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Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

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​Chronic immune-mediated and autoimmune diseases affect about 5% of the population in Europe and North America, with two thirds of the patients being female (http://www.nature.com/nbt/journal/v18/n10s/full/nbt1000_IT7.html). The incidence of disease is rising and today in the US alone more than 50 million people are affected and incur annual healthcare costs of more than US$ 100 billion, excluding extra costs due to loss of work productivity. The increase in immune-mediated diseases accounts for a large part the complex immune-mediated diseases affecting the gastrointestinal tract (celiac disease, Crohn’s disease, ulcerative colitis). Recent advances in genetic studies have revealed a vast majority of the underlying genetic risk factors and unequivocally showed that gastrointestinal immune-mediated disease share part of their genetic and immunological background with diseases like rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and multiple sclerosis (Ricaño-Ponce and Wijmenga, ARGHG 2013). The challenge we are currently facing is to translate these genetic findings into clinical use. On the one hand this means that we have to further our understanding of the disease process to contribute to development of new therapies, while on the other hand this means better ways of identifying patients before the disease becomes manifest to start treatment as early as possible. The latter also includes the development of biomarkers that can help in monitoring disease progression and regression. In 3GI this challenge is addressed by the integration of know-how and both clinical and population data available to the researchers from the Departments of Genetics and Gastroenterology and Hepatology. In particular the availability of large scale ‘omics’ data (such as genetic data, microbiome data, methylation data and RNA expression data) is instrumental in understanding how genetic changes perturb molecular and cellular pathways, and how factors like the microbiome can modulate these. 3GI is extremely well positioned to integrate different levels of ‘omics’ as clinical, molecular and computational researchers collaborate. 

Prospective patient cohorts as well as the LifeLines cohort study are explored to identify signatures of biomarkers (based on e.g. the gut microbiome and miRNAs), to test genetic risk profiles (based on the known genetic risk factors), to understand the role  of environmental factors on disease risk (e.g. smoking and diet -using prospective cohort data) and to investigate the combined effect of genetic risk variants and e.g. the gut microbial composition on disease development and outcome. 

The gut microbiome is also seen as a potential modulator for disease treatment through the use of probiotics or by the development of prebiotics.3GI also works on downstream functional analyses of identified disease-specific genetic variants and in particular how they affect the transcriptional regulation of disease-specific cell-types. Unraveling the disease-specific transcriptional networks and their corresponding biological pathways is a crucial first step for identifying targets for further drug development. Since the gut is central to the development of many immune mediated and infectious diseases and connects and integrates organ systems throughout the body, the work that is being done within 3GI has far-reaching consequences in health and disease

Scientific and Societal output   Dissertations  

See dissertations of 3GI on horafinita.nl

Principal Investigators   Programme Leaders   Description of the Programme  

In 3GI we aim to make major breakthroughs in our understanding of immune-mediated, autoimmune and infectious diseases by bridging the gap between the disease genotypes and the disease phenotypes; the immune dysregulation seen in infectious diseases can be seen as the opposite to immune-mediated diseases. By studying these two extremes we will be able to enhance our understanding of how an imbalanced immune system leads to disease in gastrointestinal immune-mediated diseases.  
 
We study three model diseases: two chronic inflammatory intestinal diseases (celiac disease and IBD (Crohn’s disease and ulcerative colitis)) and one infectious disease (systemic candidemia). All three diseases are complex in nature as they are caused by an interaction between multiple genetic and non-genetic factors and involve the host immune system. Celiac disease is characterized by a dysregulated immune response to the dietary protein gluten, while IBD is characterized by a dysregulated immune response to commensal microorganisms. In 3GI we use these model diseases to work on the crossroads of three of the major research topics in science at the moment:  

i) The genetics of complex diseases  
ii) The influence of genetic risk factors on the host immune system
iii) The role of the gut microbiome on disease development and progression

Through our understanding of these factors and the interaction between them, we will provide new avenues for treatment. Our program will lead to (1) biomarkers to identify patients before disease onset or to monitor disease progression and remission; (2) new drug targets or evidence for repurposing existing drugs to other disease; (3) insight into how the gut microbiome can be modified through pre/ pro or anti-biotics to treat or prevent disease. 3GI aims to contribute to “precision” or “personalized” medicine: giving the right treatment to the right patient at the right moment in the disease course based on genetic, metagenomic or transcriptomic biomarkers.  

3GI consists of an interdisciplinary research group of PIs from different departments, with different areas of expertise, and with a proven and excellent track record in the field of immune-mediated, autoimmune and infectious diseases.  3GI builds on previous and ongoing work in which genetic risk factors have been identified for celiac disease, Crohn’s disease, ulcerative colitis, candidemia and other immune mediated disease. The nature of many of these disease risk genes and their function is so far unknown and requires a more systems approach. The PIs in 3GI have compiled an unprecedented resource from clinical and population biobanks to develop an understanding of the underpinning of the genetic susceptibility, by translating genes to function (e.g. transcriptomics, metabolomics and proteomics) and placing them in functional ‘networks’, analyze the interaction with the gut microbiome (metagenomics, meta transcriptomics) and to perform functional studies to elucidate how genetic risk variants will lead to disease. 3GI is closely connected to the national biobanking community (through BBMRI-NL) and collaborates nationally and internationally with well-established groups with expertise in unbiased high-throughput technologies and functional genomics (with e.g. Prof. Mihai Netea, Radboud Univ; Prof. Ramnik Xavier, Harvard Medical School) and in the field of gut microbiomics (with e.g. Prof. Jeroen Reas, Univ. Leuven; Prof. Curtis Huttenhower, Harvard Medical School).

The program currently focuses on different aspects:  

i) to construct a prediction model that can be used in clinical practice to predict which IBD patients will develop severe disease course, so that treatment can be adjusted to predicted disease severity
ii) to investigate the gut microbiome in he
alth in immune-mediated diseases as the microbiome offers unique opportunities for developing new drugs and antibiotics, as well as for tailoring treatment programs to individuals
iii) to investigates the disease mechanisms in celiac disease, IBD and candidemia by using predisposing genes and genetic variants as disease initiating factors. Specifically, we will investigate if long, intergenic non-coding RNAs (lincRNAs) are causally involved in disease pathogenesis by regulating protein-coding genes and pathways associated with the disease
iv) to develop novel technologies including CRISP/CAS9, single-cell sequencing and GroSeq to comprehensively assess affected immune cell populations and assess the effect of genetic perturbation on cellular behavior and pathways
v) to follow individuals over time with strong genetic risk but no disease phenotype to identify factors that can prevent disease development. For this we will make use of LifeLines.  

The 3GI PIs have a very strong track record in genetics, genomics and the immunology of the immune-mediated diseases. For the analysis of the microbiome and infectious disease strong collaborations have been established both local, at a national level and at the international level. All the computational and bioinformatics knowledge for integration of these data are available within 3GI and also through national and international collaborations.  

The earliest ongoing translation of results from 3GI are high-content (‘omics) biomarker profiles that reflect gastro-intestinal health and disease (celiac disease, IBD). In particular biomarker profiles that are easy obtainable (e.g. in stool) and that can be tested in the large population cohort LifeLines to establish validity, sensitivity and specificity. In the next year stool will be collected from 10.000 LifeLines participants to assist in the biomarker research. In addition, the use of LifeLines as an important cohort will also allow us to identify factors that can be used to prevent disease.  

Mission  

Our mission is to contribute to personalized and precision medicine for immune-mediated diseases by developing a framework that bridges clinical and population research. 

Relevance to Healthy Ageing  

The diseases under study (celiac disease, Crohn’s disease, ulcerative colitis) are chronic diseases often start at young age with normal life expectancy, but require life-long treatment. Genetic risk factors for these diseases are multiple and commonly present in the “healthy” population. Understanding how genetic variations and the interaction with an individual’s environment leads to disease development will have major implications for healthy aging of the patients, but even more so to prevent the diseases.
Understanding of the disease pathogenesis will eventually lead to better treatment options of chronic diseases which improves quality of life and promotes healthy life. An active part of the new programme will be our focus on the gut microbiome and the interaction with both the environment and the genetic background. A “healthy gut” contributes to a healthy life.