Role of glucagon-like peptides in inflammatory bowel diseases—current knowledge and future perspectives

Naunyn-Schmiedeberg's Archives of Pharmacology https://doi.org/10.1007/s00210-019-01698-z REVIEW Role of glucagon-like peptides in inflammatory bowel diseases—current knowledge and future perspectives Hubert Zatorski 1 & Maciej Sałaga 1 & Jakub Fichna 1 Received: 5 March 2019 / Accepted: 15 July 2019 # The Author(s) 2019 Abstract Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, relapsing, intestinal inflammatory disorders with complex and yet unrevealed pathogenesis in which genetic, immunological, and environmental factors play a role. Nowadays, a higher proportion of elderly IBD patients with coexisting conditions, such as cardiovascular disease and/or diabetes is recorded, who require more complex treatment and became a great challenge for gastroenterologists. Furthermore, some patients do not respond to anti-IBD therapy. These facts, together with increasing comorbidities in patients with IBD, imply that urgent, more complex, novel therapeutic strategies in the treatment are needed. Glucagon-like peptides (GLPs) possess numerous functions in the human body such as lowering blood glucose level, controlling body weight, inhibiting gastric emptying, reducing food ingestion, increasing crypt cell proliferation, and improving intestinal growth and nutrient absorption. Thus, GLPs and dipeptidyl peptidase IV (DPP-IV) inhibitors have recently gained attention in IBD research. Several animal models showed that treatment with GLPs may lead to improvement of colitis. This review presents data on the multitude effects of GLPs in the inflammatory intestinal diseases and summarizes the current knowledge on GLPs, which have the potential to become a novel therapeutic option in IBD therapy. Keywords Crohn’s disease . GLP-1 . GLP-2 . Incretins . Inflammatory bowel disease . Ulcerative colitis Abbreviations CD Crohn’s disease DPP-IV Dipeptidyl peptidase IV DSS Dextran sulfate sodium EEC Enteroendocrine cells GI Gastrointestinal tract GIP Gastro-insulinotropic peptide GLP Glucagon-like peptide GM-CSF Granulocyte-macrophage colony-stimulating factor IBD Inflammatory bowel diseases IFN-γ Interferon γ IGF-1 Insulin-like growth factor 1 IL Interleukin LPS Lipopolysaccharide PC 1/3 Prohormone convertase 1/3 * Jakub Fichna 1 Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland PEG SCFA TNBS TNF-α UC Polyethylene glycosyl Short-chain fatty acids 2,4,6-trinitrobenzenesulfonic acid Tumor necrosis factor α Ulcerative colitis Introduction Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, relapsing, intestinal inflammatory conditions with complex and yet unrevealed pathogenesis in which genetic, immunological, and environmental factors play a role (Sobczak et al. 2014). Inflammation in CD involves the entire gut wall and may occur in any part of gastrointestinal (GI) tract, whereas in UC, only colonic mucosa is affected (Zatorski et al. 2015). Both diseases are associated with alterations of the innate and adaptive immune system, microbiota, and epithelial function (Zietek et al. 2017; Siczek et al. 2017). Thus, inappropriate response to different pathogens in epithelial surface may cause release of inflammatory cytokines and induce inflammation. Naunyn-Schmiedeberg's Arch Pharmacol The incidence and prevalence of IBD are the highest in westernized countries, suggesting the increasing role of environmental factors (Molodecky et al. 2012). Importantly, while incidence of IBD is still rising, the mortality is low and thus the prevalence of IBD escalates globally (Molodecky et al. 2012). Nowadays, a higher proportion of elderly IBD patients with coexisting diseases, such as cardiovascular disease and/ or diabetes (Román and Muñoz 2011), is recorded; these patients require more complex treatment and became a great challenge for gastroenterologists. Moreover, recent studies showed that 15–40% of IBD patients suffer from obesity, which becomes an increasing problem in IBD treatment. It has also been evidenced that obese IBD patients have shorter time to first surgery as well as lower quality of life in comparison with non-obese IBD sufferers (Singh et al. 2017). Currently, 5-aminosalicylates, immunosuppressive agents, corticosteroids, and biological therapeutics are widely used in IBD therapy. However, some patients do not respond to the treatment. Moreover, the side effects and economic costs of IBD patients’ treatment cannot be ignored (Stallmach et al. 2010; van der Valk et al. 2016). These facts, together with increasing comorbidities in patients with IBD, imply that urgent, more complex, novel therapeutic strategies in the treatment are needed. Enteroendocrine cells (EEC) comprise approximately 1% of the intestinal epithelium, but secrete more than 30 different peptide hormones, which makes them the largest endocrine system in the whole body (Worthington 2015). Most important bioactive compounds secreted by enteroendocrine L cells in the gut due to nutrient uptake are glucagon-like peptides (GLPs) including GLP-1 and GLP-2. GLP-1 plays a fundamental role in lowering blood glucose level and controlling body weight through stimulating the islet B cells to secrete insulin, inhibiting gastric emptying and reducing food ingestion (Zietek et al. 2017). Thus, GLP-1-based therapy is nowadays widely used in the treatment of type 2 diabetes, especially in obese subjects. On the other hand, GLP-2 analogs due to their effects on crypt cell proliferation, improving intestinal expansion and nutrient absorption, are used for intestinal injury and short bowel syndrome (Litvak et al. 1998; Yazbeck et al. 2010a). GLPs are rapidly degraded by dipeptidyl peptidase IV (DPP-IV), which results in their short half-lives in vivo. Thus, GLPs and DPP-IV inhibitors have recently gained attention in IBD research (Lund et al. 2011; Moran et al. 2013; Mimura et al. 2013; Duan et al. 2017; Salaga et al. 2018). Several investigations showed that treatment with GLPs may lead to improvement in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis (Table 1). This review presents data on the multitude effects of GLPs in the inflammatory intestinal diseases. It summarizes the current knowledge on GLPs, which have the potential to becoming a novel therapeutic option in IBD therapy. Glucagon-like peptides GLP-1 and GLP-2 derive from transcription product of the proglucagon gene gcg located on chromosome 2. Both GLP1 and GLP-2 are simultaneously produced via posttranslational processing of proglucagon by prohormone convertase 1/3 (PC 1/3) (Fig. 1). GLP-1 is mainly produced in the ileum and the colon and it is known as the most potent incretin in the human body, which delays gastric emptying and lowers postprandial blood glucose level through augmentation of glucose-dependent insulin release (Lim et al. 2009). M (...truncated)