Inflammatory bowel diseases (IBD) including Crohn?s disease (CD) are multifactorial diseases and although their etiology is unknown, host genetics, microbiota composition and dietary components are all demonstrated disease modifiers. Intestinal microbiome dysbiosis, and an increase in bacterial colonization of the intestinal mucosa by CD-associated pathobionts including adherent-invasive Escherichia coli (AIEC) are hallmarks of CD. While mucosal inflammation causes many of the symptoms associated with disease, the underlying factors driving inflammation are unknown. We have recently identified that an AIEC adhesin belonging to the family of Multivalent Adhesion Molecules (MAMs) specifically binds to sulfated glycans on intestinal receptors, and that the intestinal sulfation pattern, particularly of the mucosal barrier, shapes the colonization pattern and niche selection of AIEC. Here, we will address the overarching hypothesis that in the context of AIEC-specific virulence traits such as impaired immune clearance, MAM can act as an accessory factor enabling persistent colonization of the mucosal layer and submucosal epithelium, thereby driving or enhancing inflammation. To test this hypothesis, we will (1) determine how intestinal sulfation levels and sulfation-specific adhesins shape adherence, colonization patterns, and niche selection of adherent-invasive E. coli and (2) determine how sulfate-modification by microbial factors shape adherence, molonization pattern, and niche selection of adherent-invasive E. coli. This work will reveal how host genetics and microbiota composition shape the intestinal sulfation pattern, and if in doing so, they act as CD modifiers through this unifying mechanism, which would characterize intestinal sulfation as a potential new target to prevent or ameliorate disease.
Inflammatory bowel diseases including Crohn?s disease are multifactorial diseases and although their etiology is unknown, host genetics, microbiota composition and dietary components are all demonstrated disease modifiers. Our proposed work will reveal how the intestinal niche colonized by the CD-associated pathobiont adherent-invasive Escherichia coli (AIEC), is shaped as a result of host-intrinsic changes in intestinal receptor sulfation, and how the sulfation pattern is modified by constituents of the microbiota. Completion of this proposal will address how CD modifiers impact host intestinal sulfation patterns and thus, bacterial colonization, and provide a potential mechanism which unifies the influence of seemingly disparate factors on Crohn?s disease.
