Gut Inflammation from Emulsifier Perturbations of Microbiota-Host Interactions

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 DESCRIPTION (provided by applicant): The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. When maintained in a stable manner, at an appropriately safe distance from gut epithelial cells, the microbiota provides a benefit to the host, especially in terms of energy harvest, pathogen exclusion, and promotion of immune development. However, research performed under this grant has led to us hypothesize that disturbance of the microbiota-host relationship, promoted by genetic and non-genetic factors, can drive chronic gut inflammation that can manifest as inflammatory bowel disease (IBD) or metabolic syndrome. The recently completed grant whose funding this application seeks to reinstate, has largely focused on understanding how a genetic innate immune deficiency can result in chronic gut inflammation. Yet, the dramatic increase in incidence of numerous chronic inflammatory diseases, including IBD and metabolic syndrome over the last 60 years amidst relatively constant genetics highlights the importance of understanding mechanisms by which non-genetic factors might alter the microbiota-host relationship to promote gut inflammation. Hence, the goal of this renewal application is to investigate disturbance of the microbiota-host relationship by a ubiquitous class of food additives, namely emulsifiers, whose penetrance in the world's food supply roughly parallel's increases in chronic inflammatory diseases. Our focus on emulsifiers is based on the notion that these detergent-like molecules have been suggested to promote bacterial translocation across gut mucosa and, moreover, our recent findings that, in mice, administration of 2 common synthetic emulsifiers, namely polysorbate 80 (P80) and carboxymethylcellulose (CMC), via diet, at concentrations below that which they are approved for use in processed foods, promote colitis in mice with a genetically predisposed to this disorder (IL-10-/- and TLR5-/-) and, moreover, drive metabolic syndrome in 2 distinct WT mouse strains (C57BL/6 and Swiss-Webster). Such emulsifier-induced metabolic syndrome requires the presence of a microbiota in that neither P80 nor CMC promote low-grade inflammation or metabolic syndrome in germfree mice. While human studies (that we will propose elsewhere) will ultimately be required to define the role of emulsifiers in driving the increased incidence of IBD and metabolic syndrome, we submit that understanding mechanisms by which emulsifiers promote inflammatory diseases in our model systems can guide such studies and, moreover, broadly enhance our understanding of fundamental mechanisms by which any factor that disturbs the microbiota-gut relationship can promote chronic inflammatory diseases. Hence, this proposal seeks to investigate our hypothesis that emulsifiers promote pathobiont penetration through the mucus layer thus inducing inflammation that changes microbiota composition to further drive inflammation and its consequences.