Fructose malabsorption induces dysbiosis and increases anxiety in Human and animal models

Background & AimsExcessive fructose intake is a growing public health concern, yet many individuals have a lower absorption capacity than the average intake, leading to widespread chronic fructose malabsorption. This results in intestinal fructose spillover, disrupting gut microbiota and triggering peripheral inflammation, which, along with neuroinflammation, plays a key role in mood disorders. This study investigates the connection between fructose malabsorption and mood disorders by examining gut microbiota changes in a human cohort and exploring their links with neuroinflammation in a GLUT5-KO mouse model. MethodsIn a human cohort, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS) levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, Glut5-KO mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed. ResultsAmong the recruited healthy volunteers, 60% exhibited fructose malabsorption, along with elevated plasma LPS levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, Glut5-KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes. ConclusionsThese findings highlight the complex interplay between dietary fructose, gut microbiota, and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions. HIGHLIGHTSO_LIFructose malabsorption is associated with anxiety traits in healthy volunteers. C_LIO_LIFructose malabsorption enhances anxiety-like behaviors in malabsorptive Glut5-KO mice. C_LIO_LIFructose malabsorption is associated with gut microbiota dysbiosis in human and preclinical mouse model of fructose malabsorption in association with fructose intake C_LIO_LIFructose malabsorption increases neuroinflammation and alters microglia functions in malabsorptive Glut5-KO mice. C_LI