PepT1-/- microbiota therapy as a treatment for colitis

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PepT1, which is a member of the proton oligopeptide transporter (POT) superfamily, is well known to transport di/tripeptides. Our group and others have shown that PepT1 is highly expressed in epithelial cells of the small intestine, but present at low or undetectable levels in such cells of the normal large intestine. In addition, we have demonstrated that colonic PepT1 expression is up-regulated in colitis and colitis-associated cancer (CAC). By generating gain- and loss-of-function mouse models with PepT1 expression specifically in intestinal epithelial cells (IECs), we explored the role of PepT1 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. We also examined the expression and transport activities of PepT1, using mouse models of colitis and CAC, and further revealed that the function of this membrane transporter is not restricted to its classical function as a transporter of di-tripeptides. For example, we demonstrated that PepT1 expression helps maintain intestinal homeostasis by mediating intestinal miRNA expression/secretion. Importantly we demonstrated during the last funding cycle that the PepT1-/- microbiota/metabolome is sufficient to protect against colitis and CAC. The overall goal of the current proposal is to develop a drug delivery platform to treat colitis. The initial aim of this proposal will be to investigate whether oral delivery of alginate hydrogel-loaded PepT1-/- microbiota will enhance the engraftment dynamics/diversity of the donor microbiota and consequently enhance the prevention/treatment of colitis. In the second aim, we will explore the cellular targets of PepT1-/- microbiota and assess the subsequent intestinal cellular responses that decrease colitis. Finally, we will characterize and assess the in vivo colitis-preventing effects of oral administration of specific anti-inflammatory metabolites from PepT1-/- microbiota loaded into nanoparticles. The proposed research will facilitate the development of therapeutic solutions targeting intestinal inflammatory and colitis associated cancer conditions.