peptide-yy and Crohn-Disease

Crohn's disease (CD) patients suffer postprandial aversive symptoms, which can lead to anorexia and malnutrition. Changes in the regulation of gut hormones and gut dysmotility are believed to play a role.. This study aimed to investigate small-bowel motility and gut peptide responses to a standard test meal in CD by using MRI.. We studied 15 CD patients with active disease (age 36 ± 3 y; BMI 26 ± 1 kg/m 2) and 20 healthy volunteers (HVs; age 31 ± 3 years; BMI 24 ± 1 kg/m 2). They underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling following a 400-g soup meal (204 kcal). Small-bowel motility, other MRI parameters, and glucagon-like peptide-1 (GLP-1), polypeptide YY (PYY), and cholecystokinin peptides were measured. Data are presented as means ± SEMs.. HVs had significantly higher fasting motility indexes [106 ± 13 arbitrary units (a.u.)], compared with CD participants (70 ± 8 a.u.; P ≤ 0.05). Postprandial small-bowel water content showed a significant time by group interaction (P < 0.05), with CD participants showing higher levels from 210 min postprandially. Fasting concentrations of GLP-1 and PYY were significantly greater in CD participants, compared with HVs [GLP-1, CD 50 ± 8 µg/mL versus HV 13 ± 3 µg/mL (P ≤ 0.0001); PYY, CD 236 ± 16 pg/mL versus HV 118 ± 12 pg/mL (P ≤ 0.0001)]. The meal challenge induced a significant postprandial increase in aversive symptom scores (fullness, distention, bloating, abdominal pain, and sickness) in CD participants compared with HVs (P ≤ 0.05).. The decrease in fasting small-bowel motility noted in CD participants can be ascribed to the increased fasting gut peptides. A better understanding of the etiology of aversive symptoms in CD will facilitate identification of better therapeutic targets to improve nutritional status. This trial was registered at clinicaltrials.gov as NCT03052465.

Topics: Adult; Aged; Cholecystokinin; Crohn Disease; Fasting; Female; Gastrointestinal Hormones; Gastrointestinal Motility; Glucagon-Like Peptide 1; Humans; Intestine, Small; Magnetic Resonance Imaging; Male; Middle Aged; Peptide YY; Postprandial Period; Young Adult

Peptide YY (PYY) 3-36, the main circulatory form of PYY, plays important roles in gastrointestinal motility, secretion, and absorption. However, it is unknown whether PYY 3-36 has underlying functions in colitis. The Crohn's disease (CD)-like mouse model in which CD is induced by trinitrobenzene sulfonic acid (TNBS) was established and utilized to investigate this potential role for PYY 3-36. The results showed that the expression of colonic mucosal PYY and PYY receptors Y1, Y2, Y4 were significantly increased in mice with TNBS-induced colitis. In vitro, PYY 3-36 remarkably inhibited the production of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) from lipopolysaccharide (LPS)-induced macrophages. In vivo, a high concentration of PYY 3-36 robustly decreased the weight loss and death rate and attenuated the pathological colon tissue damage observed in mice with TNBS-induced colitis. Further studies uncovered that PYY 3-36 treatment reduced the levels of colon myeloperoxidase (MPO) and both colonic and systemic TNF-α and IL-6 observed in murine colitis. Furthermore, flow cytometric analysis showed PYY 3-36 altered the proportion of Th1/Th2 splenocytes in the disease model of colitis. Collectively, these results suggest that PYY 3-36 may be a promising candidate for the improvement of colitis, reflected by the attenuation of colon inflammatory responses observed in experimental murine colitis.

Topics: Animals; Colitis; Crohn Disease; Cytokines; Disease Models, Animal; Interleukin-6; Mice; Mice, Inbred BALB C; Peptide YY; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Gastric emptying (GE) is delayed in a subset of patients with inflammatory bowel disease (IBD). We have shown before that altered release of gastrointestinal hormones may contribute to GE disturbances, but overall effects of disease activity remain unclear. Thus, we aimed to evaluate GE in patients with IBD during active disease and following therapy.. A total of 20 healthy subjects (HC) and 26 patients with IBD hospitalized because of an acute episode of their disease (Crohn's disease (CD) n = 13, ulcerative colitis (UC) n = 13) underwent a standardized (13) C-octanoic acid GE breath test (baseline test). Plasma glucose, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) were measured periodically throughout the test. A total of 16 patients underwent a second GE test after 3-4 months of therapy.. At baseline, nine patients with IBD had pathologically delayed GE half-time (T½ > 150 min) (P = 0·028 vs. HC). Moreover, T½ was significantly longer in the total group of patients with IBD than in HC (129 ± 12 min vs. 96 ± 7, P = 0·030). Postprandial GLP-1 responses were elevated in IBD (P = 0·002 vs. HC) and correlated with T½ (P = 0·05). Following therapy clinical activity indices and T½ were decreased in IBD (P ≤ 0·01 vs. baseline), and T½ no longer differed from HC (P > 0·5). Moreover, GLP-1 plasma levels decreased significantly (P = 0·031).. Higher disease activity in IBD is associated with prolonged GE and increased release of GLP-1. Following effective therapy, GE is accelerated and GLP-1 release decreases significantly. Thus, increased release of GLP-1 from the inflamed mucosa might contribute to GE disturbances in IBD.

Topics: Adolescent; Adult; Aged; Blood Glucose; Breath Tests; Case-Control Studies; Cholecystokinin; Colitis, Ulcerative; Crohn Disease; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Peptide YY; Postprandial Period; Young Adult

Appetite disturbance is an important nutritional issue in Crohn's disease (CD), but the biological basis is unclear. Satiety signals such as polypeptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are produced by enteroendocrine cells (EEC). In animal models, upregulation of EEC plays a mechanistic role in feeding disturbance and weight loss. We recently showed increased EEC activity in tissue from active small bowel CD. This study investigated EEC products in plasma in CD, and appetite-related symptoms.. Active CD patients and a healthy reference group were studied. Gut peptide responses to a mixed nutrient test meal were measured by ELISA. Symptoms were assessed by visual analogue score. A patient subset was re-studied in remission.. CD subjects displayed reduced appetite (p < 0.0001) before and after eating. Total PYY was increased 2.2-fold (p = 0.04) and correlated with nausea (p = 0.036) and bloating (p = 0.037) scores only in small bowel CD. Postprandial plasma ghrelin levels were also elevated. Leptin correlated with body mass index (p = 0.0001) and weight loss (p = 0.01). GLP-1 and GIP were not elevated. In remission, postprandial PYY and ghrelin reverted to control levels.. Enhanced EEC responses may directly and adversely affect appetite in CD patients through increased gut-brain signalling.

Topics: Adult; Aged; Appetite; Case-Control Studies; Crohn Disease; Enteroendocrine Cells; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Intestine, Small; Leptin; Male; Middle Aged; Peptide YY; Postprandial Period; Visual Analog Scale; Young Adult

Enteroendocrine cells sense gut luminal contents, and orchestrate digestive physiology whilst contributing to mucosal homeostasis and innate immunity. The terminal ileum is the key site of EEC expression but detailed assessment of their subtypes, lineage transcription factors and expression products has not been undertaken in terminal ileal Crohn's disease. Recent Crohn's disease gene wide association studies have linked the neuroendocrine transcription factor Phox2b; while autoantibodies to an enteroendocrine protein, ubiquitination protein 4a, have been identified as a disease behaviour biomarker.. Terminal ileal tissue from small or large bowel Crohn's disease and normal controls was analysed for enteroendocrine marker expression by immunohistochemistry and quantitative polymerase chain reaction. Inflammation was graded by endoscopic, clinical, histological and biochemical scoring.. In small bowel disease, glucagon-like peptide 1 and chromogranin A cells were increased 2.5-fold (p=0.049) and 2-fold (p=0.031) respectively. Polypeptide YY cells were unchanged. Ileal enteroendocrine cell expression was unaffected in the presence of Crohn's colitis. Phox2b was co-localised to enteroendocrine cells and showed a 1.5-fold increase in ileal disease. Significant mRNA increases were noted for chromogranin A (3.3-fold; p=0.009), glucagon-like peptide 1 (3.1-fold; p=0.007) and ubiquitination protein 4a (2.2-fold; p=0.02). Neurogenin 3, an enteroendocrine transcription factor showed ~2 fold-upregulation (p=0.048).. Enhanced enteroendocrine cell activity is present in small bowel disease, and observed in restricted cell lineages. This may impact on the epithelial immune response, cellular homeostasis and nutrient handling and influence appetite via increased satiety signalling in the gut-brain axis.

Topics: Adult; Aged; Biomarkers; Chromogranin A; Crohn Disease; Enteroendocrine Cells; Gene Expression; Glucagon-Like Peptide 1; Homeodomain Proteins; Humans; Ileum; Male; Middle Aged; Peptide YY; RNA, Messenger; Severity of Illness Index; Statistics, Nonparametric; Transcription Factors; Ubiquitin-Protein Ligases; Young Adult

It is unclear why patients with inflammation of the distal bowel complain of symptoms referable to the upper gastrointestinal tract, specifically to gastric emptying (GE) disturbances. Thus we aimed to determine occurrence and putative pathomechanisms of gastric motor disorders in such patients. Thirteen healthy subjects (CON), 13 patients with Crohn's disease (CD), 10 with ulcerative colitis (UC), and 7 with diverticulitis (DIV) underwent a standardized (13)C-octanoic acid gastric emptying breath test. Plasma glucose, CCK, peptide YY, and glucagon-like peptide-1 (GLP-1) were measured periodically and correlated with GE parameters. Results were given in means +/- SD. Compared with CON, GE half time (T) was prolonged by 50% in CD (115 +/- 55 vs. 182 +/- 95 min, P = 0.037). Six CD, 2 DIV, and 2 UC patients had pathological T (>200 min). Postprandial plasma glucose was increased in all patients but was highest in DIV and correlated with T (r = 0.90, P = 0.006). In CD, mean postprandial CCK levels were increased threefold compared with CON (6.5 +/- 6.7 vs. 2.1 +/- 0.6 pmol/l, P = 0.027) and were correlated with T (r = 0.60, P = 0.041). Compared with CON, GLP-1 levels were increased in UC (25.1 +/- 5.2 vs. 33.5 +/- 13.0 pmol/l, P = 0.046) but markedly decreased in DIV (9.6 +/- 5.2 pmol/l, P < 0.0001). We concluded that a subset of patients with CD, UC, or DIV has delayed GE. GE disturbances are most pronounced in CD and might partly be caused by excessive CCK release. In DIV there might be a pathophysiological link between decreased GLP-1 release, postprandial hyperglycemia, and delayed GE. These explorative data encourage further studies in larger patient groups.

Topics: Acute Disease; Adult; Aged; Blood Glucose; C-Reactive Protein; Cholecystokinin; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Diverticulitis, Colonic; Fasting; Female; Gastric Emptying; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Peptide YY; Postprandial Period; Steroids; Young Adult

Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in inflammatory bowel disease (IBD), the production and secretion of GLP-2 and PYY could be affected as a part of a regulatory mechanism. Therefore, tissue levels and meal-stimulated secretion of GLP-2 and PYY were studied in IBD patients and compared to controls.. Outpatients with IBD and control patients were included. Mucosal biopsies were taken from the ileum and colon and the content of GLP-2 and PYY was measured. After colonoscopy the patients took a mixed meal and plasma was collected for 90 min for plasma measurements of GLP-2 and PYY.. Tissue levels of GLP-2 in control patients were highest in the terminal ileum (407+/-82 pmol/g tissue, n=10), whereas PYY was highest in the rectum (919+/-249 pmol/g tissue, n=10). In IBD patients with acute inflammation, the content of GLP-2 was similar to controls, whereas PYY was decreased to 72.1+/-17.7% (P=0.03, n=13) of control values. Neither the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients.. The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may contribute to the diarrhoea of some of these patients.

Topics: Colitis, Ulcerative; Colon; Crohn Disease; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Ileum; Inflammatory Bowel Diseases; Intestinal Mucosa; Peptide YY; Peptides; Postprandial Period; Radioimmunoassay

Patients with Crohn disease (CD) have an increased risk of developing gallstones. Among other factors, gallbladder motility may have a role in the pathogenesis of gallstone formation. We have evaluated whether gallbladder motor function is affected in Crohn disease with special emphasis on the influence of disease localization and previous bowel resection.. Thirty-seven patients (20 females and 17 males, age 36 +/- 2 years) with inactive Crohn disease (CDAI < 150) were studied: 15 patients after ileocecal resection and 22 non-operated patients; 12 had small bowel disease and 10 had large bowel disease. Nineteen healthy subjects (10 female; 9 male, age 30 +/- 2 years) served as controls. Gallbladder volumes were measured in the fasting state and at regular intervals for 2 h after ingestion of a solid meal (780 kcal). Blood samples were drawn at regular intervals for determination of cholecystokinin (CCK) and peptide YY (PYY).. Fasting gallbladder volumes were significantly (P < 0.05) reduced in patients with large bowel disease (20.8 +/- 2.1 ml) or after ileocecal resection (18.3 +/- 2.4 ml) compared to patients with small bowel disease (28.0 +/- 2.1 ml) and controls (27.2 +/- 1.8 ml). Fasting plasma CCK levels were significantly (P < 0.05) higher in patients with large bowel disease or after ileocecal resection compared to patients with small bowel disease and controls. Postprandial gallbladder emptying and endogenous plasma CCK and PYY secretion in patients with Crohn disease were not different from controls.. Fasting gallbladder volume is decreased and fasting plasma CCK levels are increased in patients with Crohn disease of the large bowel and patients after ileocecal resection. Postprandial gallbladder motility, CCK and PYY release were not affected in patients with Crohn disease.

Topics: Adult; Cecum; Cholecystokinin; Colon; Crohn Disease; Female; Gallbladder Emptying; Humans; Ileum; Male; Pancreatic Polypeptide; Peptide YY

The study was undertaken to examine regional differences in the concentrations of five regulatory peptides in the human colonic mucosa. Biopsies were obtained during routine colonoscopy from 33 patients whose colonic mucosa was macroscopically and histologically normal. Regulatory peptides were extracted, and measured by specific radioimmunoassays. Concentrations of three peptides that are present predominantly in endocrine cells within colonic mucosa increased significantly towards the rectum: Mean concentrations of peptide YY, enteroglucagon, and somatostatin were about three times greater in the rectum than in the cecum. However, concentrations of two peptides that are present in mucosal nerve fibers diminished significantly towards the rectum: Mean rectal concentrations of vasoactive intestinal peptide and peptide histidine methionine were both about 0.6 of mean cecal concentrations. Concentrations of all five peptides were lower in biopsies taken from colonic polyps than in normal colonic mucosa. Regional differences in colonic mucosal concentrations of regulatory peptides probably reflect differences in the physiological functions of different parts of the colon.

Topics: Adolescent; Adult; Aged; Cecum; Colitis, Ulcerative; Colon; Colonic Polyps; Crohn Disease; Female; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Male; Middle Aged; Peptide PHI; Peptide YY; Peptides; Radioimmunoassay; Rectum; Somatostatin; Vasoactive Intestinal Peptide

Peptide YY has been localized within human ileocolonic endocrine cells and may contribute to the regulation of gastric secretion and gastric emptying in man. Since our previous studies had shown decreased colonic concentrations of peptide YY in the idiopathic inflammatory bowel diseases, a specific radioimmunoassay was used to measure fasting serum concentrations of peptide YY in healthy controls and in patients with adenocarcinoma of the rectum, idiopathic chronic active liver disease and hepatic cirrhosis, ulcerative colitis, and Crohn's disease. In healthy controls and in patients with adenocarcinoma of the rectum, serum concentrations of peptide YY ranged from 50 to 260 pg/ml. Serum concentrations of peptide YY in patients with hepatic cirrhosis ranged from 59 to 717 pg/ml. Serum concentrations of peptide YY in patients with ulcerative colitis were similar to healthy controls. In patients with Crohn's disease, serum concentrations of peptide YY were less than 50 pg/ml in three patients who had had a previous proctocolectomy, and were more than 260 pg/ml in 14 patients who had had previous resection of more than 48 cm of ileum or presently had symptomatic Crohn's disease subsequently requiring surgical resection of a total of more than 75 cm of ileum. These results suggest that most circulating peptide YY is released from the colorectal region. Hepatic cirrhosis, previous ileal resection, and symptomatic Crohn's disease were associated with elevation of fasting serum peptide YY. The mechanism of increased fasting serum peptide YY in patients with Crohn's disease could be the loss of an ileal inhibitory factor or possibly an increased release of colonic peptide YY in response to fat malabsorption. The effect of alteration of serum peptide YY concentrations on the pathophysiology of Crohn's disease is yet unknown.

Topics: Adenocarcinoma; Adult; Aged; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Fasting; Female; Gastrointestinal Hormones; Humans; Ileum; Male; Middle Aged; Peptide YY; Peptides; Radioimmunoassay; Rectal Neoplasms

Plasma concentrations of peptide YY (PYY), a newly isolated peptide produced by ileal and colonic endocrine cells, were measured in several groups of patients with digestive disorders after a standardized normal breakfast. Peptide YY levels were found to be grossly elevated in patients with steatorrhea due to small intestinal mucosal atrophy (tropical sprue). Basal levels in these patients were 79 +/- 18 pM, which was nearly 10-fold higher than those seen in healthy controls (8.5 +/- 0.8 pM). Patients with steatorrhea due to chronic destructive pancreatitis also had substantially increased basal PYY levels (47.5 +/- 6.3 pM), and their postprandial response was also greater than that of normal subjects. Moderately elevated plasma PYY concentrations were seen in patients with inflammatory bowel disease and patients recovering from acute infective diarrhea. In contrast, patients with diverticular disease, duodenal ulcer, and functional bowel disease had normal PYY responses. These changes in the secretion of PYY responses. These changes in the secretion, may shed light on the physiologic role of this newly discovered peptide and on intestinal adaptation to common digestive disorders.

Topics: Adult; Aged; Celiac Disease; Chromatography, Gel; Colitis, Ulcerative; Colonic Diseases, Functional; Crohn Disease; Diarrhea; Diverticulitis; Duodenal Ulcer; Female; Food; Gastrointestinal Diseases; Gastrointestinal Hormones; Humans; Intestinal Absorption; Male; Middle Aged; Pancreatitis; Peptide YY; Peptides; Radioimmunoassay