Iwata et al. Inflammation and Regeneration (2021) 41:21 Inflammation and Regeneration https://doi.org/10.1186/s41232-021-00174-7 REVIEW Open Access Pathogenesis and management of gastrointestinal inflammation and fibrosis: from inflammatory bowel diseases to endoscopic surgery Kentaro Iwata1,2†, Yohei Mikami1*† , Motohiko Kato1,2, Naohisa Yahagi2 and Takanori Kanai1* Abstract Gastrointestinal fibrosis is a state of accumulated biological entropy caused by a dysregulated tissue repair response. Acute or chronic inflammation in the gastrointestinal tract, including inflammatory bowel disease, particularly Crohn’s disease, induces fibrosis and strictures, which often require surgical or endoscopic intervention. Recent technical advances in endoscopic surgical techniques raise the possibility of gastrointestinal stricture after an extended resection. Compared to recent progress in controlling inflammation, our understanding of the pathogenesis of gastrointestinal fibrosis is limited, which requires the development of prevention and treatment strategies. Here, we focus on gastrointestinal fibrosis in Crohn’s disease and post-endoscopic submucosal dissection (ESD) stricture, and we review the relevant literature. Keywords: Gastrointestinal fibrosis, Crohn’s disease, Endoscopic surgery Background surgical wounds. Fibrostenosis of the gastrointestinal Gastrointestinal stricture is the pathological thickening tract, in particular, is a frequent complication of Crohn’s of the wall of the gastrointestinal tract, characterized by disease. Further, a recent highly significant advance in excessive accumulation of extracellular matrix (ECM) endoscopic treatment enables resection of premalignant and expansion of the population of mesenchymal cells. and early-stage gastrointestinal cancers. This procedure Gastrointestinal stricture leads to blockage of the gastro- does not involve surgical reconstruction of the gastro- intestinal tract, which significantly reduces a patient’s intestinal tract, although fibrotic stricture after endo- quality of life. Upper gastrointestinal stricture may cause scopic treatment is an emerging clinical problem. Here, nausea, vomiting, anorexia, and abdominal pain because we focus on post-endoscopic scarring and Crohn’s dis- of food stagnation. In addition to these obstructive ease, which cause artificial and spontaneous fibrosis of symptoms, lower gastrointestinal stricture may cause in- the gastrointestinal tract, and we review shared and testinal perforation, intra-abdominal abscess, and fistu- unique mechanisms of pathogenesis. lizing disease because of increased pressure in the region of the inflamed intestinal tract. Malignant and benign processes cause gastrointestinal Current endoscopic treatment and challenges stricture as well as inflammation and the healing of Endoscopic mucosal resection (EMR) and ESD are endo- scopic techniques for resecting epithelial tumours with * Correspondence: [email protected]; [email protected] low risk of metastasis. EMR is a conventional method to † Kentaro Iwata and Yohei Mikami contributed equally to this work. resect relatively small and superficial tumours. A metal 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan ring (named snare forceps) is used to capture the lesion Full list of author information is available at the end of the article that is excised using a high-frequency electric current. © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Iwata et al. Inflammation and Regeneration (2021) 41:21 Page 2 of 8 EMR is simple and safe; however, it is limited to rela- anatomically fixed to the retroperitoneum, even large tively small (e.g. less than approximately 20-mm diam- mucosal defects are less likely to cause stricture [11]. eter) lesions. Third, stricture could be prevented by approximating ESD was first reported in 1999 by Gotoda et al. [1]. the wounds along longitudinal direction; however, this is Unlike EMR, ESD enables secure resection, regardless of not possible in the oesophagus because of the lack of ex- lesion size or location, through precise dissection of the cess of mucosa. After endoscopic surgery in the submucosal layer. The costs of ESD of the stomach were oesophagus, the oesophageal lumen is narrow so that initially covered by health insurance in Japan in 2006, in the wounds frequently contact each other or ingested 2008 for the oesophagus, and in 2011 for the colon. food and liquid, which evokes subsequent infiltration of With the widespread use of screening endoscopy, the immune cells and production of chemokines and cyto- chances of early detection of cancer have increased [2– kines. These inflammatory responses in the healing 4], and it is a standard treatment worldwide. Moreover, process direct centre-directed healing and result in when applied to gastric cancer, ESD achieves higher en- the oesophageal stricture. Recent attempts of “tissue- bloc resection rates and lower local recurrence [5, 6] for shielding therapy” such as transplantation of oral mu- oesophageal [7] and duodenal cancers [7]. cosal cell sheets and polyglycolic acid sheets aim to An advantage of ESD is its ability to securely resect le- cover the wound surface and prevent the mechanical sions independent of their size; however, fibrostenosis contact of ingested substances or the neighbouring may occur after extended resection as a relatively fre- side of the wound surface [12]. These novel methods quent late adverse event (Fig. 1). In particular, an issue show some promising preliminary results but have in clinical practice, oesophageal stricture associated with not yet achieved complete protection of oesophageal submucosal fibrosis often develops during the healing of stricture after endoscopic surgery. The postoperative post-ESD ulcers, extending to approximately 75% of the oesophageal stricture leads to decreased quality of life, circumference [8–10], whereas the clinical impact of characterized as dysphagia and vomiting, even if the post-ESD stricture is relatively less in the stomach, duo- cancer or dysplasia is successfully removed. Methods denum, and colorectum compared to oesophagus. There such as prophylactic balloon dilatation, locoregional are some possible factors causing this different suscepti- steroid injection therapy, and oral steroid therapy ef- bility for post-ESD stricture depending on the organs. fectively prevent oesophageal stricture [13]. However, First, the lumen of the oesophagus is narrow, and un- oesophageal lacerations and bleeding occur as compli- digested food passes through it; therefore, even relatively cations of balloon dilatation [7]anddelayedperfor- mild stricture can easily cause symptoms such as dys- ation of steroidal injection [14], which may require phagia. Second, in the rectum and duodenum, which are surgery. Fig. 1 Management of fibrostenosis after ESD. Prophylactic balloon dilatation, localized steroid injection therapy, and oral steroid therapy are administered to prevent fibrostenosis after ESD. If a GI stricture develops, balloon dilation or surgical treatment is considered. Multiple types of treatment lead to diminution of a patient’s QOL Iwata et al. Inflammation and Regeneration (2021) 41:21 Page 3 of 8 Recently, implantation of oral mucosal epithelial cell Clinical features and epidemiology of chronic sheets [15], PGA-felt and fibrin gluing [16], and bio- inflammatory conditions that cause strictures in degradable stents [17], although useful, are not the gastrointestinal tract employed in routine clinical practice because of their Benign oesophageal strictures are caused by different ae- cost, time required, and technical problems. Further, tiologies. Gastroesophageal reflux disease and eosino- although tissue biopsy is important for definitive diag- philic gastritis have been two major causes of the nosis before administering ESD, submucosal fibrosis oesophageal strictures, but recent technological advances often develops after biopsy. Unfortunately, progress in in cancerous treatment strategies including radiation increasing our understanding of the pathogenesis of and endoscopic surgery highlight the rapid increase in gastrointestinal fibrosis and efforts to develop preven- iatrogenic or secondary strictures after treatment [26]. It tion and treatment methods lag behind the advances is of note that most of the aetiologies are associated with in ESD technology. the inflammatory process followed by stenosis and it is important to understand both inflammatory and remod- elling phages of the gastrointestinal tract. Among the Healing of oesophageal ulcers after endoscopy multiple aetiologies of oesophageal strictures, Crohn’s After endoscopic