Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders for which there are limited treatment options, yet which results in significant impairment of quality of life and societal costs. The severity of IBS correlates in multiple paradigms with sugar, and in particular fructose, intake. The current fructose consumption often exceeds the absorption capacity of the small intestine leading to its malabsorption. Previously we showed in rodents that malabsorbed fructose spills over to distal GI tract where it modifies the microbiota composition and an unexpected enteroendocrine cell (EECs) secretory pattern resulting in increased in cholecystokinin (CCK) in the distal region of the gut. Since CCK has been associated with pain signaling, here we propose to investigate the relationships between the microbiota changes resulting from fructose malabsorption, the CCK expression and visceral hypersensitivity. Based on the complementary expertise of the 2 partners involved in the project (intestinal physiology, microbiota, IBS and EEC biology), we will first, investigate, in both rodents and humans, the relationship between the microbiota and the visceral hypersensitivity in the context of fructose malabsorption. Then, we will examine whether CCK mediates visceral hypersensitivity . Finally,we will examine the mechanisms by which malabsorbed fructose induces changes in the EEC features that result in the increase in CCK synthesis. We will use complementary approaches of microbiota analysis (in mice and humans), transfer of intestinal microbiota (mouse to mouse and human to mouse), as well as new mouse genetic models and organoids to decipher the mechanisms involved in the regulation of CCK in distal gut and its role in the development of visceral hypersensitivity. Our results will provide important clinically-relevant information about the mechanisms of hypersensitivity in IBS in the context of fructose malabsorption that may lead to better stratification of IBS patients.