Lactoferrin Modulates Intestinal Morphology and Microbiota Homeostasis in Chronic Social Defeat Stress Mice

Abstract

Chronic social stress is increasingly linked to gut–brain axis dysfunction, yet gut-targeted interventions remain underexplored. This study investigated whether oral lactoferrin (L) administration modulates the intestinal and behavioral consequences of chronic social defeat stress (CSDS) in male C57BL/6J mice. Animals were randomly assigned to four groups—Control, Control+L, CSDS, and CSDS+L—and received lactoferrin (5 mg/kg/day) or vehicle via oral gavage over 15 days concurrent with the CSDS paradigm. Behavioral assessments (fur condition scoring, splash test, open field test), intestinal permeability (FITC-dextran assay), whole gut transit, small-intestine morphology and tight junction protein expression (ZO-1, claudin-5), gut microbiota composition (16S rRNA gene sequencing), and oxidative DNA damage repair activity were evaluated. CSDS induced significant fur deterioration, body weight loss, and reduced grooming behavior, all of which were partially attenuated by L supplementation. In the ileum, CSDS increased crypt number and trended toward decreased claudin-5 expression, whereas L treatment increased crypt depth relative to stressed controls. Although alpha and beta diversity remained unchanged, CSDS prevented the physiological decline of the Firmicutes-to-Bacteroidetes ratio observed in controls, was associated with differences in gut microbiota composition, and L partially restored this trajectory. DNA repair enzyme activities were unaffected. These findings indicate that L mitigates stress-induced somatic deterioration and intestinal alterations, positioning it as a promising gut-targeted nutritional adjunct for stress-related disorders.