Research in the Gastrointestinal Genetics Lab is geared toward a translational application for therapeutic precision in gastroenterology. Our international team combines leading expertise in genomic, computational and pre-clinical research to identify causative genes and pathogenetic mechanisms predisposing to human diseases of the gastrointestinal (GI) tract. We focus on irritable bowel syndrome (IBS) and gut dysmotility, microscopic colitis (MC), inflammatory bowel diseases (IBD), gastroparesis (Gp) and other GI conditions. Nutrigenetics and diet-genome-metagenome interactions are also at the core of our research, in IBS and carbohydrate malabsorption.

Research line 1: Genetics of carbs malabsorption in IBS
Irritable bowel syndrome (IBS) affects one in ten people with gastrointestinal (GI) symptoms that are detected without an established underlying organic cause. Many patients believe certain foods trigger their symptoms, and avoidance of carbohydrates due to perceived maldigestion is common. Out studies suggest that a subgroup of patients may be identified, characterized by an otherwise unrecognized carbohydrate malabsorption due to defective (hypomoprhic) variants of the sucrase-isomaltase gene (SI), which leads to accumulation of undigested disaccharides in the large bowel (where they cause symptoms due to osmotic diarrhea and gas production following bacterial fermentation). This fuelled new interest into the relationship between food and IBS and warrants investigation of other genes involved in the process of carbohydrate digestion (among the main activities of the GenMalCarb consortium we co-lead).

Research line 2: Biobank-scale GWA studies of IBS
A heritable component of IBS has been consistently demonstrated in twin and family studies, and we apply modern approaches to IBS large-scale genetic studies in the general population. For this purpose, we conceived, promoted, developed an coordinate an international collaboration (the bellygenes initiative) to exploit existing genotype and phenotype data from several biobanks, corresponding to a target population of several million Europeans. Through genome-wide association studies (GWAS) and their meta-analyses (including several thousand IBS patients identified via questionnaire data and/or healthcare records across multiple cohorts) we identify IBS risk loci and reveal shared genetic architecture with other common disorders. Our studies contribute to the identification of pathophysiological mechanisms that may inform a molecular reclassification of IBS, and hence ultimately provide novel therapeutic targets.

Research line 3: GWAS of gut motility and other endophenotypes
There is only incomplete understanding of the physiological mechanisms regulating intestinal motility, and their perturbation in the dysmotility syndromes like IBS. Direct assessment of gastrointestinal motility in humans requires clinical procedures that are not suitable for large-scale genetic surveys, and we use an endophenotype approach to gene discovery in population-based cohorts and biobanks. Based on questionnaire data and recorded bowel habits, we study stool frequency and consistency (recognized proxies for colonic transit time) to gain insight into the (patho)physiology of gut dysmotility and IBS, via GWAS meta-analyses across millions of individuals of European descent. Functional annotation downstream these GWAS allows the identification of pathways and cell types involved in the control of gut motility, revealing therapeutically actionable mechanisms that may be targeted for the delineation of novel treatment options.

Collaborations
Fundamental to the development of our research (and the bellygenes initiative we coordinate), we have established a large network of collaboration, involving > 50 biobanks, cohorts, clinicians, scientists, and institutions across the world.

Links
Webpage: https://www.mdalabgenomics.com/

Latest Publications