Understanding the molecular mechanisms of Akkermansia glycan-binding adhesins in shaping microbial communities and balancing intestinal inflammation in response to host signals

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PROJECT SUMMARY/ABSTRACT Akkermansia muciniphila is a bacterial resident of the human intestine that is associated with protection from chronic inflammatory diseases such as inflammatory bowel diseases, colorectal cancers, and type-2 diabetes. The molecular mechanisms that determine how A. muciniphila inhabits the intestine and how it promotes host health are not known. A. muciniphila grows in dense aggregates in tight association with the glycan-rich mucin lining of the intestine. When cultured in mucin medium, A. muciniphila produces anti-inflammatory compounds and stimulates other glycan-coated gut microbes like Ruminococcus gnavus to produce butyrate, a fermentation byproduct with therapeutic properties. The board and long-term objective of this project is to learn how the glycan environment of the intestine shapes A. muciniphila’s anti-inflammatory activities and decode species- level mechanisms that drive variability among clinical isolates. This work has wide-reaching implications in fields such as probiotic and therapeutic development aimed at treating inflammatory diseases. The focus of this proposal is to develop a molecular understanding of how A. muciniphila strains regulate a diverse group of glycan-binding cell surface adhesins referred to as PbH1-containing adhesins (PbHAs) to engage with the mucin environment of the intestine, to interact with and manipulate butyrate fermentation in other symbionts, and to modulate innate immune pathways in the host. In Specific Aim 1 I will engineer a zebrafish bacterial symbiont to express each of the seven diverse PbHAs encoded by two A. muciniphila species of interest (MucT and AKK2750) and test how expression shapes their aggregation properties in culture and influences their spatial organization in the larval zebrafish gut. Further, I will use experimental evolution to uncover the genetic pathways that drive MucT and AKK2750 aggregation in mucin medium. Specific Aim 2 will investigate the role of PbHAs in co-aggregation with R. gnavus and determine how MucT and AKK2750 mucin-sensing and co-aggregation with R. gnavus influence butyrate fermentation. Lastly, Specific Aim 3 will use a zebrafish model of microbe- induced intestinal inflammation to identify PbHAs and other species-specific factors that reduce inflammation and promote intestinal health. I will use a pathogen-targeting PbHA to design therapeutic beads that bind and deplete an intestinal pathogen and restores gut health. The molecular insights I will discover, research reagents I will generate, and skills I will acquire through these studies will position me to establish my own independent research laboratory investigating the molecular mechanisms of microbiome-mediated human health.