Continuous activation of the immune system inside a tissue can lead to remodelling of the tissue structure and creation of a specific microenvironment, such as during the tumour development. Chronic inflammation is a central player in stimulating changes that alter the tissue stroma and can lead to fibrotic evolution. In the colon mucosa, regulatory mechanisms, including TGF-β1, avoid damaging inflammation in front of the continuous challenge by the intestinal microbiome. Inducing either DSS colitis or AOM colorectal carcinogenesis in AVN-Wistar rats, we evaluated at one month after the end of each treatment whether immunological changes and remodelling of the collagen scaffold were already in development. At this time point, we found in both models a general downregulation of pro-inflammatory cytokines and even of TGF-β1, but not of IL-6. Moreover, we demonstrated by multi-photon microscopy the simultaneously presence of pro-fibrotic remodelling of the collagen scaffold, with measurable changes in comparison to the control mucosa. The scaffold was significantly modified depending on the type of induced stimulation. These results suggest that at one month after the end of the DSS or AOM inductions, a smouldering inflammation is present in both induced conditions, since the pro-inflammatory cytokines still exceed, in proportion, the local homeostatic regulation of which TGF-β1 is a part (inflammatory threshold). Such an inflammation appears sufficient to sustain remodelling of the collagen scaffold that may be taken as a possible pathological marker for revealing pre-neoplastic inflammation.

Biomedical Center at Medical Faculty of Charles University alej Svobody 1655 76 323 00 Plzeň Severní Předměstí Czech Republic

Centre of Toxicology and Health Safety The National Institute of Public Health Šrobárova 49 48 100 00 Praha 10 Czech Republic

Faculty of Science Charles University Albertov 6 128 00 Praha 2 Czech Republic

Institute of Biology and Medical Genetics Charles University Purkyně Institute Albertov 4 128 00 Prague 2 Czech Republic

Institute of Experimental Medicine of the CAS v v i Vídeňská 1083 142 20 Prague 4 Czech Republic

Institute of Experimental Oncology Biomedical Research Center of the Slovak Academy of Sciences Dubravska 9 845 05 Bratislava Slovakia

Institute of Microbiology of the CAS v v i Vídeňská 1083 142 20 Prague 4 Czech Republic

Institute of Physiology of the CAS v v i Vídeňská 1083 142 20 Prague 4 Czech Republic

Pedagogical Faculty Selye Janos University Bratislavská cesta 3322 945 01 Komárno Slovakia

Thomayer University Hospital 1st Medical Faculty Charles University Vídeňská 800 140 59 Praha 4 Czech Republic

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