Could the small intestine hold key answers to understanding irritable bowel syndrome? In this interview, Tim Vanuytsel, Associate Professor and gastroenterologist at UZ Leuven, explores why research should look beyond the colon, particularly given the early onset of symptoms after food intake in many patients. The discussion examines increased nutrient-induced small intestinal motility, impaired barrier function, and mast cell activation as potentially relevant mechanisms. It also addresses the challenges of studying the small intestinal microbiome and questions the interpretation of lactulose breath tests, which may reflect accelerated intestinal transit rather than bacterial overgrowth. Moving beyond a focus on bacterial numbers, the interview highlights the need to investigate microbial composition and its relationships with permeability, immune activation, and symptom generation. Studying these interconnected mechanisms with advanced techniques could help clarify the small intestine’s contribution to IBS pathophysiology.