1
|
Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy. Int J Mol Sci 2022; 23:ijms23062995. [PMID: 35328419 PMCID: PMC8951934 DOI: 10.3390/ijms23062995] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.
Collapse
|
2
|
Intestinal Barrier Function in Gluten-Related Disorders. Nutrients 2019; 11:nu11102325. [PMID: 31581491 PMCID: PMC6835310 DOI: 10.3390/nu11102325] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 12/15/2022] Open
Abstract
Gluten-related disorders include distinct disease entities, namely celiac disease, wheat-associated allergy and non-celiac gluten/wheat sensitivity. Despite having in common the contact of the gastrointestinal mucosa with components of wheat and other cereals as a causative factor, these clinical entities have distinct pathophysiological pathways. In celiac disease, a T-cell mediate immune reaction triggered by gluten ingestion is central in the pathogenesis of the enteropathy, while wheat allergy develops as a rapid immunoglobulin E- or non-immunoglobulin E-mediated immune response. In non-celiac wheat sensitivity, classical adaptive immune responses are not involved. Instead, recent research has revealed that an innate immune response to a yet-to-be-defined antigen, as well as the gut microbiota, are pivotal in the development in this disorder. Although impairment of the epithelial barrier has been described in all three clinical conditions, its role as a potential pathogenetic co-factor, specifically in celiac disease and non-celiac wheat sensitivity, is still a matter of investigation. This article gives a short overview of the mucosal barrier of the small intestine, summarizes the aspects of barrier dysfunction observed in all three gluten-related disorders and reviews literature data in favor of a primary involvement of the epithelial barrier in the development of celiac disease and non-celiac wheat sensitivity.
Collapse
|
3
|
Nicolas JM, Bouzom F, Hugues C, Ungell AL. Oral drug absorption in pediatrics: the intestinal wall, its developmental changes and current tools for predictions. Biopharm Drug Dispos 2017; 38:209-230. [PMID: 27976409 PMCID: PMC5516238 DOI: 10.1002/bdd.2052] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Revised: 11/21/2016] [Accepted: 11/30/2016] [Indexed: 12/14/2022]
Abstract
The dissolution, intestinal absorption and presystemic metabolism of a drug depend on its physicochemical characteristics but also on numerous physiological (e.g. gastrointestinal pH, volume, transit time, morphology) and biochemical factors (e.g. luminal enzymes and flora, intestinal wall enzymes and transporters). Over the past decade, evidence has accumulated indicating that these factors may differ in children and adults resulting in age-related changes in drug exposure and drug response. Thus, drug dosage may require adjustment for the pediatric population to ensure the desired therapeutic outcome and to avoid side-effects. Although tremendous progress has been made in understanding the effects of age on intestinal physiology and function, significant knowledge gaps remain. Studying and predicting pharmacokinetics in pediatric patients remains challenging due to ethical concerns associated with clinical trials in this vulnerable population, and because of the paucity of predictive in vitro and in vivo animal assays. This review details the current knowledge related to developmental changes determining intestinal drug absorption and pre-systemic metabolism. Supporting experimental approaches as well as physiologically based pharmacokinetic modeling are also discussed together with their limitations and challenges. Copyright © 2016 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Jean-Marie Nicolas
- Non-Clinical Development Department, UCB Biopharma sprl, Braine-l'Alleud, Belgium
| | - François Bouzom
- Non-Clinical Development Department, UCB Biopharma sprl, Braine-l'Alleud, Belgium
| | - Chanteux Hugues
- Non-Clinical Development Department, UCB Biopharma sprl, Braine-l'Alleud, Belgium
| | - Anna-Lena Ungell
- Non-Clinical Development Department, UCB Biopharma sprl, Braine-l'Alleud, Belgium
| |
Collapse
|
4
|
Demehri FR, Krug SM, Feng Y, Lee IFM, Schulzke JD, Teitelbaum DH. Tight Junction Ultrastructure Alterations in a Mouse Model of Enteral Nutrient Deprivation. Dig Dis Sci 2016; 61:1524-33. [PMID: 26685910 DOI: 10.1007/s10620-015-3991-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 12/08/2015] [Indexed: 01/04/2023]
Abstract
BACKGROUND Total parenteral nutrition (TPN), a necessary treatment for patients who cannot receive enteral nutrition, is associated with infectious complications due in part to a loss of intestinal epithelial barrier function (EBF). Using a mouse model of TPN, with enteral nutrient deprivation, we previously demonstrated an increase in mucosal interferon-γ and tumor necrosis factor-α; these cytokine changes are a major mediator driving a reduction in epithelial tight junction (TJ) protein expression. However, the exact ultrastructural changes to the intestinal epithelial barrier have not been previously described. AIM We hypothesized that TPN dependence results in ultrastructural changes in the intestinal epithelial TJ meshwork. METHODS C57BL/6 mice underwent internal jugular venous cannulation and were given enteral nutrition or TPN with enteral nutrient deprivation for 7 days. Freeze-fracture electron microscopy was performed on ileal tissue to characterize changes in TJ ultrastructure. EBF was measured using transepithelial resistance and tracer permeability, while TJ expression was measured via Western immunoblotting and immunofluorescence staining. RESULTS While strand density, linearity, and appearance were unchanged, TPN dependence led to a mean reduction in one horizontal strand out of the TJ compact meshwork to a more basal region, resulting in a reduction in meshwork depth. These findings were correlated with the loss of TJ localization of claudin-4 and tricellulin, reduced expression of claudin-5 and claudin-8, and reduced ex vivo EBF. CONCLUSION Tight junction ultrastructural changes may contribute to reduced EBF in the setting of TPN dependence.
Collapse
Affiliation(s)
- Farokh R Demehri
- Section of Pediatric Surgery, Department of Surgery, Mott Children's Hospital, University of Michigan Health System, 1540 E. Hospital Dr., SPC 4211, Ann Arbor, MI, 48109-4211, USA.
| | - Susanne M Krug
- Institute of Clinical Physiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Yongjia Feng
- Section of Pediatric Surgery, Department of Surgery, Mott Children's Hospital, University of Michigan Health System, 1540 E. Hospital Dr., SPC 4211, Ann Arbor, MI, 48109-4211, USA
| | - In-Fah M Lee
- Institute of Clinical Physiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Joerg D Schulzke
- Institute of Clinical Physiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Daniel H Teitelbaum
- Section of Pediatric Surgery, Department of Surgery, Mott Children's Hospital, University of Michigan Health System, 1540 E. Hospital Dr., SPC 4211, Ann Arbor, MI, 48109-4211, USA
| |
Collapse
|
5
|
Feng Y, Barrett M, Hou Y, Yoon HK, Ochi T, Teitelbaum DH. Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model. Am J Physiol Gastrointest Liver Physiol 2016; 310:G273-84. [PMID: 26635320 PMCID: PMC4754738 DOI: 10.1152/ajpgi.00335.2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 11/24/2015] [Indexed: 01/31/2023]
Abstract
Feeding strategies to care for patients who transition from enteral nutrient deprivation while on total parenteral nutrition (TPN) to enteral feedings generally proceed to full enteral nutrition once the gastrointestinal tract recovers; however, an increasing body of literature suggests that a subgroup of patients may actually develop an increased incidence of adverse events, including death. To examine this further, we studied the effects of acute refeeding in a mouse model of TPN. Interestingly, refeeding led to some beneficial effects, including prevention in the decline in intestinal epithelial cell (IEC) proliferation. However, refeeding led to a significant increase in mucosal expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), as well as an upregulation in Toll-like receptor 4 (TLR-4). Refeeding also failed to prevent TPN-associated increases in IEC apoptosis, loss of epithelial barrier function, and failure of the leucine-rich repeat-containing G protein-coupled receptor 5-positive stem cell expression. Transitioning from TPN to enteral feedings led to a partial restoration of the small bowel microbial population. In conclusion, while acute refeeding led to some restoration of normal gastrointestinal physiology, enteral refeeding led to a significant increase in mucosal inflammatory markers and may suggest alternative strategies to enteral refeeding should be considered.
Collapse
Affiliation(s)
- Yongjia Feng
- 1Section of Pediatric Surgery, Department of Surgery, the University of Michigan Medical School and the C. S. Mott Children's Hospital, Ann Arbor, Michigan;
| | - Meredith Barrett
- 1Section of Pediatric Surgery, Department of Surgery, the University of Michigan Medical School and the C. S. Mott Children's Hospital, Ann Arbor, Michigan; ,2General Surgery, Department of Surgery, the University of Michigan Medical School, Ann Arbor, Michigan;
| | - Yue Hou
- 1Section of Pediatric Surgery, Department of Surgery, the University of Michigan Medical School and the C. S. Mott Children's Hospital, Ann Arbor, Michigan; ,3University of Michigan, Ann Arbor, Michigan; and
| | - Hong Keun Yoon
- 1Section of Pediatric Surgery, Department of Surgery, the University of Michigan Medical School and the C. S. Mott Children's Hospital, Ann Arbor, Michigan; ,3University of Michigan, Ann Arbor, Michigan; and
| | - Takanori Ochi
- 1Section of Pediatric Surgery, Department of Surgery, the University of Michigan Medical School and the C. S. Mott Children's Hospital, Ann Arbor, Michigan; ,4Department of Pediatric Surgery, Juntendo Hospital, Juntendo University, Tokyo, Japan
| | - Daniel H. Teitelbaum
- 1Section of Pediatric Surgery, Department of Surgery, the University of Michigan Medical School and the C. S. Mott Children's Hospital, Ann Arbor, Michigan;
| |
Collapse
|
6
|
Feng Y, Teitelbaum DH. Tumour necrosis factor--induced loss of intestinal barrier function requires TNFR1 and TNFR2 signalling in a mouse model of total parenteral nutrition. J Physiol 2013; 591:3709-23. [PMID: 23753529 DOI: 10.1113/jphysiol.2013.253518] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Tumour necrosis factor-α (TNF-α) has been reported to play a central role in intestinal barrier dysfunction in many diseases; however, the precise role of the TNF-α receptors (TNFRs) has not been well defined using in vivo models. Our previous data showed that enteral nutrient deprivation or total parenteral nutrition (TPN) led to a loss of intestinal epithelial barrier function (EBF), with an associated upregulation of TNF-α and TNFR1. In this study, we hypothesized that TNF-α plays an important role in TPN-associated EBF dysfunction. Using a mouse TPN model, we explored the relative roles of TNFR1 vs. TNFR2 in mediating this barrier loss. C57/BL6 mice underwent intravenous cannulation and were given enteral nutrition or TPN for 7 days. Tumour necrosis factor-α receptor knockout (KO) mice, including TNFR1KO, TNFR2KO or TNFR1R2 double KO (DKO), were used. Outcomes included small intestine transepithelial resistance (TER) and tracer permeability, junctional protein zonula occludens-1, occludin, claudins and E-cadherin expression. In order to address the dependence of EBF on TNF-α further, exogenous TNF-α and pharmacological blockade of TNF-α (Etanercept) were also performed. Total parenteral nutrition led to a loss of EBF, and this was almost completely prevented in TNFR1R2DKO mice and partly prevented in TNFR1KO mice but not in TNFR2KO mice. The TPN-associated downregulation of junctional protein expression and junctional assembly was almost completely prevented in the TNFR1R2DKO group. Blockade of TNF-α also prevented dysfunction of the EBF and junctional protein losses in mice undergoing TPN. Administration of TPN upregulated the downstream nuclear factor-B and myosin light-chain kinase (MLCK) signalling, and these changes were almost completely prevented in TNFR1R2DKO mice, as well as with TNF-α blockade, but not in TNFR1KO or TNFR2KO TPN groups. Tumour necrosis factor-α is a critical factor for TPN-associated epithelial barrier dysfunction, and both TNFR1 and TNFR2 are involved in EBF loss. Nuclear factor-B and MLCK signalling appear to be important downstream mediators involved in this TNF-α signalling process.
Collapse
Affiliation(s)
- Yongjia Feng
- Section of Pediatric Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109-4211, USA
| | | |
Collapse
|
7
|
Witte AB, D’Amato M, Poulsen SS, Laurent A, Knuhtsen S, Bindslev N, Hansen MB, Schmidt PT. Duodenal epithelial transport in functional dyspepsia: Role of serotonin. World J Gastrointest Pathophysiol 2013; 4:28-36. [PMID: 23755368 PMCID: PMC3676537 DOI: 10.4291/wjgp.v4.i2.28] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 02/19/2013] [Accepted: 04/16/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate functional duodenal abnormalities in functional dyspepsia (FD) and the role of serotonin (5-hydroxytryptamine, 5-HT) in mucosal ion transport and signalling.
METHODS: Duodenal mucosal biopsies were obtained from 15 patients with FD and 18 healthy controls. Immunohistochemistry was used to study the number of 5-HT-containing cells and real-time polymerase chain reaction for expression of 5-HT receptors 1A, 1B, 2A, 2B, 3A, 3B, 3C, 3D, 3E, 4 and 7, as well as expression of the serotonin re-uptake transporter (SERT) gene SLC6A4 and tryptophan hydroxylase 1 (TPH1). Biopsies were mounted in Ussing chambers for evaluation of basal and 5-HT-stimulated short-circuit current (SCC).
RESULTS: Conductance was lower in FD [42.4 ± 4.7 mS/cm2 (n = 15) vs 62.5 ± 4.5 mS/cm2 (n = 18), P = 0.005]. 5-HT induced a dose dependent rise in SCC in both FD (n = 8) and controls (n = 9), the rise was lower in FD (P < 0.001). Mean number of 5-HT stained cells per high power field was the same [34.4 ± 8.4 in FD (n = 15) and 30.4 ± 3.7 in controls (n = 18), P = 0.647]. The following genes were highly expressed: 5-HT receptor HTR3E, HTR4, HTR7, SERT gene (SLC6A4) and TPH1. Differences in expression levels were observed for HTR3E (higher expression in FD, P = 0.008), HTR7 (lower expression in FD, P = 0.027), SLC6A4 (higher expression in FD, P = 0.033) and TPH1 (lower expression in FD, P = 0.031).
CONCLUSION: Duodenal ion transport in response to exogenous 5-HT is abnormal in FD patients and associated with high expression of the HTR3E receptor and the serotonin transporter.
Collapse
|
8
|
Björkman E, Casselbrant A, Lundberg S, Fändriks L. In vitro assessment of epithelial electrical resistance in human esophageal and jejunal mucosae and in Caco-2 cell layers. Scand J Gastroenterol 2012; 47:1321-33. [PMID: 23003564 DOI: 10.3109/00365521.2012.722677] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE There is a need for a technique allowing studies of human mucosal specimens collected during different clinical conditions. This study elucidates if square wave pulse analysis discriminates between epithelial and transmural electrical resistance and if there is an association with transepithelial permeability of molecular probes. METHODS Mucosae from esophagus (surgical resections: n = 14; endoscopic biopsies: n = 15) and jejunum (n = 12) and Caco-2 cell monolayers were investigated in Ussing chambers. Transmural and epithelial electrical resistance were recorded by the use of standardized current pulses. Permeability was assessed using two fluorescein-labeled probes (weight 376 and 4000 Da). RESULTS Baseline epithelial electrical resistance was higher in esophageal mucosa (~280 Ω*cm(2)), than in jejunal (~10 Ω*cm(2)) and Caco-2 cells (~140 Ω*cm(2)). The subepithelial contribution to the transmural resistance was higher in jejunal preparations (+88%) and Caco-2 cells (+75%), than in esophageal (+30%). During hypoxia the subepithelial resistance was unchanged, whereas the epithelial resistance decreased significantly in jejunal mucosa and Caco-2 cells. These findings coincided with increased transepithelial probe permeability and signs of disturbed morphology. Esophageal epithelia were resistant to hypoxia. However, exposure to deoxycholic acid and trypsin abolished the esophageal epithelial resistance and increased probe permeability. Endoscopic esophageal biopsies from patients with erosive reflux disease exhibited significantly lower epithelial resistance and higher current than healthy subjects. CONCLUSION Square wave pulse analysis in Ussing chambers is suitable for assessment of epithelial electrical resistance that can reflect transepithelial permeability of molecular probes with known size. Moreover, the technique discriminated between healthy and reflux-diseased esophageal mucosal biopsies.
Collapse
Affiliation(s)
- Eleonora Björkman
- Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden.
| | | | | | | |
Collapse
|
9
|
Farrell C, Morgan M, Tully O, Wolov K, Kearney K, Ngo B, Mercogliano G, Thornton JJ, Valenzano MC, Mullin JM. Transepithelial leak in Barrett's esophagus patients: The role of proton pump inhibitors. World J Gastroenterol 2012; 18:2793-7. [PMID: 22719187 PMCID: PMC3374982 DOI: 10.3748/wjg.v18.i22.2793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 10/19/2011] [Accepted: 05/12/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine if the observed paracellular sucrose leak in Barrett’s esophagus patients is due to their proton pump inhibitor (PPI) use.
METHODS: The in vivo sucrose permeability test was administered to healthy controls, to Barrett’s patients and to non-Barrett’s patients on continuous PPI therapy. Degree of leak was tested for correlation with presence of Barrett’s, use of PPIs, and length of Barrett’s segment and duration of PPI use.
RESULTS: Barrett’s patients manifested a near 3-fold greater, upper gastrointestinal sucrose leak than healthy controls. A decrease of sucrose leak was observed in Barrett’s patients who ceased PPI use for 7 d. Although initial introduction of PPI use (in a PPI-naïve population) results in dramatic increase in sucrose leak, long-term, continuous PPI use manifested a slow spontaneous decline in leak. The sucrose leak observed in Barrett’s patients showed no correlation to the amount of Barrett’s tissue present in the esophagus.
CONCLUSION: Although future research is needed to determine the degree of paracellular leak in actual Barrett’s mucosa, the relatively high degree of leak observed with in vivo sucrose permeability measurement of Barrett’s patients reflects their PPI use and not their Barrett’s tissue per se.
Collapse
|
10
|
Geraedts MCP, Troost FJ, Saris WHM. Addition of sucralose enhances the release of satiety hormones in combination with pea protein. Mol Nutr Food Res 2012; 56:417-24. [PMID: 22378494 DOI: 10.1002/mnfr.201100297] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 10/24/2011] [Accepted: 11/06/2011] [Indexed: 12/21/2022]
Abstract
SCOPE Exposing the intestine to proteins or tastants, particularly sweet, affects satiety hormone release. There are indications that each sweetener has different effects on this release, and that combining sweeteners with other nutrients might exert synergistic effects on hormone release. METHODS AND RESULTS STC-1 cells were incubated with acesulfame-K, aspartame, saccharine, sucralose, sucrose, pea, and pea with each sweetener. After a 2-h incubation period, cholecystokinin(CCK) and glucagon-like peptide 1 (GLP-1) concentrations were measured. Using Ussing chamber technology, the mucosal side of human duodenal biopsies was exposed to sucrose, sucralose, pea, and pea with each sweetener. CCK and GLP-1 levels were measured in basolateral secretions. In STC-1 cells, exposure to aspartame, sucralose, sucrose, pea, and pea with sucralose increased CCK levels, whereas GLP-1 levels increased after addition of all test products. Addition of sucrose and sucralose to human duodenal biopsies did not affect CCK and GLP-1 release; addition of pea stimulated CCK and GLP-1 secretion. CONCLUSION Combining pea with sucrose and sucralose induced even higher levels of CCK and GLP-1. Synchronous addition of pea and sucralose to enteroendocrine cells induced higher levels of CCK and GLP-1 than addition of each compound alone. This study shows that combinations of dietary compounds synergize to enhance satiety hormone release.
Collapse
Affiliation(s)
- Maartje C P Geraedts
- Department of Human Biology, Maastricht University Medical Center +, Maastricht, The Netherlands.
| | | | | |
Collapse
|
11
|
Geraedts MCP, Troost FJ, De Ridder RJ, Bodelier AGL, Masclee AAM, Saris WHM. Validation of Ussing chamber technology to study satiety hormone release from human duodenal specimens. Obesity (Silver Spring) 2012; 20:678-82. [PMID: 21566565 DOI: 10.1038/oby.2011.104] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
By developing novel screening technologies to test effects of food ingredients on hormone release, which are comparable to the in vivo situation, fewer tests may have to be performed using volunteers, whereas it still provides information that can be extrapolated to the human situation. In an in vivo intervention study, 10 lean (BMI: 20-25 kg/m(2)) and 10 obese (BMI >30 kg/m(2)) were recruited. All subjects randomly received pea protein (PP) solutions or placebo, orally and intraduodenally. Cholecystokinin (CCK) and glucagon like peptide 1 (GLP-1) release was measured over 2 h. During the oral interventions, gastrointestinal (GI) fluids were retrieved. For the present ex vivo study, duodenal biopsies were taken and placed in Ussing chambers. The luminal side was exposed to PP, placebo, intraduodenal fluid after oral PP-intake and oral placebo-intake in vivo, and a commercial pea-hydrolysate for 2 h. CCK and GLP-1 levels were measured at the serosal side. After intraduodenal PP administration in vivo, the area under the curve (AUC) for both CCK and GLP-1 was significantly increased in both lean and obese subjects. In the ex vivo study, exposure to PP resulted in significantly elevated levels of CCK and GLP-1 compared to all other test solutions. These results indicate that the ex vivo Ussing chamber technology is a valid alternative for in vivo studies, and may therefore serve as a suitable screening tool for studying the effects of nutritional compounds on the release of satiety hormones.
Collapse
Affiliation(s)
- Maartje C P Geraedts
- Department of Human Biology, Maastricht University Medical Center+, Maastricht, The Netherlands.
| | | | | | | | | | | |
Collapse
|
12
|
Abstract
OBJECTIVES The intestinal mucosal barrier protects the body from the large numbers of microbes that inhabit the intestines and the molecules they release. Intestinal barrier function is impaired in humans with cystic fibrosis (CF), including reduced activity of the lipopolysaccharide-detoxifying enzyme intestinal alkaline phosphatase (IAP) and increased permeability. The objective of this study was to determine the suitability of using the CF mouse to investigate intestinal barrier function, and whether interventions that are beneficial for the CF mouse intestinal phenotype (antibiotics or laxative), would improve barrier function. Also tested were the effects of exogenous IAP administration. MATERIALS AND METHODS The Cftr(tm1UNC) mouse was used. IAP expression (encoded by the murine Akp3 gene) was measured by quantitative reverse transcription-polymerase chain reaction and enzyme activity. Intestinal permeability was assessed by measuring rhodamine-dextran plasma levels following gavage. RESULTS CF mice had 40% Akp3 mRNA expression and 30% IAP enzyme activity, as compared with wild-type mice. Oral antibiotics and laxative treatments normalized Akp3 expression and IAP enzyme activity in the CF intestine. CF mice had a 5-fold greater transfer of rhodamine-dextran from gut lumen to blood. Antibiotic and laxative treatments reduced intestinal permeability in CF mice. Administration of exogenous purified IAP to CF mice reduced intestinal permeability to wild-type levels and reduced small intestinal bacterial overgrowth by >80%. CONCLUSIONS The CF mouse intestine has impaired mucosal barrier function, similar to human CF. Interventions that improve other aspects of the CF intestinal phenotype (antibiotics and laxative) also increase IAP activity and decrease intestinal permeability in CF mice. Exogenous IAP improve permeability and strongly reduce bacterial overgrowth in CF mice, suggesting this may be a useful therapy for CF.
Collapse
|
13
|
Wallon C, Persborn M, Jönsson M, Wang A, Phan V, Lampinen M, Vicario M, Santos J, Sherman PM, Carlson M, Ericson AC, McKay DM, Söderholm JD. Eosinophils express muscarinic receptors and corticotropin-releasing factor to disrupt the mucosal barrier in ulcerative colitis. Gastroenterology 2011; 140:1597-607. [PMID: 21277851 DOI: 10.1053/j.gastro.2011.01.042] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Revised: 12/23/2010] [Accepted: 01/13/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropin-releasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. METHODS Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers ((51)Cr-EDTA, fluorescein isothiocyanate-dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). RESULTS Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), α-helical CRF(9-41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. CONCLUSIONS We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation.
Collapse
Affiliation(s)
- Conny Wallon
- Department of Clinical and Experimental Medicine, Division of Surgery, Linköping University, Sweden
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
14
|
Valentini L, Eggers J, Ockenga J, Haas VK, Bühner S, Winklhofer-Roob BM, Hengstermann S, Sinn B, Weigel A, Norman K, Pirlich M, Lochs H. Association between intestinal tight junction permeability and whole-body electrical resistance in healthy individuals: A hypothesis. Nutrition 2009; 25:706-14. [DOI: 10.1016/j.nut.2008.11.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Revised: 11/26/2008] [Accepted: 11/30/2008] [Indexed: 01/05/2023]
|
15
|
Larsson MH, Simrén M, Thomas EA, Bornstein JC, Lindström E, Sjövall H. Elevated motility-related transmucosal potential difference in the upper small intestine in the irritable bowel syndrome. Neurogastroenterol Motil 2007; 19:812-20. [PMID: 17883433 DOI: 10.1111/j.1365-2982.2007.00941.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The pathophysiology of irritable bowel syndrome (IBS) is complex and incompletely known. Very little has been studied regarding the role of submucous neuronal activity. We therefore measured small intestinal transmural potential difference (PD, reflecting mainly electrogenic chloride secretion), and its linkage with fasting motor activity [migrating motor complex (MMC)] in controls (n = 16) and patients with IBS [n = 23, 14 diarrhoea predominant (d-IBS) and nine constipation predominant (c-IBS)]. Transmural-PD and its relation to MMC phase III was measured by modified multilumen manometry for 3 h in the fasting state using one jejunal and one duodenal infusion line as flowing electrodes. The amplitude and duration of motor phase III was similar in controls and IBS patients, but the propagation speed of phase III was higher in IBS patients. In IBS patients, maximal PD during MMC phase III was significantly elevated in both the duodenum and jejunum (P < 0.05) and the PD decline after phase III was significantly prolonged in the jejunum (P < 0.01). The PD elevation was seen in both duodenum and jejunum in d-IBS patients, but only in the jejunum in the c-IBS patients. On the basis of previous modelling studies, we propose that the enhanced secretion may reflect disturbed enteric network behaviour in some patients with IBS.
Collapse
Affiliation(s)
- M H Larsson
- Department of Integrative Pharmacology, Gastrointestinal Biology, AstraZeneca R&D, Mölndal, Sweden.
| | | | | | | | | | | |
Collapse
|
16
|
Bibliography. Current world literature. Cardiovascular medicine. Curr Opin Pediatr 2007; 19:601-6. [PMID: 17885483 DOI: 10.1097/mop.0b013e3282f12851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|