The multi-faceted genetically-determined carbohydrate malabsorption in congenital sucrase-isomaltase deficiency and irritable bowel syndrome

• Applicant: Professor Dr. Hassan Y. Naim
• Subject Area: Gastroenterology ; Biochemistry ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445307304

The final stages of digestion of α-glycosidic carbohydrates occurs in the small intestine through the α-glycosidases sucrase-isomaltase (SI, EC 3.2.148 and 3.2.1.10) and maltase-glucoamylase (MGAM¸ EC 3.2.1.20 and 3.2.1.3). Reduced expression levels or complete absence of intestinal disaccharidases at the cell surface of the enterocytes is associated with carbohydrate maldigestion and malabsorption, most notably described in several cases of genetically-determined sucrase-isomaltase deficiency (CSID). Unlike CSID, irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder (FGID) that affects 10-15% of adults and children worldwide. Biochemical, cellular and functional analyses of SI mutations established the concept of phenotypic heterogeneity of CSID and classified SI mutants based on their intracellular location and function as well as the genetic inheritance pattern, homozygous or combined heterozygous. The concept of heterozygosity in CSID has been also recently discussed.Due to several common symptoms with CSID, such as diarrhea, abdominal cramping and flatulence, a potential role of SI (and probably also MGAM) in the pathogenesis of IBS-D (D = diarrhea) has been proposed.In this project we want to investigate the role of SI and MGAM in the pathogenesis of genetically determined carbohydrate malabsorption in CSID and IBS.1. We will first analyze the protein targeting and activity profiles of SI mutants in heterozygous inheritance pattern in CSID in comparison to wild-type SI. In parallel studies the influence of MGAM on the overall carbohydrate digestive capacity in this cellular model will be assessed.2. In a similar experimental set up we will study SI polymorphisms in IBS and their potential association with MGAM. For this purpose, the widespread gene variant V15F and other pathogenic SI variants with reduced enzymatic activities in IBS patients will be investigated.3. A wide screen will be envisaged to identify polymorphisms of SI and other carbohydrate digesting enzymes (CDE), (e.g. MGAM, lactase, pancreatic amylase) in patient samples and controls from various EU and US neurogastroenterology centers using targeted next generation sequencing. Following similar procedures as above, the effects of potential mutations found in these enzymes on their intracellular targeting and enzyme function will be analyzed with the ultimate goal of obtaining an unequivocal basic knowledge of the etiology of IBS relevant to CDE.These studies are expected to fundamentally expand our understanding of the molecular basis of carbohydrate malabsorption in functional gastrointestinal disorders.

• DFG Programme: Research Grants
• International Connection: Australia
• Cooperation Partner: Professor Mauro D' Amato, Ph.D.