Gut Microbiota, Intestinal Barrier Function, and Metabolism Across Adiposity and Glucose Tolerance.

Background/Objectives: Obesity and dysglycemia are increasingly associated with intestinal barrier dysfunction and alterations in gut microbiota. Intestinal hyperpermeability is emerging as a therapeutic target in metabolic disorders, but human data integrating barrier biomarkers, epithelial morphology, and microbial composition remain scarce. Methods: Forty-six adults (82.6% female; 38.3 ± 7.8 years) were stratified into lean normoglycemic controls (CON), individuals with obesity and normoglycemia (NOB), and those with obesity and dysglycemia (DOB). Biochemical/inflammatory biomarkers, such as lipopolysaccharide (LPS) and LPS-binding protein (LBP), were measured. Duodenal biopsies were obtained by upper digestive videoendoscopy. Histomorphometry, expression of junctional and cytoskeletal proteins, and enzymatic activity of the duodenal epithelium were used as markers of intestinal permeability. Fecal microbiota composition (FMC) was analyzed by amplifying the V4 region of the 16S rRNA gene, which was sequenced using next-generation sequencing technology. Results: Duodenal histomorphometry did not differ across groups. Intestinal alkaline phosphatase (IAP) was significantly lower in DOB compared to CON. LPS correlated positively with fat mass, and LBP with the waist-to-hip ratio. The villus-to-crypt ratio correlated negatively with BMI, while IAP correlated inversely with fasting glucose and HbA1c. β-actin expression was inversely associated with BMI, glucose, insulin, and HOMA-IR. Microbiota diversity indices were similar between groups, although specific taxa, particularly within the Clostridiales order, were reduced in dysglycemia. Conclusions: Reduced IAP activity and consistent correlations between barrier biomarkers and metabolic parameters highlight intestinal barrier dysfunction as a relevant feature of obesity and dysglycemia. Subtle microbiota alterations further support a link between gut ecology and metabolic control. These findings underscore the intestinal barrier as a promising therapeutic target in metabolic disorders.