Colonic Endocrine Cells Research Articles

Decoy bypass for appetite suppression in obese adults: role of synergistic nutrient sensing receptors GPR84 and FFAR4 on colonic endocrine cells

ObjectiveColonic enteroendocrine cells (EECs) store and release potent anorectic hormones that are key regulators of satiety. EECs express multiple nutrient sensing receptors, particularly for medium-chain fatty acids (MCFAs): GPR84 and...

Abnormalities in endocrine and immune cells are correlated in dextran‑sulfate‑sodium‑induced colitis in rats.

The interaction between the gut hormones and the immune system has been suggested to serve an important role in the pathophysiology of inflammatory bowel disease. The aims of the present study were to elucidate the possible abnormalities in the colonic endocrine cells in rats with dextran sodium sulfate (DSS)-induced colitis, and to determine whether they are correlated with alterations in the immune cells. A total of 24 male Wistar rats were divided into two groups: Control and DSS-induced colitis. Colonic tissues were harvested via postmortem laparotomy from all of the animals at the end of the experimental period, and fixed and sectioned for histology. The colonic endocrine and immune cells in those tissue samples were immunostained and their densities quantified by computerized image analysis. The densities of chromogranin A, serotonin, peptide YY and oxyntomodulin cells were significantly higher, and those of pancreatic peptide and somatostatin cells were lower in rats with DSS-induced colitis than in the controls. The densities of mucosal leukocytes, T and B lymphocytes, macrophages/monocytes, and mast cells were significantly higher than in the controls, and these changes were closely associated with the aforementioned changes in all endocrine cell types. These observations indicate an interaction between intestinal hormones and the immune system as represented by immune cells.

Changes in enteroendocrine and immune cells following colitis induction by TNBS in rats.

Approximately 3.6 million individuals suffer from inflammatory bowel disease (IBD) in the western world, with an annual global incidence rate of 3–20 cases/100,000 individuals. The etiology of IBD is unknown, and the currently available treatment options are not satifactory for long-term treatment. Patients with inflammatory bowel disease present with abnormalities in multiple intestinal endocrine cell types, and a number of studies have suggested that interactions between gut hormones and immune cells may serve a pivotal role in the pathophysiology of IBD. The aim of the present study was to investigate alterations in colonic endocrine cells in a rat model of IBD. A total of 30 male Wistar rats were divided into control and trinitrobenzene sulfonic acid (TNBS)-induced colitis groups. Colonoscopies were performed in the control and TNBS groups at day 3 following the induction of colitis, and colonic tissues were collected from all animals. Colonic endocrine and immune cells in the obtained tissue samples were immunostained and their densities were quantified. The densities of chromogranin A, peptide YY, and pancreatic polypeptide-producing cells were significantly lower in the TNBS group compared with the control group, whereas the densities of serotonin, oxyntomodulin, and somatostatin-producing cells were significantly higher in the TNBS group. The densities of mucosal leukocytes, B/T-lymphocytes, T-lymphocytes, B-lymphocytes, macrophages/monocytes and mast cells were significantly higher in the TNBS group compared with the controls, and these differences were strongly correlated with alterations in all endocrine cell types. In conclusion, the results suggest the presence of interactions between intestinal hormones and immune cells.

Effects of AP‑1 and NF‑κB inhibitors on colonic endocrine cells in rats with TNBS‑induced colitis.

Interactions between intestinal neuroendocrine peptides/amines and the immune system appear to have an important role in the pathophysiology of inflammatory bowel disease (IBD). The present study investigated the effects of activator protein (AP)-1 and nuclear factor (NF)-κB inhibitors on inflammation-induced alterations in enteroendocrine cells. A total of 48 male Wistar rats were divided into the following four groups (n=12 rats/group): Control, trinitrobenzene sulfonic acid (TNBS)-induced colitis only (TNBS group), TNBS-induced colitis with 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G) treatment (DTCM-G group), and TNBS-induced colitis with dehydroxymethylepoxyquinomicin (DHMEQ) treatment (DHMEQ group). A total of 3 days following administration of TNBS, the rats were treated as follows: The control and TNBS groups received 0.5 ml vehicle (0.5% carboxymethyl cellulose; CMC), respectively; the DTCM-G group received DTCM-G (20 mg/kg body weight) in 0.5% CMC; and the DHMEQ group received DHMEQ (15 mg/kg body weight) in 0.5% CMC. All injections were performed intraperitoneally twice daily for 5 days. The rats were sacrificed, and tissue samples obtained from the colon were examined histopathologically and immunohistochemically. Inflammation was evaluated using a scoring system. In addition, the sections were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP) and somatostatin, and immunostaining was quantified using image-analysis software. The density of cells expressing CgA, PYY and PP was significantly lower in the TNBS group compared with in the control group, whereas the density of cells expressing serotonin, oxyntomodulin and somatostatin was significantly higher in the TNBS group compared with in the control group. None of the endocrine cell types differed significantly between the control group and either the DTCM-G or DHMEQ groups. All of the colonic endocrine cell types were affected in rats with TNBS-induced colitis. The expression density of these endocrine cell types was restored to control levels following treatment with AP-1 or NF-κB inhibitors. These results indicated that the immune system and enteroendocrine cells interact in IBD.

Treatment with novel AP-1 and NF-κB inhibitors restores the colonic endocrine cells to normal levels in rats with DSS-induced colitis.

The aim of this study was to determine the effects of two anti-inflammatory agents on the abnormalities in colonic endocrine cells in dextran sodium sulfate (DSS)-induced colitis. Colitis was induced in male Wistar rats (n=45) using DSS; a further 15 rats without colitis were included in a healthy control group. The animals with DSS-induced colitis were randomly divided into 3 treatment groups as follows: i) DSS group, rats were treated with 0.5 ml of 0.5% carboxymethyl cellulose (CMC); ii) DSS-G group, rats were treated with 3-[(dodecyl thiocarbonyl)-methyl]-glutarimide (DTCM-G), a novel activator protein 1 (AP-1) inhibitor, 20 mg/kg in CMC; and iii) DSS-Q group, rats were treated with dehydroxymethylepoxyquinomicin, a nuclear factor κB (NF-κB) inhibitor, 15 mg/kg in CMC. The treatments were administered intraperitoneally, twice daily for 5 days, after which the animals were sacrificed and tissue samples from the colon were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), enteroglucagon, pancreatic polypeptide (PP), somatostatin, leukocytes, B/T lymphocytes, B lymphocytes, T lymphocytes, macrophages/monocytes and mast cells. The densities of these endocrine and immune cells were quantified by computer-aided image analysis. The densities of CgA-, serotonin-, PYY- and enteroglucagon-producing cells were significantly higher, and those of PP- and somatostatin-producing cells were significantly lower in the DSS-G, DSS-Q and control groups than in the DSS group. The densities of all the immune cells were lower in the DSS-G, DSS-Q and control groups than in the DSS group. The densities of all endocrine cell types and immune cells in both the DSS groups treated with anti-inflammatory agents were restored to control levels. In conclusion, our data demonstrate that there is an interaction between endocrine and immune cells during inflammation. This interaction with subsequent changes in endocrine cells is responsible for the clinical manifestation of colitis symptoms.

Differential Signaling by Splice Variants of the Human Free Fatty Acid Receptor GPR120

GPR120 is a long-chain fatty acid receptor that stimulates incretin hormone release from colonic endocrine cells and is implicated in macrophage and adipocyte function. The functional consequences of long (L) and short (S) human GPR120 splice variants, which differ by insertion of 16 amino acids in the third intracellular loop, are currently unknown. Here we compare signaling and intracellular trafficking of GPR120S and GPR120L receptors, using calcium mobilization and dynamic mass redistribution (DMR) assays, together with quantitative imaging measurements of β-arrestin2 association and receptor internalization. FLAG- or SNAP-tagged GPR120S receptors elicited both intracellular calcium mobilization and DMR responses in human embryonic kidney 293 cells, when stimulated with oleic acid, myristic acid, or the agonist 4-[[(3-phenoxyphenyl)methyl]amino]benzenepropanoic acid (GW9508). Responses were insensitive to pertussis toxin, but increases in intracellular calcium were attenuated by 2-aminoethoxydiphenyl borate, an inhibitor of store inositol trisphosphate receptors. Despite equivalent cell surface expression of SNAP-tagged GPR120L receptors, no specific calcium or DMR responses were observed in cells transfected with this isoform. However, agonist-stimulated GPR120S and GPR120L receptors both recruited β-arrestin2 and underwent robust internalization, with similar agonist potencies in each case. After oleic acid-induced internalization, neither GPR120 isoform recycled rapidly to the cell surface. In both cases, confocal microscopy indicated receptor targeting to lysosomal compartments. Thus, the third intracellular loop insertion in GPR120L prevents G protein-dependent intracellular calcium and DMR responses, but this receptor isoform remains functionally coupled to the β-arrestin pathway, providing one of the first examples of a native β-arrestin-biased receptor.

High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis

To investigate colonic endocrine cells in lymphocytic colitis (LC) patients. Fifty-seven patients with LC were included. These patients were 41 females and 16 males, with an average age of 49 years (range 19-84 years). Twenty-seven subjects that underwent colonoscopy with biopsies were used as controls. These subjects underwent colonoscopy because of gastrointestinal bleeding or health worries, where the source of bleeding was identified as haemorrhoids or angiodysplasia. They were 19 females and 8 males with an average age of 49 years (range 18-67 years). Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. Biopsies were fixed in 4% buffered paraformaldehyde, embedded in paraffin and cut into 5 μm-thick sections. The sections immunostained by the avidin-biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP) enteroglucagon and somatostatin cells. The cell densities were quantified by computerised image analysis using Olympus software. The colon of both the patient and the control subjects were macroscopically normal. Histopathological examination of colon biopsies from controls revealed normal histology. All patients fulfilled the diagnosis criteria required for of LC: an increase in intraepithelial lymphocytes (> 20 lymphocytes/100 epithelial cells) and surface epithelial damage with increased lamina propria plasma cells and absent or minimal crypt architectural distribution. In the colon of both patients and control subjects, serotonin-, PYY-, PP-, enteroglucagon- and somatostatin-immunoreactive cells were primarily located in the upper part of the crypts of Lieberkühn. These cells were basket- or flask-shaped. There was no statistically significant difference between the right and left colon in controls with regards to the densities of serotonin- and PYY-immunoreactive cells (P = 0.9 and 0.1, respectively). Serotonin cell density in the right colon in controls was 28.9 ± 1.8 and in LC patients 41.6 ± 2.6 (P = 0.008). In the left colon, the corresponding figures were 28.5 ± 1.9 and 42.4 ± 2.9, respectively (P = 0.009). PYY cell density in the right colon of the controls was 10.1 ± 1 and of LC patients 41 ± 4 (P = 0.00006). In the left colon, PYY cell density in controls was 6.6 ± 1.2 and in LC patients 53.3 ± 4.6 (P = 0.00007). The change in serotonin cells could be caused by an interaction between immune cells and serotonin cells, and that of PYY density might be secondary.

Low densities of serotonin and peptide YY cells in the colon of patients with irritable bowel syndrome.

BackgroundThe gut hormones are important in regulating gastrointestinal motility. Disturbances in gastrointestinal motility have been reported in patients with irritable bowel syndrome (IBS). Reduced endocrine cell density, as revealed by chromogranin A, has been reported in the colon of IBS patients.AimsTo investigate a possible abnormality in the colonic endocrine cells of IBS patients.MethodsA total of 41 patients with IBS according to Rome Criteria III and 20 controls were included in the study. Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. The biopsies were immunostained for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), entroglucagon, and somatostatin cells. Cell densities were quantified by computerized image analysis.ResultsSerotonin and PYY cell densities were reduced in the colon of IBS patients. PP, entroglucagon, and somatostatin-immunoreactive cells were too few to enable reliable quantification.ConclusionThe cause of these observations could be primary genetic defect(s), secondary to altered serotonin and/or PYY signaling systems and/or subclinical inflammation. Serotonin activates the submucosal sensory branch of the enteric nervous system and controls gastrointestinal motility and chloride secretion via interneurons and motor neurons. PYY stimulates absorption of water and electrolytes, and inhibits prostaglandin (PG) E2, and vasoactive intestinal peptide, which stimulates intestinal fluid secretion and is a major regulator of the “ileal brake”. Although the cause and effect relationship of these findings is difficult to elucidate, the abnormalities reported here might contribute to the symptoms associated with IBS.

Changes of colonic endocrine cells in trinitrobenzene sulfonic acid (TNBS)-induced rat colitis

In this study, immunohistochemistry was used to examine the changes in the density of colonic endocrine cells - argyrophil and argentaffin cells, chromogranin A (CGA), serotonin, somatostatin and glucagon-containing cells in trinitrobenzene sulfonic acid (TNBS)-induced rat colitis. Ulcerative colitis was induced by the instillation of 10 mg of TNBS into the colonic lumen through the anus. To confirm the inducement of ulcerative colitis, the macroscopic and microscopic scores as well as the colonic myeloperoxidase (MPO) activities were monitored for 8 days after TNBS instillation in the colonic lumens. In addition, the number of argyrophil and argentaffin cells, CGA, serotonin, somatostatin and glucagon-immunoreactive cells were counted in the colonic mucosa, respectively. After TNBS instillation into the lumen of the colon from the anus in rats, increases in macroscopic and microscopic scores in the colon tissues were observed along with increases in the colonic MPO activities. Therefore, ulcerative colitis was relatively well induced by the TNBS instillations. Marked decreases in the number of colonic endocrine cells were detected in the TNBS-treated animal compared to the sham control. These results suggest that colonic endocrine cells were also disrupted by TNBS-induced ulcerative colitis.

Is constipation caused by a loss of colonic interstitial cells of Cajal?

Is constipation caused by a loss of colonic interstitial cells of Cajal?

Neuroendocrine changes in colon of mice with a disrupted IL-2 gene.

Neuroendocrine peptides have a variety of physiological functions in the gastrointestinal tract. This study was carried out to investigate the impact of IL-2 deficiency on the neuroendocrine system in normal colon, and the neuroendocrine changes during colonic inflammation. Mice with homozygous disrupted IL-2 gene (IL-2-/-) spontaneously developed a bowel disease with similarities to human ulcerative colitis. Different types of colonic endocrine cells and myenteric nerves were analysed in the IL-2-/- mice using immunomorphometry. The neuropeptide contents in the colonic tissues were determined by radioimmunoassay. Age-matched healthy IL-2+/- and IL-2+/+ mice served as controls and the colonic IL-2 levels were compared between these two groups of mice by ELISA. Our data showed that less than half the amount of IL-2 was synthesized in the colon of IL-2+/- mice compared with the IL-2+/+ wild-type mice. Two major differences in the neuroendocrine colon were found between the mice with an intact and disrupted IL-2 gene. One was age-related. The frequencies of various endocrine cells and myenteric nerves increased with age in the IL-2+/+ mice. However, no such increases were seen in the mice with a disrupted IL-2 gene. Instead, the volume densities of enteroglucagon, serotonin cells and substance P (SP), vasoactive intestinal polypeptide (VIP) and total myenteric nerves were lower in the older IL-2+/- and IL-2-/- mice compared with the wild type. The other was disease-related. Polypeptide YY (PYY) cells and tissue levels of PYY, SP and VIP were significantly decreased in the IL-2-/- mice during the course of bowel inflammation compared with the healthy IL-2+/- and IL-2+/+ controls. These findings indicate that colonic neuroendocrine alterations did occur in the mice with a disrupted IL-2 gene and diminished local IL-2 level, suggesting a role of IL-2 in the regulation of the neuroendocrine system and a prevalent interaction between the immune and neuroendocrine systems in normal colon. On the other hand, there were some changes that seemed to correlate with the bowel inflammatory process. They might be associated with the impaired function in inflamed gut and contribute to the development and/or prolongation of disease.

Colonic endocrine cells in rats with chemically induced colon carcinoma.

Colonic carcinoma was induced in male Sprague-Dawley rats by injecting them with 1,2-dimethylhydrazine dihydrochloride. Control rats were injected with EDTA solution. Tissue specimens of colon from four groups of animals: (i) rats without tumour, (ii) with dysplasia and lymphoid hyperplasia, (iii) with colonic adenocarcinoma, and (iv) controls, were investigated. The colonic endocrine cells were detected by immunocytochemistry and quantified by computerised image analysis. Peptide YY (PYY)- and serotonin-immunoreactive cells were found in the colon of all the groups investigated. There were few somatostatin- or enteroglucagon-immunoreactive cells and no pancreatic polypeptide (PP)-immunoreactive cells in the colon of any of the groups studied. The density of PYY-immunoreactive cells increased significantly in rats with dysplasia and lymphoid hyperplasia and in rats with colon carcinoma. There was no statistically significant difference as regards cell secretory index (CSI) or nuclear area of PYY-immunoreactive cells in any of treated groups examined. Nor was there any statistically significant difference between all treated animal groups and controls, as regards cell density, CSI, or nuclear area of serotonin-immunoreactive cells. The present observations in an animal model of human colon carcinoma support the assumption that neuroendocrine peptides in the gut are involved in the carcinogenesis of colorectal carcinoma. However, The nature of the changes in the colonic endocrine cells observed here differed from those in patients with colon carcinoma, possibly due to a difference between the response of young rats to an induced colon carcinoma and a spontaneously developed carcinoma in elderly humans, or due to a species difference.

Colonic endocrine cells in patients with familial amyloidotic polyneuropathy.

To establish whether the endocrine cell number is affected in the colon in Japanese FAP patients. Department of Medicine, Umeå University Hospital and Department of Internal Medicine and Pathology, University Hospital, Kumamoto, Japan. Autopsy colon tissue specimens from 11 FAP patients and nine controls as well as 12 control biopsy specimens were included in the study. Endocrine cells in the colon were detected by immunohistochemistry and quantified by computerized image analysis. The autopsy material showed a slight autolysis. Neither enteroglucagon nor pancreatic polypeptide positive cells could be detected in the autopsy material, but were present in biopsy material. There was no statistical difference between autopsy and biopsy specimens regarding the number of peptide YY (PYY), somatostatin and serotonin cells. No significant differences were noted in PYY, somatostatin and serotonin immunoreactive cells in FAP patients compared to autopsy controls, though PYY cells tended to be decreased and serotonin and somatostatin cells tended to be increased in FAP patients. The difference between the Swedish and Japanese patients in the endocrine cell content points to the possibility of involvement of other factors than the endocrine cell depletion of the colon might be involved in the pathogenesis of gastro-intestinal dysfunction in FAP. The tendency of PYY to decrease in Japanese FAP might contribute to the development of diarrhoea in these patients.

Abnormal Colonic Endocrine Cells in Patients with Chronic Idiopathic Slow-Transit Constipation

Background: The aim of the present study was to investigate the colonic endocrine cells in patients with slow-transit constipation, to ascertain the presence of a possible abnormality. Methods: Ten patients with chronic slow-transit constipation were investigated. As controls, macroscopically and histologically normal tissues from the colon of 12 patients were examined. These patients had polyps, prolapsis, chronic diverticulitis, volvulus, and haemorrhoids. The endocrine cells were stained by immunocytochemistry and quantified by computerized image analysis. Results: There were significantly fewer enteroglucagon- and serotonin-immunoreactive cells in patients with chronic slow-transit constipation. There was no statistically significant difference between patients and controls with regard to the number of peptide YY (PYY)-, pancreatic polypeptide (PP)-, and somatostatin-immunoreactive cells. The cell secretory indexes (CSI) of enteroglucagon- and somatostatin-immunoreactive cells were significantly decreased. There was no statistically significant difference in the CSI between the patients and controls with regard to PYY-, PP-, and serotonin-immunoreactive cells. Conclusion: The changes in colonic endocrine cells in patients with slow-transit constipation may be one cause of the decreased motility in the colon and consequent development of constipation.

Effect of Ageing on Colonic Endocrine Cell Population in Mouse

Background: Dysmotility in the gastrointestinal tract increases with age. Colonic endocrine cells play an important role in regulating intestinal secretion and motility. The objective was to study possible age-related changes in the colonic endocrine cells of an animal model. Methods: The colonic endocrine cells in four different age groups of mice were investigated by immunocytochemistry and quantified by computerized image analysis. The ages of these groups were 1, 3, 12 and 24 months old. Results: The numbers of peptide YY (PYY), enteroglucagon and serotonin immunoreactive (IR) cells in 1-month-old mice were significantly increased compared with those of 3-month-old mice. Similarly, the numbers of these cells were significantly greater in 12- and 24-month-old mice than in 3-month-old mice. The cell secretory index (CSI) of enteroglucagon and serotonin IR cells was higher in 1-, 12- and 24-month-old mice than in 3-month-old mice. There was no significant difference between the different age groups regarding the CSI of PYY IR cells, nor was there any statistical difference between females and males in all endocrine cell types regarding numbers and CSI. Conclusion: It is suggested that the increase in colonic endocrine cells prior to puberty might reflect the role of gut hormones in the development of the gastrointestinal tract. It is speculated further that the increase in colonic endocrine cells with ageing may compensate for increased receptor resistance and/or weakened response of effector organs. It is suggested that the increase in numbers and unchanged CSI of PYY cells with advancing age may be responsible for the slow colonic transit and constipation, both of which increase with age.

Large Intestinal Endocrine Cells in Non-Obese Diabetic Mice

Colonic endocrine cells from prediabetic and diabetic non-obese diabetic mice as well as of the sister strain, BALB/cJ, were investigated by immunocytochemistry and computer image analysis. In prediabetic mice, enteroglucagon- and serotonin-immunoreactive cells were significantly increased in number, whereas the cell secretory index of these two cell types was significantly reduced. No significant differences were found in numbers or cell secretory index of peptide YY (PYY)-immunoreactive cells. In diabetic mice, PYY-immunoreactive cells were significantly fewer, but there were no significant differences in the numbers of enteroglucagon- and serotonin-immunoreactive cells. Whereas the cell secretory index was reduced in serotonin-producing cells, no significant differences were found between diabetic and control mice regarding the cell secretory index of PYY- and enteroglucagon-immunoreactive cells. Nor was any statistically significant difference found between controls, prediabetic and diabetic non-obese diabetic mice, regarding the thickness of submucosa, of circular and longitudinal-muscle layers, or of the mucosal area/μm baseline. The present study showed that abnormalities in colonic endocrine cells do occur, in both prediabetic and diabetic mice, but they are different in nature and can be divided into primary and secondary to the diabetes onset. The present findings of abnormal colonic endocrine cells in non-obese diabetic mice, an animal model for human insulin-dependent diabetes mellitus, might help explain the gastrointestinal disorders observed in patients with diabetes. The study also showed that the change in the colonic endocrine cells is dynamic and started before the onset of the diabetic condition.

Colonic endocrine cells in patients with carcinoma of the colon.

To investigate the colonic endocrine cells in patients with colon carcinoma in order to establish a possible abnormality. Twelve patients with colon adenocarcinoma (eight women and four men; mean age 69 years; range 52-88 years) were studied. As controls, macroscopically and histologically normal tissues from the colon of 12 patients (eight women and four men; mean age 66 years; range 34-86 years) were examined. These patients suffered from polyps, prolapsus, chronic diverticulitis, volvulus or haemorrhoids. Macroscopically and histologically normal tissues from the colon of the patients, about 10 cm from the tumour, and of the controls were examined. Endocrine cells were immunostained with the avidin-biotin-complex method, and were quantified by computer image analysis using an automatic standard sequence analysis operation. Three parameters were used: (1) the number of endocrine cells per mm3 of epithelial cells; (2) the cell secretory index (CSI); and (3) the nuclear volume. The numbers of somatostatin- and serotonin-immunoreactive cells were significantly reduced in patients with colon carcinoma (P = 0.03 and 0.009, respectively). There was no difference between patients and controls regarding the numbers of PYY-, PP-, and enteroglucagon-immunoreactive cells. The CSI of somatostatin- and serotonin-immunoreactive cells were significantly decreased. There was no difference in the CSI between the patients and controls regarding PYY-, PP- or enteroglucagon-immunoreactive cells. The nuclear volumes of PYY- and enteroglucagon-immunoreactive cells increased significantly in the patients. The nuclear volume of PP-, somatostatin- and serotonin cells did not differ from those of the controls. The present results support the assumption that a disturbance in the colonic neuroendocrine system occurs in patients with colon carcinoma, which might affect the development of the tumour. The decrease in the number and CSI of somatostatin cells may account for the decrease of the colonic content of this peptide observed previously in these patients. The decrease in the number and CSI of serotonin-immunoreactive cells in patients with colon adenocarcinoma might be a method by which the body defends itself against this mitogenic substance.

Colonic endocrine cells in inflammatory bowel disease.

To study colonic endocrine cell types in patients with ulcerative colitis (UC) and Crohn's disease (CD). Departments of Medicine and Pathology, University Hospitals, Umeå and Uppsala, Sweden. Seventeen patients with UC (seven females and 10 males) and 11 patients with CD (five females and six males). Twenty-two patients (eight females and 14 males) operated on for colon carcinoma and without signs of inflammatory bowel disease were used as controls. The colonic endocrine cell types were identified by immunohistochemical methods and quantified by computed image analysis. The areas of the argyrophil cells as well as those immunoreactive to chromogranin A and serotonin were significantly increased in patients with both UC and CD, compared with those in the controls. In patients with CD, the areas of polypeptide YY(PYY)- and pancreatic polypeptide (PP)-immunoreactive cells were significantly reduced, whilst the area of enteroglucagon-immunoreactive cells was increased. There was no statistical difference in endocrine cell area between specimens with slight versus severe inflammation, except for PYY and enteroglucagon cell areas in patients with CD. Whilst the former cell area decreased, the latter increased in specimens with severe inflammation. The mean cellular area for each endocrine cell type did not differ between the controls and patients with UC or CD. The increase in the serotonin-immunoreactive cell area in patients with both UC and CD might be one of the factors causing reduced colonic contraction and increased intraluminal pressure observed in patients with inflammatory bowel disease. Furthermore, in patients with CD, the decreased PYY-immunoreactive cell area may explain the decreased absorption and increased secretion found in these patients.

Deoxycholate-stimulated release of peptide YY from the isolated perfused rabbit left colon

The purpose of this study was 1) to measure the effect of graded concentrations of oleic acid and deoxycholic acid (DCA) on the release of peptide YY (PYY) and enteroglucagon and 2) to test whether DCA-stimulated release of PYY was neurally mediated by blocking neuronal conduction with tetrodotoxin. Studies were performed in isolated left colons from New Zealand White rabbits. Oleic acid in concentrations from 0.22 to 22 mM suspended in 10 mM DCA significantly stimulated release of PYY (P less than 0.01) but resulted in no graded response (Bartlett's test, P = 0.15). Similarly, oleic acid (2.2 mM) suspended with ursodeoxycholic acid (10 mM) produced no increased release of PYY above that achieved by ursodeoxycholic acid alone. In contrast, oleic acid (2.2 and 22 mM suspended with 10 mM DCA) produced a graded release of enteroglucagon during the stimulated period. Deoxycholic acid caused a concentration-dependent release of PYY (1, 3.3, 10, and 25 mM) during the stimulated period. Deoxycholic acid (1 and 10 mM) did not significantly increase enteroglucagon release. Tetrodotoxin blockade had no effect on release of PYY stimulated by 10 mM DCA. Because PYY and enteroglucagon are both found in colonic endocrine cells, these results suggest that the release of PYY and enteroglucagon are mediated by specific secretagogues and not simply caused by noxious effects of the agonists. Also, this study has demonstrated that DCA-stimulated release of PYY is not dependent on neuronally mediated mechanisms.

Lack of peptide YY immunoreactivity in adenomatous colonic polyps: Evidence in favor of an adenoma-carcinoma sequence

The aim of endoscopic polypectomy is to prevent colorectal cancer, as it is assumed that most, if not all, large bowel cancers are derived from adenomatous polyps. While it is now recognized that colonic endocrine cells, like other mucosal epithelial cells, have an endodermal origin, they are relatively sparse components of large bowel tumors. Peptide YY (PYY) is the most abundant endocrine regulatory peptide localized to the distal bowel. Endocrine cells, like the other cells of the mucosal epithelia, are derived from a common stem cell in the base of the crypts. The presence of endocrine peptides may thus be viewed as a marker for cellular differentiation in the gut. PYY was therefore measured in colonic carcinomas and adenomatous polyps, as its absence would be evidence in favor of genetic alterations in epithelial stem cell maturation. PYY concentrations in extracts of surgically removed colonic carcinomas ( n = 22) from all regions were very low compared with those of adjacent normal bowel. Similarly, PYY concentrations in extracts of polyps ( n = 39) obtained during endoscopic polypectomy were also very low when compared with those of adjacent normal mucosa. These varied between 1 and 11% of the normal epithelial content, depending upon the region. Low PYY levels appeared to reflect the malignant potential of these lesions: highest in tubular polyps, lower in villous polyps, and lowest in carcinomas. The very low concentrations of PYY in adenomatous polyps, like those of colonic cancer, are consistent with epithelial dysplasia and the incomplete formation of mucosal endocrine cells. These findings support the hypothesis of an adenoma to carcinoma sequence in colonic cancer.