Immune Metabolic signature in the natural history of celiac disease – ImCeliac

Grant: 009/2024

• Title: Immune Metabolic signature in the natural history of celiac disease – ImCeliac.
• Duration: 3 Years Project
• Principal Investigator: Valentina Discepolo, Federico II University, Naples, Italy

THE STUDY

Background

Celiac Disease (CD) is an autoimmune-like disorder elicited by dietary gluten in genetically susceptible individuals. Neither genetic heritability, nor gluten consumption can explain the increase in incidence and other environmental factors must play a role. Overweight and obesity have been associated with increased risk of several autoimmune disorders and a higher birth weight was associated with higher risk of later CD in male twins. Altogether these evidences seem to suggest that metabolic alterations can favor immune dysregulation, thus sustaining loss of immune tolerance and onset of autoimmune diseases.

Hypothesis, Rationale and Aims

An increased metabolic pressure, such as that resulting from changes in dietary habits observed in westernized countries, may promote autoimmunity, thus we hypothesize that metabolic perturbations can elicit pathological processes leading to Treg cells disfunction and loss of immune tolerance and tissue destruction in CD.

To date the immune-metabolic status and the role of Tregs in the context of the CD spectrum have been understudied, thus we would like to fill this gap.

Specific Aims:

(I) Delineate the systemic and tissue specific immuno-metabolic asset in patients at different stages of CD

(II) Investigate the effect of microenvironmental metabolic changes on the activation and function of T cell subsets in the intestinal mucosa

(III) Define whether any of the above-identified immune-metabolic markers could help to predict progression from PCD to full-blown CD

(IV) Associate immune-metabolic profiles of CD patients with distinct dietary pa􀁇erns/habits to delineate protective and inflammatory dietary regimens.

Research Plan (Experimental design and Methodologies)

(I) Delineate the systemic and tissue specific immuno-metabolic asset in patients at different stages of CD (PCD vs ACD vs GFD vs CTR). 1.1 To assess peripheral Immune-metabolic profiling across the CD spectrum and in relation with antropometric, dietary and clinical data. looking at circulating cytokines, adipocytokines by Luminex analyzer and at immune-metabolic phenotyping of circulating T cells by polychromatic flow cytometry. 1.2 Immune-metabolic profiling of mucosal T lymphocytes – isolated from small intestinal biopsies by flow cytometry and IHC.

(II) Investigate the effect of microenvironmental metabolic changes on the activation and function of T cell subsets in the intestinal mucosa in ex vivo organ culture experiments

(III) Identify immune-metabolic markers able to predict progression from PCD to full-blown CD – retrospectively. Perform RNA-sequencing of serial FFPE sections from PCD to gain knowledge on which pathways are activated at diagnosis of PCD in relation with the PCD outcome (and immune-metabolic asset).

(IV) Associate immune-metabolic profiles of CD patients with distinct dietary pa􀁇erns/habits to delineate protective vs pro-inflammatory dietary regimens.

Expected results and Impact on Celiac disease

This proposal aims at dissecting for the first time the immune metabolic profile of peripheral and mucosal T cells in the context of the celiac spectrum (with a particular focus on the mTOR pathway and on Tregs). The project will also investigate these pathways and markers in a longitudinal cohort of PCD with the aim of identifying early markers that may be used at diagnosis to predict future progression of PCD to full blown tissue damage. These immuno-metabolic markers will be also associated with dietary regimens of celiac patients with the aim of delineate protective vs pro-inflammatory dietary habits that may be implemented or discouraged respectively in PCD at risk to develop full-blown CD.