Dermal injury drives a skin-gut axis that disrupts the intestinal microbiome and intestinal immune homeostasis

The composition of the microbial community in the intestine influences the functions of distant organs such as the brain, lung, and skin. These microbes can promote disease or have beneficial functions, leading to the hypothesis that microbes in the gut explain the co-occurrence of intestinal and skin diseases. Here, we show that the reverse can occur, and that skin directly alters the gut microbiome. Disruption of the dermis by skin wounding or the digestion of dermal hyaluronan results in increased expression in the colon of antimicrobial genes Reg3 and Muc2 and changed the composition and behavior of remaining intestinal bacteria. Enhanced expression Reg3 and Muc2 was induced in vitro by exposure to hyaluronan released by these skin interventions. The change in the colon microbiome after skin wounding was functionally important as these bacteria penetrated the intestinal epithelium and enhanced colitis from dextran sodium sulfate (DSS) as shown by the ability to rescue skin associated DSS colitis with oral antibiotics, in germ-free mice, and fecal microbiome transplantation to unwounded mice from mice with skin wounds. These observations provide direct evidence of a skin-gut axis by demonstrating that damage to the skin disrupts homeostasis in intestinal host defense and alters the gut microbiome.