Short term overfeeding disrupts small intestinal barrier integrity and activates hepatic immunity in healthy men.

Obesity is associated with intestinal barrier dysfunction and low-grade inflammation, prompting investigations of early human adaptations to overnutrition. In a controlled "holiday-style" overfeeding model, healthy men underwent a 2-week hypercaloric, sedentary lifestyle with 8-week follow-up (ClinicalTrials.gov NCT04859322). A targeted gastrointestinal uptake and translocation (GUT) plasma panel showed increased citrulline, consistent with enhanced epithelial absorptive capacity, and mucosa-restricted immune activation, reflected by elevated anti-lipopolysaccharide (LPS) immunoglobulin (Ig)A, without systemic 16S rRNA changes. A dynamic zonulin-like signal and hepatic inflammatory markers (serum amyloid A (SAA), C-reactive protein, interleukin-32) also increased after overfeeding. Most perturbations normalized after return to habitual lifestyle, but anti-LPS IgA, SAA, lipocalin-2, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 remained elevated, indicating a partially persistent inflammatory imprint. These findings reveal how overfeeding episodes reshape epithelial, mucosal, and hepatic immune responses and highlight plasma biomarker panels as scalable tools to interrogate intestinal function and gut-liver crosstalk in human studies.