SKIN INJURY INDUCES A CHANGE IN INTESTINAL IMMUNE HOMEOSTASIS AND ALTERS THE GUT MICROBIOME

The composition of the microbial community in the intestine is known to influence the functions of distant organs such as the brain, lung, and skin. While it is well-established that these microbes can either promote disease or offer beneficial functions, our research advances the understanding of this dynamic interaction. Contrary to the conventional understanding that gut microbes primarily explain the co-occurrence of intestinal and skin diseases, our findings unveil a bidirectional axis, revealing that alterations in the skin can directly impact the gut microbiome and its homeostasis.
Using spatial transcriptome analysis, we observed that disruption limited to the skin by surgical incision, or transgenic expression of hyaluronidase gene HYAL1 in the epidermis which genetically mimicking skin inflammation, results in increased expression of antimicrobial genes regenerating islet-derived 3 (Reg3) and mucin 2 (Muc2) in the mouse colon. In vitro and extra vivo models provided further mechanistic insights into the observed alterations. Exposure to hyaluronan fragments in the models induced enhanced expression of Reg3 and Muc2 through TLR4 signaling. Shotgun sequencing provided additional insights into the specific shifts in the gut microbiome composition and the behavior of intestinal bacteria in response to these skin-induced changes and host epithelial defense responses. A critical finding of our research is the enhanced penetration of bacteria in the intestinal epithelium following skin wounding, exacerbating colitis induced by dextran sodium sulfate (DSS) model. Remarkably, we successfully alleviated severe colitis in these mice following skin intervention through the administration of oral antibiotics and using germ-free mouse models. Furthermore, when the fecal microbiome from skin-wounded mice was transplanted into unwounded recipients, it exacerbated DSS colitis compared to recipient mice with a control microbiome. These observations strongly indicate that the altered microbiome plays a critical role in the response to severe colitis following skin injury.
Collectively, these observations provide a direct link from the skin to the gut, substantiating the existence of a dynamic skin to gut axis. By revealing that the skin wounding can alter the gut microbiome, our study contributes to unraveling the intricate connections between distant organs, and potential therapeutic avenues for diseases with skin-gut axis involvement.