From tissue to blood: an integrated multi-omics signature identifies fibrogenesis and neutrophil activation as key drivers of ulcerative colitis severity.

Introduction: Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon characterized by severe disease burden and multiple co-morbidities. Currently, the endoscopic Mayo score is considered the gold standard for assessing disease severity in UC. However, the molecular mechanisms underlying severity are still poorly understood. This study aimed to better understand the molecular alterations associated with severity in UC. To achieve this goal, gene expression and DNA methylation were measured in paired blood and colonic tissue samples from UC patients at different severity stages. Methods: Differential gene expression and methyl-ation analyses, as well as integrative multi-omics network analysis including both omics layers and tissues were performed. A hybrid framework combining prior knowledge and text-mining was deployed to contextualize the associations retrieved from the multi-omics network. Results: Our analyses suggested that mild UC was associated with molecular alterations affecting mainly the colon, while severe UC had systemic consequences. Moreover, the combination of the differentially expressed genes and methylated regions found in blood and colonic tissue allowed us to suggest potential associations between them and formulate hypothesis on novel mechanisms associated with different UC severity stages. Discussion: Among them, fibrogenesis, colonic epithelial cell death, and Tuft cell-related processes seemed to be associated with milder disease stages. In contrast, neutrophil-driven innate immune response and complex B cell and CD4 T cell interactions were suggested as potential mechanisms involved in severe UC. Finally, the findings of this study led to the formulation of a hypothesis suggesting that impaired PPARG anti-inflammatory regulation associated with colonic LCN2 activity might play a relevant role in UC severity.