Mucin-degrading bacteria in ulcerative colitis: a translational approach

INTRODUCTION

Ulcerative colitis (UC) represents a major form of Inflammatory Bowel Diseases (IBD), which are chronic relapsing disorders affecting the gastrointestinal tract. There is growing evidence that changes in nutritional habits and microbiota-associated alterations contribute to increasing UC incidences, especially in industrialized countries, where diets characterised by insufficient fiber intake are common(1,2).

We have previously shown that a diet devoid of fiber led to overgrowth of mucin glycan-degrading bacteria in mice, resulting in decreased colonic mucus thickness, heightened susceptibility to enteropathogenic infection, and increased mucosal immune responses(3–5). Additionally, we have demonstrated that genetically susceptible mice develop severe forms of IBD in the face of increased microbial mucin foraging(6).

AIM AND HYPOTHESIS

In line with our published work and given that UC patients typically demonstrate defects in mucus layer integrity, we hypothesize that mucin-degrading commensals play a pivotal role not only in the pathogenesis of UC, but also in the success of biological therapies targeting the immune responses of the host.

METHODS

The proposed project will make use of already collected samples (between 2020 to 2022) from one cross-sectional and one longitudinal IBD cohort study involving UC patients. Both studies have been conducted in collaboration with the CHL, Luxembourg. The cross-sectional study targeted UC patients with currently active, moderate disease irrespective of medical treatment. Meanwhile, the longitudinal study targeted patients that were newly diagnosed with UC and were to be treated with antibodies targeting the host immune response (Infliximab, interfering with TNF response; Vedolizumab interfering with T cell homing to the gut).

Using these patient cohorts, we will test the hypothesis that dysregulated mucin glycan degradation by commensal gut bacteria is associated with acute inflammation in UC patients and impacts success of antibody-based therapies. Dietary therapeutics could be employed in the mid-term to reduce mucin-degrading activity by the gut microbiota and improve the success of IBD therapies.

This translational PhD project will involve clinical samples, cutting-edge microbiome-related omics analyses, broad immune cell profiling from patient blood samples and high-throughput culturing of patients’ mucin-degrading intestinal microbial populations followed by in vitro phenotyping. This interdisciplinary project will prepare the PhD student for a career in academia or industry or clinical settings.

REFERENCES

Wolter, M. et al. Leveraging diet to engineer the gut microbiome. Nat. Rev. Gastroenterol. Hepatol. 0123456789, (2021).
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Desai, M. S. et al. A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell 167, 1339-1353.e21 (2016).
Martens, E. C., Neumann, M. & Desai, M. S. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nat. Rev. Microbiol. 16, 457–470 (2018).
Neumann, M. et al. Deprivation of dietary fiber in specific-pathogen-free mice promotes susceptibility to the intestinal mucosal pathogen Citrobacter rodentium . Gut Microbes 13, (2021).
Pereira, G. et al. Unravelling specific diet and gut microbial contributions to inflammatory bowel disease. BioRxiv https://doi.org/10.1101/2022.04.03.486886 (2022).