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Therap Adv Gastroenterol. Jul 2008; 1(1): 51–60.
PMCID: PMC3002486
Enteroendocrine Cells: Neglected Players in Gastrointestinal Disorders?
Gordon W. Moran, Fiona C. Leslie, Scott E. Levison, and John T. McLaughlin
Gordon W. Moran, Department of Gastroenterology, University Hospital of North Staffordshire, Stoke-on-Trent, UK; Gastrointestinal Sciences, University of Manchester, Manchester, UK;
Correspondence to: Dr John T. McLaughlin GI Sciences, CSB, Hope Hospital, University of Manchester, Salford M6 8HD, UK ; john.mclaughlin/at/manchester.ac.uk
Enteroendocrine cells (EEC) form the basis of the largest endocrine system in the body. They secrete multiple regulatory molecules which control physiological and homeostatic functions, particularly postprandial secretion and motility. Their key purpose is to act as sensors of luminal contents, either in a classical endocrine fashion, or by a paracrine effect on proximate cells, notably vagal afferent fibres. They also play a pivotal role in the control of food intake, and emerging data add roles in mucosal immunity and repair. We propose that EEC are fundamental in several gastrointestinal pathologies, notably Post-infectious Irritable Bowel Syndrome, infectious enteritis, and possibly inflammatory bowel disease. Further work is needed to fully illustrate the importance, detailed biology and therapeutic potential of these frequently overlooked cells.
Keywords: Enteroendocrine cells, innate immunity, inflammation, inflammatory bowel disease, irritable bowel syndrome, anendocrinosis
The largest endocrine system, in terms of total number of cells, is the enteroendocrine system of the digestive tract. In contrast to other endocrine systems, enteroendocrine cells (EEC) are scattered as single cells throughout the intestinal tract, located within the intestinal crypts and villi, and comprising ~1% of the epithelial cell population [Sternini et al. 2008]. There are at least 15 subtypes of EEC, secreting multiple peptide hormones which elaborately control physiological and homeostatic functions in the digestive tract, particularly postprandial secretion and motility. A set of biogenic amines are also synthesized and secreted, particularly 5-HT from the extremely diffuse enterochromaffin cell (EC) type. As with extra-gastrointestinal endocrine systems, co-expression, and presumably co-secretion, of more than one mediator is widely observed. Recent research has centered upon the potential role of EEC in immune regulation, a novel theme which will be discussed in detail below.
It has become clear that the key function of EEC is to act as sensors of luminal contents, particularly nutrients. Those EEC ‘open’ to the lumen thereby function as transepithelial signal transduction conduits, with apical physiochemical signals resulting in basolateral exocytosis of biological mediators. These act either in a classical endocrine fashion or by a paracrine effect on proximate cells, notably vagal afferent fibers. Their diffuse distribution is thus functionally appropriate, the EEC network forming an intimate first-line component of the brain-gut axis. For example, EEC are central to the gastrointestinal (GI) regulation of food intake via nutrient sensing, and have recently been shown to express ‘taste’ G-protein coupled receptors (the T1 sweet-sensing and T2 bitter-sensing families) and the associated small G-protein a-gustducin [Sternini et al. 2008; Cummings and Overduin, 2007]. Non-nutrient chemical factors also regulate EEC activity, for example secretin is secreted in response to duodenal acidification, and 5-HT secreting EC have mechanosensory properties [Lal et al. 2004; Bozkurt et al. 1999; Grundy et al. 1995; Dockray et al. 1985].
Unlike other endocrine systems, there is rapid cell turnover in the EEC population. Notch signaling plays a central role in development and proliferation in several systems, including the nervous system, pancreas and EEC, in a manner involving lateral inhibition. This cell–cell interaction allows a differentiating cell to inhibit neighboring cells from doing the same and is mediated by the transmembrane receptor Notch, and by Delta, its transmembrane ligand. The transcription factor Neurogenin-3 (ngn3) is at the apex of this pathway. It can stimulate Neuro D (both ngn-3 and Neuro D are part of the bHLH family transcription factors, also involved in pancreatic endocrine cell differentiation) which stimulates cellular expression and differentiation, and it can stimulate Delta to activate Notch. This downregulates cellular expression of Hes-1 stimulation, the key transcription factor favoring the absorptive enterocyte pathway [Bjerknes and Cheng, 2006; Skipper et al. 2000].
Experiments utilizing ngn3 null mice have however provided evidence for the existence of both ngn3 -/- dependent and independent EEC lineages [Lee et al. 2002]. Two models have been proposed. The first suggests that ngn3 is initially needed for the proliferation of all EEC, and subsequently required for terminal differentiation of a restricted subset e.g., A, D, and G cells, but not serotonergic EC cells. Thus ngn3 deficiency provides a smaller pool of precursors from which EC can differentiate. The other model suggests that ngn3 is required for the terminal differentiation of A, D, and G cells.
Loss of Neuro D results in diminished a and ß cells in the pancreas, as well as decreased secretin and CCK expression in the gut. Ngn3 deletion results in total absence of the four pancreatic endocrine cell types. Very recent data have also identified a role for the transcription factor NKx2.2 in EEC cell type determination [Desai et al. 2008]. In contrast, Hes-1 ablation leads to excessive differentiation of EEC in the gut. More broadly, bHLH transcription factors play a vital role in the determination of various cell fates. For example, loss of Math-1 leads to deletion of all three secretory cell lineages in the intestine, i.e. Goblet, Paneth and EEC [Yang et al. 2001] (Figure 1).
Figure 1.
Figure 1.
Intestinal stem cell pathways for terminal differentiation into absorptive enterocytes and secretory (EEC, Goblet and Paneth) cell lineages.
Over expression of the pancreatic-duodenal homebox 1 gene (pdx-1) has been shown in vitro to induce the differentiation of intestinal epithelial cells into hormone producing EEC, although this gene plays a minor role when compared to Notch signaling [Yamada et al. 2001].
EEC are terminally differentiated cells, which together with Goblet cells and Paneth cells constitute the secretory cell types in the small intestine lineages, whilst ^90% of the healthy epithelium is lined by absorptive columnar enterocytes. It is now clear that all lineages share a common crypt stem cell origin. Notch signaling and lateral inhibition lead to a Hes-1 directed population following the absorptive pathway, whilst the secretory lineages are directed by Math-1, with EEC progenitor differentiation further regulated by ngn3 [Bjerknes and Cheng, 2006]. EEC also turnover very rapidly, with a lifespan in the order of 4-6 days, in distinction to nondiffuse endocrine organs, perhaps suggesting more plasticity and acute reactivity applies in this archeobiologically more ancient system.
In view of the size, diversity and functional complexity of the enteroendocrine system it is therefore surprising how little is known about their roles in GI diseases. Given the multiple hypo-and hypersecretory states that are well characterized in nonGI endocrine systems, it seems barely conceivable that similar disorders will not exist in the GI tract. However, with the exception of rare endocrine tumors, which will not be discussed, there are very few reports of primary functional abnormalities of these cells. These extreme cases will be discussed below, but it is timely to speculate what the clinical phenotype of more subtle enteroendocrinopathies would be. Functional gastrointestinal symptoms, appetite disorders or altered bowel habit? How would these be recognized and diagnosed? It is probable that gut hormone profiles in peripheral blood are far too insensitive to detect moderate but important secretory dysfunction in the paracrine environment or the splanchnic endocrine compartment. Recent research has however begun to look at their potential roles in well known GI disorders, particularly irritable bowel syndrome (IBS), GI infection and inflammatory bowel disease (IBD). EEC are also attractive targets in the regulation and dysregulation of GI physiology in disease, and in the control of energy homeostasis.
The evidence for, and potential applications of, this evolving story will be reviewed. Since a key physiological role of gut hormones likely to be pertinent to GI disease is in the control of food intake, this will be addressed initially. This will be followed by a review of pathophysiological situations in which EEC may be relevant. This is a field in its infancy, likely to generate novel patho-biological understandings in gastroenterology, leading to tractable therapeutic approaches.
Satiation, the process by which a meal is terminated, has two main GI components: mechanical gastric distension, mediated via vagal afferent stimulation and EEC peptide hormone secretion. The hindbrain is the principal inputting site for short-acting satiation signals which are transmitted vagally, with signals relayed to the nucleus of the solitary tract, and hormonally, the area postrema being sited outside the blood–brain barrier. Long–term weight stability is achieved with adiposity hormones such as leptin, adiponectin and the downstream targets of insulin [Cummings et al. 2007].
The regulatory peptide cholecystokinin (CCK) plays a role as the primary proximal intestinal signal reducing food intake. It is secreted by the I cells of the duodenum and jejunum in response to luminal nutrients especially lipids and proteins [Furness et al. 1999]. CCK causes a delay in gastric emptying, therefore potentiating mechanical satiety signals [Lal et al. 2004]. When CCK is injected peripherally before meals it decreases meal size through CCK, receptor stimulation [Gibbs et al. 1973]. Rats lacking CCK1R show increased meal size and gradually become obese, a phenotype possibly driven by concomitant neu-ropeptide Y over-expression [Moran et al. 2006, 2008]. The obesity is mild and inconsistent, possibly reflecting the role of CCK in short term satiety signaling. CCK has also been shown to play a role in human satiety induced by fat [Lal et al. 2004; Matzinger et al. 1999].
Two important EEC products of the preproglucagon gene are glucagon-like peptide-1 (GLP-1) and oxyntomodulin. These gut hormones play a role in distal intestinal satiety signaling, and are secreted by L cells in the distal ileum and colon secondary to ingested fats and carbohydrates. Injected peripherally, they elicit satiety in normal weight and obese subjects through stimulation of GLP1 receptor. GLP1 enhances insulin secretion as well, this incretin effect contributing further to energy homeostasis [Drucker et al. 2006]. An anorectic effect of peptide YY (PYY) has been shown in animal and human studies [Le Roux et al. 2008; Pironi et al. 1993; Baynes, et al. 2006]. Interestingly, PYY secretion is reported to be attenuated in obesity lean persons [Cummings et al. 2007]. Although, intravenous infusions of biologically active PYY3-36 reduce food intake in humans, supraphysiological levels induced nausea [Le roux et al. 2008]. The same has been reported for CCK [Chua et al. 1994], and release of 5-HT by chemotherapy drugs underpins the severe nausea and emesis they elicit [Cubeddu et al. 1990]. These observations therefore add credence to the possibility that unrecognized EEC dysfunction may be present in unexplained nausea or appetite disturbance.
Ghrelin, to date the sole GI orexigenic peptide, secreted by gastric endocrine cells, conversely increases food intake in humans and animals. It has a role in both short-and long-term food control, and genomic deletion of the murine pep-tide or its receptor protects against weight gain on a high fat diet [Wortley et al. 2005; Zigman et al. 2005; Baynes, et al. 2006].
Further evidence that EEC and their products are biologically central to food and weight regulation in humans comes from bariatric surgery studies. Human subjects with severe obesity are increasingly treated thus to promote weight loss, simplistically considered to reflect either decreased gastric volume or small intestinal surface area. Increased plasma levels of PYY and GLP-1 in Roux-en-Y gastric bypass patients and in jejunointestinal bypass rats have been noted [Le Roux et al. 2006]. Altered gut anatomy, innervation or motility certainly plays a role in the aetiology of these hormonal changes. An increased exposure of the distal gut to partially undigested food is associated with decreased release of proximally secreted hormones and increased secretion of distally secreted anorectic hormones such as PYY, oxyntomodulin and GLP-1 [Le Roux et al. 2006; Sarson et al. 1981]. An increase in GLP-1 has been attributed to the sudden amelioration of diabetes control in postoperative patients [Le Roux et al. 2006], therefore preceding weight loss and peripheral resensitization to insulin. Hypoglycaemic episodes in patients post Roux-en-Y gastric bypass surgery has also been attributed to GLP-1 hypersecretion, stimulating beta cells [Patti et al. 2005].
These physiological and allied observations therefore place EEC and their targets, especially the vagus, centrally in the frame for emergent research into the mechanisms of abnormal appetite and satiety observed in GI disorders.
Host defence against invading microbial organisms is maintained by an intact epithelial barrier and by the immune system. Immunity has innate and acquired components, recognizing microorganisms as nonself and triggering an immune response. Cells of the innate immune system principally sense microbial presence via activation of Toll-like receptors (TLR). TLR are differentially distributed in multiple cell types, but are chiefly expressed by dendritic cells, macrophages, and myofibroblasts [Otte et al. 2004].
TLRs recognize a broad range of pathogen-derived components, signaling to induce the expression of pro-inflammatory genes and cytokines as a co-ordinated immune response. This, in conjunction with phagocytosis-mediated antigen presentation, instructs the development of antigen-specific adaptive immunity, especially via Th1 cells [Takeda and Akira 2005]. Recent exciting data have demonstrated that TLRs are also found on EEC. This assigns a novel role to EEC as innate immunity sensors, in addition to their canonical role as nutrient sensors. Whether this is a constitutive role or active only in certain circumstances is not yet known. In an elegant immunohistochemistry study by Bogunovic et al. scattered intestinal epithelial cells (IEC) were shown to co-express TLR1, TLR2, TLR4, co-localizing with multicytokeratin (a marker for IEC) in cells immunoreactive to TLR2 antibodies; and serotonin (a marker for EEC) in IEC immunoreactive to TLR1, TLR2, TLR4 antibodies. A murine EEC line, STC-1, was also shown to express mRNA transcripts for TLR 1, TLR 2, TLR 4, TLR 6 and the co-receptor MD-2. In the same cell line, the TLR4 ligand lipopolysac-charide (LPS) induced the phosphorylation of ERK½ and MAPK and activated NF-?B activation, the pivotal downstream signaling target of TLR occupancy. STC-1 exposure to LPS also triggered a calcium flux and induced the expression of the proinflammatory cytokine TNFa and the anti-inflammatory cytokine TGF-ß, in conjunction with increased in CCK secretion [Bogunovic et al. 2007]. Similar results have been shown by Palazzo et al. with TLR 5 and 9 also evident [Palazzo et al. 2007].
CCK may also have immunomodulatory properties, increasing the translocation of secretory IgA into the lumen and lymph [Freier et al. 1991; Imaeda et al. 1993; Freier et al. 1989]. It has also been reported that corticosteroids reduce CCK activity, which may contribute to increased bacterial adherence and impaired IgA secretion [Alverdy et al. 1991, 1997]. This may also be important in the reduced mucosal immunity observed in TPN-fed mice [Keith Hannah et al. 2000].
A further key development was the recent description of a ‘hard-wired’ CCK-vagal-immune reflex circuit. Nutrient-stimulated CCK secretion (a high fat diet) was shown to ameliorate the inflammatory response and to abrogate the increased epithelial permeability triggered by haemorrhagic shock [Luyer et al. 2005; Tracey et al. 2005]. Taken together with the above new data demonstrating that EEC can operate as innate immune sensors, it seems likely that inherent or acquired abnormalities in EEC function (or simple nutrient-privation), would predispose to poorer defensive responses to an infective or inflammatory challenge. In the gut, such challenges are of course the permanent norm. Whether similar biology exists for EEC types other than CCK now needs to be urgently explored.
The epithelial barrier is also a key component in host defence. A further preproglucagon splice product, GLP-2, is secreted by enteroendocrine L-cells in the distal small intestine and has been shown to improve intestinal wound healing in a TGF-yß mediated process, small bowel responding better than large bowel. Proliferation and migration of epithelial cells in ‘wounded’ IEC-6 confluent monolayers was enhanced when TGF-yß was added in cells lines incubated in GLP-2 [Bulut et al. 2004]. GLP-2 has also been shown to ameliorate the barrier dysfunction induced by experimental stress and food allergy [Cameron et al. 2005; Cameron et al. 2003] Again, L-cells are activated by luminal nutrients, and the barrier compromise observed in TPN may partly reflect its hyposecretion in the absence of enteral stimuli. Moreover, GLP-2 is also responsible, at least in part for growth and adaptation observed in short-bowel models [Liu et al. 2006; Martin et al. 2006; Lovshin et al. 2000].
Therefore, these data suggest that abnormal EEC function might predispose to GI inflammatory disorders, and advocate that the underlying nutrient-EEC-vagal pathways should be explored as therapeutic targets in the injured gut.
Intestinal inflammation is associated with increased intestinal secretions and motility, and a parallel decrease in food intake with consequent nutritional imbalances and weight loss [Rigaud et al. 1994; McHugh et al. 1993; Gee et al. 1985]. Early evidence that EEC function was abnormal in GI infection came from veterinary studies, food intake in lambs infected with the parasite Trichostrongylus colubriformis was increased by the administration of a specific CCK antagonist loxiglumide [Dynes et al. 1998]. Increased plasma CCK has also been observed in pigs infected with Ascaris suum [Yang et al. 1990], and in humans infected with Giardia lamblia [Leslie et al. 2003].
Recent work has sought to study this mechanistically using experimental models of parasitization. Enteritis can be induced in rodents by the nematode Trichinella spiralis and colitis by Trichuris muris. These offer a more biologically meaningful approach than the more established chemical methods, as in 2,4,6 trinitrobenzene sulfonic acid (TNBS) and in dextran sodium sulphate (DSS) [Oshima et al. 1999]. T.spiralis was shown to induce CCK and 5-HT hyperplasia and hypersecretion in mice, coinciding with the peak severity of enteritis, at about day nine postinfection. Food intake was reduced by about half at this time point, and was significantly improved by the administration of the same CCK1 receptor antagonist, loxiglumide. It was also shown that immunocompetence was essential, and the CD4 T-lymphocyte population was identified as the key effector cell, inducing secretory cell hyperplasia via an IL-4 receptor alpha subunit-dependent mechanism. The parasite was not the primary driver of the EEC response, since in animals undergoing CD4 immunoneutralization, the nematodes remain in the lumen, yet EEC hyperplasia fails to occur. This model of the immuno-enteroendocrine axis is therefore likely to have broader applicability to other forms of GI infection and inflammation, and offers an excellent platform to explore the biological role of EEC in innate immunity, in crosstalk with other immune cell types, and in the mechanisms linking gut inflammation to abnormal feeding behavior [McDermott et al. 2006]. Subsequently, it has been demonstrated that T.muris-induced colitis drives colonic EC proliferation by very similar mechanisms. However, this was advanced by the discovery that adoptive transfer of CD4+ cells from immunocompetent infected mice to immunodeficient (SCID) mice induced EC hyperplasia in the recipient [Wang et al. 2007]. This was also more marked in Th2-predominont responders and dependent upon STAT-6. Therefore, might ongoing immune responses perpetuate EEC hyperplasia if unregulated or in susceptible genotypes?
TNBS-induced ileitis in mice also causes an increase in 5HT-immunoreactive EEC, a decrease in serotonin reuptake transporter (SERT) and an increase in 5-HT release [O'Hara et al. 2004]. Neurotensin (N) cells and Somatostatin (D) cells where also changed, but the mucosal content of other gut peptides was not significantly altered. In human colitis, data are surprisingly sparse. There has been a single report that chromogranin A and 5-HT cells positive are increased in both Crohn's disease and ulcerative colitis [El Salhy et al. 1997]. In Crohn's colitis only, PYY and PP cells were reduced whilst enteroglucagon cells were increased. However, our recent studies (unpublished data) suggest that all endocrine cell types are reduced in active proctitis, and that this persists when the inflammation resolves. Increased 5-HT EC cells have also been demonstrated in a single study of Crohn's ileitis [Bishop et al. 1987]. A newly ascribed Crohn's-associated gene, Phox2b, is a homeodomain transcription factor predominantly expressed in differentiated neurones. Work using Genome Wide Analysis (GWA) has shown a close association between this single nuclear polymorphism and Crohn's disease [Rioux et al. 2007]. It is potentially mechanistically relevant here: immunostaining suggests it is expressed by epithelial neuroendocrine cells, and this is known to be linked to Delta-Notch signaling. The role of T cells in EEC proliferation is further supported by studies in T-cell receptor a -/- mice, which express reduced cytokines (IL-2, IL-10, TGF-ß) and display decreased CCK, 5-HT, and NT immunostaining cell numbers whilst developing an ulcerative colitis-like phenotype [Rubin et al. 2000].
Taken together, these results suggest that the complex regulation of EEC development and differentiation operates under immune control, so may be dynamically altered by the state of inflammation. Given that the likely switch takes place along the lineage commitment pathway from the stem cell precursor niche, the time lag of 3-7 days is appropriate. The increased EEC population may have biological consequences, most simply in mediating altered gut motility, sensation and secretory activity noted in inflammatory and infective bowel disease. It may also be advantageous to inhibit food intake in the short term. More specifically, the recent assignment of EEC as part of the innate immune system suggests that up-regulating these cells maybe a programmed and adaptive response, enhancing mucosal immunity and barrier function whilst contributing to repair mechanisms. Therefore, careful consideration and dissection of these roles is necessary before advocating these as therapeutic targets. Finally, recent data have suggested that EEC may also be an autoimmune target in Crohn's disease. An ileal cDNA library approach was used to identify ubiquination factor 4A, a U-box-type ubiquitin-protein ligase, as a target for antibodies in serum from Crohn's patients. Subsequent immunolocalization suggested that the target protein was upregulated in EEC of Crohn's patients, and these patients particularly displayed an increased predisposition for active, penetrative and structuring disease, and increased needs for surgery [Sakiyama et al. 2007].
The last section dealt with abnormal EEC in overtly diseased gut. However, most clinical practitioners find that a larger proportion of their practice constitutes patients with IBS. From 6-17% of hospital referrals to gastroenterologists in the US and the UK, respectively, are IBS-related [Longstreth et al. 2000]. A small, but significant subgroup of patients report a sudden onset of IBS post gastroenteritis. It has been noted that infections caused by Campylobacter sp., and to a lesser extent Shigella, are associated with a high chance of developing IBS-like symptoms. In addition to the infective agent and the ambient psychosocial state of the index case, there are some data to suggest that the host response to the infective agent plays a major role in developing IBS. Polymorphisms associated with an overproduction of anti-inflammatory cytokines such as interleukin-10 (IL-10) and TGF-ß were underrepresented in a cohort of IBS patients [Chan et al. 2000]. Although, conventional biopsies are all by definition normal in IBS, more rigorous analysis suggests that subtle inflammatory abnormalities and altered inflammatory cell populations exist [Chadwick et al. 2002; Spiller et al. 2000].
The seminal supportive data published by Spiller show that a low grade, long-lasting T-cell mediated inflammation is present in patients with post-infectious IBS. Mucosal biopsies taken early post-Campylobacter infection show acute superficial ulcerations. This rapidly regresses however on serial rectal biopsies. In most cases, the mucosa looked normal at 2 weeks; however quantitative histology showed a persistently high T cell lymphocyte count (CD3 subtype) and newly recruited calprotectin-positive macrophages. This gradually decreased by three months. However, in a cohort of patients with typical symptoms of PI-IBS these microscopic changes were still persistent at 1 year. A similar but more striking response was seen by immunohistochemical staining using the universal EEC marker, synaptophysin. Synaptophysin-positive cell expression was 5-fold above normal in 85% at two weeks. Similarly, persistent high results were present at 1 year. At three months, T lymphocyte and EEC counts both remained significantly elevated. There was also a change in chemical coding of the CgA positive cells, reversing from predominantly PYY to serotonin. In keeping with ongoing low grade inflammation, there is also increased gut permeability as measured by an increased lactulose/mannitol flux [Spiller et al. 2000; Spiller et al. 2003, Dunlop et al. 2003].
Further supportive evidence of serotoninergic dysfunction in IBS lies in the detailed observations that plasma and platelet 5-HT concentrations are significantly elevated [Houghton et al. 2003]. Therefore, it is likely that the chronic inflammatory state is driving this form of EEC hyperplasia or hyperfunctionality, perhaps by similar (but more subtle) mechanisms to the more overt inflammatory processes described in the previous section. What perpetuates the inflammation in a minority of individuals experiencing infection is unclear. Clinically, the functional increase in EEC might be directly driving symptoms, perhaps contributing to the looser and more frequent motions that persist, or encoding increased rectal mechanosensitivity. The increased expression of EEC with altered 5-HT or SERT expression [Wheatcroft et al. 2005] might also partly explain the therapeutic benefit of serotonin receptor modulating drugs in a subset of IBS patients.
Endocrine cell dysgenesis has recently been reported, in three infants presenting with intestinal failure of unknown cause. The patients presented with a life-threatening malabsorptive congenital diarrhea syndrome effecting all nutrients from birth apart from water. Both small and large bowel are affected, with a histological picture characterized by a near complete absence of endocrine cells in the mucosa (anendocrinosis). This defect was discovered to be secondary to point mutations in ngn3 resulting in arrest in endocrine cell development [Cortina et al. 2007]. Might more subtle functional variants cause relative changes in EEC activity, basally or under inflammatory perturbation?
There have also been limited case reports of abnormal EEC in autoimmune enteropathy (AIE), autoimmune polyglandular syndrome type 1 and IPEX syndrome (Immune dysoregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) [Al Khalidi et al. 2006; Hogenauer et al. 2001]. Most striking was a case report of a patient with profound malabsorption and autoimmune polyglandular syndrome type 1, in whom CCK in plasma and intestinal biopsies was undetectable concurrently with episodes of hypocalcaemia [Hogenauer et al. 2001]. This raises the intriguing possibility that autoimmune disorders of the EEC might more broadly exist: they clearly do for all other endocrine systems and cells outside the gut, and indeed are relatively common, so this possibility is almost a certainty. But a possibility that has never been rigorously sought. It is also interesting to speculate that ion channelopathies, a growing area of interest in other neuroendocrine systems, may also pertain to the EEC system.
Finally, it is broadly overlooked that patients with untreated celiac disease, presenting with intra-epithelial lymphocytosis and villus atrophy, also show decreased CCK mRNA, CCK mucosal content and blunted postprandial CCK rise. The decreased CCK levels observed in celiac patients are not strictly related to the mucosal atrophy but rather to the lymphocytic mucosal infiltrate [Deprez et al. 2002]. An association between coeliac disease and chronic pancreatitis has already been described [Sood et al. 2007], but in isolated coeliae disease functional hypopancreatism also comes into play due to blunted gut-pancreas signaling responses. It is probable that the reduced expression of the CCK gene related to suppressive immunomodulatory factors induced by the inflammatory infiltrate, and would therefore merit comparison to the processes described above which lead to gain-of-function in the enteroendocrine system. Certainly these data continue to corroborate a potential role of autoimmunity in EEC dysfunction.
Enter the enteroendocrinologist?
It is clear that EEC play important roles in both health and disease, but up to now have been relegated to a rather neglected role in the GI clinical and scientific literature. More basic and translational research work is now urgently required in enteroendocrinology, as it seems highly likely that these fascinating but neglected cells are therapeutically tractable players in a broad range of GI diseases.
Contributor Information
Gordon W. Moran, Department of Gastroenterology, University Hospital of North Staffordshire, Stoke-on-Trent, UK. Gastrointestinal Sciences, University of Manchester, Manchester, UK.
Fiona C. Leslie, Department of Gastroenterology, University Hospital of North Staffordshire, Stoke-on-Trent, UK.
Scott E. Levison, Gastrointestinal Sciences, University of Manchester, Manchester, UK.
John T. McLaughlin, Gastrointestinal Sciences, University of Manchester, Manchester, UK.
  • Al Khalidi H., Kandel G., Streutker C.J. (2006) Enteropathy with loss of enteroendocrine and paneth cells in a patient with immune dysregulation: a case of adult autoimmune enteropathy. Hum Pathol 37(3):373–376. [PubMed]
  • Alverdy J., Aoys E. (1991) The effect of gluco-corticoid administration on bacterial translocation. Evidence of an acquired mucosal immunodeficient state. Ann Surg 214(6):719–723. [PubMed]
  • Alverdy J., Stern E., Poticha S., Baunoch D., Adrian T. (1997) Cholecystokinin modulates mucosal immunoglobulin A function. Surgery 122(2):286–292. [PubMed]
  • Baynes K.C., Dhillo W.S., Bloom S.R. (2006) Regulation of food intake by gastrointestinal hormones. Curr Opin Gastroenterol 22(6):626–631. [PubMed]
  • Bishop A., Pietroletti R., Taat C., Brummelkamp W., Polak J. (1987) Increased populations of endocrine cells in Crohn's ileitis. Virchows Arch A 410:391–396. [PubMed]
  • Bjerknes M., Cheng H. (2006) Neurogenin 3 and eteroendocrine cell lineage in the adult mouse small intestinal epithelium. Dev Biol 300(2):722–735. [PubMed]
  • Bogunovic M., Dave S., Tilstra J., Chang D., Harpaz N., Xiong H. et al. (2007) Enteroendocrine cells express functional Toll-like receptors. Am J Physiol Gastrointest Liver Physiol 292:1783. [PMC free article] [PubMed]
  • Bozkurt A., Oktar B., Kurtel H., Alican I., Coskun T., Yegen B. (1999) Capsaicin-sensitive vagal fibres and 5-HT3-gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat. Regul Pept 83(2-3):81–86. [PubMed]
  • Bulut K., Meier J.J., Ansorge N., Feiderbauer P., Schmitz F., Hoffmann P. et al. (2004) Glucagon-like peptide 2 improves intestinal wound healing through induction of epithelial cell migration in vitro-evidence for a TGF-beta mediated effect. Regul Pept 121(1-3):137–143. [PubMed]
  • Cameron H., Perdue M. (2005) Stress impairs murine type Intestinal Barrier Function: Improvement by Glucagon-like peptide-2. J Pharmacol and Experiment Therapeuthic 314:214–220. [PubMed]
  • Cameron H., Yang P.-C., Perdue M. (2003) Glucagon-like peptide-2-enhanced barrier function reduces pathophysiology in a model of food allergy. Am J Physiol Gastroint Liver Physiol 284:G905–G912. [PubMed]
  • Chan J., Gonsalkorale W., Perrey C., Previca V., Hajeer A., Whorwell P. et al. (2000) IL-10 and TGF-B genotypes in Irritable bowel syndrome: Evidence to support and inflamatory component. Gastroenterology 118(4):184.
  • Chua A., Dinan T., Rovati L., Keeling P. (1994) Cholecystokinin hyperresponsiveness in Dysmotility-Type nonulcer Dyspepsia. Annals of the New York Academ Sci 713(1):298–299. [PubMed]
  • Cortina G., Smart Cn., Farmer D.G., Bhuta S., Treem W.R., Hill I.D. (2007) Enteroendocrine cell dysgenesis and malabsorption, a histologic and immunohistochemical characterization. Human Pathol 38(4):570–580. [PubMed]
  • Cubeddu L., Hoffmann I., Feunmayor N., Finn A. (1990) Efficacy of Ondansetron (GR 38032F) and he role of serotonin in cisplatin-induced nausea and vomiting. N Eng J Med 322(12):810–816. [PubMed]
  • Cummings D., Overduin J. (2007) Gastrointestinal regulation of food intake. The J Clin Invest 117(1) [PMC free article] [PubMed]
  • Deprez P., Sempoux C., De Saeger C., Rahier J., Mainguet P., Pauwels S. et al. (2002) Expression of cholecystokinin in the duodenum of patients with coeliac disease: respective role of atrophy and lymphocytic infiltration. Clin Sci (Lond) 103(2):171–77. [PubMed]
  • Desai S., Loomis Z., Pugh-Bernard A., Schrunk J., Doyle M., Minic A. et al. (2008) Nkx2.2 regulates cell fate choice in the enteroendocrine cell lineages of the intestine. Dev Biol 313(1):58–66. [PMC free article] [PubMed]
  • Dockray G., Desmond H., Gayton R., Jonsson A., Raybould H., Sharkey K.A. et al. (1985) Cholecystokinin and gastrin forms in the nervous system. Ann N Y Acad Sci 448:32–43. [PubMed]
  • Drucker D. (2006) The biology of incretin hormones. Cell Metab 3(3):153–165. [PubMed]
  • Dunlop S.P., Jenkins D., Neal K., Spiller R. (2003) Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology 125(6):1651–1659. [PubMed]
  • Dynes R., Poppi D., Barrell G., Sykes A. (1998) Elevation of food intake in parasite-infected lambs by central administration of a cholecystokinin receptor antagonist. Br J Nutrition 79(1):47–54. [PubMed]
  • El-Salhy M., Danielsson A., Stenling R., Grimelius L. (1997) Colonic endocrine cells in Inflammatory Bowel Disease. J Intern Med 242(5):413–419. [PubMed]
  • Freier S., Eran M., Alon I., Elath U. (1991) Verapamil and frsemide prevent cholecystokinin-induced tanslocation of immunoglobulins in rat intestine. Dig Dis Sci 36(11):1619–1624. [PubMed]
  • Freier S., Eran M., Alon I. (1989) A study of stimuli operative in the release of antibodies in the rat intestine. Immunol Invest 18(1-4):431–437. [PubMed]
  • Furness J.B., Kunze W., Clerc N. (1999) Nutrient tasting and signalling mechanisms in the gut II. The intestine as a sensory organ: neural, endocrine, and immune responses. Am J Physiol Gastrointest Liver Physiol 277:G922–G928. [PubMed]
  • Gee M., Grace M., Wensel R., Sherbaniuk R., Thomson A. (1985) Protein energy malnutrition in gastroenterology outpatients:increased risk in Crohn's disease. J Am Diet Assoc 85(11):1466–1474. [PubMed]
  • Gibbs J., Young R., Smith G. (1973) Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245:323–325. [PubMed]
  • Grundy D., Bagaev V., Hillsley K. (1995) Inhibition of gastric mechanoreceptor discharge by cholecystokinin in the rat. Am J Physiol 268(2 Pt 1):355–360. [PubMed]
  • Keith Hanna M., Zarzaur B., Fukatsu K., DeWitt R., Renegar K., Sherrell C. et al. (2000) Individual neuropeptides regulate gut-associated lymphoid tissue integrity, intestinal immunoglobin A levels, and respiratory antibacterial immunity. J Parenter and Enter nutr 24(5):261–268. [PubMed]
  • Hogenauer C., Meyer R., Netto G., Bell D., Little K., Ferries L. et al. (2001) Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type 1. The New England J Med 344(4):270–274. [PubMed]
  • Houghton L., Atkinson W., Whitaker R., Whorwell P. (2003) Increased platelet depleted plasma 5-hydoxytryptamine following meal ingestion in symptomatic female subjects in predominant irritable bowel syndrome. Gut 52(5):663–670. [PMC free article] [PubMed]
  • Imaeda H., Miura S., Serizawa H., Toda K., Ohkubo N., Kimura H. (1993) Influence of fatty acid absorption on bidirectional release of immunoglobulin A into the intestinal lumen and intestinal lymp in rats. Immuno Lett 38(3):253–258. [PubMed]
  • Lal S., McLaughlin J., Barlow J., D'Amato M., Giacovelli G., Varro A. (2004) Cholecystokinin pathways modulate sensations induced by gastric distension in humans. Am J Phsiol Gastroint Liver Physiol 287(1):72–79. [PubMed]
  • Le Roux C., Aylwin S., Batterham R., Borg C., Coyle F., Prasad V. et al. (2006) Gut hormone profiles following bariatric surgery favor a anorectic state, facilitate weigh loss, and improve metabolic parameters. Ann Surg 243(1):108–114. [PubMed]
  • Le Roux C., Borg C., Murphy K., Vincent R., Ghatel M., Bloom S. (2008) Supraphysiological doses of intravenous PYY(3-36) cause nausea, but no additional reduction in food intake. Ann Clin Biochem 45(1):93–95. [PubMed]
  • Lee C., Perreault N., Brestelli J., Kaestner K. (2002) Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity. Genes and Develop 16(12):1488–1497. [PubMed]
  • Leslie FC., Thompson D., McLaughlin J., Varro A., Dockray G., Mandal B. (2003) Plasma cholecystokinin concentrations are elevated in acute upper gastrointestinal infections. Q J Med 96:870–871. [PubMed]
  • Linden D., Chen J.-X., Gershon M., Sharkey K., Mawe G. (2003) Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am J Physiol Gastroint Liver Physiol 285:G207–G216. [PubMed]
  • Liu X., Nelson D., Holst J., Ney D. (2006) Synergistic effect of supplemental enteral nutrients and exogenous glucagon-like peptide 2 on intestinal adaptation in a rat model of short bowel syndrome. Am J Clin Nutri 84:1142–1150. [PubMed]
  • Longstreath G., Hawkey C., Ham J., Jones R., Mayer E., Naesdal J. et al. (2000) Demographic and clinical characteristics of patients with irritable bowel syndrome (IBS) from three practice settings; Gastroenterology 118(4):A146.
  • Lovshin J., Drucker D. (2000) New frontiers in the biology of GLP-2. Regulatory Peptides 90(1-3):27–32. [PubMed]
  • Luyer M., Greve J., Hadfoune M., Dejing C., Buurman W. (2005) Nutritional stimulation of cholecystokinin receptorsinhibits inflammation via the vagus. J Exp Med 202(8):1023–1029. [PMC free article] [PubMed]
  • Martin G., Beck P., Sigalet D. (2006) Gut hormones, and short bowel syndrome: The enigmatic role of glucaon-like peptide-2 in the regulation of intestinal adaptation. World J Gastroenterol 12(26):4117–4129Review. [PubMed]
  • Matzinger D., Degen L., Drewe J., Duebendorfer R., Ruckstuhl N., D'Amato M. (2000) The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans. Gut 46:689–694. [PMC free article] [PubMed]
  • Matzinger D., Gutzwiller J., Drewe J., Orban A., Engel R., D'Amato M. (1999) Inhibition of food intake in response to intestinal lipid is mediated by cholecystokinin in humans. Am J Phsiol 277(6 Pt 2):R1718–1724. [PubMed]
  • McDermott J.R., Leslie F., D'Amato M., Thompson D., Grencis R., McLaughlin J. (2006) Immune control of food intake: enteroendocrine cells are regulated by CD4+ T lymphocytes during small intestinal inflammation. Gut 55:492–497. [PMC free article] [PubMed]
  • McHugh K., Castonguay T., Collins S., Weingarten H. (1993) Characterisation of suppression of food intake following acute colon inflammation in the rat. Am J Physiol Regul Integr Comp Physiol 265:R1001–R1005. [PubMed]
  • Moran T., Bi S. (2006) Hyperphagia and obesity of OLETF rats lacking CCK1 receptors: developmental aspects. Dev Psychobiol 48(5):360–367. [PubMed]
  • Moran T., Katz L., Plata-Salaman C., Schwartz G. (1998) Disordered food intake and obesity in rats lacking cholecustokinin A receptors. Am J Physiol Regu Integr Comp Physiol 274:R618–R625. [PubMed]
  • O'Hara J., Ho W., Linden D., Mawe G., Sharkey K. (2004) Enteroendocrine cells and 5-HT availability in mucosa of guinea pigs with TNBS ileitis. Am J Physiol Gastrointest Liver Physiol 287:G998–G1007. [PubMed]
  • Oshima S., Fujimura M., Fukimiya M. (1999) Changes in the number of serotonin-containing cell and serotonin levels in the intestinal mucosa of rats with colitis induced by dextran sodium sulphate. Histochem and Cell Biol 112(4) [PubMed]
  • Otte J., Cario E., Podolsky D. (2004) Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126(4):1054–1070. [PubMed]
  • Palazzo M., Balsari A., Rossini A., Selleri S., Calcaterra C., Gariboldi S. et al. (2007) Activation of enteroendocrine cells via TLRs induces hormone, chemokine, and defensin secretion. The J Immunol 178:4296–4303. [PubMed]
  • Patti M., McMahon G., Mun E., Bitton A., Holst J. et al. (2005) Severe Hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence of inappropriate insulin secretion and pancreatic islet cell hyperplasia. Diabetologia 48:2236–2240. [PubMed]
  • Pironi L., Stanghellini V., Miglioli M., Corinaldesi R., De Giorgio R., Ruggeri E. et al. (1993) Fat-induced ileal brake in humans: a dose-dependent phenomenon correlated to the plasma levels of peptide YY. Gastroenterology 105(3):733–739. [PubMed]
  • Rigaud D., Angel L., Cerf M., Carduner M., Melchior J.-C., Sautier C. et al. (1994) Mechnisms of decreased food intake during weight loss in ault Crohn's disease patients without obvious malabsorption. Am J Clin Nutrition 60:775–781. [PubMed]
  • Rioux J., Xavier R., Taylor K., Silverberg M., Goyette P., Huett A. (2007) Genome-wide association study identifies new susceptibility loci for Crohn's disease an implicates autophagy in disease pathogenesis. Nature Genet 39(5) [PMC free article] [PubMed]
  • Rubin D., Zhang H., Qian P., Lorenz R., Hutton K., Peters M. (2000) Altered Enteroendocrine Cell Expression in T cell Receptor Alpha Chain Knock-Out Mice. Microscopy Res and Tech 51:112–120. [PubMed]
  • Sakiyama T., Fujita H., Tsubouchi H. (2007) Autoantibodies against ubiquitination factor E4A (UBE4A) are associated with severity of Crohn's disease. Inflamm Bowel Dis 14(3):310–317. [PubMed]
  • Sarson D.L. (1981) Gut hormone changes after jejunoileal or biliopancreatic bypass surgery for morbid obesity. Int J Obes 5:471–480. [PubMed]
  • Skipper M., Lewis J. (2000) Getting to the Guts of enteroendocrine differentiation. Nature Genet 24:3–4. [PubMed]
  • Sood A., Midha V., Sood N., Bansal M., Kaur M., Goyal A. et al. (2007) Coexistence of chronic calcific pancreatitis and celiac disease. Indian J Gastroenterol 26(1):41–42. [PubMed]
  • Spiller R. (2003) Postinfectious irritable bowel syndrome. Gastroenterology 124(6):1662–1671. [PubMed]
  • Spiller R.C., Jenkins D., Thornley J., Hebden J., Wright T., Skinner M. et al. (2000) Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut 47:804–811. [PMC free article] [PubMed]
  • Sternini C., Anselmi L., Rozengurt E. (2008) Enteroendocrine, cells: a site of ‘taste’ in gastrointestinal chemosensing. Curr Opin Endocrinol Diabetes Obes 15(1):73–78. [PMC free article] [PubMed]
  • Takeda K., Akira S. (2005) Toll like receptors in innate immunity. Int Immunol 17(1):1–14. [PubMed]
  • Tracey K. (2005) Fat meets cholinergic anti-inflammatory pathway. JEM 202(8):1017–1021. [PMC free article] [PubMed]
  • Wang H., Steeds J., Motomura Y., Deng Y., Verma-Gandhu M., El-Sharkwawy R. et al. (2007) CD4 T cell-mediated immunological control of enterochromaffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection. Gut 56:949–957. [PMC free article] [PubMed]
  • Wheatcroft J., Wakelin D., Smith A., Mahoney C., Mawe G., Spiller R. (2005) Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunction. Neurogastroenterol Motil 17(6):863–870. [PubMed]
  • Wortley K., Del Rincon J.P., Murray J., Garcia K., Iida K., Thorner M. (2005) Absence of ghrelin protects against early-onset obesity. J Clin Invest 115(12):3573–3578. [PMC free article] [PubMed]
  • Yamada S., Kojima H., Fujimiya M., Nakamura T., Kashiwagi A., Kikkawa R. (2001) Differentiation of immature enterocytes in enteroendocrine cells by Pdx1 overexpression. Am J Physiol Gastrointest. Liver Physiol 281:G229–G236. [PubMed]
  • Yang Qi., Bermingham N., Finegold M., Zoghbi H. (2001) Requirement of Math1 for secretory cell lineae commitment in the mouse intestine. Science 294(5549):2155–2158. [PubMed]
  • Yang S., Gaafar S., Bottoms G. (1990) Serum levels of gastrin, insulin and glucagon as possible factors of anorexia in pigs infected once with ascaris suum. Vet Parasitol 36(3-4):211–219. [PubMed]
  • Zigman J., Nakano Y., Coppari R., Balthasar N., Marcus J., Lee C. (2005) Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 115(12):3564–3572. [PMC free article] [PubMed]
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