The maintenance of a healthy skin barrier is crucial to prevent and treat atopic dermatitis (AD) lesions and avoid infections. Glycomacropeptide (GMP) is a bioactive peptide that has demonstrated promising results as an anti-inflammatory and antipruritic therapy for experimental AD. This study aimed to analyze the effect of GMP on impaired cutaneous barrier-related signs in a rat model of AD lesions. AD-like dermatitis was induced on the skin by repeated topical applications of 2,4-dinitrochlorobenzene, and animals were orally administered GMP before or after AD induction. The expression of skin structural proteins and antimicrobial peptides (AMPs) was evaluated by immunoblot or immunohistochemistry, epidermal thickening was evaluated by histochemistry, the level of IFN-γ and changes in the microbiota were evaluated by quantitative polymerase chain reaction, and the quantity of fecal short-chain fatty acids (SCFAs) was evaluated by gas chromatography. GMP administration significantly increased filaggrin, β-defensin 2, and cathelicidin-related AMP expression in AD-like lesions. Involucrin expression was not modified. In GMP-treated animals, epidermal thickening and IFN-γ expression were strongly reduced in damaged skin. GMP treatment impacted the skin microbiota and prevented Staphylococcus aureus colonization, which is associated with AD. In addition, high levels of Bifidobacterium were detected in the feces of GMP-treated animals, and the acetic acid and butyric acid contents increased in animals prophylactically administered GMP. These results suggest that GMP markedly prevents or reverses skin barrier damage in rat AD-like lesions through a bifidogenic effect that induces fecal SCFA production with prolonged treatment. Our findings provide evidence that GMP may represent an optimum strategy for the therapy of the dysfunctional cutaneous barrier in AD.

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