| 1. |
- Al-Saffar, Anas Kh. 1969-
(författare)
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Gastrointestinal Permeability and Motility in Inflammatory Bowel Disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Synchronized motility, permeability and secretory (hormones and enzymes) events are integral to normal physiology. Smooth muscle syncytium operates with enteric nervous system (ENS) and endocrine signalling to accommodate, mix and control passage of ingested materials. The intestinal epithelial cells (IECs) drive digestion and absorption while repelling harmful compounds.This thesis investigated GI barrier function (permeability, mucosal integrity), motility and hormonal patterns in inflammatory bowel disease (IBD) by: 1) assessing GI motility using a wireless motility capsule (WMC, SmartPill®) and video capsule endoscopy (VCE, Pillcam®), 2) investigation of intestinal fatty acid binding protein (I-FABP) as a biomarker of Crohn’s disease (CD) disease activity, 3) evaluation of small intestinal permeability in IBD, 4) investigating meal-related WMC motility and simultaneous hormonal (e.g., Ghrelin, GLP-1, GIP, PYY) patterns in IBD. Reference WMC motility values for transit times for gastric emptying, small bowel, orocecal, small+large bowel, colon and whole gut were established. Software-generated estimates and visually determined values were nearly identical. Compared with VCE estimates (represents fasting conditions), the WMC records longer GET and SBTT. Variations in intra-subject reproducibility must be considered in clinical investigations. This data was then used to investigate IBD patients. I-FABP was primarily expressed in the epithelium of the small bowel and to lesser extent also in the colon and stomach. Circulating I-FABP was elevated in active CD with a magnitude comparable to TNFα. I-FABP lowers and rises again in parallel with TNFα and HBI during infliximab treatment. I-FABP can be used as a jejunum and ileum selective prognostic biomarker for monitoring disease activity. Increased small intestine mucosal barrier permeability to lactulose in both CD and UC was found. Sucralose can serve a dual purpose in quantifying small and large intestinal permeability. Small intestinal hyper-permeability was not revealed as a transporter dependent nutrient (riboflavin) malabsorption. Using the WMC, consistent motility disturbances in IBD were limited, as were differences in pH. However, disturbances within many individuals were found. As part of the investigation, defects in gut peptide and metabolic hormone meal responses were found, typically higher plasma levels. No clear associations between hormones and motility were found. Effects on hunger/satiety signaling in IBD are anticipated.The present thesis shows the utility of the WMC and gut barrier tests in monitoring IBD patients.
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| 2. |
- Halim, Md. Abdul, 1983-
(författare)
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Gut peptides in gastrointestinal motility and mucosal permeability
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.
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| 3. |
- Björner, Kajsa, et al.
(författare)
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High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 128
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown.AIM: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC.METHODS: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases.RESULTS: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases.CONCLUSION: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.
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