Grant Abstract: Vitamin D Mediated Protection in Inflammatory Bowel Disease

Grant Number: 5K01OD021420-02
PI Name: Meeker
Project Title: Vitamin D Mediated Protection in Inflammatory Bowel Disease

Abstract: Recent studies indicate that diet may significantly affect IBD and CAC development in part by altering the gut microbiome. Our preliminary data show that increased dietary vitamin D3 alters the microbiome in Smad3-/- mice independent of inflammation. We hypothesize that vitamin D3-associated changes in the microbiome directly modulate IBD/CAC. Thus, we will investigate the role of the microbiome shaped by dietary vitamin D3 in altering the risk for IBD/CAC using GF Smad3-/- mice colonized with microbiomes from mice fed control diet vs. those fed high vitamin D3 diet (Aim 2).

Aim 1. Determine the efficacy window of dietary vitamin D3 in the treatment of IBD and prevention of colitis-associated colon cancer (CAC). We previously showed that dietary vitamin D3 is protective against CAC in Smad3-/- mice when it is given before the IBD trigger by decreasing early stage inflammation, however, we hypothesize that dietary vitamin D3 treatment will also influence tumor initiation and/or progression even if initiated following the onset of inflammation. We will therefore determine the efficacy of dietary vitamin D3 supplementation in altering IBD/CAC when started at different stages of disease and investigate mechanisms of vitamin D3 action during the disease process. We will feed Smad3-/- mice a diet containing either 1 IU (control) or 15 IU vitamin D3 / gram (high vitamin D3) diet. Both diets are commercially manufactured and will be formulated based on AIM93M specifications except for the vitamin D3 content. The vitamin D3 content in all diets will be confirmed by LC-MS/MS (Covance Laboratories). CAC incidence will be determined by histological analysis. In addition, we will evaluate changes in inflammatory cytokine/chemokine expression, gut permeability and microbiome composition in response to high vitamin D3 diet fed at different disease stages.

Aim 2. Determine if the gut microbial community associated with dietary vitamin D3 supplementation directly modulates IBD and / or CAC development / severity. GF Smad3-/- mice are an invaluable tool to assess the functional capacity of gut microbiota to induce and modulate IBD/CAC development, severity and progression in a genetically susceptible host. We hypothesize that changes in microbiota play a direct role in vitamin D3-mediated protection against IBD and CAC that we observe in Smad3-/- mice. To test this hypothesis, we will transfer the fecal microbiota from mice fed control vs. high vitamin D3 diet into GF Smad3-/- mice and then will trigger IBD. We will determine incidence and severity of IBD and CAC, changes in epithelial barrier function, and immune responses in colonized Smad3-/- mice in association with each diet-induced microbiome.

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