212 Skin Controls the Gut Immune Response Through Innate ECM Cross Talk

Inflammatory bowel diseases (IBD) associate with skin inflammatory diseases but why this occurs is unknown. Inflammation or wounding of the skin induces Cemip hyaluronidase in the dermal extracellular matrix (ECM) and production of HA fragments that have been shown to be recognized by TLR4. We hypothesized that such HA fragments may enable the skin to promote inflammation in the gut. To test this, mice expressing hyaluronidase in the skin (K14/Hyal1 mice), or mice with skin wounds (Wd), were compared to their littermate controls. Both groups showed HA digestion in the dermis but expression of Hyal1 did not induce skin inflammation. Remarkably, both skin interventions enhanced disease in the colon when mice were fed DSS, seen histologically, by increased weight loss (p<0.0001), lower survival rates (Control 100% survived, K14/Hyal1: 20%, Wd; 80%), and FACS. Even in the absence of DSS challenge, scRNA Seq of colons from K14/Hyal1 revealed large changes in the abundance of stromal fibroblast subsets; cluster 5 increased from 1.21% to 43.2%, clusters 0, 2 and 7 decreased from 29.8 to 4.16%, 18.9 to 0% and 4.5 to 0%, respectively). Pseudotime analysis distinguished three lineages within these populations with HA-induced shift from Cluster 2 toward 5 in lineage 3 most associated with fat cell differentiation. Genes altered in these subsets were validated by whole tissue RNA Seq and qRT-PCR. Colon fibroblasts from TLR4-/- mice failed to respond to HA fragments. DSS challenge in mice further induced genes related to adipogenesis. Reanalysis of scRNA-Seq data from healthy human subjects and patients with newly diagnosed IBD was consistent with our observations in mice of increased fat cell differentiation. Taken together, these results show the role of fibroblasts and reactive adipogenesis in tissue inflammation and directly demonstrate how the skin can control intestinal inflammation.