Early microbiome changes and its antigenic potential in individuals at high-risk for inflammatory bowel diseases

Introduction

The interaction of lifestyle and environmental factors with the well-studied predisposing genetic susceptibility is currently thought to trigger inflammatory bowel diseases (IBDs). Due to its mere size, its prominent presence at the inflamed intestinal sites, and its metabolic and immunological importance, the gut microbiome has been identified as a major disease-relevant intermediate phenotype and a potential driving factor of IBD development and its clinical course. IBDs develop progressively, i.e. microbial changes (dysbiosis) can be detected years before the onset of IBD with relatives of IBD patients being at particular risk for developing the disease through genetic and environmental proximity. It is assumed that dysregulated or inappropriate T cell reactions against otherwise harmless members of the microbiome play a central role for disease pathogenesis and/or chronification. However, which microbes are the targets of pathogenic T cell reactions and how these reactions develop is currently unknown. Patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies and information on the magnitude and importance of early changes in the microbiome and the human immune system is still lacking.

Aims

We will perform standardized metagenomic analyses of biosamples from different time points and analyze potential disease-associated alterations of the T cell reaction against candidate microbes from members of our KINDRED (family) cohort for IBD (see Biobank Popgen for more details on the cohort).

We here aim:

• to identify genetic and non-genetic factors that shape the gut microbiome in IBD patients and their first-degree relatives,
• to analyze the function of the gut microbiome in IBD patients and their first-degree relatives over time,
• to identify disease-associated metabolites, microbial signatures, and patterns thereof, and
• to identify early changes in the immunological responses against candidate microbes.

Outlook

This project holds the potential to identify molecular signatures, microbial and metabolic biomarkers, or even antigens that predict and explain the clinical onset and disease course of IBD. We will accurately describe pre-clinical changes in the microbiome of high-risk individuals to improve the etiological understanding of subclinical disease forms. Direct analyses of the T cell reaction against selected candidate microbes will enable us to investigate the missing link between microbial dysbiosis and altered immune reactions. In a potential second RU funding phase our findings could be followed up by targeted intervention studies in at-risk individuals of the KINDRED cohort, additional integration and analyses of new onset cases, and by working further on the HLA-antigen and TCR candidates in order to identify novel targets for treatment.