High‐Sugar Diet and Intestinal Diseases: A Shared Microbiota–Barrier–Immunity–Metabolism Axis in Inflammatory Bowel Disease, Food Allergy, and Colorectal Cancer

ABSTRACT

The global incidence of intestinal diseases—including food allergy, inflammatory bowel disease (IBD), and colorectal cancer (CRC)—continues to escalate in parallel with the expansion of the “Western diet,” within which the high‐sugar diet (HSD) has emerged as a pivotal yet under‐recognized dietary driver. This review aims to define how HSD disrupts intestinal homeostasis and to establish a unified mechanistic framework that links three traditionally separate disorders—IBD, food allergy, and CRC—through a shared pathogenic axis. Preclinical and clinical studies over the past decades, along with foundational studies, where appropriate, were synthesized and stratified by evidence type (animal models, epidemiological cohorts, and clinical intervention trials), with particular attention to the distinct biological effects of fructose, glucose, sucrose, and high‐fructose corn syrup. The evidence indicates that HSD perturbs intestinal homeostasis through four interconnected mechanisms: remodeling of the gut microbiota toward dysbiosis with suppression of beneficial symbionts and short‐chain fatty acid (SCFA) production; dysregulation of host metabolism via SCFA depletion and a skewed bile acid profile; compromise of the intestinal barrier through mucus‐layer erosion and tight junction disassembly (“leaky gut”); and activation of innate and adaptive immune responses accompanied by immunometabolic reprogramming. These upstream events converge on a common “microbiota–barrier–immunity–metabolism” axis but diverge downstream into Th17/Th1‐driven mucosal inflammation in IBD, Th2/IgE‐mediated sensitization in food allergy, and a protumor microenvironment in CRC. In summary, HSD acts as a critical environmental stressor whose shared upstream mechanisms and divergent downstream outcomes help explain the concurrent rise of these intestinal disorders. Defining intestinal sugar‐sensing pathways and interindividual microbiome heterogeneity is expected to enable precision nutritional interventions—such as targeted dietary sugar management—for the prevention and treatment of intestinal diseases.