P3: Molecular mechanisms of microbiome-led colonic mucosal barrier dysfunction in colorectal cancer and inflammatory bowel diseases

Principal Investigator                        Mahesh S. Desai

Host Institution                                  LIH

Project Research Question:               How do mucus-degrading microbes drive pathogenesis in colorectal cancer and inflammatory bowel disease?

Abstract

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), which is a chronic condition that leads to severe inflammations in the colon and is a risk factor for the development of colorectal cancer (CRC).  Currently, there is no treatment available for UC, the remission rates remain low and the pathogenesis mechanisms are poorly understood. During the last decade, one of the major contributors of UC is thought to be the gut microbiome, as its composition during remission and exacerbation of the disease is known to be different. Thus, a close link between inflammation and the presence of certain microbial populations has been proposed. Using a gnotobiotic mouse model containing a human gut microbiota, we have recently shown that a dietary fiber-deprived gut microbiome erodes the colonic mucus barrier and enhances susceptibility to enteric pathogens (Desai et al. (2016), Cell 167, 1339). Based on our published work, for the current DTU project, we intend to investigate how the mucus-foraging bacterial populations change from remission versus exacerbation of the disease as well as during development and progression of CRC. This study will involve patient cohorts, synthetic gut microbial communities and gnotobiotic mouse models, state-of-the-art sequencing/bioinformatics and microscopy methods. The project will involve national and international collaborators; and will shed important light on the pathogenesis mechanisms of CRC and UC.

Recent relevant publications

1. Martens, E. C.^*, Neumann, M., and Desai, M. S.* (2018) Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nature Reviews Microbiology 16:457–470. *Corresponding author.

2. Desai, M. S.*, Seekatz, A. M., Koropatkin, N. M., Kamada, N., Hickey, C. A., Wolter, M., Pudlo, N. A., Kitamoto, S., Terrapon, N., Muller, A., Young, V. B., Henrissat, B., Wilmes, P., Stappenbeck, T. S., Nunez, G., and Martens, E. C.^* (2016) A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167: 1339. ^*Corresponding author.

Methods

• Patient cohorts, synthetic human gut microbial communities, and Specific pathogen free (SPF)/gnotobiotic mouse models

• Next-generation sequencing methods/bioinformatics (including both metagenomics and transcriptomics) and metabolomics

• Florescence microscopy methods

• Florescence-activated cell sorting (FACS) and Time-of-flight mass cytometry (CyTOF) techniques

MICROH-DTU Collaborators

Paul Wilmes (LCSB)

Elisabeth Letellier (LRSU)

Dirk Brenner (LIH)

Jonathan Turner (LIH)

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