Cellular and Molecular Mechanisms of Intestinal Fibrosis

Wu Xiaomin,Lin Xiaoxuan,Tan Jinyu,Liu Zishan,He Jinshen,Hu Fan,Wang Yu,Chen Minhu,Liu Fen,Mao Ren 거트앤리버 소화기연관학회협의회 2023 Gut and Liver Vol.17 No.3

Intestinal fibrosis associated stricture is a common complication of inflammatory bowel disease usually requiring endoscopic or surgical intervention. Effective anti-fibrotic agents aiming to control or reverse intestinal fibrosis are still unavailable. Thus, clarifying the mechanism underpinning intestinal fibrosis is imperative. Fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins at the injured sites. Multiple cellular types are implicated in fibrosis development. Among these cells, mesenchymal cells are major compartments that are activated and then enhance the production of ECM. Additionally, immune cells contribute to the persistent activation of mesenchymal cells and perpetuation of inflammation. Molecules are messengers of crosstalk between these cellular compartments. Although inflammation is necessary for fibrosis development, purely controlling intestinal inflammation cannot halt the development of fibrosis, suggesting that chronic inflammation is not the unique contributor to fibrogenesis. Several inflammation-independent mechanisms including gut microbiota, creeping fat, ECM interaction, and metabolic reprogramming are involved in the pathogenesis of fibrosis. In the past decades, substantial progress has been made in elucidating the cellular and molecular mechanisms of intestinal fibrosis. Here, we summarized new discoveries and advances of cellular components and major molecular mediators that are associated with intestinal fibrosis, aiming to provide a basis for exploring effective anti-fibrotic therapies in this field.

Gene and protein expression of epithelial to mesenchymal transition for intestinal and anal fistula: a systematic review

Osman Nadila Haryani,Jailani Ruhi Fadzlyana,Rahman Hayati Abd,Hamid Nazefah Abdul 대한대장항문학회 2023 Annals of Coloproctolgy Vol.39 No.2

Purpose: Intestinal fibrosis is a common complication of inflammatory bowel diseases. However, the possible involvement of epithelial-mesenchymal transition (EMT) has been scarcely investigated. This systematic review aims to search through research papers that are focusing on messenger RNA (mRNA) and protein expression profile in EMT in fistula or in intestinal fibrosis.Methods: Electronic exploration was performed until April 24, 2019 through PubMed, Ovid, Science Direct, and Scopus databases with the terms of “fistula” OR “intestinal fibrosis” AND “epithelial-mesenchymal transition”. Two independent reviewers scrutinized the suitability of the title and abstract before examining the full text that met the inclusion criteria. For each study, the sample types that were used, methods for analysis, and genes expressed were identified. The list of genes was further analyzed using DAVID (Database for Annotation, Visualization, and Integrated Discovery) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway.Results: There were 896 citations found; however, only 3 studies fulfilled the requirements. Among the EMT-related genes, 5 were upregulated genes at mRNA level while 6 were at protein level. However, only 2 downregulated genes were found at each mRNA and protein level. Of the 4 inflammation-related genes found, 3 genes were upregulated at mRNA level and 1 at protein level. These genes were confirmed to be involved in the development of inflammatory induced fibrosis and fistula through EMT. Results from quantitative real-time polymerase chain reaction analysis were consistent with the process of EMT, confirmed by the western blot protein analysis.Conclusion: Many significant genes which are involved in the process of EMT in fistula and intestinal fibrosis have been identified. With high-end technology many more genes could be identified. These genes will be good molecular targets in the development of biomarkers for precision drug targeting in the future treatment of intestinal fibrosis and fistula.

Influence of Chongcao Yigan Capsule on Function of Intestinal Flora and Chemoprevention for Patients with Chronic Hepatitis B-Induced Liver Fibrosis

Zhao, Xiao-Hu,Cao, Zheng-Yu,Shen, Yang,Lv, Yu-Feng,Tao, Guang-Rong,Chen, Sheng Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.21

Objective: Hapatitis B visus (CHB)-induced fibrosis is a precancerous condition of liver. To explore the influence of Chongcao Preparation (Chongcao Yigan Capsule) on the function of intestinal flora and chemoprevention for patients with CHB-induced liver fibrosis. Methods: A total of 136 patients with CHB-induced liver fibrosis were randomly divided into control group treated with lamivudine (LAM) and research group added with Chongcao Yigan Capsule for totally 48 weeks. The changes of intestinal flora, secretory immunoglobin A (SIgA), serum albumin (ALB), prealbumin (PALB), IgA and IgG at different time points in both groups were observed. Results: Before treatment, there was no significant difference between two groups in each index (P>0.05). After treatment, the intestinal flora were evidently optimized in research group than treatment before (P<0.05 or P<0.01), and were apparently better than those in control group (P<0.05 or P<0.01); SIgA was obviously increased and ALB, PALB, IgA and IgG were markedly improved in research group than treatment before (P<0.05 or P<0.01), and were significantly better than those in control group (P<0.05 or P<0.01). Conclusions: Chongcao Yigan Capsule could regulate the intestinal flora, increase SIgA, serum ALB and PALB concentrations and significantly improve serum IgA and IgG as well as strengthen the immunological function and autologous repair capacity of patients with CHB-induced liver fibrosis.

Animal models of inflammatory bowel disease: novel experiments for revealing pathogenesis of colitis, fibrosis, and colitis-associated colon cancer

( Chan Hyung Lee ),( Seong-joon Koh ),( Zaher A Radi ),( Aida Habtezion ) 대한장연구학회 2023 Intestinal Research Vol.21 No.3

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a lifelong disease that manifests with chronic intestinal inflammation, sequential fibrosis, and an increased risk of colitis-associated colon cancer (CAC). The combined effects of genetic, immunological, environmental, and microbial factors render it difficult to determine the specific mechanism underlying the induction and perpetuation of IBD. Various animal models of IBD have contributed enormously to the understanding of IBD pathogenesis in terms of genomics, transcriptomics, proteomics, microbiome, and drug development of novel therapeutics. Although comprehensive research on IBD has been enabled by advanced technologies, such as genetically engineered models, there is a great need to develop relevant in vivo models of colitis and fibrosis. Here, we review 4 categories of animal models of acute and chronic intestinal inflammation, fibrosis, and CAC: chemically induced, genetically engineered, T cell transfer, and spontaneous gene mutation models. (Intest Res 2023;21:295-305)

Encapsulating peritoneal sclerosis in liver transplant recipients

Kyo Won Lee,Chan Woo Cho,Nuri Lee,Sanghoon Lee,Jong Man Kim,Gyu-Seong Choi,Choon Hyuck David Kwon,Jae-Won Joh,Suk-Koo Lee 대한외과학회 2017 Annals of Surgical Treatment and Research(ASRT) Vol.92 No.3

Encapsulating peritoneal sclerosis (EPS) is a rare cause of intestinal obstruction by a thick fibrous membrane wrapping around the small intestine. It is a possible complication after liver transplantation (LT) that can be fatal. This report describes 2 cases of EPS after LT that were successfully treated with surgery, corticosteroids, tamoxifen, and mammalian target of rapamycin inhibitor. After treatment in both cases, the patients were able to start oral feeding and have been symptom free for more than 1 year. These cases suggests that for the management of EPS, surgical treatment is mandatory when the patients present with symptoms of intestinal obstruction or if there are findings suggestive of decreased mural perfusion. Surgery should be accompanied with medical treatment to prevent the relapse of EPS.

Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice

( Jin Imai ),( Takashi Yahata ),( Hitoshi Ichikawa ),( Abd Aziz Ibrahim ),( Masaki Yazawa ),( Hideaki Sumiyoshi ),( Yutaka Inagaki ),( Masashi Matsushima ),( Takayoshi Suzuki ),( Tetsuya Mine ),( Kiyo 대한장연구학회 2020 Intestinal Research Vol.18 No.2

Background/Aims: Intestinal fibrosis is a major complication of Crohn’s disease (CD). The profibrotic protein transforming growth factor-β (TGF-β) has been considered to be critical for the induction of the fibrotic program. TGF-β has the ability to induce not only the expression of extracellular matrix (ECM) including collagen, but also the production of plasminogen activator inhibitor-1 (PAI-1) that prevents enzymatic degradation of the ECM during the onset of fibrotic diseases. However, the significance of PAI-1 in the developing intestinal fibrosis has not been fully understood. In the present study, we examined the actual expression of PAI-1 in fibrotic legion of intestinal inflammation and its correlation with the abnormal ECM deposition. Methods: Chronic intestinal inflammation was induced in BALB/c mice using 8 repeated intrarectal injections of 2,4,6-trinitrobenzene sulfonic acid (TNBS). TM5275, a PAI-1 inhibitor, was orally administered as a carboxymethyl cellulose suspension each day for 2 weeks after the sixth TNBS injection. Results: Using a publicly available dataset (accession number, GSE75214) and TNBS-treated mice, we observed increases in PAI-1 transcripts at active fibrotic lesions in both patients with CD and mice with chronic intestinal inflammation. Oral administration of TM5275 immediately after the onset of intestinal fibrosis upregulated MMP-9 (matrix metalloproteinase 9) and decreased collagen accumulation, resulting in attenuation of the fibrogenesis in TNBS-treated mice. Conclusions: PAI-1-mediated fibrinolytic system facilitates collagen degradation suppression. Hence, PAI-1 inhibitor could be applied as an anti-fibrotic drug in CD treatment. (Intest Res 2020;18:219-228)

Mast Cells Tryptase Promotes Intestinal Fibrosis in Natural Decellularized Intestinal Scaffolds

Wan Jian,Wu Tianqi,Liu Ying,Yang Muqing,Fichna Jakub,Guo Yibing,Yin Lu,Chen Chunqiu 한국조직공학과 재생의학회 2022 조직공학과 재생의학 Vol.19 No.4

BACKGROUND: Standard two-dimensional (2D) culture has confirmed the mechanism of mast cells (MCs) in the pathogenesis of inflammatory bowel disease (IBD), but the regulation of signaling responses of MCs may well differ in three-dimensional (3D) microenvironments. The aim of the study was to develop a 3D culture model based on decellularized intestinal scaffolds (DIS) and verify how MCs influenced fibroblasts phenotype in the 3D model. METHODS: DIS were achieved using the detergent technique and extracellular matrix (ECM) components were verified by histologic analysis, quantification and scanning electron microscope. After human colon fibroblasts recellularized into the scaffolds and activated by MCs tryptase and TGFb1, the changes in genes and signaling pathways during fibroblasts activation in 3D were studied and compared with the changes in 2D cell culture on plastic plates. RESULTS: Decellularization process effectively removed native cell debris while retaining natural ECM components and structure. The engrafted fibroblasts could penetrate into the scaffolds and maintain its phenotype. No matter whether fibroblasts were cultured in 2D or 3D, MCs tryptase and transforming growth factor b1 (TGF-b1) could promote the differentiation of fibroblasts into fibrotic-phenotype myofibroblasts through Akt and Smad2/3 signaling pathways. Furthermore, the pro-collagen1a1 and fibronectin synthesis of myofibroblasts in 3D was higher than in 2D culture. CONCLUSION: Our results demonstrated that the DIS can be used as a bioactive microenvironment for the study of intestinal fibrosis, providing an innovative platform for future intestinal disease modeling and screening of genes and signaling pathways.

Unusual intestinal obstruction due to idiopathic sclerosing encapsulating peritonitis

Chun-Seok Yang,Daedong Kim 대한외과학회 2016 Annals of Surgical Treatment and Research(ASRT) Vol.90 No.4

Sclerosing encapsulating peritonitis (SEP) is a rare cause of intestinal obstruction that is characterized by a thick fibrotic membrane encasing the small intestine like a cocoon. Accurate preoperative diagnosis is often difficult. We present 2 cases of SEP that were diagnosed preoperatively by contrast-enhanced computed tomography scan. A 38-year-old man and a 56-year-old woman were admitted to Daegu Catholic University Medical Center because of recurrent intestinal obstruction. We performed exploratory laparotomy with doubt of the preoperative diagnosis of SEP. We confirmed the diagnosis of SEP on laparotomy and performed adhesiolysis. Both patients recovered successfully and had no signs of recurrence. A better awareness of SEP and its radiological features should lead to more correct preoperative diagnosis and result in more appropriate management, including surgery.

Fibrostenotic strictures in Crohn’s disease

( Jun Hwan Yoo ),( Stefan Holubar ),( Florian Rieder ) 대한장연구학회 2020 Intestinal Research Vol.18 No.4

The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn’s disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD. (Intest Res 2020;18:379-401)