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Tao H, Wang J, Bao Z, Jin Y, Xiao Y. Acute chlorothalonil exposure had the potential to influence the intestinal barrier function and micro-environment in mice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 894:165038. [PMID: 37355131 DOI: 10.1016/j.scitotenv.2023.165038] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/02/2023] [Accepted: 06/18/2023] [Indexed: 06/26/2023]
Abstract
The intestinal barrier maintains intestinal homeostasis and metabolism and protects against harmful pollutants. Some environmental pollutants seriously affect intestinal barrier function. However, it remains unclear whether or how chlorothalonil (CTL) impacts the intestinal barrier function in animals. Herein, 6-week-old male mice were acutely exposed to different CTL concentrations (100 and 300 mg/kg BW) via intragastric administration once a day for 7 days. Histopathological examination revealed obvious inflammation in the mice' colon and ileum. Most notably, CTL exposure increased the intestinal permeability, particularly in the CTL-300 group. CTL exposure reduced the secretion of colonic epithelial mucus and changed the transcription levels of genes bound up with ion transport and ileal antimicrobial peptide (AMP) secretion, indicating intestinal chemical barrier damage. The results of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and Ki67 staining revealed abnormal apoptosis and increased intestinal epithelial cell proliferation, suggesting that CTL exposure led to cytotoxicity and inflammation. The results of 16S rRNA sequencing revealed that CTL exposure altered the intestinal microbiota composition and reduced its diversity and richness in the colon contents. Thus, acute CTL exposure affected the different intestinal barrier- and gut microenvironment-related endpoints in mice.
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Affiliation(s)
- Huaping Tao
- Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life and Environmental Sciences, Hangzhou Normal University, 311121 Hangzhou, China; College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Juntao Wang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Zhiwei Bao
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Yuanxiang Jin
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
| | - Yingping Xiao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Agro-Product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China.
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Guo F, Liu D, Zhou Y, Yu Y, Xu Y, Zou Y, Li C, Zhang F, Yu Z. Pharmacokinetic study of single and multiple oral administration of glutamine in healthy Beagles. Front Pharmacol 2022; 13:1014474. [PMID: 36249805 PMCID: PMC9563617 DOI: 10.3389/fphar.2022.1014474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/12/2022] [Indexed: 11/21/2022] Open
Abstract
Glutamine is an amino acid that is mainly used for the treatment of gastrointestinal diseases in clinic, but there is a lack of such medicine in veterinary clinic, and its research in dogs has never been seen. This study aimed to investigate the pharmacokinetics of single and multiple administration of glutamine (Gln) tablets in Beagles. Twenty-four healthy Beagles were randomly selected for the pharmacokinetic study of a single dose of low (120 mg/kg), medium (240 mg/kg), and high (360 mg/kg) Gln tablets. After 7 days of washout period, six Beagles in the medium group were selected for a multiple-dose pharmacokinetic study, 240 mg/kg twice a day for 7 days. The Gln concentration in plasma was determined by a validated UPLC-MS/MS method. The results of single oral administration of different doses of Gln tablets showed that Cmax, AUC0→t, AUC0→∝ had a certain linear relationship with the dosage. T-tests were performed for single and multiple administration of Tmax, Cmax, t1/2λz, AUC0→t, and AUC0→∝, and the results showed no significant differences (p > 0.05). Therefore, Gln tablets were absorbed quickly by oral administration, and there was no accumulation in Beagles after 7 days of administration.
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Assay considerations for fluorescein isothiocyanate-dextran (FITC-d): an indicator of intestinal permeability in broiler chickens. Poult Sci 2021; 100:101202. [PMID: 34111612 PMCID: PMC8192867 DOI: 10.1016/j.psj.2021.101202] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/12/2021] [Accepted: 03/26/2021] [Indexed: 12/16/2022] Open
Abstract
Fluorescein isothiocyanate-dextran (FITC-d) is being used as an indicator of intestinal paracellular permeability in poultry research. Especially with the industry moving toward antibiotic-free production, intestinal function and integrity issues have been a research focus. An increasing number of scientific conference abstracts and peer-reviewed journal publications have shown that 4-kDa FITC-d is an efficient marker candidate for measurement of intestinal permeability and can be applied in broiler research. However, experimental protocols vary by personnel, instruments used, and research institution, and potential concerns related to this assay have yet to receive the same amount of attention. Understanding protocol consistency within and across laboratories is vital for obtaining accurate, consistent, and comparable experimental results. This review is aimed to 1) summarize different FITC-d assays in broiler research from peer-reviewed publications during the past 6 yr and 2) discuss factors that can potentially affect intestinal permeability results when conducting the FITC-d assay. In summary, it is essential to pay attention to details, including gavage dose, fasting period, sample handling and lab analysis details when conducting the assay in broiler research. Differences in birds (breed/strain, age, and gender) and experimental design (diet, health status/challenge model, and sampling age) need to be considered when comparing serum FITC-d concentration results between different in vivo animal trials.
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Noninvasive Biomarkers of Gut Barrier Function in Patients Suffering from Diarrhea Predominant-IBS: An Update. DISEASE MARKERS 2020; 2020:2886268. [PMID: 33110455 PMCID: PMC7582069 DOI: 10.1155/2020/2886268] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 09/23/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
The intestinal barrier plays a crucial role in the absorption of nutrients and in preventing the entry of pathogenic microorganisms and toxic molecules. Several studies have shown a compromised intestinal barrier associated with low-grade inflammation in the small intestinal mucosa in celiac disease, inflammatory bowel disease, and irritable bowel syndrome (IBS), particularly in IBS with diarrhea (IBS-D). In light of these new data, IBS is no longer considered a functional disease but rather a heterogeneous syndrome that has yet to be carefully studied. Therefore, investigating the integrity and function of the intestinal barrier is now essential to improving knowledge of the pathophysiology of IBS-D and to improving the management of IBS-D patients. However, the study of the intestinal barrier must clarify some still unsolved methodological aspects and propose standardised assays before becoming a useful diagnostic tool. In this framework, this review will discuss data about the tests that noninvasively evaluate the integrity and functionality of the human intestinal barrier, paying particular attention to patients with IBS-D, in both clinical and research situations.
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Takakura W, Pimentel M. Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome - An Update. Front Psychiatry 2020; 11:664. [PMID: 32754068 PMCID: PMC7366247 DOI: 10.3389/fpsyt.2020.00664] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 06/26/2020] [Indexed: 12/11/2022] Open
Abstract
Small intestinal bacterial overgrowth (SIBO) is one manifestation of gut microbiome dysbiosis and is highly prevalent in IBS (Irritable Bowel Syndrome). SIBO can be diagnosed either by a small bowel aspirate culture showing ≥103 colony-forming units (CFU) per mL of aspirate, or a positive hydrogen lactulose or glucose breath test. Numerous pathogenic organisms have been shown to be increased in subjects with SIBO and IBS, including but not limited to Enterococcus, Escherichia coli, and Klebsiella. In addition, Methanobrevibacter smithii, the causal organism in a positive methane breath test, has been linked to constipation predominant irritable bowel syndrome (IBS-C). As M. smithii is an archaeon and can overgrow in areas outside of the small intestine, it was recently proposed that the term intestinal methanogen overgrowth (IMO) is more appropriate for the overgrowth of these organisms. Due to gut microbiome dysbiosis, patients with IBS may have increased intestinal permeability, dysmotility, chronic inflammation, autoimmunity, decreased absorption of bile salts, and even altered enteral and central neuronal activity. As a consequence, SIBO and IBS share a myriad of symptoms including abdominal pain, distention, diarrhea, and bloating. Furthermore, gut microbiome dysbiosis may be associated with select neuropsychological symptoms, although more research is needed to confirm this connection. This review will focus on the role of the gut microbiome and SIBO in IBS, as well as novel innovations that may help better characterize intestinal overgrowth and microbial dysbiosis.
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Affiliation(s)
- Will Takakura
- Department of Medicine, Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Mark Pimentel
- Department of Medicine, Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Medicine, Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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Sipahi AM, Baptista DM. Helminths as an alternative therapy for intestinal diseases. World J Gastroenterol 2017; 23:6009-6015. [PMID: 28970717 PMCID: PMC5597493 DOI: 10.3748/wjg.v23.i33.6009] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 07/05/2017] [Accepted: 08/09/2017] [Indexed: 02/06/2023] Open
Abstract
Animal models and clinical studies have shown that helminth infections exert immunomodulatory activity, altering intestinal permeability and providing a potential beneficial action on autoimmune and inflammatory disorders in human beings, such as inflammatory bowel disease (IBD) and celiac disease. This is consistent with the theory that intestinal microbiota is responsible for shaping human immunological responses. With the arrival of the immunobiologic era and the use of antibodies, we propose a distinctive pathway for treating patients with IBD and celiac disease. We have some evidence about the safety and tolerability of helminth use, but evidence about their impact on disease activity is lacking. Using worms to treat diseases could be a possible way to lower treatment costs, since the era of immunobiologic agents is responsible for a significant rise in expenses. Some questions remain to be investigated regarding the use of helminths in intestinal disease, such as the importance of the specific species of helminths used, appropriate dosing regimens, optimal timing of treatment, the role of host genetics, diet, environment, and the elucidation of the exact mechanisms of action. One promising approach is the use of helminth-derived anti-inflammatory molecules as drugs. Yet there are still many challenges with this method, especially with regard to safety. Studies on intestinal permeability point to Strongyloides stercoralis as a useful nematode for these purposes.
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Affiliation(s)
- Aytan Miranda Sipahi
- LIM 07-Laboratory of Experimental Clinical Gastroenterology, Department of Gastroenterology and Hepatology, Clínicas Hospital of University of São Paulo-HCFMUSP and, School of Medicine at the University of São Paulo, São Paulo 04023-062, Brazil
| | - Daniel Machado Baptista
- LIM 07-Laboratory of Experimental Clinical Gastroenterology, Department of Gastroenterology and Hepatology, Clínicas Hospital of University of São Paulo-HCFMUSP and, School of Medicine at the University of São Paulo, São Paulo 04023-062, Brazil
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Montalto M, Rapaccini GL. Teduglutide and Intestinal Permeability in Short Bowel Syndrome. JPEN J Parenter Enteral Nutr 2016; 40:1087. [PMID: 27875268 DOI: 10.1177/0148607116637847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Abstract
The aetiology and pathology of IBS, a functional bowel disorder thought to lack an organic cause, is largely unknown. However, studies suggest that various features, such as altered composition of the gut microbiota, together with increased intestinal permeability, a changed balance in the enteroendocrine system and a dysregulated immune system in the gut, most likely have an important role in IBS. Exactly how these entities act together and give rise to symptoms is still unknown, but an altered gut microbiota composition could lead to dysregulation of the intestinal barrier as well as the enteroendocrine and the immune systems, which (through interactions with the nervous system) might generate symptoms. This Review highlights the crosstalk between the gut microbiota, the enteroendocrine system, the immune system and the role of intestinal permeability in patients with IBS.
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Spiller R. Editorial: abnormal permeability and altered mucosal serotonin metabolism in the irritable bowel syndrome - is there a link? Aliment Pharmacol Ther 2014; 40:1116-8. [PMID: 25280258 DOI: 10.1111/apt.12952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- R Spiller
- Nottingham Digestive Diseases Biomedical Research Unit, Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.
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Camilleri M, Lasch K, Zhou W. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012; 303:G775-85. [PMID: 22837345 DOI: 10.1152/ajpgi.00155.2012] [Citation(s) in RCA: 283] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal ailments among those seeking health care for gastrointestinal disorders. Despite its prevalence, IBS pathophysiology is still not completely understood. Continued elucidation of IBS etiological mechanisms will lead to a greater appreciation of possible therapeutic targets. In the past decade, there has been increasing focus on the possible connection between increased intestinal mucosal permeability, inflammation, and visceral hypersensitivity. Increased permeability in subsets of IBS patients has been observed and the possible mechanisms underlying this defect are just beginning to be understood. The objectives of this review are to summarize the role of the healthy intestinal epithelium as a barrier between the lumen and the rest of the body with a focus on tight junctions; to examine the lines of evidence that suggest that different triggers lead to increased intestinal mucosal permeability and disruption of tight junctions in IBS patients; and to explore how this increased permeability may elicit immune responses that affect afferent nerves, resulting in the pain associated with IBS.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Charlton 8-110, 200 First St. S.W., Rochester, MN 55905, USA.
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van Wijck K, Bessems BA, van Eijk HM, Buurman WA, Dejong CH, Lenaerts K. Polyethylene glycol versus dual sugar assay for gastrointestinal permeability analysis: is it time to choose? Clin Exp Gastroenterol 2012; 5:139-50. [PMID: 22888267 PMCID: PMC3414379 DOI: 10.2147/ceg.s31799] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background Increased intestinal permeability is an important measure of disease activity and prognosis. Currently, many permeability tests are available and no consensus has been reached as to which test is most suitable. The aim of this study was to compare urinary probe excretion and accuracy of a polyethylene glycol (PEG) assay and dual sugar assay in a double-blinded crossover study to evaluate probe excretion and the accuracy of both tests. Methods Gastrointestinal permeability was measured in nine volunteers using PEG 400, PEG 1500, and PEG 3350 or lactulose-rhamnose. On 4 separate days, permeability was analyzed after oral intake of placebo or indomethacin, a drug known to increase intestinal permeability. Plasma intestinal fatty acid binding protein and calprotectin levels were determined to verify compromised intestinal integrity after indomethacin consumption. Urinary samples were collected at baseline, hourly up to 5 hours after probe intake, and between 5 and 24 hours. Urinary excretion of PEG and sugars was determined using high-pressure liquid chromatography-evaporative light scattering detection and liquid chromatography-mass spectrometry, respectively. Results Intake of indomethacin increased plasma intestinal fatty acid-binding protein and calprotectin levels, reflecting loss of intestinal integrity and inflammation. In this state of indomethacin-induced gastrointestinal compromise, urinary excretion of the three PEG probes and lactulose increased compared with placebo. Urinary PEG 400 excretion, the PEG 3350/PEG 400 ratio, and the lactulose/rhamnose ratio could accurately detect indomethacin-induced increases in gastrointestinal permeability, especially within 2 hours of probe intake. Conclusion Hourly urinary excretion and diagnostic accuracy of PEG and sugar probes show high concordance for detection of indomethacin-induced increases in gastrointestinal permeability. This comparative study improves our knowledge of permeability analysis in man by providing a clear overview of both tests and demonstrates equivalent performance in the current setting.
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Affiliation(s)
- Kim van Wijck
- Top Institute Food and Nutrition, Wageningen, The Netherlands
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Di Paola R, Impellizzeri D, Torre A, Mazzon E, Cappellani A, Faggio C, Esposito E, Trischitta F, Cuzzocrea S. Effects of palmitoylethanolamide on intestinal injury and inflammation caused by ischemia-reperfusion in mice. J Leukoc Biol 2012; 91:911-20. [DOI: 10.1189/jlb.0911485] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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CAMILLERI M, MADSEN K, SPILLER R, VAN MEERVELD BG, VERNE G, Verne GN. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol Motil 2012; 24:503-12. [PMID: 22583600 PMCID: PMC5595063 DOI: 10.1111/j.1365-2982.2012.01921.x] [Citation(s) in RCA: 622] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Defects in intestinal barrier function are associated with diseases of the gastrointestinal (GI) tract. There is growing evidence that increases in intestinal permeability plays a pathogenic role in diseases, such as inflammatory bowel disease (IBD) and celiac disease, and functional bowel disorders, such as irritable bowel syndrome (IBS). This review takes a unique translational approach to discuss the physiological and pathophysiological mechanisms involved in the regulation of intestinal barrier function in IBS. The review summarizes the components of the intestinal barrier including the tight junction complex within the epithelium, and the methods used to assess gut permeability both in vitro and in vivo. Throughout the review, the authors have attempted to critically review the latest research from both experimental animal models and human studies to appraise whether intestinal barrier dysfunction is a primary cause of functional GI disorders, such as IBS.…
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Affiliation(s)
- M. CAMILLERI
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA
| | - K. MADSEN
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | - R. SPILLER
- NIHR Biomedical Research Unit in the Nottingham Digestive Diseases Centre University Hospital, Nottingham, UK
| | - B G. VAN MEERVELD
- Department of Physiology, Oklahoma Center for Neuroscience, VA Medical Center, University of Oklahoma Health Sciences Center, OK, USA
| | - G.N. VERNE
- Division of Gastroenterology & Hepatology, University of Texas Medical Branch Galveston, TX, USA
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Hope H, Skar V, Sandstad O, Husebye E, Medhus AW. Small intestinal malabsorption in chronic alcoholism: a retrospective study of alcoholic patients by the ¹⁴C-D-xylose breath test. Scand J Gastroenterol 2012; 47:428-34. [PMID: 22229732 DOI: 10.3109/00365521.2011.648951] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The ¹⁴C-D-xylose breath test was used at Ullevål University Hospital in the period from 1986 TO 1995 for malabsorption testing. The objective of this retrospective study was to reveal whether patients with chronic alcoholism may have intestinal malabsorption. MATERIALS AND METHODS The consecutive ¹⁴C-D-xylose breath test database was reviewed and patients with the diagnosis of chronic alcoholism were identified. ¹⁴C-D-xylose breath test results of the alcoholic patients were compared with the results of untreated celiac patients and patient and healthy controls. In the ¹⁴C-D-xylose breath test, ¹⁴C-D-xylose was dissolved in water and given orally after overnight fast. Breath samples were taken at 30-min intervals for 210 min, and ¹⁴CO₂ : ¹²CO₂ ratios were calculated for each time point, presenting a time curve for ¹⁴C-D-xylose absorption. Urine was collected after 210 min and the fraction of the total d-xylose passed was calculated (U%). ¹⁴CO₂ in breath and ¹⁴C-D-xylose in urine were analyzed using liquid scintillation. RESULTS Both breath and urine analysis revealed a pattern of malabsorption in alcoholics comparable with untreated celiac patients, with significantly reduced absorption of d-xylose compared with patient and healthy controls. CONCLUSION Alcoholic patients have a significantly reduced ¹⁴C-D-xylose absorption, comparable with untreated celiac patients. This indicates a reduced intestinal function in chronic alcoholism.
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Affiliation(s)
- Håvar Hope
- Medical Department, Lovisenberg Diakonale Hospital, Oslo, Norway.
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Enteroendocrine and neuronal mechanisms in pathophysiology of acute infectious diarrhea. Dig Dis Sci 2012; 57:19-27. [PMID: 22001941 PMCID: PMC3809758 DOI: 10.1007/s10620-011-1939-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 09/30/2011] [Indexed: 12/30/2022]
Abstract
BACKGROUND While enterocyte secretion is the predominant mechanism considered responsible for secretory diarrhea in response to acute enteric infections, there are several lines of evidence that support alternative mechanisms controlling fluid and electrolyte secretion in diarrhea. AIM To review enteroendocrine and neuronal mechanisms that participate in the development of acute infectious diarrhea. RECENT ADVANCES Acute infectious diarrheas due to bacterial toxins (e.g., cholera, E. coli heat-stable enterotoxin, C. difficile) and rotavirus are all associated with secretion of transmitters from enteroendocrine cells (e.g., 5-HT) and activation of afferent neurons that stimulate submucosal secretomotor neurons. The latter secrete acetylcholine (which binds to muscarinic receptors on epithelial cells) and VIP. Involvement of nerves was demonstrated by inhibition of bacterial toxin-induced secretion by hexamethonium (nicotinic), tetrodotoxin (Na(+) channel blocker), and lidocaine (visceral/mucosal afferents). Nicotinic receptors are present on secretomotoneurons and these are activated by release of acetylcholine from enteric interneurons or extrinsic efferent fibers. Specific organisms also modify other mechanisms that may contribute to development of acute diarrhea. Thus, mucin secretion, activation of motor mechanisms, increased mucosal permeability and inhibition of bile acid absorption have been reported in specific types of acute infectious diarrhea. CONCLUSION New therapies targeting neural and transmitter mediation including 5-HT, VIP, NPY, as well as toxin receptors and channels activated during acute infectious diarrhea could usher in a novel approach to enhancing glucose-electrolyte solutions used in the treatment of acute diarrhea.
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PPAR-alpha Contributes to the Anti-Inflammatory Activity of Verbascoside in a Model of Inflammatory Bowel Disease in Mice. PPAR Res 2010; 2010:917312. [PMID: 20671911 PMCID: PMC2910492 DOI: 10.1155/2010/917312] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Accepted: 05/11/2010] [Indexed: 12/14/2022] Open
Abstract
The previous results suggest that peroxisome proliferator-activated receptor-alpha (PPAR)-α, an intracellular transcription factor activated by fatty acids, plays a role in control of inflammation. There is persuasive epidemiological and experimental evidence that dietary polyphenols have anti-inflammatory activity. In this regard, it has been demonstrated that verbascoside (VB) functions as intracellular radical scavenger and reduces the microscopic and macroscopic signs of experimental colitis. With the aim to characterize the role of PPAR-α in VB-mediated anti-inflammatory activity, we tested the efficacy of VB in an experimental model of inflammatory bowel disease induced by dinitrobenzene sulfonic acid, comparing mice lacking PPAR-α (PPAR-αKO) with wild type (WT) mice. Results indicate that VB-mediated anti-inflammatory activity is weakened in PPAR-αKO mice, compared to WT controls, especially in the inhibition of neutrophil infiltration, intestinal permeability and colon injury. These results indicate that PPAR-α can contribute to the anti-inflammatory activity of VB in inflammatory bowel disease.
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Swystun VA, Renaux B, Moreau F, Wen S, Peplowski MA, Hollenberg MD, MacNaughton WK. Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase Czeta. Am J Physiol Gastrointest Liver Physiol 2009; 297:G60-70. [PMID: 19460843 DOI: 10.1152/ajpgi.00096.2009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Epithelial permeability to ions and larger molecules in the gut is essential for fluid balance, and its dysregulation contributes to intestinal pathology. We investigated the effect of digestive serine proteases on epithelial paracellular permeability. Trypsin, chymotrypsin, and elastase elicited sustained increases in transepithelial resistance (R(TE)) in polarized monolayers of three intestinal epithelial cell lines. This effect was reflected by decreases in paracellular conductances of Na+ and Cl- and a concomitant decrease in permeability to 3,000 molecular weight dextran. The enzyme activities of the proteases were required, yet activators of known protease-activated receptors (PARs) did not reproduce the effect of these proteases on R(TE). PKCzeta isoform-specific inhibitor significantly reduced the trypsin-induced increase in R(TE) whereas PKCzeta activity was increased in cells treated with trypsin and chymotrypsin compared with control cells; this activity was reduced to control levels in the presence of PKCzeta-specific inhibitor. Ca2+ chelators and pharmacological inhibitors of cell signaling support the role for PKCzeta in the protease-induced effect. Finally, we showed that treatment with the serine proteases increased occludin immunostaining and zonula occludin-1 coimmunoprecipitation with occludin in the detergent-insoluble fraction of cell lysates, and these increases were ablated by pretreatment with PKCzeta-specific inhibitor. This finding indicates increased insertion of occludin into the cell junctional complex. These data demonstrate a role for serine proteases in the facilitation of epithelial barrier function through a mechanism that is independent of PARs and is mediated by activation of PKCzeta.
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Affiliation(s)
- Veronica A Swystun
- Inflammation Research Network, Department of Physiology and Pharmacology, University of Calgary, Calgary T2N 4N1, Canada
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Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Mascianà R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009; 49:1877-1887. [PMID: 19291785 DOI: 10.1002/hep.22848] [Citation(s) in RCA: 1088] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of (51)Cr-ethylene diamine tetraacetate ((51)Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. CONCLUSIONS Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition.
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Affiliation(s)
- Luca Miele
- Institute of Internal Medicine, Catholic University of Rome, Rome, Italy
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Dunlop SP, Hebden J, Campbell E, Naesdal J, Olbe L, Perkins AC, Spiller RC. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol 2006; 101:1288-94. [PMID: 16771951 DOI: 10.1111/j.1572-0241.2006.00672.x] [Citation(s) in RCA: 346] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls. METHODS Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N=15), constipation-predominant IBS (N=15), and healthy controls (N=15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N=15) and the other without such a history (nonpostinfectious) (N=15) both compared with healthy controls (N=12). RESULTS Permeability expressed as percentage of total dose excreted in urine (median [inter-quartile range]). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 [0.12-0.23]) in contrast to constipated IBS (0.085 [0.043-0.13]) and controls (0.07 [0.035-0.19]) (p=0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p=0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 [0.69-1.49]) compared with postinfectious IBS (0.43 [0.29-0.63], p=0.028) or controls (0.27 [0.2-0.39]), p=0.001). CONCLUSIONS Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.
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Affiliation(s)
- Simon P Dunlop
- Wolfson Digestive Diseases Centre and Division of Medical Physics, University Hospital, Nottingham, United Kingdom
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Cuzzocrea S, Rossi A, Mazzon E, Di Paola R, Genovese T, Muià C, Caputi AP, Sautebin L. 5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration. J Transl Med 2005; 85:808-22. [PMID: 15821759 DOI: 10.1038/labinvest.3700276] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes makes it as therapeutic target for inflammatory conditions like inflammatory bowel disease (IBD). In the present study, by comparing the responses in wild-type mice (5-LOWT) and mice lacking the 5-lipoxygenase (5-LOKO), we investigated the role played by this enzyme in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated 5-LOWT mice, DNBS-treated 5-LOKO mice experienced a reduced rate of the extent and severity of the histological signs of colon injury. After administration of DNBS 5-LOWT mice showed hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon. Neutrophil infiltration was associated with the expression of ICAM-1, VCAM-1, P-selectin, E-selectin that were mainly localized around vessels. Absence of a functional 5-LO resulted in a significant reduction of all the above-described parameters. In particular, we have observed a significant reduction of: (i) the degree of colon injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in staining (immunohistochemistry) for ICAM-1, VCAM-1, P-selectin, E-selectin caused by DNBS in the colon. Similarly, the treatment of 5-LOWT with zileuton (50 mg/kg per os twice a day) resulted in a significant reduction of all the above-described parameters. In addition, in in vitro study a significantly reduced chemotactic response to IL-8 was observed in peripheral blood leukocytes from 5-LOKO in comparison to 5-LOWT polymorphonuclear leukocyte. Similar results were obtained when we analyzed the chemotactic response of 5-LOWT cell incubated for 15 min with zileuton (50 microg/ml). Taken together, our results clearly demonstrate that 5-LO modulates neutrophil infiltration in experimental colitis through the expression of adhesion molecules.
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Affiliation(s)
- Salvatore Cuzzocrea
- Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Torre Biologica, Policlinico Universitario, Messina, Italy.
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Ait-Belgnaoui A, Bradesi S, Fioramonti J, Theodorou V, Bueno L. Acute stress-induced hypersensitivity to colonic distension depends upon increase in paracellular permeability: role of myosin light chain kinase. Pain 2005; 113:141-7. [PMID: 15621374 DOI: 10.1016/j.pain.2004.10.002] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2004] [Revised: 09/24/2004] [Accepted: 09/30/2004] [Indexed: 12/15/2022]
Abstract
Hypersensitivity to rectal or colonic distension characterizes most patients with IBS and increased gut permeability has been described in post-dysenteric IBS patients. However, no link has been established between these two events. The aim of this study was to determine (i) whether chemical blockade of stress-induced increase of colonic paracellular permeability by 2,4,6 triaminopyrimidine (TAP) affects the concomitant hypersensitivity to colonic distension, (ii) the role of epithelial cell contraction in the stress-induced increased permeability and hyperalgesia, using a myosin light chain kinase inhibitor (ML-7). The effect of acute partial restraint stress (PRS) on visceral sensitivity to colorectal distension (RD) was assessed by abdominal muscle electromyography. Colonic paracellular permeability was determined by measuring percentage of urinary 51Cr-EDTA recovery after intracolonic infusion. The effect of stress on both parameters was evaluated after TAP, ML-7 or vehicle pretreated animals. PRS significantly increased colonic paracellular permeability and the number of spike bursts for all volumes of RD applied compared to sham. TAP suppressed the stress-induced increase of colonic paracellular permeability and sensitivity to colonic distension. Similarly, ML-7 blocked the stress-induced increase of colonic paracellular permeability and sensitivity. Neither ML-7 nor TAP had any effect on both permeability and sensitivity in absence of stress. The increase of colonic permeability induced by PRS results from epithelial cell cytoskeleton contraction through myosin light chain kinase activation and this increase is responsible for stress-induced rectal hypersensitivity.
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Affiliation(s)
- Afifa Ait-Belgnaoui
- Neuro-Gastroenterology and Nutrition Unit, INRA, 180, chemin de Tournefeuille BP 03, 31931 Toulouse cedex 9, France
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22
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Di Leo V, D'Incà R, Diaz-Granado N, Fries W, Venturi C, D'Odorico A, Martines D, Sturniolo GC. Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea. Am J Gastroenterol 2003; 98:2245-52. [PMID: 14572575 DOI: 10.1111/j.1572-0241.2003.07697.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Diagnosis in chronic diarrhea in the absence of a distinctive clinical pattern is often challenging, as biochemical tests prescribed at the first evaluation do not show enough sensitivity and specificity to tailor further investigation. Intestinal permeability to sugars is an accurate test for detecting intestinal damage. The aim of this study was to evaluate the diagnostic value of the lactulose/mannitol (L/M) test in patients with chronic diarrhea. METHODS We conducted a prospective cohort study to evaluate the diagnostic value of the L/M test in chronic diarrhea. The test was administered to 261 consecutive patients presenting with three or more bowel movements daily for at least 3 wk. Biochemical tests including complete blood cell count, acute phase reactive proteins, serum albumin and iron, and stool cultures for bacteria, ova, and parasites were assessed at the same time. Additional diagnostic investigations were directed by clinical features as well as first-line test results. RESULTS Over 3 yr, 120 (46%) of our patients were found to have an organic cause for chronic diarrhea, whereas in 141 (54%) a functional condition was diagnosed. Multivariate logistic regression analysis revealed that the L/M test and C-reactive protein were independent predictors for the final diagnosis of organic cause of chronic diarrhea, with odds ratios of 1.5 (95% CI = 1.29-1.78) and 5.2 (95% CI = 1.90-14.12), respectively. The area under the receiver operating characteristic (ROC) curve of the adjusted model was 0.82, with positive predictive value of 80.4% and negative predictive value of 77.7%. CONCLUSIONS The L/M test is a powerful tool for workup in patients with chronic diarrhea. Introducing the L/M test as first-level test effectively improves the selection of patients who need further evaluation.
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Affiliation(s)
- Vincenza Di Leo
- Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
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Arslan G, Atasever T, Cindoruk M, Yildirim IS. (51)CrEDTA colonic permeability and therapy response in patients with ulcerative colitis. Nucl Med Commun 2001; 22:997-1001. [PMID: 11505209 DOI: 10.1097/00006231-200109000-00009] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Orally administered (51)Cr-labelled ethylenediaminetetraacetic acid ((51)CrEDTA) has been used to evaluate intestinal permeability in inflammatory bowel disease, especially Crohn's disease. However, information about colonic permeability in ulcerative colitis (UC) is relatively scarce. The aim of this study was to investigate the urinary excretion of orally administered (51)CrEDTA, its relation to disease activity and its response to medical therapy in patients with UC. Forty-three patients with UC and 19 controls were examined. Disease activity was evaluated by endoscopy. In 19 patients with active UC, the (51)CrEDTA permeability test was repeated after medical therapy. (51)CrEDTA (95 microCi; 26 MBq) was given orally after an overnight fast and urine was collected over a 24 h period. The first urine samples were taken 5 h and the second 24 h after the oral administration of (51)CrEDTA. Urine samples were counted in a gamma counter. In controls, the median 5 h and 24 h excretions were 0.10% and 0.93%, respectively. Patients with UC showed significantly increased urine (51)CrEDTA excretion at both time intervals (5 h: 2.41%, P<0.0002; 24 h: 6.72%, P<0.0001). There was also a significant correlation between intestinal permeability and disease activity (5 h: r=0.45, P=0.0025; 24 h: r=0.51 P=0.0006). After medical therapy, (51)CrEDTA urinary excretion was significantly decreased (pre-treatment UC: 7.87%; post-treatment UC: 2.50%; P<0.0002). Briefly, the (51)CrEDTA test reflected colonic permeability in UC and might be useful as an indicator of disease severity. Moreover, this study suggested that, in patients with UC, medical therapy not only leads to the recovery of acute inflammation but also restores mucosal barrier integrity and function.
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Affiliation(s)
- G Arslan
- Division of Gastroenterology, Department of Medicine, Social Security Hospital, University of Gazi, Ankara, Turkey
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Pascual S, Martínez J, Pérez-Mateo M. [The intestinal barrier: functional disorders in digestive and non-digestive diseases]. GASTROENTEROLOGIA Y HEPATOLOGIA 2001; 24:256-67. [PMID: 11412597 DOI: 10.1016/s0210-5705(01)70167-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- S Pascual
- Unidad Hepática. Sección de Aparato Digestivo. Servicio de Medicina Interna. Hospital General Universitario de Alicante, Pintor Baeza, 03010 Alicante
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Werneck-Silva AL, Sipahi AM, Damião AO, Buchpigue CA, Iriya K, Laudanna AA. Intestinal permeability in strongyloidiasis. Braz J Med Biol Res 2001; 34:353-357. [PMID: 11262586 DOI: 10.1590/s0100-879x2001000300009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The objective of the present study was to assess intestinal permeability in patients with infection caused by Strongyloides stercoralis. Twenty-six patients (16 women and 10 men), mean age 45.9, with a diagnosis of strongyloidiasis were evaluated. For comparison, 25 healthy volunteers (18 women and 7 men), mean age 44.9, without digestive disorders or intestinal parasites served as normal controls. Intestinal permeability was measured on the basis of urinary radioactivity levels during the 24 h following oral administration of chromium-labeled ethylenediaminetetraacetic acid ((51)Cr-EDTA) expressed as percentage of the ingested dose. The urinary excretion of (51)Cr-EDTA was significantly reduced in patients with strongyloidiasis compared to controls (1.60 +/- 0.74 and 3.10 +/- 1.40, respectively, P = 0.0001). Intestinal permeability is diminished in strongyloidiasis. Abnormalities in mucus secretion and intestinal motility and loss of macromolecules could explain the impaired intestinal permeability.
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Affiliation(s)
- A L Werneck-Silva
- Laboratório de Investigação Médica (LIM 07), Departamento de Gastroenterologia, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brasil
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Zuckerman MJ, al-Samman M, Boman DA. Granulomatous gastroenteritis. Case report with comparison to idiopathic isolated granulomatous gastritis. Dig Dis Sci 1994; 39:1649-54. [PMID: 8050313 DOI: 10.1007/bf02087771] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
A woman with epigastric pain, vomiting, weight loss, and an upper gastrointestinal series showing antral rigidity suggestive of linitis plastica was found to have granulomatous inflammation of the stomach. Additional investigations disclosed more extensive gastrointestinal involvement, with noncaseating granulomas found in esophageal and colonic mucosa, despite normal appearances at endoscopy. Intestinal permeability to [51Cr]EDTA was increased, suggesting intestinal mucosal injury. No specific entity, including disseminated sarcoidosis or Crohn's disease, was diagnosed. This patient with granulomatous gastroenteritis had a clinical and histologic response to medical therapy with prednisone and recurrence of symptoms when prednisone was tapered. Her clinical course was similar to that of previous cases of idiopathic isolated granulomatous gastritis treated nonsurgically. Cases of idiopathic isolated granulomatous gastritis should be categorized as such only if a thorough evaluation has been performed to determine extent of disease, as well as to exclude other entities.
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Affiliation(s)
- M J Zuckerman
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso 79905
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Abstract
Blastocystis hominis is an enteric protozoan associated with clinical illness. To determine the prevalence of intestinal injury in patients with B. hominis infection, the authors prospectively evaluated 18 patients with B. hominis infection by endoscopy and a test of intestinal permeability. Seventeen patients had gastrointestinal symptoms. Colonic mucosa appeared normal by lower endoscopy in 12 of 13 patients, and was friable slightly in 1. Duodenal mucosa was normal by upper endoscopy in nine patients. Pathologic examination of mucosal biopsy specimens did not demonstrate evidence of mucosal invasion. 51Cr-edetic acid (51Cr-EDTA) was given to the 18 patients with stools positive for B. hominis and to 32 healthy control subjects. Approximately 100 uCi of 51Cr-EDTA was given orally after an overnight fast, and urine was collected for the following 24 hours. Mean 24-hour urinary excretion of 51Cr-EDTA, calculated as a percent of the administered dose, was 1.31% (0.34-2.76%) in patients with B. hominis infection and 1.99% (0.59-3.48%) in the control subjects. The intestinal permeability to 51Cr-EDTA in blastocystis-infected individuals was not increased, but was decreased significantly compared with healthy subjects (p < 0.005). Therefore, in a group of symptomatic patients with B. hominis infection, endoscopy typically did not show evidence of significant intestinal inflammation, and results of intestinal permeability testing with 51Cr-EDTA did not suggest impaired barrier function of the intestinal mucosa. The clinical literature on B. hominis infection and intestinal injury is reviewed.
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Affiliation(s)
- M J Zuckerman
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso 79905
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