catalytic steps exist, which may be contributed by different
species that work synergistically to degrade mucus. We will test this hypothesis by first defining the sequential
action, positional specificity and key structural facets of bacterial enzymes required for degradation of
gastrointestinal mucins. We will use sequential and combinatorial treatments of various forms of mucin with
pure recombinant enzymes, which we have already identified in the members of our synthetic microbiota. In
parallel, we will measure the requirement for individual, discrete mucus-degrading steps within genetically-
manipulable model species using in vitro and mouse in vivo models as readouts. The research team is
composed of four leaders in the disciplines of gut bacterial physiology and molecular biology, structural biology
and enzymology, mucin biology and glycoanalytics, all with a shared interest in the mechanisms of mucus
degradation and the consequences for human disease. Successful completion of thes...

## Key facts

- **NIH application ID:** 10027431
- **Project number:** 1R01DK125445-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Nicole M Koropatkin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $567,962
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10027431

## Citation

> US National Institutes of Health, RePORTER application 10027431, Unraveling the enzymatic pathway of gut bacterial mucus degradation to treat inflammation (1R01DK125445-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10027431. Licensed CC0.

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