Genetics of carbs malabsorption in IBS 

Irritable 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 IBS symptoms may manifest in some patients because of 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). We also demonstrated that SI genotype (and corresponding levels of disaccharidase activity) may influence the response to carbohydrate-focused diets, which holds promise for improving efficacy and personalising dietary treatment in IBS patients. 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). (key publications including original breakthrough findings:  Gut 2024; Gut 2023; Gut 2022; Gastroenterology 2021; Gut 2020; Gut 2018).

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. (key publications: Cell Mol Gastroenterol Hepatol 2024; Nat Rev Gastroenterol Hepatol 2022; Nat Genet 2021; Gastroenterology 2018; Gut 2015).

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. (key publications: Cell Genom 2021; PNAS 2020; Gut 2017; Gastroenterology 2010).

Other gastrointestinal diseases

We work at the identification of genetic risk factors for several other gastrointestinal diseases, often participating in the coordination of activities of large international consortia focusing on inflammatory bowel diseases, (IIBDGC), microscopic colitis (EMCG), hemorrhoids, diverticulitis and other diseases. These efforts have led to major discoveries (more than 200 risk loci for IBD; the role of HLA molecules in MC), especially for conditions like diverticulitis and hemorrhoidal disease that were poorly characterized at the molecular level. We reveal that these conditions have a lot in common in terms of genetic architecture and predisposing factors, and that mechanisms not suspected before are central to their pathophysiology, including pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis in diverticular disease and hemorrhoids. We constantly expand our research to other GI conditions via international collaboration (a few disease-specific papers: J Crohns Colitis 2024; Gut 2021; Gut 2019; Gut 2017; Nature 2017).

Genetics of human-microbe interactions

We are interested in host-microbe interactions, with special focus on human genes affecting such interactions in health and disease, via large-scale population-based GWAS meta-analyses. Out studies span from the heritability of human gut-microbiota composition to the risk of infection and severe disease course in COVID-19. (some key publications in this area of research: Nature 2021; NEJM 2020; Nat Genet 2021; Nat Genet 2016).