cholecystokinin and Inflammatory-Bowel-Diseases

In patients with Crohn's disease, the prevalence of gallstones is increased, especially in patients with ileal disease or after ileal resection. Recent studies point to alterations in enterohepatic bilirubin cycling, resulting in increased biliary bilirubin levels leading to pigment rather than cholesterol gallstones. Gallbladder (hypo)motility is another important factor in the pathogenesis of gallstones leading to bile stasis, crystallisation and stone formation. Postprandial gallbladder emptying is not markedly reduced in patients with Crohn's disease but lower fasting gallbladder volumes have been observed in patients with colonic disease or after ileocaecal resection. Prolonged and repeated bowel rest before and after intestinal surgery has been recognised as a significant risk factor for gallstone formation in patients with Crohn's disease.

Topics: Cholecystokinin; Fasting; Gallbladder; Gallstones; Humans; Inflammatory Bowel Diseases; Postprandial Period

Enteroendocrine cells are hormone-secreting cells spread along the intestinal epithelium. Their principal function is to promote the digestion of food. However, little is known about other functions that these cells may play, since they are difficult to study as a whole endocrine organ due to their diffuse localization. It is known that the intestinal epithelial barrier is actively involved in the host defense against pathogen invasion. Here we applied gene expression profiling to characterize the response of the human LCC-18 enteroendocrine cell line to physiological and pathological stimuli mimicked by fatty acids (FAs), flagellin and LPS exposure. We observed that these cells participate in an innate immune reaction to pathogens through the expression of pro-inflammatory factors (i.e. CXCL1 and 3 and IL-32) that we could validate by molecular and proteomic approach. Interestingly, IL-32 has been recently found over-expressed in the inflamed mucosa of patients affected by inflammatory bowel disease. This is very important because modifications of enteroendocrine cells during intestinal inflammation have been so far considered as secondary effects of the inflammatory status rather than due to direct pathogen/enteroendocrine cell interaction. As expected, FAs exposure up-regulates pro-differentiative genes and the production of cholecystokinin but it does not enhance the expression of pro-inflammatory genes. The present observations enlighten a new aspect of the cross talk between immune and endocrine system and suggest enteroendocrine cells as important contributors of inflammatory processes occurring in the gut in response to pathogen exposure and direct enhancers of the inflammatory status associated with human inflammatory bowel disease.

Topics: Cell Line, Tumor; Chemokine CXCL1; Cholecystokinin; Enteroendocrine Cells; Escherichia coli; Fatty Acids; Flagellin; Gene Expression Profiling; Humans; Immunity, Mucosal; Inflammatory Bowel Diseases; Interleukins; Intestinal Mucosa; Lipopolysaccharides; Neuroimmunomodulation; Toll-Like Receptors

Crypts of Lieberkühn were isolated from human colon, and differential interference contrast microscopy distinguished goblet and columnar cells. Activation with carbachol (CCh, 100 microM) or histamine (10 microM) released contents from goblet granules. Stimulation with prostaglandin E(2) (PGE(2), 5 microM) or adenosine (10 microM) did not release goblet granules but caused the apical margin of columnar cells to recede. Goblet volume was lost during stimulation with CCh or histamine ( approximately 160 fl/cell), but not with PGE(2) or adenosine. Three-quarters of goblet cells were responsive to CCh but released only 30% of goblet volume. Half-time for goblet volume release was 3.7 min. PGE(2) stimulated a prolonged fluid secretion that attained a rate of approximately 350 pl/min. Columnar cells lost approximately 50% of apical volume during maximal PGE(2) stimulation, with a half-time of 3.3 min. In crypts from individuals with ulcerative colitis, goblet cells were hypersensitive to CCh for release of goblet volume. These results support separate regulation for mucus secretions from goblet cells and from columnar cells, with control mechanisms restricting total release of mucus stores.

Topics: Adenosine; Biological Transport; Body Fluids; Carbachol; Cell Size; Cholecystokinin; Cholinergic Agonists; Colon; Cytoplasmic Granules; Dinoprostone; Goblet Cells; Histamine; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Mathematics; Microscopy, Interference; Microtomy; Mucus

Plasma cholecystokinin increases with enteral feeding. Cholecystokinin increases intracellular calcium in lymphocytes/monocytes and is a lymphocyte co-mitogen. We hypothesize that decreased cholecystokinin production with "bowel rest" and parenteral nutrition may be beneficial in inflammatory bowel disease by down-regulating gut immune/inflammatory mechanisms. The majority of cells observed in mucosa of inflammatory bowel disease are monocytes and neutrophils. Cholecystokinin effect was therefore measured on monocyte production of proinflammatory mediators (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6) and neutrophil chemotaxins/activators (interleukin-8, granulocyte-macrophage colony stimulating factor, and leukotriene B4).. Peripheral blood monocytes (0.5 x 10(6)) from healthy donors in 1 mL of RPMI 1640 plus 5% fetal calf serum were cultured for 24 h in 5% CO2 at 37 degrees C with 5 micrograms/mL endotoxin, 1 x 10(-7) M cholecystokinin, or no agonist. Supernatants were analyzed by ELISA for cytokines and leukotriene B4.. Endotoxin-stimulated monocytes produced 1130 pg/mL tumor necrosis factor versus 81 pg/mL for cholecystokinin, 612 pg/mL interleukin-1 versus 10 pg/mL, 694 pg/mL interleukin-6 versus 30 pg/mL, 4531 pg/mL of interleukin-8 versus 3848 pg/mL, 21 pg/mL granulocyte-macrophage colony stimulating factor versus 9 pg/mL, and 21 pg/mL leukotriene B4 versus 12 pg/mL. Controls produced no cytokines/eicosanoids (N = 8, p < 0.001).. Cholecystokinin increase with enteral feeding may up-regulate gut immune response. Cholecystokinin suppression with parenteral alimentation may decrease inflammatory mediator production.

Topics: Cells, Cultured; Cholecystokinin; Cytokines; Dose-Response Relationship, Drug; Eicosanoids; Enteral Nutrition; Enzyme-Linked Immunosorbent Assay; Humans; Inflammatory Bowel Diseases; Monocytes; Sincalide; Up-Regulation