Skin injury alters the gut microbiome and intestinal immune homeostasis in mice, establishing a skin-to-gut axis. Skin damage or hyaluronan digestion increases expression of host defense genes Reg3 and Muc2 in the colon, altering intestinal bacteria composition and behavior. These changes enhance colitis from dextran sodium sulfate (DSS) as shown by oral antibiotic treatment, germ-free mice, and fecal microbiome transplantation. Skin injury increases the abundance of bacteria like Akkermansia muciniphila and Lachnospiraceae bacterium A4, while decreasing beneficial bacteria such as those involved in propionate catabolism. Skin injury also increases bacterial penetration through the intestinal epithelium, potentially leading to increased disease severity. The skin-to-gut axis is mediated by hyaluronan fragments, which act as damage-associated molecular patterns (DAMPs) to induce host defense gene expression. This study shows that skin inflammation can alter the gut microbiome, increasing susceptibility to DSS-induced colitis. The findings suggest that skin health is crucial for maintaining gut microbiome balance and that skin-related changes can influence intestinal immune homeostasis. The study highlights the importance of the skin-gut axis in disease pathogenesis and the potential for therapeutic interventions targeting the microbiome in inflammatory bowel disease (IBD).Skin injury alters the gut microbiome and intestinal immune homeostasis in mice, establishing a skin-to-gut axis. Skin damage or hyaluronan digestion increases expression of host defense genes Reg3 and Muc2 in the colon, altering intestinal bacteria composition and behavior. These changes enhance colitis from dextran sodium sulfate (DSS) as shown by oral antibiotic treatment, germ-free mice, and fecal microbiome transplantation. Skin injury increases the abundance of bacteria like Akkermansia muciniphila and Lachnospiraceae bacterium A4, while decreasing beneficial bacteria such as those involved in propionate catabolism. Skin injury also increases bacterial penetration through the intestinal epithelium, potentially leading to increased disease severity. The skin-to-gut axis is mediated by hyaluronan fragments, which act as damage-associated molecular patterns (DAMPs) to induce host defense gene expression. This study shows that skin inflammation can alter the gut microbiome, increasing susceptibility to DSS-induced colitis. The findings suggest that skin health is crucial for maintaining gut microbiome balance and that skin-related changes can influence intestinal immune homeostasis. The study highlights the importance of the skin-gut axis in disease pathogenesis and the potential for therapeutic interventions targeting the microbiome in inflammatory bowel disease (IBD).