Chromogranin A and other enteroendocrine markers in inflammatory bowel disease.

YNPEP-01698; No of Pages 8 Neuropeptides xxx (2016) xxx–xxx

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Chromogranin A and other enteroendocrine markers in inflammatory bowel disease Sara Massironi a,⁎, Alessandra Zilli a,b, Federica Cavalcoli a,b, Dario Conte a,b, Maddalena Peracchi a,b a b

Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy Postgraduate School of Gastroenterology, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy

a r t i c l e

i n f o

Article history: Received 2 November 2015 Received in revised form 10 January 2016 Accepted 10 January 2016 Available online xxxx Keywords: Chromogranin A Enteroendocrine cell Inflammatory bowel disease Crohn's disease Ulcerative colitis

a b s t r a c t Changes in the distribution and products of enteroendocrine cells may play a role in immune activation and regulation of gut inflammation. This review aims at critically evaluating the main enteroendocrine markers in inflammatory bowel diseases (IBD). A narrative review was performed by searching inflammatory bowel diseases and enteroendocrine biomarkers in PubMed. Relevant modifications of some enteroendocrine markers, such as Chromogranin A, and their correlation with disease activity have been reported in patients with inflammatory bowel diseases. Even if data about neuroendocrine markers are sometimes contrasting, they may be potentially useful for the diagnosis and clinical management of these patients. © 2016 Published by Elsevier Ltd.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . 3.1. Chromogranin A (CgA) . . . . . . . 3.2. Serotonin (5-HT) . . . . . . . . . . 3.3. Somatostatin (SS) . . . . . . . . . . 3.4. Vasoactive intestinal peptide (VIP) . . 3.5. Substance P (SP) . . . . . . . . . . 3.6. Neurotensin (NT) . . . . . . . . . . 3.7. Ghrelin . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . Conflict-of-interest and source of funding statement Acknowledgments . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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1. Introduction The gastrointestinal (GI) endocrine system is the largest endocrine organ of the human body with more than one hundred different hormonally active peptides produced (Engelstoft et al., 2013; Miller,

⁎ Corresponding author at: Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. E-mail addresses: [email protected] (S. Massironi), [email protected] (A. Zilli), [email protected] (F. Cavalcoli), [email protected] (D. Conte), [email protected] (M. Peracchi).

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0 0 0 0 0 0 0 0 0 0 0 0 0 0

2009; Schonhoff et al., 2004; Shulkes, 1990; Solcia et al., 1993; Zissimopoulos et al., 2014). In healthy subjects, enteroendocrine cells (EECs) produce a variety of chemical transmitters involved in gastrointestinal motility, secretion, absorption, response to food, thus maximizing the digestion and absorption of nutrients, maintaining epithelial integrity and contributing to the mucosal innate immune system (Table 1). Many of the GI tract peptides are also found in the enteric nervous system and the central nervous system and the interaction between the central and enteric nervous system accounts for the brain-gut axis, which exerts control over digestive processes, secretion, motility, immune function and

http://dx.doi.org/10.1016/j.npep.2016.01.002 0143-4179/© 2016 Published by Elsevier Ltd.

Please cite this article as: Massironi, S., et al., Chromogranin A and other enteroendocrine markers in inflammatory bowel disease, Neuropeptides (2016), http://dx.doi.org/10.1016/j.npep.2016.01.002

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S. Massironi et al. / Neuropeptides xxx (2016) xxx–xxx

Table 1 Gastroenteropancreatic endocrine cells and their products. Substance

Cell type

GI location

Major actions

Secretin Ghrelin

S P/D1

Duodenum, jejunum Stomach

Gastrin Cholecystokinin Glucagon

G I α

Gastric antrum, duodenum Duodenum, jejunum Pancreas

Glucagon-like peptide

L

Small and large intestine

Insulin

β

Pancreas

Pancreatic polypeptide Somatostatin

F δ

Glucose-dependent insulinotropic peptide (GIP) Motilin Histamine

K

Pancreas Pancreas, stomach, small and large intestine Small intestine

It stimulates pancreatic bicarbonate secretion. It promotes intestinal cell proliferation and inhibits apoptosis during inflammatory states. It suppresses pro-inflammatory mechanisms and augments anti-inflammatory mechanisms Gastric acid and pepsin secretion Pancreatic enzyme secretion, gallbladder contraction. It lowers the glucose concentration, promotes insulin secretion, gluconeogenesis and glycogenolysis. It increases insulin secretion, inhibits gastric acid secretion and gastric emptying, decreases glucagon secretion. It controls glucose balance. It increases glycogen synthesis and esterification of fatty acids. It decreases proteolysis, lipolysis, gluconeogenesis. It controls glucose balance. It inhibits pancreatic bicarbonates and protein secretion. Inhibitory effects on several functions (motility, secretion, etc.…)

EC2 ECL

Small intestine Stomach

Peptide YY Vasointestinal Peptide (VIP)

L D1

Neuropeptide (NPY) Neurotensin Serotonin (5-HT)

… N EC

Small and large intestine Pancreas, small and large intestine Small intestine Ileum Small intestine

It enhances glucose-mediated insulin release. It inhibits gastric secretion. It initiates interdigestive intestinal motility. It is primarily involved in vasodilation. Also, it stimulates gastric acid secretion. It inhibits pancreatic bicarbonates and protein secretion. It induces smooth muscle relaxation. It stimulates pancreatic bicarbonate secretion. It inhibits pancreatic bicarbonates and protein secretion. Vasodilation It promotes smooth muscle gut contraction, gastric acid secretion, emesis, vasoconstriction.

ECL: enterochromaffin-like; EC: enterochromaffin.

blood flow (Bonaz & Bernstein, 2013; El-Salhy et al., 1997; Miller, 2009). The NE cells share a number of common features, including the production of secretory granules, maturation and exocytosis of granule products, and the synthesis of specific proteins, e.g. hormones, neuropeptides and chromogranins, including chromogranin A (CgA). CgA is co-stored and co-released with regulatory peptides with impact on a wide range of normal and pathophysiological functions (D'amico et al., 2014; Helle, 2010). Moreover, the EEC products influence immune functions, such as lymphocyte proliferation and immunoglobulin production, by modulating T helper cell differentiation, cytokine secretion, natural killer cell activity and phagocytosis. Inflammatory processes may influence the diffuse neuroendocrine system via the production of cytokines and neuropeptides (Bedoui et al., 2007; Hernanz et al., 1996; Wheway et al., 2007) and this interaction between the enteric nervous system and the immune system probably plays a role in the pathophysiology of inflammatory bowel diseases (IBD), even if contrasting data about the actual role of these neuropeptides have been reported. EECs can be grouped into three main cell types: 1) pan-GI tract EECs (somatostatin and 5-HT secreting cells), which can be found throughout the GI tract; 2) gastro-selective ones (gastrin, histamine and ghrelin secreting cells); 3) an intestinal-selective cell lineage, which can produce cholecystokinin (CCK), secretin, glucose-dependent insulinotropic peptide (gastric inhibitory peptide: GIP), glucagon-like peptide-1 and -2 (GLP-1/-2), peptide YY (PYY) and neurotensin (Egerod et al., 2012; Habib et al., 2012). In the gastrointestinal wall close anatomical associations among the terminal axons of enteric neurons, entero-endocrine cells and inflammatory cells facilitate neuroimmune communications (Castagliuolo et al., 1999; Liu et al., 2002). In particular, neuropeptides have shown to act as chemical messengers (Collins, 1996) and to modulate immunoglobulin production, lymphocyte proliferation, chemotaxis, phagocytosis, release of granular proteins from neutrophils, and also the migration and homing patterns of lymphocytes (Collins, 1996; Mantyh, 1991; Renzi et al., 1998). The most abundant EECs expression has been reported in the duodenum (producing CCK from the socalled I cells and secretin from S cells) and the terminal ileum (producing PYY and GLP-1/-2) (Cox, 2007a; Cox, 2007b; Ekblad & Sundler,

2002; McGowan & Bloom, 2004; Moran & Dailey, 2011; Ueno et al., 2008), the segment of the gut most commonly affected by CD. Finally, PYY is also produced in smaller quantities by the enteric neurons of the stomach and pancreatic endocrine cells (Böttcher et al., 1993). CCK and PYY exert appetite-controlling effects. Differently from PYY and PP, which are produced mainly in the EECs, NPY, the major source of which is from enteric neurons, can be found at all levels of the gut– brain axis (Holzer et al., 2012). NPY and PYY inhibit gastrointestinal motility and electrolyte secretion (Holzer-Petsche et al., 1991; Hubel & Renquist, 1986). In the GI tract, NPY plays an important role in regulating inflammatory processes (El-Salhy & Hausken, 2015), as demonstrated by the close contact between NPY-containing nerve fibers and immune cells, such as IgA-producing lymphocytes in mice's ileal lamina propria (Shibata et al., 2008). The ability of NPY to promote colonic inflammation is supported by the evidence that NPY knockout mice are resistant to the induction of dextran sulfate sodium (DSS)-induced colitis (Chandrasekharan et al., 2008; Painsipp et al., 2011). A decrease of colonic PYY levels has been reported in rats with DSS-induced colitis (Hirotani et al., 2008) and in IBD patients (Schmidt et al., 2005; Tari et al., 1988) while the circulating levels of PYY and NPY are enhanced (Adrian et al., 1986). The release of PP inhibits gastric emptying through an action that involves the vagus nerve (Field et al., 2010; Murphy et al., 2006) and has an inhibitory action on the intestinal motor activity and peristalsis (Fujimiya & Inui, 2000). This review will highlight some of the studies aimed at identifying the role of neuropeptides in the development of IBD.

2. Methods We conducted a literature search of PubMed using the following key words: “inflammatory bowel disease” OR “Crohn's disease” OR “ulcerative colitis” AND “enteroendocrine markers” OR “chromogranin A” OR “somatostatin” OR “vasointestinal active peptide” OR “serotonin” OR “substance P” OR “ghrelin”. We repeated the search using the terms “IBD” OR “CD” OR “UC” AND “CgA” OR “VIP” OR “SS” OR “5-HT” OR “SP” OR “NT”. Additional information was retrieved by a hand search of the reference lists of relevant articles.



3. Results 3.1. Chromogranin A (CgA) CgA, which is a 49-kDa acidic glycoprotein, represents the main soluble protein co-stored and co-released together with other bioactive peptides. CgA is found in the secretory vesicles of endocrine cells and also in NE cells of the GI tract under both physiologic and pathologic conditions. An increase in the total number of endocrine cells defined as CgAimmunoreactive has been described in IBD. Moreover, slightly elevated circulating CgA levels have recently been reported in IBD patients, although the CgA pattern in this setting remains to be elucidated. CgA and its N-terminal fragment, called vasostatin-1 (VS-1), are important modulators of the endothelial barrier function and potent inhibitors of the endothelial cell activation caused by inflammatory and pro-angiogenic cytokines, with potential implications in angiogenesis, inflammation and cancer. Accordingly, the recombinant VS-1 fragment is able to protect vessel from TNF-induced vascular leakage in vivo and to inhibit the paracellular flux of radiolabelled albumin through endothelial cell monolayers in vitro (Corti & Ferrero, 2012). Considering the inhibitory effect of CgA on TNF-induced vascular leakage observed in mice it is possible that the production of circulating CgA contributes to reducing the potentially dangerous effect of TNF on the vascular endothelium. To date there are only a few reports about the role of circulating CgA as a marker of disease activity in IBD (Table 2). Elevated CgA levels have been noted in ca. 30% to 50% of IBD patients, mainly with clinically active disease (Sciola et al., 2009; Sidhu et al., 2010; Spadaro et al., 2005). In a large cohort of patients with active ulcerative colitis (UC) or Crohn's disease (CD) the CgA concentration has been reported as significantly increased compared to controls (Sciola et al., 2009). The pivotal role of inflammation was proved by higher CgA levels in the active rather than quiescent disease. CgA expression was correlated to TNFα expression, the extent of disease, and disease activity, independently on the IBD type. As suggested by Moran et al. (Moran et al., 2012), EEC upregulation in intestinal inflammation is not a mere bystander of the inflammatory process but is actually an integral part of the process: elevated CgA levels are therefore a putative biomarker for that. In fact, the enteroendocrine system has been further shown to have a central role in appetite disturbances and in mucosal immune reactions in IBD, so that it can represent a novel treatable therapeutic target.

In their recent study, Zissimopoulos et al. (Zissimopoulos et al., 2014) aimed at assessing the role of CgA in evaluating the disease activity and responsiveness to medical treatment in IBD patients. Overall, serum CgA resulted significantly higher in patients with IBD than in those with irritable bowel syndrome (IBS) and predominant diarrhea or healthy volunteers. Furthermore, serum CgA was higher in CD than in UC patients, with significant reduction following a biological agents-based regimen, whereas a slight increase was observed in the conventional treatment group. However, the exact meaning of CgA elevation in IBD remains to be better clarified, as well as it remains unknown whether neuroendocrine cell hyperplasia is a feature of IBD. Overall, according to the above findings, CgA may be a marker of disease activity and responsiveness to biologic therapy in IBD patients. The tissue origin of circulating CgA in subjects with inflammatory diseases is unknown, but the role for CgA as a modulator of inflammatory processes has been postulated (D'amico et al., 2014). Various organs and tissues potentially contribute to the pool of circulating CgA, including adrenal medulla, the sympathoadrenergic and diffuse neuroendocrine systems (Corti & Ferrero, 2012; Helle et al., 2007). Interestingly, polymorphonuclear neutrophils (PMN) have emerged as a significant source of CgA. After accumulation at the site of inflammation, PMN can release CgA and CgA-derived fragments for paracrine modulation of target cells, such as endothelial ones. Also, a regulatory link between CgA secretion and tumor necrosis factor (TNF) activation has been postulated (Corti & Ferrero, 2012). The terminal ileum is the key site of EECs expression, but its detailed assessment in CD has not been fully undertaken. Moran et al. (Moran et al., 2012) described enhanced EEC activity in the small bowel. Weak evidence of the presence of CgA-positive cells in the bowels results from a study that demonstrated increased areas of CgA-positive cells in the colonic mucosa of UC and CD patients (Bonaz & Bernstein, 2013). Accordingly, Strid et al. (Strid et al., 2013) recently reported higher levels of fecal CgA and secretogranins in UC patients both with active disease and in remission as compared to healthy controls. Moreover, there has been quite a number of reports (Dodd, 1986; Grassia et al., 2009; Miller & Sumner, 1982; Sigel & Goldblum, 1998; Strid et al., 2013) of neuroendocrine carcinoma associated with UC and it may be hypothesized that pancellular dysplasia or neuroendocrine differentiation could be responsible for the development of this kind of tumor. In addition to the evaluation of circulating CgA in IBD patients, some recent studies have investigated the value of fecal chromogranin in UC and CD patients (Strid et al., 2013; Wagner et al., 2013). In 2013 Strid et al. reported higher levels of fecal CgA in UC patients with active

Table 2 Studies reporting results on the role of Chromogranin A (CgA) in inflammatory bowel diseases. Patients

Main findings

Zissimopoulos A et al. Scand Original Circulating CgA J Gastroenterol, (2014) article

29 UC patients, 27 CD patients, 17 IBS-D patients

Strid H et al. J Crohns Colitis, Original Analyses of CgA, CgB, SgII, SgIII (2013) article and calprotectin in stool samples Review Circulating chromogranins Khan WI and Ghia JE. Clin Exp Immunol, (2010) Role of enteroendocrine cells Moran GW and McLaughlin Letter (EEC) in IBD JT. Inflamm Bowel Dis, (2010) Sidhu R et al. Inflamm Letter Serum CgA Bowel Dis, (2010) Sciola V et al. Inflamm Original Circulating CgA Bowel Dis, (2009) article

41 UC patients and 29 healthy controls

Baseline serum CgA levels are significantly higher in IBD patients than in controls and IBS-D patients. CgA levels significatively decreased in patients treated with biologic. Fecal chromogranins and secretogranins significatively increased in UC. CgA was not associated with disease activity. The role of chromogranins in inflammation was not clear. Chromogranins may contribute to the inflammatory mechanisms.

Article (authors, source)

Type of article

Object of study

3

–

–

39 patients with IBD, 87 patients with IBS-D 75 patients with UC, 44 with CD, in active and quiescent phases

Intestinal inflammation was intrinsically associated with changes in EEC. This would be an explanation for the increase in plasma CgA. CgA levels were elevated in 30.8% (n = 12) of patients with IBD and 50.6% (n = 44) of patients with IBS-D. CgA levels were significantly higher in IBD patients than in controls. Disease activity and TNF-α levels seem to influence the CgA pattern.

UC = ulcerative colitis, CD = crohn disease, IBS-D = irritable bowel syndrome-diarrhea, entero-endocrine cells (EEC).


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disease as compared to healthy controls (Strid et al., 2013). Moreover, the same group showed a correlation between fecal chromogranin B and secretogranin II and disease duration, thus concluding that fecal granins were not correlated to acute inflammation in UC, but they seem to reflect mucosal alteration evolving over time. Further studies, also extended to CD patients, are required to fully understand the role of fecal granins in patients with IBD. Based on the aforementioned reports and data, CgA could be potentially useful in the diagnosis and clinical management of IBD patients, although further studies are necessary to support this hypothesis. With regard to any possible diagnostic value, CgA determination possibly helps in discriminating IBD from IBS, as Zissimopoulos et al. (Zissimopoulos et al., 2014) reported significantly higher circulating CgA levels in IBD than in IBS, with mild overlap, greater for the UC subset. However, the role of CgA would be of greater importance in CD than in UC patients, as the onset of UC is typically acute or sub-acute, while the presentation of CD is often misleading owing to a significant diagnostic delay. Thus, the measurement of circulating CgA and/or fecal granins may be included in the panel of exams currently used for the diagnostic evaluation of patients with symptoms consistent with CD. In the same study, patients treated with anti-TNF agents presented a significant reduction in CgA levels after 4 weeks of treatment. The relation between TNFα and CgA has already been evaluated in a previous study on rheumatoid arthritis (Di Comite et al., 2009a), a disease presenting some common features with IBD. In this context, a significant correlation between CgA circulating levels and the TNF receptor was reported (Di Comite et al., 2006), whereas a treatment with infliximab eliminates this relationship, thus suggesting a possible role of CgA and TNF assay in the selection of the best candidates for biological therapy and the monitoring of their therapeutic response. Otherwise, in the study by Zissimipoulos et al. patients treated with steroids showed a significant increase of the CgA values, although most patients were in remission (Zissimopoulos et al., 2014). Similarly, an increase in fecal CgA levels in patients treated with thiopurines and steroids has been reported (Strid et al., 2013). It has already been suggested that treatment with steroids can activate CgA gene expression (Rozansky et al., 1994), thus increasing the levels of CgA mRNA. Similar findings were reported in a previous study by Di Comite et al. (Di Comite et al., 2009b) with a mild elevation of CgA levels in giant cell arteritis treated with steroids. In this setting, however markedly elevated circulating levels of CgA were observed in patients refractory to corticosteroid treatment, reflecting a persistent arterial inflammation despite proper treatment. Accordingly, particularly high CgA levels in patients with IBD may help to identify those patients at increased risk of recurrence at the tapering of steroids, making them suitable for alternative immunosuppressant regimens. Finally, several studies have reported elevated CgA levels in patients with tumors of different origin (Spadaro et al., 2005; Wu et al., 2000) including the colonic ones. Thus, persistently high CgA levels can identify the subset of patients at higher risk of developing cancer. Moreover, in UC patients the hyperplasia of colonic neuroendocrine cells (Miller & Sumner, 1982; Sciola et al., 2009) and onset of microcarcinoids have been reported in hyperplastic areas (Matsumoto et al., 2003). Finally, carcinoid tumors in patients with IBD, which were considered a rare event, seem to occur more frequently than previously reported. In this setting, the diagnosis of neuroendocrine tumors can be a clinical challenge; however, the study of Sciola et al. (2009) reported that CgA values above four-times ULN can safely distinguish patients with neuroendocrine tumors from those with IBD alone (Sciola et al., 2009). 3.2. Serotonin (5-HT) EECs are the main source of 5-HT, which is implicated in intestinal secretion, peristalsis and modulation of immune cell function in the gut (Gershon, 2013). Conflicting data about the 5-HT levels in the

mucosa/submucosa of IBD patients have been reported. In fact, a study by Magro et al. (Magro et al., 2002) showed lower 5-HT levels in the inflamed mucosa of IBD patients than in controls, differently from most studies indicating high serotonin content in the colonic mucosa of rats with DSS-induced colitis (Oshima et al., 1999) and high serotonin levels in UC and CD patients (Sikander et al., 2014). Of the 5-HT receptors expressed in the gut, the 5-HT3 receptor has been one of the most widely studied: it modulates T-cell activation and proliferation. In the study by Motavallian et al. (Motavallian et al., 2013), the administration of tropisetron, a 5-HT3 receptor antagonist, reduced the inflammatory response to TNBS-induced colitis in rats, whereas this effect is antagonized by the administration of a selective 5-HT3 agonist. Furthermore, decreased colonic macroscopic and microscopic damage scores have been observed in experimental rats treated with tropisetron, even if its beneficial effects were lower than those from dexamethasone (Mousavizadeh et al., 2009). Therefore, further studies are needed to evaluate the efficacy and effectiveness of 5-HT agonist in IBD. Dysregulation of 5-HT is associated with constipation or diarrhea and an upregulation of the colonic tryptophan hydroxylase 1 (TPH1) mRNA has been observed by Minderhoud et al. (Minderhoud et al., 2007) in CD patients in remission, but presenting IBS-like symptoms. Ghia et al. (Ghia et al., 2009) showed that the blocking of 5-HT production by disruption of TPH1 reduced the clinical, macroscopic and histologic severity of colitis in experimental models, thus supporting a pro-inflammatory role of 5-HT. Noteworthy, in this context, a significant association has recently been reported between serum serotonin levels and the Pouchitis Disease Activity Index endoscopy score in patients with ileal pouch-anal anastomosis Wang et al. (Wang et al., 2013). The serotonin reuptake transporter vehicles released 5-HT into neurons or epithelial cells; the presence of the l allele is associated with more serotonin reuptake (Sikander et al., 2014). The function and expression of this transporter is reduced in mice with TNBS-colitis with consequent increased mucosal 5-HT content (Linden et al., 2005). However, the impact of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitor on patients with IBD has not been systematically studied.

3.3. Somatostatin (SS) Most of the total somatostatin (SS) content of the human body is stored in the digestive tract, mainly in the pancreas and gut (Patel et al., 1981; Shulkes, 1994): 90% of gut SS is localized in the endocrine cells, while the remaining 10% in the enteric nerves of the muscular layer (Penman et al., 1983). The immunomodulatory effects of SS depend on local SS levels, as in vitro low SS concentrations inhibit the gastrointestinal motility and secretion, immunoglobulin synthesis and the proliferation of granulocytes and lymphocytes (Eglezos et al., 1993; Goetzl & Payan, 1984; Malec et al., 1989; Payan et al., 1984), whereas high SS concentrations lead to stimulation of granulocytes and lymphocytes proliferation (Pawlikowski et al., 1985). Moreover, SS has been reported to reduce inflammation mediated by substance P (SP) (Kataeva et al., 1994). However, to date there are no systematic in vivo or in vitro studies on the effects of SS in IBD. Biochemical and morphological analyses of intestinal and blood samples from IBD patients indicate that a decrease of the number of mucosal SS-containing cells in the distal colon of IBD patients, parallels to the degree of inflammation (Ahonen et al., 1976; Watanabe et al., 1992), even if this reduction is not so evident in CD patients. In murine acetic-acid-induced colitis, SS prevents mucosal damage (Yamamoto et al., 1996), probably by reducing interleukin-2 receptor expression in lamina propria lymphocytes, inhibiting lymphocytic proliferation (Eliakim et al., 1993; Elitsur & Luk, 1990; Fais et al., 1991) and modulating the expression of tight junction proteins, which play a role in the intestinal barrier protection (Li et al., 2014).



3.4. Vasoactive intestinal peptide (VIP) VIP has been suggested to be an excellent candidate for the treatment of inflammatory/autoimmune diseases (Abad et al., 2006; Smalley et al., 2009). It modulates both innate and adaptive immunity, with a predominant anti-inflammatory action, decreases the Th1/Th2 cytokine balance and promotes T regulatory functions (Ganea et al., 2006; Gonzalez-Rey et al., 2007; Leceta et al., 2006). Its biological effects are mediated by two G protein-coupled receptors, VPAC1 and VPAC2. Studies about VIP expression in IBD patients are limited and conflicting, possibly because of the diversity of tissue sampling methods and patient populations. A preliminary report indicated an abnormal appearance and a significant increase of VIPergic nerves in rectal biopsies of CD patients, independently of rectal involvement, while in UC patients such an increase was limited to the cases with active proctitis, whereas the morphology of VIP nerves was normal (O'Morain et al., 1984). In contrast, Kubota et al. (1992) observed an increase of VIPimmunoreactive nerves in the lamina propria of IBD patients, which was significantly associated with the severity of disease (Kubota et al., 1992). As to the expression of VIP receptors, Yukawa et al. (Yukawa et al., 2007) found increased numbers of VIP receptors on CD3+ and CD68+ cells in the UC mucosa and on CD68+ cells in the CD mucosa. Finally, Duffy et al. (Duffy et al., 1989) highlighted a strong positive association between circulating VIP levels and clinical activity with twofold increases in VIP levels during active disease, thus suggesting a possible role of VIP in gauging disease activity. In a murine model of intestinal inflammation – 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis – the prophylactic treatment using high doses of VIP obtained the inhibition of leucocyte chemotaxis, but failed to reduce the severity and mortality of colitis (Newman et al., 2005) while in another murine TNBS-colitis VIP treatment resulted in: the recovery of clinical items (e.g. body weight gain, disappearance of macroscopic and microscopic signs of colitis, decrease of serum amyloid A levels), the balance of inflammatory mediators from T lymphocytes and granulocytes and the modulation of TLR2 and 4 receptors not only in the colon but also in different cell populations from the mesenteric lymph nodes, including macrophages, dendritic cells, T and B lymphocytes (Arranz et al., 2008a). The ex vivo treatment of mesenteric lymph node cells with VIP reduced their responsiveness to TLR4 and TLR2 ligands, thus downregulating the TLR-induced Th1 cytokine profile (Arranz et al., 2008b). In fact, the VIP treatment reduced interferon (Abad et al., 2003) and TNF-α, a Th1-related cytokine implicated in the epithelial changes in CD (Salim & Söderholm, 2010). Based on the above findings, VIP has potential therapeutic application in IBD, even if further studies are needed to confirm these results and to evaluate possible secondary effects of VIP treatment.

3.5. Substance P (SP) SP is a neuropeptide secreted by nerves and inflammatory cells, such as macrophages, eosinophils and lymphocytes. SP acts by binding to the neurokinin-1 receptor (NK-1R) and reportedly exhibits pro-inflammatory effects in the acute phase of colitis (O'Connor et al., 2004), whereas it participates in mucosal healing in the chronic phase (Carraway & Leeman, 1975). The gut is one of the most abundant sources of SP. However, the studies about the role of SP in the pathophysiology of IBD are conflicting: the quantity of SP binding was significantly increased in the inflamed mucosa of IBD patients (Ter Beek et al., 2007), but the levels of colonic SP in IBD patients vs. controls have been reported to be higher, lower or normal (Derocq et al., 1996; Goetzl et al., 2008; O'Connor et al., 2004). A difference between CD and UC is that NK-1R seems to be upregulated only in the affected areas in UC but ubiquitously in CD patients. There is lack of data on the neurokinin-1 antagonists in humans, even if the studies from animal models indicate that they seem to

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ameliorate the severity and/or suppress experimentally induced colitis (Margolis & Gershon, 2009). 3.6. Neurotensin (NT) Neurotensin (NT), produced in small quantities in the brain and in large amounts in the gastrointestinal tract, acts mainly through the high-affinity neurotensin receptor 1 (NTSR1), which is a member of the G-protein-coupled receptor family (Najimi et al., 2002). A possible role of NTS/NTSR1 in the pathogenesis of IBD and colitis-associated neoplasia has recently been reported (Gui et al., 2013). NT seems to have contrasting effects on the colonic mucosa of IBD patients. In fact, it enhances mast cell degranulation and neutrophil recruitment (Cooke, 1994). In addition, NTSR1 expression is increased in the human colonic mucosa with UC, as well as in rodent colitis induced by Clostridium difficile toxin A or by dextran sulfate sodium (DSS) (Kokkotou et al., 2009). On the other hand, NT promotes mucosal healing after the acute phase, by transactivating the receptor for the epithelial growth factor receptor, which facilitates repair of a wounded epithelium (Brun et al., 2005). 3.7. Ghrelin Ghrelin, which is a 28-amino-acid peptide involved in multiple homeostatic functions in humans, is produced by A-like cells mainly localized in the oxyntic mucosa of the stomach. A smaller proportion of ghrelin originates from the small and large intestines and pancreas (Hosoda et al., 2003). Ghrelin exerts various endocrine and nonendocrine functions, including control of food intake, energy homeostasis and regulation of gastrointestinal motility (Cheung & Wu, 2013; Korbonits et al., 2004). It has been shown that different gastrointestinal disorders involving infection, inflammation, and malignancy may alter ghrelin production and secretion (Cheung & Wu, 2013). Moreover, ghrelin can play a role in modulating immune responses and inflammatory processes as it exerts potent anti-inflammatory effects in vitro and in vivo (Dixit et al., 2004; Peracchi et al., 2006). As to the role of ghrelin in IBD, its circulating levels were significantly increased in UC and CD patients (Eissa & Ghia, 2015; Karmiris et al., 2006). Moreover, in patients with active IBD, there is a positive correlation demonstrated between ghrelin and serum inflammatory markers, such as TNFα, C-reactive protein, erythrocyte sedimentation rate, and fibrinogen (Ates et al., 2008; Peracchi et al., 2006). Furthermore, ghrelin normalization has been observed in IBD patients in remission (Peracchi et al., 2006) and an increase of colonic ghrelin production has been reported in IBD patients compared with normal controls (Hosomi et al., 2008). To date, ghrelin treatment in IBD has been evaluated in animal models of colitis, in which it showed with a positive impact on both the clinical and histopathologic severity of colitis, thus prompting the authors to suggest that it may be a new therapeutic target in IBD (Gonzalez-Rey et al., 2006). 4. Discussion The diffuse neuroendocrine system consists of specialized EECs, widely dispersed throughout the GI tract and responsible for the production of gastrointestinal regulatory peptides and biogenic amines (Miller, 2009; Schonhoff et al., 2004; Shulkes, 1990; Solcia et al., 1993; Zissimopoulos et al., 2014). EEC-derived peptides are involved in the control of GI tract motility, gastrointestinal inflammation and play a role in the gut–brain axis (Engelstoft et al., 2013). The recent and growing evidence herein presented suggests that intestinal inflammation is intrinsically associated with changes in EEC biology, and this would be a clinically relevant explanation for the increase in plasma CgA and other NE peptides described. A significant increase in expression of distal ileal EECs in biopsy tissue from patients with small-bowel Crohn's


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disease (CD) has recently been described (Miller & Sumner, 1982) and reported to be confined to the site of active inflammation, since it was not observed in the terminal ileum of CD patients without ileal involvement, nor in quiescent ileitis. The only specific subpopulation of EECs reported to show a significant increase in number in Crohn's mucosa are the 5-HT secreting EC cells (Kidd et al., 2009) and glucagon-like peptide 1. Furthermore, EECs are direct sources of cytokines, such as the proinflammatory cytokine IL- 17C during CD and UC (Friedrich et al., 2015) and in vitro/in vivo studies have demonstrated that EECs have functional toll-like receptors (Bogunovic et al., 2007) and can directly respond to metabolites produced from commensal bacteria (Cani et al., 2013), thus suggesting a possible critical role of EECs in regulating intestinal immune responses to pathogens and commensal bacteria. Indeed, preclinical studies have already shown the efficacy of certain neuropeptide inhibitors in ameliorating colitis phenotypes. For example, GLP-1-secreting cells have receptors for many microbiome metabolites and can secrete GLP-1, GLP-2 and PYY in response to stimulation (Cani et al., 2013; Worthington, 2015). Therefore, it is highly likely that the intestinal microbiome can influence the entire immune system by regulating the production of immunomodulatory enteroendocrine hormone peptides. Future research will be necessary to elucidate the exact nature and roles of these neuropeptides in IBD pathogenesis; EECs and neuropeptides may become a novel treatable therapeutic target. Conflict-of-interest and source of funding statement The authors declare that they have no conflict of interest. This article has not been previously published and is not under consideration for publication elsewhere. Acknowledgments The authors acknowledge Marcello Hinxman-Allegri for the linguistic revision. References Abad, C., Martinez, C., Juarranz, M.G., et al., 2003. Therapeutic effects of vasoactive intestinal peptide in the trinitrobenzene sulfonic acid mice model of Crohn's disease. Gastroenterology 124, 961–971. http://dx.doi.org/10.1053/gast.2003.50141 (PMID: 12671893). Abad, C., Gomariz, R.P., Waschek, J.A., 2006. Neuropeptide mimetics and antagonists in the treatment of inflammatory disease: focus on VIP and PACAP. Curr. Top. Med. Chem. 6, 151–163. http://dx.doi.org/10.2174/156802606775270288 (PMID: 16454764). Adrian, T.E., Savage, A.P., Bacarese-Hamilton, A.J., Wolfe, K., Besterman, H.S., Bloom, S.R., 1986. Peptide YY abnormalities in gastrointestinal diseases. Gastroenterology 90, 379–384 (PMID: 3753594). Ahonen, A., Kyösola, K., Penttilä, O., 1976. Enterochromaffin cells in macrophages in ulcerative colitis and irritable colon. Ann. Clin. Res. 8, 1–7 (PMID: 937988). Arranz, A., Abad, C., Juarranz, Y., Leceta, J., Martinez, C., Gomariz, R.P., 2008a. Vasoactive intestinal peptide as a healing mediator in Crohn's disease. Neuroimmunomodulation 15, 46–53. http://dx.doi.org/10.1159/000135623 (PMID: 18667799). Arranz, A., Juarranz, Y., Leceta, J., Gomariz, R.P., Martinez, C., 2008b. VIP balances innate and adaptive immune responses induced by specific stimulation of TLR2 and TLR4. Peptides 29, 948–956. http://dx.doi.org/10.1016/j.peptides.2008.01.019 (PMID: 18359536). Ates, Y., Degertekin, B., Erdil, A., Yaman, H., Dagalp, K., 2008. Serum ghrelin levels in inflammatory bowel disease with relation to disease activity and nutritional status. Dig. Dis. Sci. 53, 2215–2221. http://dx.doi.org/10.1007/s10620–007-0113-x (PMID: 18080768). Bedoui, S., von Hörsten, S., Gebhardt, T., 2007. A role for neuropeptide Y (NPY) in phagocytosis: implications for innate and adaptive immunity. Peptides 28, 373–376. http:// dx.doi.org/10.1016/j.peptides.2006.07.029 (PMID: 17239992). Bogunovic, M., Dave, S.H., Tilstra, J.S., et al., 2007. Enteroendocrine cells express functional Toll-like receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1770–G1783. Bonaz, B.L., Bernstein, C.N., 2013. Brain-gut interactions in inflammatory bowel disease. Gastroenterology 144, 36–49. http://dx.doi.org/10.1053/j.gastro.2012.10.003 (PMID: 23063970). Böttcher, G., Sjöberg, J., Ekman, R., Håkanson, R., Sundler, F., 1993. Peptide YY in the mammalian pancreas: immunocytochemical localization and immunochemical characterization. Regul. Pept. 43, 115–130. http://dx.doi.org/10.1016/0167–0115(93)90146-Y (PMID: 8441818).

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