Melatonin-mediated intestinal microbiota homeostasis improves skin barrier damage involvement of gut-skin axis dysfunction in aging mice.

Abstract

Researches suggested a close connection between the gut microbiome homeostasis and skin health. Melatonin, as a multifunctional molecule, has the potential to regulate intestinal homeostasis and skin function. The study further explored the potential mechanism of melatonin in ameliorating skin barrier damage from the perspective of the association between intestinal microbiota and gut-skin axis in aging mice. We established a natural aging-induced skin barrier damage mouse model with or without melatonin supplementation and fecal microbiota transplantation (FMT) to clarify the crucial role of intestinal microbiota-mediated gut-skin axis in melatonin improving skin barrier damage. Furthermore, lipopolysaccharide (LPS)-treated mice and human keratinocytes cells (HaCaT) explored the modulation mechanism of melatonin. Our results suggested that aging induced skin barrier damage, including skin microbiota disorder and epidermal barrier structure disruption, and intestinal dysbiosis. Similarly, FMT from aging mice and LPS treatment rebuild the aging-like skin barrier damage. Whereas, melatonin or resatorvid (TAK242, the antagonist of LPS) supplementation restored all consequence in aging and LPS-treated mice. In vitro, melatonin restored LPS-induced skin barrier proteins deficiency in HaCaT via decreasing the expression level of TLR4 and MyD88 and increasing the content of p-ERK, p-GSK-3β and β-catenin proteins, while the improving effects was mimicked by pretreatment with a TLR4 antagonist but were blocked by GSK-3β agonists. Our study revealed that melatonin-mediated intestinal microbiota homeostasis suppresses LPS escape to restore the skin barrier function, including skin dysbiosis and epidermal structural disruption via LPS/TLR4/MyD88/ERK/GSK-3β/β-catenin loop, further improving skin aging in mice.