Title: Targeting ‘Leaky Gut’ with combined dietary zinc and plant derived Aryl Hydrocarbon Receptor agonists
Funder: Guts UK

Abstract: Background: Both zinc and natural ligands of the Aryl Hydrocarbon Receptor (AHR) are dietary components which regulate intestinal epithelial barrier function and protect against Inflammatory Bowel Disease (IBD). Zinc stimulates intestinal stem cell (ISC) proliferation, promotes tight junction formation, and increases mucin secretion. AHR is an environmental sensing receptor and its activation by natural dietary ligands from plants attenuates ISC proliferation and improves barrier function. We have identified explicit intersections between the zinc and AHR pathways, which work together to maintain the intestinal mucosa to prevent IBD. The understanding of this interaction is essential since plant-based diets which have abundance of natural AHR agonists are poor sources of zinc, and vice versa, causing imbalance and potential vulnerability to IBD. Hypothesis and objectives: Our overarching hypothesis is that combined dietary zinc and AHR ligands improves the epithelial barrier function of the human intestine which would be of benefit in reducing risk of (IBD). The aim of this project is to map the nature of the zinc-AHR pathway interactions within the functional context of the intestinal epithelium. This will be achieved through the following objectives: Objective 1: Determine transcriptional control of zinc homeostasis by the AHR. Objective 2: Establish how zinc changes AHR-driven gene expression. Objective 3: Delineate the mechanisms by which zinc and AHR elicit improved barrier function. Design and methods: For activation of AHR, we will use the natural agonist, 6-formylindolo(3, 2-b)carbazole (FICZ) in our experiments. We will initially exploit the Caco-2 immortalised cell line to study the reciprocal transcriptional control between zinc and AHR pathways (Obj. 1-2) as well as mapping the shared elements of the two cell signalling pathways (Obj. 3) and study the outcome relevant to epithelial barrier integrity. Although Caco-2 cells is a useful model, experiments on intestinal organoids are more representative of the in vivo condition. Therefore, human gut organoids derived from ileum ISC will be used to corroborate findings from Caco-2 cells and to determine how these processes impact on the different cell types within the gut, including their differentiation. By exploiting pharmaceutical blockers and molecular tools we will perturb the network at precise points and characterise the nature of the interactions. Clinical and scientific impact: Manipulation of dietary Zinc together with ‘micro-nutraceutical’ AHR ligands may provide significant benefits to gut health and therapeutic options for diseases, such as IBD. The project outcomes will establish a causative link to why people in low- and middle-income countries eating predominantly plant-based diets are zinc deficient and have poor health whilst vegans in industrialised countries are generally healthy. The issue is important because of sustainability issues with meat and dairy products and because about 1/3 of the World’s population is zinc deficient and prevalence is highest where diets are dominated by plant-based foods high both in AHR pre-ligands and in the zinc antinutrient, phytate (WHO Health Report 2013). The proposed research will generate the data needed to develop projects with human intervention studies with the ultimate aim to harness these pathways for prevention and/or remedy of IBD.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: ORAL AND GASTROINTESTINAL