Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis.

OBJECTIVE: Intestinal fibrosis is considered an inevitable consequence of chronic IBD, leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterised the composition and function of ECM in fibrostenosing Crohn's disease (CD) and control tissues. DESIGN: Decellularised full-thickness intestinal tissue platforms were tested using three different protocols, and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative PCR (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMFs) treated with milk fat globule-epidermal growth factor 8 (MFGE8) were evaluated regarding the mechanism of their antifibrotic response, and the action of MFGE8 was tested in two experimental intestinal fibrosis models. RESULTS: We established and validated an optimal decellularisation protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured (CDs) tissue, which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control HIMF but not CDs HIMF. Next-generation sequencing uncovered functionally relevant integrin-mediated signalling pathways, and blockade of integrin αvß5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo. CONCLUSION: MFGE8 displays antifibrotic effects, and its administration may represent a future approach for prevention of IBD-induced intestinal strictures.

Fibrosis in IBD: from pathogenesis to therapeutic targets.

BACKGROUND: Intestinal fibrosis resulting in stricture formation and obstruction in Crohn's disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking. OBJECTIVE: We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development. DESIGN: Data presented and discussed in this review derive from the past and recent literature and the authors' own research and experience. RESULTS AND CONCLUSIONS: Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.

Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease.

Advanced liver diseases account for approximately 2 million deaths annually worldwide. Roughly, half of liver disease-associated deaths arise from complications of cirrhosis and the other half driven by viral hepatitis and hepatocellular carcinoma. Unfortunately, the development of therapeutic strategies to treat subjects with advanced liver disease has been hampered by a lack of mechanistic understanding of liver disease progression and a lack of human-relevant animal models. An important advance has been made within the past several years, as several genome-wide association studies have discovered that an SNP near the gene encoding membrane-bound O-acyltransferase 7 (MBOAT7) is associated with severe liver diseases. This common MBOAT7 variant (rs641738, C>T), which reduces MBOAT7 expression, confers increased susceptibility to nonalcoholic fatty liver disease, alcohol-associated liver disease, and liver fibrosis in patients chronically infected with viral hepatitis. Recent studies in mice also show that Mboat7 loss of function can promote hepatic steatosis, inflammation, and fibrosis, causally linking this phosphatidylinositol remodeling enzyme to liver health in both rodents and humans. Herein, we review recent insights into the mechanisms by which MBOAT7-driven phosphatidylinositol remodeling influences liver disease progression and discuss how rapid progress in this area could inform drug discovery moving forward.