Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

The fourth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal fibrosis in the disease course of inflammatory bowel disease (IBD). The objective was to better understand the pathophysiological mechanisms of intestinal fibrosis, to identify useful markers and imaging modalities of fibrosis in order to assess its presence and progression, and, finally, to point out possible approaches for the prevention and the treatment of fibrosis. The results of this workshop are presented in three separate manuscripts. This first section describes the most important mechanisms that contribute to the initiation and progression of intestinal fibrosis in IBD including the cellular and molecular mediators, the extracellular matrix molecules and matrix metalloproteinases/tissue inhibitors of metalloproteinases-system, the microbiota products, the role of fat, genetic and epigenetic factors, as well as the currently available experimental models. Furthermore, it identifies unanswered questions in the field of intestinal fibrosis and provides a framework for future research.

Background and Purpose: Intestinal mucositis refers to mucosal damage caused by cancer treatment, and irinotecan is one of the agents most associated with this condition. Focusing on the development of alternatives to prevent this important adverse effect, we evaluated the activity of the flavonoid luteolin, which has never been tested for this purpose despite its biological potential.Experimental Approach: The effects of luteolin were examined on irinotecan‐induced intestinal mucositis in mice. Clinical signs were evaluated. Moreover, histological, oxidative, and inflammatory parameters were analysed, as well as the possible interference of luteolin in the anti‐tumour activity of irinotecan.Key Results: Luteolin (30 mg·kg⁻¹; p.o. or i.p.) prevented irinotecan‐induced intestinal damage by reducing weight loss and diarrhoea score and attenuating the shortening of the duodenum and colon. Histological analysis confirmed that luteolin (p.o.) prevented villous shortening, vacuolization, and apoptosis of cells and preserved mucin production in the duodenum and colon. Moreover, luteolin treatment mitigated irinotecan‐induced oxidative stress, by reducing the levels of ROS and LOOH and augmenting endogenous antioxidants, and inflammation by decreasing MPO enzymic activity, TNF, IL‐1β, and IL‐6 levels and increasing IL‐4 and IL‐10. Disruption of the tight junctions ZO‐1 and occludin was also prevented by luteolin treatment. Importantly, luteolin did not interfere with the anti‐tumour activity of irinotecan.Conclusion and Implications: Luteolin prevents intestinal mucositis induced by irinotecan and therefore could be a potential adjunct in anti‐tumour therapy to control this adverse effect, increasing treatment adherence and consequently the chances of cancer remission.

Intestinal fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent fibrosis once it has started. The processes that regulate fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of intestinal fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.

Background. Intestinal fibrosis is mainly associated with Crohn's disease and is defined as a progressive and excessive deposition of extracellular matrix comp