The identification of molecular signatures that aid early diagnosis of complex tissue pathologies, ‎such as inflammatory diseases, ‎poses a major scientific and clinical challenge due to their genetic ‎and phenotypic heterogeneity. We have been able to unprecedentedly discover a distinct tissue ‎state occurring before the onset of inflammatory clinical symptoms by integrating quantitative ‎proteomics with advanced microscopy analyses. Through monitoring colonic extracellular matrix ‎‎(ECM) ‎remodeling in colitis animal models we have unexpectedly revealed that pre-‎symptomatic ‎tissues display a unique ECM signature in terms of molecular ‎composition, morphology and ‎stiffness. By applying‏ ‏advanced computational analyses we were able to project quantitative ‎proteomics data onto an axis correlating with spatially resolved tissue damage originating from ‎the ECM. These results bridge the gap between tissue structure and composition while outlining ‎the predictive ‎power of the cellular microenvironment in early diagnostics of ‎inflammatory ‎diseases. ‎