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Castellanos-Ruiz D, Ojeda-Borbolla JG, Ruiz-García OV, Peña-Corona SI, Martínez-Peña AA, Ibarra-Rubio ME, Gavilanes-Ruiz M, Mendoza-Rodríguez CA. Uterine Microbiota and Bisphenols: Novel Influencers in Reproductive Health. J Xenobiot 2025; 15:26. [PMID: 39997369 PMCID: PMC11856463 DOI: 10.3390/jox15010026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/10/2025] [Accepted: 01/24/2025] [Indexed: 02/26/2025] Open
Abstract
Infertility affects 8-12% of couples worldwide, and 30-75% of preclinical pregnancy losses are due to a failure during the implantation process. Exposure to endocrine disruptors, like bisphenols, among others, has been associated with the increase in infertility observed in the past decades. An increase in infertility has correlated with exposure to endocrine disruptors like bisphenols. The uterus harbors its own microbiota, and changes in this microbiota have been linked to several gynecological conditions, including reproductive failure. There are no studies on the effects of bisphenols on the uterine-microbiota composition, but some inferences can be gleaned by looking at the gut. Bisphenols can alter the gut microbiota, and the molecular mechanism by which gut microbiota regulates intestinal permeability involves Toll-like receptors (TLRs) and tight junction (TJ) proteins. TJs participate in embryo implantation in the uterus, but bisphenol exposure disrupts the expression and localization of TJ proteins. The aim of this review is to summarize the current knowledge on the microbiota of the female reproductive tract (FRT), its association with different reproductive diseases-particularly reproductive failure-the effects of bisphenols on microbiota composition and reproductive health, and the molecular mechanisms regulating uterine-microbiota interactions crucial for embryo implantation. This review also highlights existing knowledge gaps and outlines research needs for future risk assessments regarding the effects of bisphenols on reproduction.
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Affiliation(s)
- Dafne Castellanos-Ruiz
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico (M.E.I.-R.)
| | - J. Gerardo Ojeda-Borbolla
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico (M.E.I.-R.)
| | - Olga V. Ruiz-García
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico (M.E.I.-R.)
| | - Sheila I. Peña-Corona
- Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Annia A. Martínez-Peña
- División de Ciencias de la Salud, Universidad Intercontinental, A. C., Ciudad de México 14420, Mexico
| | - María Elena Ibarra-Rubio
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico (M.E.I.-R.)
| | - Marina Gavilanes-Ruiz
- Facultad de Química, Departamento de Bioquímica, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - C. Adriana Mendoza-Rodríguez
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico (M.E.I.-R.)
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Wu X, Cao Y, Liu Y, Zheng J. A New Strategy for Dietary Nutrition to Improve Intestinal Homeostasis in Diarrheal Irritable Bowel Syndrome: A Perspective on Intestinal Flora and Intestinal Epithelial Interaction. Nutrients 2024; 16:3192. [PMID: 39339792 PMCID: PMC11435304 DOI: 10.3390/nu16183192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Although a reasonable diet is essential for promoting human health, precise nutritional regulation presents a challenge for different physiological conditions. Irritable Bowel Syndrome (IBS) is characterized by recurrent abdominal pain and abnormal bowel habits, and diarrheal IBS (IBS-D) is the most common, seriously affecting patients' quality of life. Therefore, the implementation of precise nutritional interventions for IBS-D has become an urgent challenge in the fields of nutrition and food science. IBS-D intestinal homeostatic imbalance involves intestinal flora disorganization and impaired intestinal epithelial barrier function. A familiar interaction is evident between intestinal flora and intestinal epithelial cells (IECs), which together maintain intestinal homeostasis and health. Dietary patterns, such as the Mediterranean diet, have been shown to regulate gut flora, which in turn improves the body's health by influencing the immune system, the hormonal system, and other metabolic pathways. METHODS This review summarized the relationship between intestinal flora, IECs, and IBS-D. It analyzed the mechanism behind IBS-D intestinal homeostatic imbalance by examining the interactions between intestinal flora and IECs, and proposed a precise dietary nutrient intervention strategy. RESULTS AND CONCLUSION This increases the understanding of the IBS-D-targeted regulation pathways and provides guidance for designing related nutritional intervention strategies.
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Affiliation(s)
- Xinyu Wu
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China; (X.W.); (Y.C.)
| | - Yilong Cao
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China; (X.W.); (Y.C.)
| | - Yixiang Liu
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China; (X.W.); (Y.C.)
| | - Jie Zheng
- School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, China
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Chen B, Li D, Tong B, Wang L, Lin H, Xu H, Hu S. Oral alginate microspheres for the efficient site-specific delivery of epidermal growth factor attenuated murine ulcerative colitis via repairing the mucosal barrier. Int J Pharm 2024; 661:124394. [PMID: 38944169 DOI: 10.1016/j.ijpharm.2024.124394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/18/2024] [Accepted: 06/25/2024] [Indexed: 07/01/2024]
Abstract
Ulcerative colitis (UC) is a chronic bowel inflammatory disease affecting the colorectum. Epidermal growth factor (EGF) has been demonstrated to be effective to counteract UC. However, there exists the gastrointestinal challenges such as stomach acid, enzyme and bile salts for oral delivery of EGF. Herein, calcium alginate microsphere was prepared by the microfluidic technique to encapsulate EGF. The morphology of EGF-loaded microsphere (MS-EGF) was spherical and its average particle size was 80 ± 23 μm. The encapsulation efficiency of EGF was reaching to 93.8 % ± 1.6 %. In vitro release experiments showed that MS-EGF presented the good pH-sensitive properties, that was, it could effectively resist the gastric acid and small intestinal fluids, and undergone the rapid dissolution in the artificial colon fluid. In vitro cellular experiments demonstrated that the bioactivity of EGF was well preserved by microsphere. Moreover, in vivo murine colitis model showed that MS-EGF presented the obvious colitis alleviation. Furthermore, the colonic morphology of colitis mice was effectively recovered and the tight junction between the gut epithelium was obviously repaired. In conclusion, calcium alginate microsphere might be a promising vehicle of EGF for UC treatment.
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Affiliation(s)
- Ben Chen
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Dingwei Li
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Bingjie Tong
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Lifen Wang
- Research Center for Drug Safety Evaluation, Hainan Medical University, Haikou City, Hainan Province, China
| | - Haoran Lin
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Helin Xu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; Key Laboratory of Novel Nuclide Technologies on Precision Diagnosis and Treatment & Clinical Transformation of Wenzhou City, China.
| | - Sunkuan Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
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Aguilera-Lizarraga J, Ritoux A, Bulmer DC, Smith ESJ. Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights. Am J Physiol Gastrointest Liver Physiol 2024; 327:G188-G201. [PMID: 38915279 DOI: 10.1152/ajpgi.00080.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/10/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024]
Abstract
The intestinal barrier plays a crucial role in homeostasis by both facilitating the absorption of nutrients and fluids and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues. Therefore, a deeper understanding of physiological aspects related to an enhanced barrier function is of significant scientific and clinical relevance. The naked mole-rat has many unusual biological features, including attenuated colonic neuron sensitivity to acid and bradykinin and resistance to chemical-induced intestinal damage. However, insight into their intestinal barrier physiology is scarce. Here, we observed notable macroscopic and microscopic differences in intestinal tissue structure between naked mole-rats and mice. Moreover, naked mole-rats showed increased number of larger goblet cells and elevated mucus content. In measuring gut permeability, naked mole-rats showed reduced permeability compared with mice, measured as transepithelial electrical resistance, especially in ileum. Furthermore, intestinal ion secretion induced by serotonin, bradykinin, histamine, and capsaicin was significantly reduced in naked mole-rats compared with mice, despite the expression of receptors for all these agonists. In addition, naked mole-rats exhibited reduced prosecretory responses to the nonselective adenylate cyclase activator forskolin. Collectively, these findings indicate that naked mole-rats possess a robust and hard-to-penetrate gastrointestinal barrier that is resistant to environmental and endogenous irritants. Naked mole-rats may therefore provide valuable insights into the physiology of the intestinal barrier and set the stage for the development of innovative and effective therapies.NEW & NOTEWORTHY This is the first study to characterize the intestinal function of naked mole-rats. We found that these animals show a robust gut tissue structure, displaying thicker intestinal layers, longer villi, and larger crypts. Naked mole-rats showed more and larger goblet cells, with increased mucus content. Intestinal permeability, especially in the ileum, was substantially lower than that of mice. Finally, naked mole-rats showed reduced intestinal anion secretion in response to serotonin, bradykinin, histamine, capsaicin, and forskolin.
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Affiliation(s)
| | - Anne Ritoux
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - David C Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Ewan St John Smith
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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Niu XT, Wang XY, Wang Y, Han K, Ru N, Xiang JY, Linghu EQ. Transcriptome analysis suggests broad jejunal alterations in Linghu's obesity-diarrhea syndrome: A pilot study. World J Gastroenterol 2024; 30:2777-2792. [PMID: 38899329 PMCID: PMC11185300 DOI: 10.3748/wjg.v30.i21.2777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/03/2024] Open
Abstract
BACKGROUND Obesity is associated with a significantly increased risk for chronic diarrhea, which has been proposed as Linghu's obesity-diarrhea syndrome (ODS); however, its molecular mechanisms are largely unknown. AIM To reveal the transcriptomic changes in the jejunum involved in ODS. METHODS In a cohort of 6 ODS patients (JOD group), 6 obese people without diarrhea (JO group), and 6 healthy controls (JC group), high-throughput sequencing and bioinformatics analyses were performed to identify jejunal mucosal mRNA expression alterations and dysfunctional biological processes. In another cohort of 16 ODS patients (SOD group), 16 obese people without diarrhea (SO group), and 16 healthy controls (SC group), serum diamine oxidase (DAO) and D-lactate (D-LA) concentrations were detected to assess changes in intestinal barrier function. RESULTS The gene expression profiles of jejunal mucosa in the JO and JC groups were similar, with only 1 differentially expressed gene (DEG). The gene expression profile of the JOD group was significantly changed, with 411 DEGs compared with the JO group and 211 DEGs compared with the JC group, 129 of which overlapped. The enrichment analysis of these DEGs showed that the biological processes such as digestion, absorption, and transport of nutrients (especially lipids) tended to be up-regulated in the JOD group, while the biological processes such as rRNA processing, mitochondrial translation, antimicrobial humoral response, DNA replication, and DNA repair tended to be down-regulated in the JOD group. Eight DEGs (CDT1, NHP2, EXOSC5, EPN3, NME1, REG3A, PLA2G2A, and PRSS2) may play a key regulatory role in the pathological process of ODS, and their expression levels were significantly decreased in ODS patients (P < 0.001). In the second cohort, compared with healthy controls, the levels of serum intestinal barrier function markers (DAO and D-LA) were significantly increased in all obese individuals (P < 0.01), but were higher in the SOD group than in the SO group (P < 0.001). CONCLUSION Compared with healthy controls and obese individuals without diarrhea, patients with Linghu's ODS had extensive transcriptomic changes in the jejunal mucosa, likely affecting intestinal barrier function and thus contributing to the obesity and chronic diarrhea phenotypes.
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Affiliation(s)
- Xiao-Tong Niu
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xiang-Yao Wang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yan Wang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Ke Han
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Nan Ru
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Jing-Yuan Xiang
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing 100853, China
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - En-Qiang Linghu
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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Yanar KE, Baysal S, Ulaş N, Aktaş MS, Timurkan MÖ, Aydın H. Prognostic potential of copper, zinc, copper/zinc ratio, cobalamin, and serum amyloid A in cats with panleukopenia. J Vet Intern Med 2024; 38:1535-1541. [PMID: 38613433 PMCID: PMC11099764 DOI: 10.1111/jvim.17077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/03/2024] [Indexed: 04/15/2024] Open
Abstract
BACKGROUND Copper (Cu), zinc (Zn), and the copper/zinc ratio (Cu/Zn), which have been studied in gastrointestinal disorders of humans, may facilitate disease prognosis. OBJECTIVE Evaluate the predictive potential of Cu, Zn, cobalamin, and serum amyloid A (SAA) as prognostic indicators in cats with feline panleukopenia (FPV) on admission. ANIMALS Client-owned cats diagnosed with FPV and controls. METHODS Serum Cu and Zn concentrations were assessed using the spectrophotometric method and serum concentrations of SAA and cobalamin were measured by chemiluminescent immunoassay. RESULTS On admission, survivor cats with FPV had significantly higher serum Cu and SAA concentrations and Cu/Zn ratios and significantly lower serum Zn and cobalamin concentrations than controls. Furthermore, non-survivor cats with FPV had significantly higher serum Cu and SAA concentrations and Cu/Zn ratios and significantly lower cobalamin concentrations than survivors and controls. Prognostic thresholds were calculated, with positive predictive value (PPV) for survival of 90% for Cu (≥120.3 μg/dL), 90% for Cu/Zn (≥1.34), 90% for cobalamin (≤430.4 pg/mL), and 90% for SAA (≥0.85 mg/L). CONCLUSIONS AND CLINICAL IMPORTANCE Cu (0.93 area under curve [AUC]), Cu/Zn (0.95 AUC), cobalamin (0.98 AUC), and SAA (0.98 AUC) were excellent biomarkers for predicting prognosis in cats with FPV. Their effectiveness, as assessed by sensitivity (100%), specificity (80%), AUC (0.98), and PPV (90%) from receiver operating characteristic analysis, emphasizes the performance of cobalamin and SAA.
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Affiliation(s)
- Kerim Emre Yanar
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Sümeyye Baysal
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Nergis Ulaş
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Mustafa Sinan Aktaş
- Department of Internal MedicineFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Mehmet Özkan Timurkan
- Department of VirologyFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
| | - Hakan Aydın
- Department of VirologyFaculty of Veterinary Medicine, Atatürk UniversityErzurum 25240Turkey
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Zhang H, Liu M, Song F, Zhu X, Lu Q, Liu R. Fermentation enhances the amelioration effect of bee pollen on Caco-2 monolayer epithelial barrier dysfunction based on NF-κB-mediated MLCK-MLC signaling pathway. Food Res Int 2024; 178:113938. [PMID: 38309866 DOI: 10.1016/j.foodres.2024.113938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/19/2023] [Accepted: 01/02/2024] [Indexed: 02/05/2024]
Abstract
Intestinal barrier integrity is essential for normal nutrient digestion and absorption and disease resistance. This study aims to investigate how fermentation affects the ameliorative effect of bee pollen on the intestinal barrier dysfunction stimulated by interferon-γ and tumor necrosis factor (IFN-γ/TNF-α) cytokines. The results indicated that fermentation enhances the alleviating effect of bee pollen on intestinal barrier dysfunction (including elevated trans epithelial electrical resistance and decreased paracellular permeability). In addition, fermented bee pollen (FBP) significantly decreased (p < 0.05) the secretion levels of interleukin (IL)-6, IL-8, and IL-1β and expression of cyclooxygenase (COX)-2 protein in intestinal barrier cells. Furthermore, fermentation improved the ability of bee pollen to up-regulate the expression of tight junction proteins including zonula occludens (ZO)-1, occluding, and claudin-1. Notably, FBP showed stronger ability to inhibit the expression of nuclear factor kappa-B (NF-κB) mediated myosin light chain kinase (MLCK) and myosin light chain (MLC) signaling pathway associated with phosphorylated proteins. Overall, our results indicated that fermentation enhances the protective effect of bee pollen on the intestinal barrier, and FBP has promising potential to be used as a novel functional food to protect the intestinal barrier.
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Affiliation(s)
- Huifang Zhang
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430070, China
| | - Min Liu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430070, China
| | - Fanfen Song
- Research Unit VEG-i-TEC, Faculty of BioscienceEngineering, Ghent University, Sint-Martens-Latemlaan2B, 8500 Kortrijk, Belgium
| | - Xiaoling Zhu
- Key Laboratory of Detection Technology of Focus Chemical Hazards in Animal-derived Food for State Market Regulation, Wuhan 430075, China
| | - Qun Lu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430070, China; Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China.
| | - Rui Liu
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; Wuhan Engineering Research Center of Bee Products on Quality and Safety Control, Wuhan 430070, China; Key Laboratory of Environment Correlative Dietology (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China; Key Laboratory of Urban Agriculture in Central China, Ministry of Agriculture and Rural Affairs, Wuhan 430070, China.
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Chen S, Huang J, Liu T, Zhang F, Zhao C, Jin E, Li S. PI3K/Akt signaling pathway mediates the effect of low-dose boron on barrier function, proliferation and apoptosis in rat intestinal epithelial cells. Sci Rep 2024; 14:393. [PMID: 38172276 PMCID: PMC10764725 DOI: 10.1038/s41598-023-50800-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 12/26/2023] [Indexed: 01/05/2024] Open
Abstract
Boron is an essential trace element with roles in growth, development, and physiological functions; however, its mechanism of action is still unclear. In this study, the regulatory roles of the PI3K/Akt signaling pathway on boron-induced changes in barrier function, proliferation, and apoptosis in rat intestinal epithelial cells were evaluated. Occludin levels, the proportion of cells in the G2/M phase, cell proliferation rate, and mRNA and protein expression levels of PCNA were higher, while the proportions of cells in the G0/G1 and S phases, apoptosis rate, and caspase-3 mRNA and protein expression levels were lower in cells treated with 0.8 mmol/L boron than in control IEC-6 cells (P < 0.01 or P < 0.05). However, 40 mmol/L boron decreased ZO-1 and Occludin levels, the proportion of cells in the G2/M phase, cell proliferation rate, and mRNA and protein levels of PCNA and increased the apoptosis rate and caspase-3 mRNA expression (P < 0.01 or P < 0.05). After specifically blocking PI3K and Akt signals (using LY294002 and MK-2206 2HCL), 0.8 mmol/L boron had no effects on Occludin, PCNA level, apoptosis rates, and caspase-3 levels (P < 0.05); however, the proliferation rate and PCNA levels decreased significantly (P < 0.01 or P < 0.05). The addition of 40 mmol/L boron did not affect ZO-1 and Occludin levels and did not affect the apoptosis rate or PCNA and caspase-3 levels. These results suggested that the PI3K/Akt signaling pathway mediates the effects of low-dose boron on IEC-6 cells.
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Affiliation(s)
- Shuqin Chen
- College of Animal Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China
| | - Jialiang Huang
- College of Animal Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China
| | - Ting Liu
- College of Animal Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China
| | - Feng Zhang
- College of Animal Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China
| | - Chunfang Zhao
- College of Animal Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China
| | - Erhui Jin
- College of Animal Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China.
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China.
| | - Shenghe Li
- College of Animal Science, Anhui Science and Technology University, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China.
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, No. 9, Donghua Road, Fengyang County, Chuzhou City, Anhui Province, China.
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9
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Singh SV, Ganguly R, Jaiswal K, Yadav AK, Kumar R, Pandey AK. Molecular signalling during cross talk between gut brain axis regulation and progression of irritable bowel syndrome: A comprehensive review. World J Clin Cases 2023; 11:4458-4476. [PMID: 37469740 PMCID: PMC10353503 DOI: 10.12998/wjcc.v11.i19.4458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 05/09/2023] [Accepted: 06/06/2023] [Indexed: 06/30/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional disorder which alters gastrointestinal (GI) functions, thus leading to compromised health status. Pathophysiology of IBS is not fully understood, whereas abnormal gut brain axis (GBA) has been identified as a major etiological factor. Recent studies are suggestive for visceral hyper-sensitivity, altered gut motility and dysfunctional autonomous nervous system as the main clinical abnormalities in IBS patients. Bidirectional signalling interactions among these abnormalities are derived through various exogenous and endogenous factors, such as microbiota population and diversity, microbial metabolites, dietary uptake, and psychological abnormalities. Strategic efforts focused to study these interactions including probiotics, antibiotics and fecal transplantations in normal and germ-free animals are clearly suggestive for the pivotal role of gut microbiota in IBS etiology. Additionally, neurotransmitters act as communication tools between enteric microbiota and brain functions, where serotonin (5-hydroxytryptamine) plays a key role in pathophysiology of IBS. It regulates GI motility, pain sense and inflammatory responses particular to mucosal and brain activity. In the absence of a better understanding of various interconnected crosstalks in GBA, more scientific efforts are required in the search of novel and targeted therapies for the management of IBS. In this review, we have summarized the gut microbial composition, interconnected signalling pathways and their regulators, available therapeutics, and the gaps needed to fill for a better management of IBS.
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Affiliation(s)
- Shiv Vardan Singh
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Risha Ganguly
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Kritika Jaiswal
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Aditya Kumar Yadav
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Allahabad (Prayagraj) 211002, Uttar Pradesh, India
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Yoon JW, Shin S, Park J, Lee BR, Lee SI. TLR/MyD88-Mediated Inflammation Induced in Porcine Intestinal Epithelial Cells by Ochratoxin A Affects Intestinal Barrier Function. TOXICS 2023; 11:toxics11050437. [PMID: 37235251 DOI: 10.3390/toxics11050437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023]
Abstract
The intestinal epithelium performs vital functions such as nutrient absorption and acting as an intestinal barrier to maintain the host's homeostasis. Mycotoxin, which affects the processing and storage of animal feedstuff, is a problematic pollutant in farming products. Ochratoxin A generated by Aspergillus and Penicillium fungi causes inflammation, intestinal dysfunction, decline in growth, and reduced intake in porcine and other livestock. Despite these ongoing problems, OTA-related studies in intestinal epithelium are lacking. This study aimed to demonstrate that OTA regulates TLR/MyD88 signaling in IPEC-J2 cells and induces barrier function impairment through tight junction reduction. We measured expression of TLR/MyD88 signaling-related mRNAs and proteins. The indicator of intestinal barrier integrity was confirmed through immunofluorescence and transepithelial electrical resistance. Additionally, we confirmed whether inflammatory cytokines and barrier function were affected by MyD88 inhibition. MyD88 inhibition alleviated inflammatory cytokine levels, tight junction reduction, and damage to barrier function due to OTA. These results indicate that OTA induces TLR/MyD88 signaling-related genes and impairs tight junctions and intestinal barrier function in IPEC-J2 cells. MyD88 regulation in OTA-treated IPEC-J2 cells mitigates the tight junction and intestinal barrier function impairments. Our findings provide a molecular understanding of OTA toxicity in porcine intestinal epithelial cells.
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Affiliation(s)
- Jung Woong Yoon
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju-si 37224, Republic of Korea
| | - Sangsu Shin
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju-si 37224, Republic of Korea
- Research Center for Horse Industry, Kyungpook National University, Sangju-si 37224, Republic of Korea
- Department of Animal Biotechnology, Kyungpook National University, Sangju-si 37224, Republic of Korea
| | - JeongWoong Park
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju-si 37224, Republic of Korea
- Research Center for Horse Industry, Kyungpook National University, Sangju-si 37224, Republic of Korea
| | - Bo Ram Lee
- Animal Biotechnology Division, National Institute of Animal Science, Rural Development Administration, Wanju-gun 55365, Republic of Korea
| | - Sang In Lee
- Department of Animal Science and Biotechnology, Kyungpook National University, Sangju-si 37224, Republic of Korea
- Research Center for Horse Industry, Kyungpook National University, Sangju-si 37224, Republic of Korea
- Department of Animal Biotechnology, Kyungpook National University, Sangju-si 37224, Republic of Korea
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11
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Dong LW, Chen YY, Chen CC, Ma ZC, Fu J, Huang BL, Liu FJ, Liang DC, Sun DM, Lan C. Adenosine 2A receptor contributes to the facilitation of post-infectious irritable bowel syndrome by γδ T cells via the PKA/CREB/NF-κB signaling pathway. World J Gastroenterol 2023; 29:1475-1491. [PMID: 36998428 PMCID: PMC10044852 DOI: 10.3748/wjg.v29.i9.1475] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/11/2023] [Accepted: 02/22/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome (PI-IBS). γδ T cells play a crucial role in innate and adaptive immunity. Adenosine receptors expressed on the surface of γδ T cells participate in intestinal inflammation and immunity regulation. AIM To investigate the role of γδ T cell regulated by adenosine 2A receptor (A2AR) in PI-IBS. METHODS The PI-IBS mouse model has been established with Trichinella spiralis (T. spiralis) infection. The intestinal A2AR and A2AR in γδ T cells were detected by immunohistochemistry, and the inflammatory cytokines were measured by western blot. The role of A2AR on the isolated γδ T cells, including proliferation, apoptosis, and cytokine production, were evaluated in vitro. Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction (RT-PCR). The animals were administered with A2AR agonist, or A2AR antagonist. Besides, γδ T cells were also injected back into the animals, and the parameters described above were examined, as well as the clinical features. Furthermore, the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR. RESULTS PI-IBS mice exhibited elevated ATP content and A2AR expression (P < 0.05), and suppression of A2AR enhanced PI-IBS clinical characteristics, indicated by the abdominal withdrawal reflex and colon transportation test. PI-IBS was associated with an increase in intestinal T cells, and cytokine levels of interleukin-1 (IL-1), IL-6, IL-17A, and interferon-α (IFN-α). Also, γδ T cells expressed A2AR in vitro and generated IL-1, IL-6, IL-17A, and IFN-α, which can be controlled by A2AR agonist and antagonist. Mechanistic studies demonstrated that the A2AR antagonist improved the function of γδ T cells through the PKA/CREB/NF-κB signaling pathway. CONCLUSION Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function of γδ T cells via the PKA/CREB/NF-κB signaling pathway.
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Affiliation(s)
- Li-Wei Dong
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Yi-Yao Chen
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Chao-Chao Chen
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Zhi-Chao Ma
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Jiao Fu
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Bai-Li Huang
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Fu-Jin Liu
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
| | - Dong-Chun Liang
- Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90033, United States
| | - De-Ming Sun
- Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90033, United States
| | - Cheng Lan
- Department of Gastroenterology, Hainan General Hospital, Affiliated Hainan Hospital, Hainan Medical University, Haikou 570311, Hainan Province, China
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12
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Cui Y, Li F, Zhu X, Xu J, Muhammad A, Chen Y, Li D, Liu B, Wang C, Wang Z, Ma S, Liu X, Shi Y. Alfalfa saponins inhibit oxidative stress-induced cell apoptosis through the MAPK signaling pathway. Redox Rep 2022; 27:1-8. [PMID: 34931598 PMCID: PMC8725750 DOI: 10.1080/13510002.2021.2017681] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
BACKGROUND Oxidative stress could seriously affect the growth performance of piglets. As natural extracts of Alfalfa (Medicago sativa), alfalfa saponins have been shown to function as antioxidants in piglets in vivo. However, few studies have investigated the effects and mechanism of alfalfa saponins against oxidative stress in piglet cells in vitro. In the current study, piglets' small intestinal epithelial cell line (IPEC-J2) was explored to investigate the protective effects of alfalfa saponins on injured cells induced by H2O2. METHODS To investigate the effects and mechanism of alfalfa saponins against oxidative stress in piglet cells, the cell viability, activity of antioxidant enzymes, LDH and the amount of MDA were detected in H2O2-treated cells after the cells were pre-incubated with alfalfa saponins. The mechanism of alfalfa saponins against H2O2-induced oxidative cell damage was explored by detecting the expression of mitochondrial apoptosis-related proteins. Furthermore, the signaling pathway of alfalfa saponins in IPEC-J2 cells under oxidative stress was also investigated. RESULTS The results indicated that alfalfa saponins could rescue cell viability, elevate the activity of antioxidant enzymes and down-regulate the activity of LDH and the amount of MDA in H2O2-induced cells. CONCLUSION Alfalfa saponins could inhibit oxidative stress-induced cell mitochondrial apoptosis through the MAPK signaling pathway, thereby providing a new method for improving antioxidant stress ability by means of nutritional regulation.
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Affiliation(s)
- Yalei Cui
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Innovation and Utilization of Grassland Resources, Zhengzhou, People’s Republic of China
- Henan Herbage Engineering Technology Research Center, Zhengzhou, People’s Republic of China
| | - Fen Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Xiaoyan Zhu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Innovation and Utilization of Grassland Resources, Zhengzhou, People’s Republic of China
- Henan Herbage Engineering Technology Research Center, Zhengzhou, People’s Republic of China
| | - Junying Xu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Abaidullah Muhammad
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Yanyan Chen
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Defeng Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Innovation and Utilization of Grassland Resources, Zhengzhou, People’s Republic of China
- Henan Herbage Engineering Technology Research Center, Zhengzhou, People’s Republic of China
| | - Boshuai Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Chengzhang Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Innovation and Utilization of Grassland Resources, Zhengzhou, People’s Republic of China
- Henan Herbage Engineering Technology Research Center, Zhengzhou, People’s Republic of China
| | - Zhichang Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Innovation and Utilization of Grassland Resources, Zhengzhou, People’s Republic of China
- Henan Herbage Engineering Technology Research Center, Zhengzhou, People’s Republic of China
| | - Sen Ma
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Innovation and Utilization of Grassland Resources, Zhengzhou, People’s Republic of China
- Henan Herbage Engineering Technology Research Center, Zhengzhou, People’s Republic of China
| | - Xule Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
| | - Yinghua Shi
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, People’s Republic of China
- Henan Key Laboratory of Innovation and Utilization of Grassland Resources, Zhengzhou, People’s Republic of China
- Henan Herbage Engineering Technology Research Center, Zhengzhou, People’s Republic of China
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13
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Wang F, Sun N, Zeng H, Gao Y, Zhang N, Zhang W. Selenium Deficiency Leads to Inflammation, Autophagy, Endoplasmic Reticulum Stress, Apoptosis and Contraction Abnormalities via Affecting Intestinal Flora in Intestinal Smooth Muscle of Mice. Front Immunol 2022; 13:947655. [PMID: 35874733 PMCID: PMC9299101 DOI: 10.3389/fimmu.2022.947655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/07/2022] [Indexed: 12/17/2022] Open
Abstract
Selenium (Se) is a micronutrient that plays a predominant role in various physiological processes in humans and animals. Long-term lack of Se will lead to many metabolic diseases. Studies have found that chronic Se deficiency can cause chronic diarrhea. The gut flora is closely related to the health of the body. Changes in environmental factors can cause changes in the intestinal flora. Our study found that Se deficiency can disrupt intestinal flora. Through 16s high-throughput sequencing analysis of small intestinal contents of mice, we found that compared with CSe group, the abundance of Lactobacillus, Bifidobacterium, and Ileibacterium in the low selenium group was significantly increased, while Romboutsia abundance was significantly decreased. Histological analysis showed that compared with CSe group, the small intestine tissues of the LSe group had obvious pathological changes. We examined mRNA expression levels in the small intestine associated with inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junctions, and smooth muscle contraction. The mRNA levels of NF-κB, IκB, p38, IL-1β, TNF-α, Beclin, ATG7, ATG5, LC3α, BaK, Pum, Caspase-3, RIP1, RIPK3, PERK, IRE1, elF2α, GRP78, CHOP2, ZO-1, ZO-2, Occludin, E-cadherin, CaM, MLC, MLCK, Rho, and RhoA in the LSe group were significantly increased. The mRNA levels of IL-10, p62 BcL-2 and BcL-w were significantly decreased in the LSe group compared with the CSe group. These results suggest that changes in the abundance of Lactobacillus, bifidobacterium, ileum, and Romboutsia may be associated with cellular inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junction, and abnormal smooth muscle contraction. Intestinal flora may play an important role in chronic diarrhea caused by selenium deficiency.
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Affiliation(s)
| | | | | | | | - Naisheng Zhang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Wenlong Zhang
- College of Veterinary Medicine, Jilin University, Changchun, China
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14
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Wan Y, Zhang B. The Impact of Zinc and Zinc Homeostasis on the Intestinal Mucosal Barrier and Intestinal Diseases. Biomolecules 2022; 12:biom12070900. [PMID: 35883455 PMCID: PMC9313088 DOI: 10.3390/biom12070900] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/06/2022] [Accepted: 06/11/2022] [Indexed: 02/04/2023] Open
Abstract
Zinc is an essential trace element for living organisms, and zinc homeostasis is essential for the maintenance of the normal physiological functions of cells and organisms. The intestine is the main location for zinc absorption and excretion, while zinc and zinc homeostasis is also of great significance to the structure and function of the intestinal mucosal barrier. Zinc excess or deficiency and zinc homeostatic imbalance are all associated with many intestinal diseases, such as IBD (inflammatory bowel disease), IBS (irritable bowel syndrome), and CRC (colorectal cancer). In this review, we describe the role of zinc and zinc homeostasis in the intestinal mucosal barrier and the relevance of zinc homeostasis to gastrointestinal diseases.
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15
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Layer P, Andresen V, Allescher H, Bischoff SC, Claßen M, Elsenbruch S, Freitag M, Frieling T, Gebhard M, Goebel-Stengel M, Häuser W, Holtmann G, Keller J, Kreis ME, Kruis W, Langhorst J, Jansen PL, Madisch A, Mönnikes H, Müller-Lissner S, Niesler B, Pehl C, Pohl D, Raithel M, Röhrig-Herzog G, Schemann M, Schmiedel S, Schwille-Kiuntke J, Storr M, Preiß JC, Andus T, Buderus S, Ehlert U, Engel M, Enninger A, Fischbach W, Gillessen A, Gschossmann J, Gundling F, Haag S, Helwig U, Hollerbach S, Karaus M, Katschinski M, Krammer H, Kuhlbusch-Zicklam R, Matthes H, Menge D, Miehlke S, Posovszky MC, Schaefert R, Schmidt-Choudhury A, Schwandner O, Schweinlin A, Seidl H, Stengel A, Tesarz J, van der Voort I, Voderholzer W, von Boyen G, von Schönfeld J, Wedel T. Update S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM) – Juni 2021 – AWMF-Registriernummer: 021/016. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:1323-1415. [PMID: 34891206 DOI: 10.1055/a-1591-4794] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- P Layer
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - V Andresen
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - H Allescher
- Zentrum für Innere Medizin, Gastroent., Hepatologie u. Stoffwechsel, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Deutschland
| | - S C Bischoff
- Institut für Ernährungsmedizin, Universität Hohenheim, Stuttgart, Deutschland
| | - M Claßen
- Klinik für Kinder- und Jugendmedizin, Klinikum Links der Weser, Bremen, Deutschland
| | - S Elsenbruch
- Klinik für Neurologie, Translational Pain Research Unit, Universitätsklinikum Essen, Essen, Deutschland.,Abteilung für Medizinische Psychologie und Medizinische Soziologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - M Freitag
- Abteilung Allgemeinmedizin Department für Versorgungsforschung, Universität Oldenburg, Oldenburg, Deutschland
| | - T Frieling
- Medizinische Klinik II, Helios Klinikum Krefeld, Krefeld, Deutschland
| | - M Gebhard
- Gemeinschaftspraxis Pathologie-Hamburg, Hamburg, Deutschland
| | - M Goebel-Stengel
- Innere Medizin II, Helios Klinik Rottweil, Rottweil, und Innere Medizin VI, Psychosomat. Medizin u. Psychotherapie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - W Häuser
- Innere Medizin I mit Schwerpunkt Gastroenterologie, Klinikum Saarbrücken, Saarbrücken, Deutschland
| | - G Holtmann
- Faculty of Medicine & Faculty of Health & Behavioural Sciences, Princess Alexandra Hospital, Brisbane, Australien
| | - J Keller
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - M E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | | | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Deutschland
| | - P Lynen Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, Berlin, Deutschland
| | - A Madisch
- Klinik für Gastroenterologie, interventionelle Endoskopie und Diabetologie, Klinikum Siloah, Klinikum Region Hannover, Hannover, Deutschland
| | - H Mönnikes
- Klinik für Innere Medizin, Martin-Luther-Krankenhaus, Berlin, Deutschland
| | | | - B Niesler
- Abteilung Molekulare Humangenetik Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - C Pehl
- Medizinische Klinik, Krankenhaus Vilsbiburg, Vilsbiburg, Deutschland
| | - D Pohl
- Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Schweiz
| | - M Raithel
- Medizinische Klinik II m.S. Gastroenterologie und Onkologie, Waldkrankenhaus St. Marien, Erlangen, Deutschland
| | | | - M Schemann
- Lehrstuhl für Humanbiologie, TU München, Deutschland
| | - S Schmiedel
- I. Medizinische Klinik und Poliklinik Gastroenterologie, Universitätsklinikum Hamburg-Eppendorf, Deutschland
| | - J Schwille-Kiuntke
- Abteilung für Psychosomatische Medizin und Psychotherapie, Medizinische Universitätsklinik Tübingen, Tübingen, Deutschland.,Institut für Arbeitsmedizin, Sozialmedizin und Versorgungsforschung, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - M Storr
- Zentrum für Endoskopie, Gesundheitszentrum Starnberger See, Starnberg, Deutschland
| | - J C Preiß
- Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Hepatologie, Vivantes Klinikum Neukölln, Berlin, Deutschland
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Klüber P, Meurer SK, Lambertz J, Schwarz R, Zechel-Gran S, Braunschweig T, Hurka S, Domann E, Weiskirchen R. Depletion of Lipocalin 2 (LCN2) in Mice Leads to Dysbiosis and Persistent Colonization with Segmented Filamentous Bacteria. Int J Mol Sci 2021; 22:ijms222313156. [PMID: 34884961 PMCID: PMC8658549 DOI: 10.3390/ijms222313156] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 12/15/2022] Open
Abstract
Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut microbiota. Consequently, complete or hepatocyte-specific ablation of the Lcn2 gene is associated with higher susceptibility to bacterial infections. In the present study, we comparatively profiled microbiota in fecal samples of wild type and Lcn2 null mice and show, in contrast to previous reports, that the quantity of DNA in feces of Lcn2 null mice is significantly lower than that in wild type mice (p < 0.001). By using the hypervariable V4 region of the 16S rDNA gene and Next-Generation Sequencing methods, we found a statistically significant change in 16 taxonomic units in Lcn2-/- mice, including eight gender-specific deviations. In particular, members of Clostridium, Escherichia, Helicobacter, Lactococcus, Prevotellaceae_UCG-001 and Staphylococcus appeared to expand in the intestinal tract of knockout mice. Interestingly, the proportion of Escherichia (200-fold) and Staphylococcus (10-fold) as well as the abundance of intestinal bacteria encoding the LCN2-sensitive siderphore enterobactin (entA) was significantly increased in male Lcn2 null mice (743-fold, p < 0.001). This was accompanied by significant higher immune cell infiltration in the ileum as demonstrated by increased immunoreactivity against the pan-leukocyte protein CD45, the lymphocyte transcription factor MUM-1/IRF4, and the macrophage antigen CD68/Macrosialin. In addition, we found a higher expression of mucosal mast cell proteases indicating a higher number of those innate immune cells. Finally, the ileum of Lcn2 null mice displayed a high abundance of segmented filamentous bacteria, which are intimately associated with the mucosal cell layer, provoking epithelial antimicrobial responses and affecting T-helper cell polarization.
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Affiliation(s)
- Patrick Klüber
- German Centre for Infection Research, Institute of Medical Microbiology, Justus-Liebig-University, D-35392 Giessen, Germany; (P.K.); (S.Z.-G.)
| | - Steffen K. Meurer
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, D-52074 Aachen, Germany; (S.K.M.); (J.L.)
| | - Jessica Lambertz
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, D-52074 Aachen, Germany; (S.K.M.); (J.L.)
| | - Roman Schwarz
- Labor Mönchengladbach, Medical Care Centre, D-41169 Mönchengladbach, Germany;
| | - Silke Zechel-Gran
- German Centre for Infection Research, Institute of Medical Microbiology, Justus-Liebig-University, D-35392 Giessen, Germany; (P.K.); (S.Z.-G.)
| | - Till Braunschweig
- Institute of Pathology, RWTH Aachen University Hospital, D-52074 Aachen, Germany;
| | - Sabine Hurka
- Institute for Insect Biotechnology, Justus-Liebig-University, D-35392 Giessen, Germany;
| | - Eugen Domann
- German Centre for Infection Research, Institute of Hygiene and Environmental Medicine, Justus-Liebig-University, D-35392 Giessen, Germany
- Correspondence: (E.D.); (R.W.); Tel.: +49-(0)641-99-41280 (E.D.); +49-(0)241-80-88683 (R.W.)
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, D-52074 Aachen, Germany; (S.K.M.); (J.L.)
- Correspondence: (E.D.); (R.W.); Tel.: +49-(0)641-99-41280 (E.D.); +49-(0)241-80-88683 (R.W.)
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Yu LM, Mao LQ, Wu CY, Ye W, Wang X. Chlorogenic acid improves intestinal barrier function by downregulating CD14 to inhibit the NF-κB signaling pathway. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104640] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Aziz MNM, Kumar J, Muhammad Nawawi KN, Raja Ali RA, Mokhtar NM. Irritable Bowel Syndrome, Depression, and Neurodegeneration: A Bidirectional Communication from Gut to Brain. Nutrients 2021; 13:nu13093061. [PMID: 34578939 PMCID: PMC8468817 DOI: 10.3390/nu13093061] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with irritable bowel syndrome (IBS) are increasingly presenting with a wide range of neuropsychiatric symptoms, such as deterioration in gastroenteric physiology, including visceral hypersensitivity, altered intestinal membrane permeability, and gastrointestinal motor dysfunction. Functional imaging of IBS patients has revealed several abnormalities in various brain regions, such as significant activation of amygdala, thinning of insular and anterior cingulate cortex, and increase in hypothalamic gray matter, which results in poor psychiatric and cognitive outcomes. Interrelations between the enteric and central events in IBS-related gastrointestinal, neurological, and psychiatric pathologies have compelled researchers to study the gut-brain axis-a bidirectional communication that maintains the homeostasis of the gastrointestinal and central nervous system with gut microbiota as the protagonist. Thus, it can be disrupted by any alteration owing to the gut dysbiosis or loss of diversity in microbial composition. Available evidence indicates that the use of probiotics as a part of a balanced diet is effective in the management of IBS and IBS-associated neurodegenerative and psychiatric comorbidities. In this review, we delineate the pathogenesis and complications of IBS from gastrointestinal and neuropsychiatric standpoints while also discussing the neurodegenerative events in enteric and central nervous systems of IBS patients and the therapeutic potential of gut microbiota-based therapy established on clinical and preclinical data.
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Affiliation(s)
- Muhammad Nazirul Mubin Aziz
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (M.N.M.A.); (J.K.)
| | - Jaya Kumar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (M.N.M.A.); (J.K.)
- Gut Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (K.N.M.N.); (R.A.R.A.)
| | - Khairul Najmi Muhammad Nawawi
- Gut Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (K.N.M.N.); (R.A.R.A.)
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Raja Affendi Raja Ali
- Gut Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (K.N.M.N.); (R.A.R.A.)
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
| | - Norfilza M. Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (M.N.M.A.); (J.K.)
- Gut Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (K.N.M.N.); (R.A.R.A.)
- Correspondence:
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19
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Nordström EA, Teixeira C, Montelius C, Jeppsson B, Larsson N. Lactiplantibacillus plantarum 299v (LP299V ®): three decades of research. Benef Microbes 2021; 12:441-465. [PMID: 34365915 DOI: 10.3920/bm2020.0191] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This review aims to provide a comprehensive overview of the in vitro, animal, and clinical studies with the bacterial strain Lactiplantibacillus plantarum 299v (L. plantarum 299v; formerly named Lactobacillus plantarum 299v) published up until June 30, 2020. L. plantarum 299v is the most documented L. plantarum strain in the world, described in over 170 scientific publications out of which more than 60 are human clinical studies. The genome sequence of L. plantarum 299v has been determined and is available in the public domain (GenBank Accession number: NZ_LEAV01000004). The probiotic strain L. plantarum 299v was isolated from healthy human intestinal mucosa three decades ago by scientists at Lund University, Sweden. Thirty years later, a wealth of data coming from in vitro, animal, and clinical studies exist, showing benefits primarily for gastrointestinal health, such as reduced flatulence and abdominal pain in patients with irritable bowel syndrome (IBS). Moreover, several clinical studies have shown positive effects of L. plantarum 299v on iron absorption and more recently also on iron status. L. plantarum 299v is safe for human consumption and does not confer antibiotic resistance. It survives the harsh conditions of the human gastrointestinal tract, adheres to mannose residues on the intestinal epithelial cells and has in some cases been re-isolated more than ten days after administration ceased. Besides studying health benefits, research groups around the globe have investigated L. plantarum 299v in a range of applications and processes. L. plantarum 299v is used in many different food applications as well as in various dietary supplements. In a freeze-dried format, L. plantarum 299v is robust and stable at room temperature, enabling long shelf-lives of consumer healthcare products such as capsules, tablets, or powder sachets. The strain is patent protected for a wide range of indications and applications worldwide as well as trademarked as LP299V®.
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Affiliation(s)
| | - C Teixeira
- Probi AB, Ideongatan 1A, 22370 Lund, Sweden
| | | | - B Jeppsson
- Department of Surgery, Lund University, Universitetssjukhuset, 22184 Lund, Sweden
| | - N Larsson
- Probi AB, Ideongatan 1A, 22370 Lund, Sweden
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20
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Liu Y, Li W, Yang H, Zhang X, Wang W, Jia S, Xiang B, Wang Y, Miao L, Zhang H, Wang L, Wang Y, Song J, Sun Y, Chai L, Tian X. Leveraging 16S rRNA Microbiome Sequencing Data to Identify Bacterial Signatures for Irritable Bowel Syndrome. Front Cell Infect Microbiol 2021; 11:645951. [PMID: 34178718 PMCID: PMC8231010 DOI: 10.3389/fcimb.2021.645951] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain or discomfort. Previous studies have illustrated that the gut microbiota might play a critical role in IBS, but the conclusions of these studies, based on various methods, were almost impossible to compare, and reproducible microorganism signatures were still in question. To cope with this problem, previously published 16S rRNA gene sequencing data from 439 fecal samples, including 253 IBS samples and 186 control samples, were collected and processed with a uniform bioinformatic pipeline. Although we found no significant differences in community structures between IBS and healthy controls at the amplicon sequence variants (ASV) level, machine learning (ML) approaches enabled us to discriminate IBS from healthy controls at genus level. Linear discriminant analysis effect size (LEfSe) analysis was subsequently used to seek out 97 biomarkers across all studies. Then, we quantified the standardized mean difference (SMDs) for all significant genera identified by LEfSe and ML approaches. Pooled results showed that the SMDs of nine genera had statistical significance, in which the abundance of Lachnoclostridium, Dorea, Erysipelatoclostridium, Prevotella 9, and Clostridium sensu stricto 1 in IBS were higher, while the dominant abundance genera of healthy controls were Ruminococcaceae UCG-005, Holdemanella, Coprococcus 2, and Eubacterium coprostanoligenes group. In summary, based on six published studies, this study identified nine new microbiome biomarkers of IBS, which might be a basis for understanding the key gut microbes associated with IBS, and could be used as potential targets for microbiome-based diagnostics and therapeutics.
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Affiliation(s)
- Yuxia Liu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenhui Li
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hongxia Yang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoying Zhang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenxiu Wang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Sitong Jia
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Beibei Xiang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yi Wang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lin Miao
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Han Zhang
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Laboratory of Pharmacology of Traditional Chinese Medical Formulae Co-Constructed by the Province-Ministry, Tianjin University of TCM, Tianjin, China
| | - Lin Wang
- Tianjin Zhongxin Pharmaceutical Group Co., Ltd. Le Ren Tang Pharmaceutical Factory, Tianjin, China
| | - Yujing Wang
- Tianjin Zhongxin Pharmaceutical Group Co., Ltd. Le Ren Tang Pharmaceutical Factory, Tianjin, China
| | - Jixiang Song
- Tianjin Zhongxin Pharmaceutical Group Co., Ltd. Le Ren Tang Pharmaceutical Factory, Tianjin, China
| | - Yingjie Sun
- Tianjin Zhongxin Pharmaceutical Group Co., Ltd. Le Ren Tang Pharmaceutical Factory, Tianjin, China
| | - Lijuan Chai
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Laboratory of Pharmacology of Traditional Chinese Medical Formulae Co-Constructed by the Province-Ministry, Tianjin University of TCM, Tianjin, China
| | - Xiaoxuan Tian
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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21
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The utility of faecal and urine biomarkers for small bowel diseases. Curr Opin Gastroenterol 2021; 37:284-294. [PMID: 33769381 DOI: 10.1097/mog.0000000000000730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW Small bowel diseases pose a unique diagnostic and management challenge and often requires tertiary specialist referral. The use of biomarkers may provide a cheap, noninvasive tool to assess the small bowel in terms of diagnosis, offering a better way to triage referrals and select patients for early management. This review looks at the most recent evidence behind the use of several faecal and urine biomarkers for small bowel diseases. RECENT FINDINGS Faecal calprotectin shows the most promise, with evidence to support its role in predicting relapse postsurgery and monitoring treatment response in patients with Crohn's disease. A faecal calprotectin less than 50 μg/g may also be used as a cut-off to triage further investigation. Faecal lactoferrin also appears promising as a marker of small bowel inflammation. A positive faecal immunohistochemistry test precapsule may help to prioritize referrals for obscure bleeding. SUMMARY The use of biomarkers in the diagnosis and management of small bowel disease is still controversial and remains unclear. More studies are required to further develop their potential and before societal guidelines can be developed to direct their appropriate use in clinical practice.
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22
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Alonso-Cotoner C, Abril-Gil M, Albert-Bayo M, Mall JPG, Expósito E, González-Castro AM, Lobo B, Santos J. The Role of Purported Mucoprotectants in Dealing with Irritable Bowel Syndrome, Functional Diarrhea, and Other Chronic Diarrheal Disorders in Adults. Adv Ther 2021; 38:2054-2076. [PMID: 33738725 PMCID: PMC7971407 DOI: 10.1007/s12325-021-01676-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022]
Abstract
Chronic diarrhea is a frequent presenting symptom, both in primary care medicine and in specialized gastroenterology units. It is estimated that more than 5% of the global population suffers from chronic diarrhea. and that about 40% of these subjects are older than 60 years. The clinician is frequently faced with the need to decide which is the best therapeutic approach for these patients. While the origin of chronic diarrhea is diverse, impairment of intestinal barrier function, dysbiosis. and mucosal micro-inflammation are being increasingly recognized as underlying phenomena characterizing a variety of chronic diarrheal diseases. In addition to current pharmacological therapies, there is growing interest in alternative products such as mucoprotectants, which form a mucoadhesive film over the epithelium to reduce and protect against the development of altered intestinal permeability, dysbiosis, and mucosal micro-inflammation. This manuscript focuses on chronic diarrhea in adults, and we will review recent evidence on the ability of these natural compounds to improve symptoms associated with chronic diarrhea and to exert protective effects for the intestinal barrier.
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Affiliation(s)
- Carmen Alonso-Cotoner
- Servei de Aparell Digestiu, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
- Universitat Autònoma de Barcelona, Facultat de Medicina, Bellaterra, Barcelona, Spain
- CIBER de Enfermedades Hepaticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain
| | - Mar Abril-Gil
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Mercé Albert-Bayo
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - John-P Ganda Mall
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Elba Expósito
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Ana M González-Castro
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Beatriz Lobo
- Servei de Aparell Digestiu, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.
- Universitat Autònoma de Barcelona, Facultat de Medicina, Bellaterra, Barcelona, Spain.
| | - Javier Santos
- Servei de Aparell Digestiu, Vall d'Hebron Hospital Universitari, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
- Grup de Neuro-Inmuno-Gastroenterología, Unitat de Fisiología I Fisiopatología Digestiva, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.
- Universitat Autònoma de Barcelona, Facultat de Medicina, Bellaterra, Barcelona, Spain.
- CIBER de Enfermedades Hepaticas y Digestivas (CIBERHED), Instituto de Salud Carlos III, Madrid, Spain.
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23
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Wang XJ, Carlson P, Chedid V, Maselli DB, Taylor AL, McKinzie S, Camilleri M. Differential mRNA Expression in Ileal Mucosal Biopsies of Patients With Diarrhea- or Constipation-Predominant Irritable Bowel Syndrome. Clin Transl Gastroenterol 2021; 12:e00329. [PMID: 33843785 PMCID: PMC8043738 DOI: 10.14309/ctg.0000000000000329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/17/2021] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Previous studies in patients with irritable bowel syndrome (IBS) showed immune activation, secretion, and barrier dysfunction in duodenal, jejunal, or colorectal mucosa. This study aimed to measure ileal mucosal expression of genes and proteins associated with mucosal functions. METHODS We measured by reverse transcription polymerase chain reaction messenger RNA (mRNA) expression of 78 genes (reflecting tight junction proteins, chemokines, innate immunity, ion channels, and transmitters) and 5 proteins (barrier, bile acid receptor, and ion exchanger) in terminal ileal mucosa from 11 patients with IBS-diarrhea (IBS-D), 17 patients with IBS-constipation (IBS-C), and 14 healthy controls. Fold changes in mRNA were calculated using 2(-Δ, ΔCT) formula. Group differences were measured using analysis of variance. Protein ratios relative to healthy controls were based on Western blot analysis. Nominal P values (P < 0.05) are reported. RESULTS In ileal mucosal biopsies, significant differences of mRNA expression in IBS-D relative to IBS-C were upregulation of barrier proteins (TJP1, FN1, CLDN1, and CLDN12), repair function (TFF1), and cellular functions. In ileal mucosal biopsies, mRNA expression in IBS-C relative to healthy controls was reduced GPBAR1 receptor, myosin light chain kinase (MYLK in barrier function), and innate immunity (TLR3), but increased mRNA expression of cadherin cell adhesion mechanisms (CTNNB1) and transport genes SLC9A1 (Na-H exchanger [NHE1]) and INADL (indirect effect on ion transport). DISCUSSION These data support a role of ileal mucosal dysfunction in IBS, including barrier dysfunction in IBS-D and alterations in absorption/secretion mechanisms in IBS-C.
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Affiliation(s)
- Xiao Jing Wang
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Paula Carlson
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Victor Chedid
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel B. Maselli
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Ann L. Taylor
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Sanna McKinzie
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
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24
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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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25
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Martínez C, Lasitschka F, Thöni C, Wohlfarth C, Braun A, Granzow M, Röth R, Dizdar V, Rappold GA, Hausken T, Langeland N, Hanevik K, Niesler B. Comparative expression profiling in the intestine of patients with Giardia-induced postinfectious functional gastrointestinal disorders. Neurogastroenterol Motil 2020; 32:e13868. [PMID: 32391639 DOI: 10.1111/nmo.13868] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/13/2020] [Accepted: 04/07/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND A Giardia outbreak in Bergen, Norway, caused postinfectious functional gastrointestinal disorders (PI-FGIDs). Despite the devastating effects of this outbreak, it presented a unique chance to investigate the implication on the dysregulation of genetic pathways in PI-FGID. METHODS We performed the first comparative expression profiling of miRNAs and their potential target genes in microdissected rectal biopsies from 20 Giardia-induced PI-FGID patients vs 18 healthy controls by nCounter analysis. Subsequently, candidates were validated on protein level by immunostaining. KEY RESULTS miRNA profiling on rectal biopsy samples from 5 diarrhea-predominant PI-IBS cases compared to 10 healthy controls revealed differential expression in the epithelial layer. The top five regulated miRNAs were implicated in GI disease, inflammatory response, and immunological disease. Subsequently, these miRNAs and 100 potential mRNA targets were examined in 20 PI-FGID cases and 18 healthy controls in both the mucosal epithelium and the lamina propria. Although deregulation of the selected miRNAs could not be verified in the larger sample set, mRNAs involved in barrier function were downregulated in the epithelium. Pro-inflammatory genes and genes implicated in epigenetic modifications were upregulated in the lamina propria. Immunostaining for selected candidates on 17 PI-FGID cases and 16 healthy controls revealed increased tryptase levels as well as a decreased and aberrant subcellular expression of occludin. CONCLUSIONS AND INFERENCES Genes relevant to immune and barrier function as well as stress response and epigenetic modulation are differentially expressed in PI-FGIDs and may contribute to disease manifestation.
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Affiliation(s)
- Cristina Martínez
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.,Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Lleida, Spain.,Genes in Irritable Bowel Syndrome (GENIEUR) Research Network Europe, Heidelberg, Germany
| | - Felix Lasitschka
- Institute of Pathology, Heidelberg University, Heidelberg, Germany
| | - Cornelia Thöni
- Institute of Pathology, Heidelberg University, Heidelberg, Germany
| | - Carolin Wohlfarth
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Alexander Braun
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Martin Granzow
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Ralph Röth
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.,nCounter Core Facility Heidelberg, Institute of Human Genetics, Heidelberg, Germany
| | - Vernesa Dizdar
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Gudrun A Rappold
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.,nCounter Core Facility Heidelberg, Institute of Human Genetics, Heidelberg, Germany
| | - Trygve Hausken
- Genes in Irritable Bowel Syndrome (GENIEUR) Research Network Europe, Heidelberg, Germany.,Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Nina Langeland
- Genes in Irritable Bowel Syndrome (GENIEUR) Research Network Europe, Heidelberg, Germany.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Kurt Hanevik
- Genes in Irritable Bowel Syndrome (GENIEUR) Research Network Europe, Heidelberg, Germany.,Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Medicine, National Advisory Center for Tropical Infectious Diseases, Haukeland University Hospital, Bergen, Norway
| | - Beate Niesler
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.,Genes in Irritable Bowel Syndrome (GENIEUR) Research Network Europe, Heidelberg, Germany.,nCounter Core Facility Heidelberg, Institute of Human Genetics, Heidelberg, Germany
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26
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Zhu K, Zhao Y, Yang Y, Bai Y, Zhao T. Icariin Alleviates Bisphenol A Induced Disruption of Intestinal Epithelial Barrier by Maintaining Redox Homeostasis In Vivo and In Vitro. ACS OMEGA 2020; 5:20399-20408. [PMID: 32832793 PMCID: PMC7439398 DOI: 10.1021/acsomega.0c02364] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/20/2020] [Indexed: 05/17/2023]
Abstract
Bisphenol A (BPA), a globally prevalent environmental contaminant, has been shown to have the potential to disrupt intestinal barrier function. This study explored the mechanisms of BPA-induced intestinal barrier dysfunction. In addition, the protective effect of the natural product icariin (ICA) on BPA-induced intestinal barrier dysfunction was evaluated. BPA relieved oxidative stress (reactive oxygen species (ROS), reactive nitrogen species (RNS), malondialdehyde (MDA), and hydrogen peroxide (H2O2)), suppressed antioxidant enzyme (superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total antioxidant capacity (T-AOC)) activity, and increased gene expression and protein content of p38 mitogen-activated protein kinase (MAPK), giving rise to the dysfunctional gut in mice. ICA therapy effectively eased intestinal barrier dysfunction caused by BPA in vivo and in vitro. Treatment with p38 MAPK inhibitor (SB203580) significantly rescued the MODE-K cell barrier function disrupted by BPA challenge. However, treatment with p38 MAPK activator (anisomycin) did not attenuate the MODE-K cell barrier function impaired by BPA challenge. Overall, our data suggested that BPA disrupted intestinal barrier function in a p38 MAPK-dependent manner. Furthermore, we demonstrated that ICA regulated the redox equilibrium of intestinal epithelial cells by inhibiting the expression of p38 MAPK, thereby alleviating BPA-induced disruption of intestinal barrier function. These findings contributed to a better understanding of the mechanisms of BPA-induced intestinal barrier dysfunction and provided new insights into the prevention and treatment of BPA-induced intestinal diseases.
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Affiliation(s)
- Kun Zhu
- Department
of Pharmacy, The Third Hospital of Jilin
University, Xiantai Street
No. 126, Changchun 130021, China
| | - Yanan Zhao
- Department
of Oncology and Hematology, The Third Hospital
of Jilin University, Xiantai Street No. 126, Changchun 130021, China
| | - Yang Yang
- Department
of Oncology and Hematology, The Third Hospital
of Jilin University, Xiantai Street No. 126, Changchun 130021, China
| | - Yuansong Bai
- Department
of Oncology and Hematology, The Third Hospital
of Jilin University, Xiantai Street No. 126, Changchun 130021, China
| | - Tianyu Zhao
- College
of Basic Medical Sciences, Jilin University, Xinmin Street No. 126, Changchun 130021, China
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27
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Heenan P, Creemers RH, Sharma S, Keenan J, Bayer S, Young W, Cooney J, Armstrong K, Fraser K, Skidmore PM, Talley NJ, Roy N, Gearry RB. Cohort Profile: The Christchurch IBS cOhort to investigate Mechanisms FOr gut Relief and improved Transit (COMFORT). Inflamm Intest Dis 2020; 5:132-143. [PMID: 32999886 PMCID: PMC7506285 DOI: 10.1159/000508160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 04/23/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS This cross-sectional observational case-control study was initiated in July 2016 with the aim of increasing an understanding of the underlying disease mechanisms in functional gastrointestinal disorders (FGIDs) including irritable bowel syndrome (IBS), functional diarrhoea (FD), and functional constipation (FC). Specific areas of interest include the effect of food, microbiome, host and microbial genetics, metabolome, and psychological variables on unexplained chronic gastrointestinal (GI) symptoms. METHODS This study recruited consecutive patients who were attending one of two endoscopy centres in Christchurch, New Zealand, for colonoscopy and a subgroup of participants from the general public who did not undergo colonoscopy. Participants with known GI disease other than an FGID were excluded. Those with symptoms were recruited as cases, whilst those without symptoms were recruited as controls. In the days prior to preparation for colonoscopy, or an agreeable time for those not undergoing colonoscopy, demographic, symptom, psychological, dietary, and health data were collected in addition to biological samples (breath, faeces, blood, and urine). Colonic biopsies were taken at the time of colonoscopy from participants in the colonoscopy subgroup. RESULTS Between July 2016 and December 2018, 349 participants were recruited, 315 of whom completed the study, 220 participants were from the colonoscopy subgroup, and 95 from the non-colonoscopy subgroup. This included 129 controls and 186 cases (57 IBS-diarrhoea predominant, 30 IBS-constipation predominant, 41 IBS-mixed, 42 FC, and 16 FD). The mean age of FGID cases was 53.4 years and controls 54.4 years. Cases (149/186, 80.1%) and controls (57/72, 55.8%) were predominantly female. Education levels were similar across the cohort. Smoking and alcohol rates were also similar. Biological samples were collected as planned from participants. CONCLUSIONS The COMFORT cohort is a unique clinical cohort of FGID cases and controls with a wide range of demographic, dietary, clinical, psychological, and health data in addition to biological samples. Future research will aim to use a systems biology approach to establish the potential role of diet, host-microbiome interactions, and other factors in the pathogenesis of FGIDs.
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Affiliation(s)
- Phoebe Heenan
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Rob H. Creemers
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Shriya Sharma
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Jacqueline Keenan
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | - Simone Bayer
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Wayne Young
- Food Nutrition and Health, Grasslands Research Centre, AgResearch, Palmerston North, New Zealand
- Riddet Institute, Massey University, Palmerston North, New Zealand
- High Value Nutrition Science Challenge, University of Newcastle, Newcastle, New South Wales, Australia
| | - Janine Cooney
- High Value Nutrition Science Challenge, University of Newcastle, Newcastle, New South Wales, Australia
- Massey University, Biological Chemistry & Bioactives Group and Food Innovation, Palmerston North, New Zealand
| | - Kelly Armstrong
- Food Nutrition and Health, Grasslands Research Centre, AgResearch, Palmerston North, New Zealand
| | - Karl Fraser
- Food Nutrition and Health, Grasslands Research Centre, AgResearch, Palmerston North, New Zealand
- Riddet Institute, Massey University, Palmerston North, New Zealand
- High Value Nutrition Science Challenge, University of Newcastle, Newcastle, New South Wales, Australia
| | - Paula M. Skidmore
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Nicholas J. Talley
- Plant & Food Research, Research and Innovation Division, Hamilton, New Zealand
| | - Nicole Roy
- Riddet Institute, Massey University, Palmerston North, New Zealand
- High Value Nutrition Science Challenge, University of Newcastle, Newcastle, New South Wales, Australia
- Department of Human Nutrition, University of Otago, Dunedin, New Zealand
| | - Richard B. Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand
- High Value Nutrition Science Challenge, University of Newcastle, Newcastle, New South Wales, Australia
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Caviglia GP, Tucci A, Pellicano R, Fagoonee S, Rosso C, Abate ML, Olivero A, Armandi A, Vanni E, Saracco GM, Bugianesi E, Astegiano M, Ribaldone DG. Clinical Response and Changes of Cytokines and Zonulin Levels in Patients with Diarrhoea-Predominant Irritable Bowel Syndrome Treated with Bifidobacterium Longum ES1 for 8 or 12 Weeks: A Preliminary Report. J Clin Med 2020; 9:2353. [PMID: 32717980 PMCID: PMC7464152 DOI: 10.3390/jcm9082353] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022] Open
Abstract
Bifidobacterium longum (B. longum) ES1 is a probiotic strain capable of modulating microbiome composition, anti-inflammatory activity and intestinal barrier function. We investigated the use of B. Longum ES1 in the treatment of patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). Sixteen patients were treated for 8 or 12 weeks with B. Longum ES1 (1 × 109 CFU/day). Serum zonulin and cytokines were measured at baseline (T0) and at the end of therapy (T1). Clinical response to therapy was assessed by IBS Severity Scoring System. Interleukin (IL)-6, IL-8, IL-12p70 and tumor necrosis factor (TNF) α levels decreased from T0 to T1, irrespective of treatment duration (p < 0.05), while zonulin levels diminished only in patients treated for 12 weeks (p = 0.036). Clinical response was observed in 5/16 patients (31%): 4/8 (50%) treated for 12 weeks and 1/8 (13%) treated for 8 weeks. Abdominal pain improved only in patients treated for 12 weeks (5/8 vs. 0/8, p = 0.025), while stool consistency improved regardless of therapy duration (p < 0.001). In conclusion, the results of this pilot study showed, in IBS-D patients treated for 12 weeks with B. longum ES1, a reduction in the levels of pro-inflammatory cytokines, and intestinal permeability as well as an improvement in gastrointestinal symptoms, but further studies including a placebo-control group are necessary to prove a causal link.
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Affiliation(s)
- Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (C.R.); (M.L.A.); (A.O.); (G.M.S.); (E.B.)
| | - Alessandra Tucci
- Unit of Gastroenterology, Città della Salute e della Scienza di Torino—Molinette Hospital, 10126 Turin, Italy; (A.T.); (R.P.); (A.A.); (E.V.); (M.A.)
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Città della Salute e della Scienza di Torino—Molinette Hospital, 10126 Turin, Italy; (A.T.); (R.P.); (A.A.); (E.V.); (M.A.)
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, CNR c/o Molecular Biotechnology Centre, 10126 Turin, Italy;
| | - Chiara Rosso
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (C.R.); (M.L.A.); (A.O.); (G.M.S.); (E.B.)
| | - Maria Lorena Abate
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (C.R.); (M.L.A.); (A.O.); (G.M.S.); (E.B.)
| | - Antonella Olivero
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (C.R.); (M.L.A.); (A.O.); (G.M.S.); (E.B.)
| | - Angelo Armandi
- Unit of Gastroenterology, Città della Salute e della Scienza di Torino—Molinette Hospital, 10126 Turin, Italy; (A.T.); (R.P.); (A.A.); (E.V.); (M.A.)
| | - Ester Vanni
- Unit of Gastroenterology, Città della Salute e della Scienza di Torino—Molinette Hospital, 10126 Turin, Italy; (A.T.); (R.P.); (A.A.); (E.V.); (M.A.)
| | - Giorgio Maria Saracco
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (C.R.); (M.L.A.); (A.O.); (G.M.S.); (E.B.)
| | - Elisabetta Bugianesi
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (C.R.); (M.L.A.); (A.O.); (G.M.S.); (E.B.)
| | - Marco Astegiano
- Unit of Gastroenterology, Città della Salute e della Scienza di Torino—Molinette Hospital, 10126 Turin, Italy; (A.T.); (R.P.); (A.A.); (E.V.); (M.A.)
| | - Davide Giuseppe Ribaldone
- Department of Medical Sciences, University of Turin, 10124 Turin, Italy; (C.R.); (M.L.A.); (A.O.); (G.M.S.); (E.B.)
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Shulman RJ, Devaraj S, Heitkemper M. Gut permeability is affected by sex and increased in children with irritable bowel syndrome but not in functional abdominal pain. Neurogastroenterol Motil 2020; 32:e13765. [PMID: 31820520 PMCID: PMC7050934 DOI: 10.1111/nmo.13765] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/28/2019] [Accepted: 10/30/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Gut permeability is increased in some children and adults with irritable bowel syndrome (IBS). We investigated whether this also is true for children with functional abdominal pain (FAP). We also determined whether sex affected permeability results. METHODS Sucrose, lactulose, mannitol, and sucralose were ingested after an overnight fast in well-phenotyped children with IBS (n = 95), FAP (n = 25), and healthy controls (HC) (n = 60). Urine was collected for 24 hours. Percent sucrose recovery was calculated based on the 0- to 3-hour collection; lactulose/mannitol ratio both on the 0- to 3-hour and 0- to 24-hour collections; and percent sucralose recovery on the 0- to 24-hours collection. KEY RESULTS Age was similar among the groups (P = .26). The lactulose/mannitol ratio was increased in IBS compared with HC at 0-3 and 0-24 hours (P = .023, P = .05, respectively). Percent sucralose recovery was greater in FAP than in HC (P = .045). No differences were noted among the groups in percent sucrose recovery. Taking sex into account, percent sucrose recovery was greater in girls with IBS vs HC girls (P = .008). The lactulose/mannitol ratio was greater in boys with IBS compared with HC boys at both time points (both P = .02). Percent sucralose recovery was greater in boys with IBS than in FAP or HC (both P < .001). CONCLUSIONS AND INFERENCES Sex is a critically important factor when measuring gut permeability. Boys with IBS have increased lactulose/mannitol ratios and percent sucralose recovery. Girls with IBS have increased percent recovery of sucrose. Children with FAP do not demonstrate abnormal gut 0permeability even taking sex into account.
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Affiliation(s)
- Robert J. Shulman
- Department of Pediatrics, Baylor College of Medicine, Houston, TX,Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX,Texas Children’s Hospital, Baylor College of Medicine, Houston, TX
| | - Sridevi Devaraj
- Texas Children’s Hospital, Baylor College of Medicine, Houston, TX,Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX
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McOmber M, Rafati D, Cain K, Devaraj S, Weidler EM, Heitkemper M, Shulman RJ. Increased Gut Permeability in First-degree Relatives of Children with Irritable Bowel Syndrome or Functional Abdominal Pain. Clin Gastroenterol Hepatol 2020; 18:375-384.e1. [PMID: 31100459 PMCID: PMC6854304 DOI: 10.1016/j.cgh.2019.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 04/30/2019] [Accepted: 05/06/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Increased gut permeability might contribute to the pathogenesis of irritable bowel syndrome or functional abdominal pain (IBS or FAP). We investigated whether siblings and parents of children with IBS or FAP have increased gut permeability. METHODS We performed permeability tests (using sucrose, lactulose, mannitol, and sucralose) on 29 siblings and 43 parents of children with IBS or FAP, and 43 children (controls) and 42 parents of controls, from primary and secondary care. Permeability studies were repeated in 7 siblings and 37 parents of children with IBS or FAP and 23 controls and 36 parents of controls following ingestion of 400 mg of ibuprofen. Percent recovery of sucrose was calculated based on analyses of urine collected overnight; the lactulose/mannitol ratio and percent recovery of sucralose were based on analyses of urine samples collected over a 24-hour period. RESULTS When we controlled for age, sex, and family membership, siblings of children with IBS or FAP had increased small bowel permeability (urinary lactulose/mannitol ratio) vs controls (P = .004). There was no difference in gastroduodenal (percent sucrose recovery) or colonic (percent sucralose recovery) permeability between groups. Similarly, parents of children with IBS or FAP also had increased small bowel permeability, compared with parents of controls (P = .015), with no differences in gastric or colonic permeability. After administration of ibuprofen, gastroduodenal and small bowel permeability tended to be greater in IBS or FAP siblings (P = .08) and gastroduodenal permeability tended to be greater in IBS or FAP parents (P = .086). CONCLUSIONS Siblings and parents of children with IBS or FAP have increased baseline small intestinal permeability compared with control children and their parents. These results indicate that there are familial influences on gastrointestinal permeability in patients with IBS or FAP.
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Affiliation(s)
- Mark McOmber
- Department of Pediatrics, Phoenix Children's Hospital, Phoenix, Arizona
| | - Danny Rafati
- Cook Children's Health Care System, Fort Worth, Texas
| | - Kevin Cain
- University of Washington, Seattle, Washington
| | - Sridevi Devaraj
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Erica M Weidler
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas; Children's Nutrition Research Center, Houston, Texas
| | | | - Robert J Shulman
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas; Children's Nutrition Research Center, Houston, Texas.
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Kemppinen A, Howell C, Allgar V, Dodd M, Gregson J, Knowles C, McLaughlin J, Pandya P, Whorwell P, Markaryan E, Yiannakou Y. Randomised, double-blind, placebo controlled multi-centre study to assess the efficacy, tolerability and safety of Enterosgel® in the treatment of irritable bowel syndrome with diarrhoea (IBS-D) in adults. Trials 2020; 21:122. [PMID: 32000822 PMCID: PMC6993329 DOI: 10.1186/s13063-020-4069-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 01/13/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) with diarrhoea (IBS-D) is a common and chronic condition that can significantly impair quality of life. The emergence of new drugs for IBS-D has been slow and there is a need for new treatments, including drug-free treatments, which are easy to use and suitable for different patient groups. Currently available drug-free treatments include Enterosgel®, an intestinal adsorbent approved for use in IBS-D and acute diarrhoea and available over-the-counter in the UK and 30 countries worldwide. The aim of this randomised, double-blind, placebo-controlled, multi-centre study is to test the efficacy and safety of Enterosgel® compared to placebo in symptomatic treatment in IBS-D. METHODS/DESIGN We will recruit 430 participants with IBS-D from approximately 30 primary and secondary care sites in England. Participants meeting the required abdominal pain and stool consistency criteria over a 2-week screening period will be randomly allocated to receive blinded treatment (Enterosgel® or placebo) for 8 weeks. This will be followed by an 8-week open-label treatment phase with Enterosgel®. Participants will be allowed to adjust their daily dosage during both phases based on their symptoms. Participants will then return to standard care and those who responded to treatment will receive a follow-up call 8 weeks later. Co-medication with loperamide will be permitted and use recorded. The primary outcome measure is the percentage of participants defined as responders for abdominal pain and stool consistency during at least 4 weeks in the 8-week blinded phase. Secondary outcome measures include stool frequency, stool consistency, abdominal pain, bloating, urgency, adequate relief, questionnaire scores and rescue medication use. Exploratory outcomes will be assessed in subsets of participants including qualitative and quantitative data on faecal microorganisms and biomarkers and gut-related measurements from magnetic resonance imaging data. DISCUSSION This is the first large scale randomised controlled trial investigating Enterosgel® in IBS-D. A study design with blinded phase followed by an open-label phase was chosen to encourage participation and study completion. Demonstrating that Enterosgel® is effective and safe in IBS-D could encourage adoption by patients and healthcare professionals and foster future clinical trials assessing its use in related conditions. TRIAL REGISTRATION ISRCTN17149988. Prospectively registered on 14 November 2017.
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Affiliation(s)
| | | | | | - Matthew Dodd
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | - John Gregson
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | | | - John McLaughlin
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Salford Royal NHS Foundation Trust, Salford, UK
| | | | - Peter Whorwell
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Centre for Gastrointestinal Sciences, University of Manchester, Manchester, UK
| | | | - Yan Yiannakou
- County Durham and Darlington NHS Foundation Trust, University Hospital of North Durham, Durham, UK
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Hou Q, Huang Y, Zhu Z, Liao L, Chen X, Han Q, Liu F. Tong-Xie-Yao-Fang improves intestinal permeability in diarrhoea-predominant irritable bowel syndrome rats by inhibiting the NF-κB and notch signalling pathways. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:337. [PMID: 31775739 PMCID: PMC6882330 DOI: 10.1186/s12906-019-2749-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/08/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Tong-Xie-Yao-Fang (TXYF) has been shown to be effective in diarrhoea-predominant irritable bowel syndrome (IBS-D) patients. However, the underlying mechanism remains to be clarified. The aim of this study was to investigate the efficacy and related mechanisms of TXYF in an IBS-D rat model. METHODS The IBS-D rat model was established with 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. Then, IBS-D rats were divided into control, TXYF and rifaximin groups and treated intragastrically with normal saline, TXYF and rifaximin, respectively, for 14 days. The following indicators were measured before and after treatment: defecation frequency, faecal water content (FWC) and colorectal distension (CRD). Histopathological changes in the distal colon were observed after treatment. The expression of OCLN and ZO1 in the distal colon of IBS-D rats reflected the intestinal mucosal permeability, as measured by qRT-PCR, western blot, and enzyme-linked immunosorbent assays (ELISAs). The NF-κB and Notch signalling pathways and inflammation-related factors were investigated. RESULTS After treatment with TXYF, the defecation frequency, FWC and CRD were significantly lower than those in the model group (P < 0.05). HE staining showed that colonic epithelial cells (CECs) in the IBS-D rats displayed significant oedema, impaired intestinal mucosal integrity and an increased influx of inflammatory cells. A significant reduction in granulocyte and CEC oedema was observed after the administration of TXYF and rifaximin compared to that of the model group and blank group (P < 0.05). TXYF significantly upregulated the expression of OCLN and ZO-1 and downregulated inflammation-related factors (IL-6, IL-1β, and TNF-α and the chemokine KC) in IBS-D rats compared to those in the model group rats (P < 0.05). In terms of the NF-κB and Notch signalling pathways, the expression of NICD, p-ERK, Hes-1 and p-P65 decreased significantly in the TXYF and rifaximin groups, while the expression of ATOH1 increased significantly compared to that in the model group (P < 0.05). CONCLUSION TXYF can effectively improve intestinal permeability and enhance intestinal mucosal barrier function, which may be related to inhibition of the inflammatory cascade and the NF-κB and Notch signalling pathways.
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Affiliation(s)
- Qiuke Hou
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yongquan Huang
- Department of Orthopaedics, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhaoyang Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Liu Liao
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Xinlin Chen
- Department of Preventive Medicine and Health Statistics, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Quanbin Han
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Fengbin Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.
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Feng L, Chen S, Zhang L, Qu W, Chen Z. Bisphenol A increases intestinal permeability through disrupting intestinal barrier function in mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2019; 254:112960. [PMID: 31394344 DOI: 10.1016/j.envpol.2019.112960] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/20/2019] [Accepted: 07/25/2019] [Indexed: 05/28/2023]
Abstract
That an alteration of the intestinal permeability is associated with gut barrier function has been increasingly evident, which plays an important role in human and animal health. Bisphenol A (BPA), an industrial compound used worldwide, has recently been classified as an environmental pollutant. One of our earlier studies has demonstrated that BPA disrupts the intestinal barrier function by inducing apoptosis and inhibiting cell proliferation in the human colonic epithelial cells line. In this study, we investigated the effects of dietary BPA uptake on the colonic barrier function in mice, as well as the intestinal permeability. Dietary BPA uptake was observed to destroy the morphology of the colonic epithelium and increase the pathology score. The levels of endotoxin, diamine peroxidase, D-lactate, and zonulin were found to have been significantly elevated in both plasma and colonic mucosa. A decline in the number of intestinal goblet cells and in mucin 2 gene expression was observed in the mice belonging to the BPA group. The results of immunohistochemistry revealed that the expression of tight junction proteins (ZO-1, occludin, and claudin-1) in colonic epithelium of BPA mice decreased significantly, and their gene abundance was also inhibited. Moreover, dietary BPA uptake was also found to have significantly reduced colonic microbial diversity and altered microbial structural composition. The functional profiles of colonic bacterial community exhibited adverse effects of dietary BPA intake on the endocrine and digestive systems, as well as the transport and catabolism functions. Collectively, our study highlighted that dietary BPA increased the colonic permeability, and this effect was closely related to the disruption of intestinal chemistry and physical and biological barrier functions.
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Affiliation(s)
- Ling Feng
- Jiangyin Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangyin 214400, Jiangsu, China.
| | - Sijin Chen
- Department of Pharmacy, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, People's Republic of China.
| | - Lijin Zhang
- Department of Urinary Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, People's Republic of China.
| | - Wei Qu
- Department of Pharmacy, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, People's Republic of China.
| | - Zhigao Chen
- Department of Pharmacy, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, Jiangsu 214400, People's Republic of China.
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Wang L, Alammar N, Singh R, Nanavati J, Song Y, Chaudhary R, Mullin GE. Gut Microbial Dysbiosis in the Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Case-Control Studies. J Acad Nutr Diet 2019; 120:565-586. [PMID: 31473156 DOI: 10.1016/j.jand.2019.05.015] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 05/16/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is the most common functional digestive condition in the industrialized world. The gut microbiota plays a key role in disease pathogenesis. OBJECTIVE A systematic review and meta-analysis on case-control studies was conducted to determine whether there is gut microbial dysbiosis in participants with IBS in comparison with healthy controls and, if so, whether the dysbiosis pattern differs among IBS subtypes and geographic regions. METHODS This review was conducted and reported according to the MOOSE (Meta-Analysis of Observational Studies in Epidemiology) 2000 and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2009 guidelines. Research articles published up to May 9, 2018 were identified through MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (Cochrane Library), ClinicalTrials.gov, EMBASE, and Web of Science. Study quality was assessed using the Newcastle-Ottawa Scale. Case-control studies of participants with IBS who had undergone quantitative gut microbial stool analysis were included. The primary exposure measure of interest is log10 bacterial counts per gram of stool. Meta-analyses were performed to estimate the mean difference (MD) in gut microbiota between participants with IBS and healthy controls using the random-effects model with inverse variance in Revman 5.3 and R 3.5.1. Publication bias was assessed with funnel plots and Egger's test. Between-study heterogeneity was analyzed using Higgins I2 statistic with 95% CIs. RESULTS There were 6,333 unique articles identified; 52 qualified for full-text screening. Of these, 23 studies were included for analysis (n=1,340 participants from North America, Europe, and Asia). Overall, the studies were moderate in quality. Comparing participants with IBS to healthy controls, lower fecal Lactobacillus (MD= -0.57 log10 colony-forming unit [CFU]/g; P<0.01) and Bifidobacterium (MD= -1.04 log10CFU/g; P<0.01), higher Escherichia coli (MD=0.60 log10CFU/g; P<0.01), and marginally higher Enterobacter (MD=0.74 log10CFU/g; P=0.05). No difference was found between participants with IBS and healthy controls in fecal Bacteroides and Enterococcus (P=0.18 and 0.68, respectively). Publication bias was not observed except in Bifidobacterium (P=0.015). Subgroup analyses on participants with diarrhea-predominant and constipation-predominant IBS showed consistent results with the primary results. A subgroup analysis of Chinese studies was consistent with the primary results, except for fecal Bacteroides, which was increased in participants with IBS vs healthy controls (MD=0.29; 95% CI 0.13 to 0.46; P<0.01). Although substantial heterogeneity was detected (I2>75%) in most comparisons, the direction of the effect estimates is relatively consistent across studies. CONCLUSIONS IBS is characterized by gut microbial dysbiosis. Prospective, large-scale studies are needed to delineate how gut microbial profiles can be used to guide targeted therapies in this challenging patient population.
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Vergnolle N, Cirillo C. Neurons and Glia in the Enteric Nervous System and Epithelial Barrier Function. Physiology (Bethesda) 2019; 33:269-280. [PMID: 29897300 DOI: 10.1152/physiol.00009.2018] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The intestinal epithelial barrier is the largest exchange surface between the body and the external environment. Its functions are regulated by luminal, and also internal, components including the enteric nervous system. This review summarizes current knowledge about the role of the digestive "neuronal-glial-epithelial unit" on epithelial barrier function.
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Affiliation(s)
- Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse , France.,Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary , Calgary, Alberta , Canada
| | - Carla Cirillo
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse , France.,Laboratory for Enteric Neuroscience, TARGID, University of Leuven , Leuven , Belgium
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36
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Sharkey KA, Beck PL, McKay DM. Neuroimmunophysiology of the gut: advances and emerging concepts focusing on the epithelium. Nat Rev Gastroenterol Hepatol 2018; 15:765-784. [PMID: 30069036 DOI: 10.1038/s41575-018-0051-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The epithelial lining of the gastrointestinal tract serves as the interface for digestion and absorption of nutrients and water and as a defensive barrier. The defensive functions of the intestinal epithelium are remarkable considering that the gut lumen is home to trillions of resident bacteria, fungi and protozoa (collectively, the intestinal microbiota) that must be prevented from translocation across the epithelial barrier. Imbalances in the relationship between the intestinal microbiota and the host lead to the manifestation of diseases that range from disorders of motility and sensation (IBS) and intestinal inflammation (IBD) to behavioural and metabolic disorders, including autism and obesity. The latest discoveries shed light on the sophisticated intracellular, intercellular and interkingdom signalling mechanisms of host defence that involve epithelial and enteroendocrine cells, the enteric nervous system and the immune system. Together, they maintain homeostasis by integrating luminal signals, including those derived from the microbiota, to regulate the physiology of the gastrointestinal tract in health and disease. Therapeutic strategies are being developed that target these signalling systems to improve the resilience of the gut and treat the symptoms of gastrointestinal disease.
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Affiliation(s)
- Keith A Sharkey
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. .,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada. .,Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada. .,Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.
| | - Paul L Beck
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada.,Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada.,Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada.,Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Derek M McKay
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada.,Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
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Linsalata M, Riezzo G, D'Attoma B, Clemente C, Orlando A, Russo F. Noninvasive biomarkers of gut barrier function identify two subtypes of patients suffering from diarrhoea predominant-IBS: a case-control study. BMC Gastroenterol 2018; 18:167. [PMID: 30400824 PMCID: PMC6219148 DOI: 10.1186/s12876-018-0888-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 10/17/2018] [Indexed: 12/19/2022] Open
Abstract
Background Alterations of the small-intestinal permeability (s-IP) might play an essential role in both diarrhoea-predominant IBS (D-IBS) and celiac disease (CD) patients. Our aims were to analyse in D-IBS patients the symptom profile along with the levels of urinary sucrose (Su), lactulose (La), mannitol (Ma), and circulating biomarkers (zonulin, intestinal fatty acid binding protein - I-FABP, and diamine oxidase - DAO) of the gastrointestinal (GI) barrier function. The pro-inflammatory interleukins 6 and 8 (IL-6 and IL-8), the plasma values of lipopolysaccharide (LPS), and Toll-like receptor 4 (TLR-4) were also investigated. Besides, these biomarkers were compared with those in CD and healthy controls (HC). Finally, comparisons were performed between D-IBS patients with [D-IBS(+)] and without [D-IBS(−)] increased s-IP according to normal or altered La/Ma ratio. Methods The study included 39 D-IBS patients, 32 CD patients, and 20 HC. GI permeability was assayed by high-performance liquid chromatography determination in the urine of Su and La/Ma ratio. ELISA kits assayed circulating concentrations of zonulin, I-FABP, DAO, IL-6, IL-8, LPS, and TLR-4. The Mann–Whitney or the Kruskal–Wallis with Dunn’s post-test was used to assess differences among the groups. Results As for the La/Ma ratio, %Su, and I-FABP levels, D-IBS patients were significantly different from CD, but not HC. IL-6 levels were significantly higher in CD than HC, whereas IL-8 levels were significantly higher in both D-IBS and CD patients than HC. By opposite, LPS, and TLR-4 concentrations did not differ significantly among the groups. When D-IBS patients were categorised according to normal or altered s-IP, D-IBS(+) patients had %La, %Su, I-FABP, and DAO levels significantly higher than D-IBS(−) ones. The inflammatory parameters and markers of bacterial translocation (namely, IL-6 and LPS) were significantly higher in D-IBS(+) patients than D-IBS(−) ones. Conclusions The present study suggests that two distinct D-IBS subtypes could be identified. The investigation of possible s-IP alterations (i.e., considering the La/Ma ratio) might be useful to assess better and categorise this heterogeneous D-IBS population. Trial registration NCT01574209. Registered March 2012. First recruitment started in April 2012.
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Affiliation(s)
- Michele Linsalata
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Via Turi 27, I-70013 Castellana Grotte, Bari, Italy
| | - Giuseppe Riezzo
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Via Turi 27, I-70013 Castellana Grotte, Bari, Italy
| | - Benedetta D'Attoma
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Via Turi 27, I-70013 Castellana Grotte, Bari, Italy
| | - Caterina Clemente
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Via Turi 27, I-70013 Castellana Grotte, Bari, Italy
| | - Antonella Orlando
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Via Turi 27, I-70013 Castellana Grotte, Bari, Italy
| | - Francesco Russo
- Laboratory of Nutritional Pathophysiology, National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Via Turi 27, I-70013 Castellana Grotte, Bari, Italy.
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38
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Lin MJ, Yu BP. Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome. J Neurogastroenterol Motil 2018; 24:643-655. [PMID: 30347940 PMCID: PMC6175564 DOI: 10.5056/jnm18040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 07/13/2018] [Accepted: 07/31/2018] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Irritable bowel syndrome (IBS) is a common disease characterized by intestinal dysmotility, the mechanism of which remains elusive. We aim to determine whether the high-affinity choline transporter 1 (CHT1), a determinant of cholinergic signaling capacity, modulates intestinal motility associated with stress-induced IBS. Methods A rat IBS model was established using chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically and intestinal motility was assessed by intestinal transit time and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response to colorectal distension. RT-PCR, western blotting, and immunostaining were performed to identify colonic CHT1 expression. Contractility of colonic muscle strips was measured using isometric transducers. enzyme-linked immunosorbent assay was used to measure acetylcholine (ACh). We examined the effects of MKC-231, a choline uptake enhancer, on colonic motility. Results After 10 days of WAS, intestinal transit time was decreased and fecal water content increased. Visceromotor response magnitude in WAS rats in response to colorectal distension was significantly enhanced. Protein and mRNA CHT1 levels in the colon were markedly elevated after WAS. The density of CHT1-positive intramuscular interstitial cells of Cajal and myenteric plexus neurons in WAS rats was higher than in controls. Ammonium pyrrolidine dithiocarbamate partly reversed CHT1 upregulation and alleviated colonic hypermotility in WAS rats. Pharmacological enhancement of CHT1 activity by MKC-231 enhanced colonic motility in control rats via upregulation of CHT1 and elevation of ACh production. Conclusion Upregulation of CHT1 in intramuscular interstitial cells of Cajal and myenteric plexus neurons is implicated in chronic stress-induced colonic hypermotility by modulation of ACh synthesis via nuclear factor-kappa B signaling.
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Affiliation(s)
- Meng-Juan Lin
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei, China
| | - Bao-Ping Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei, China
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Zhu S, Min L, Guo Q, Li H, Yu Y, Zong Y, Wang L, Li P, Gu J, Zhang S. Transcriptome and methylome profiling in a rat model of irritable bowel syndrome induced by stress. Int J Mol Med 2018; 42:2641-2649. [PMID: 30106160 PMCID: PMC6192760 DOI: 10.3892/ijmm.2018.3823] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 08/09/2018] [Indexed: 12/13/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is associated with psychological stress. However, the full landscape of IBS-related epigenetic factors remains unveiled and needs to be elucidated. The water-avoidance stress (WAS) method was used to induce a rat IBS model. Each rat was monitored, and its defecation and behavior were recorded. Total colon RNA was isolated and subjected to Affymetrix GeneChip analysis. Reduced Representation Bisulfate Sequencing (RRBS) was applied to determine the genome-wide methylation pattern in both IBS and control rats. Rats with IBS egested a significantly increased amount of dry and loose stools compared with the control animals, without significant changes in body weight. Compared with the control group, 309 genes were upregulated and 224 genes were downregulated in the colon of the IBS rats. Notch signaling and focal adhesion were increased in the differentially expressed genes (DEGs). A total of 541 genes had significant lower methylation level and 626 genes had significantly higher methylation level in their promoter regions. Adherens junction and leukocyte transendothelial migration were enriched in the differentially methylated genes (DMGs). Few genes were identified in common in both DEGs and DMGs, suggesting that gene expression was not altered by promoter methylation. Reverse transcription-quantitative polymerase chain reaction validation revealed that the mRNA levels of SSX2IP, PARD3 and VCL were significantly downregulated in the IBS group, in accordance with hypermethylation of their promoters. In summary, the present study used a WAS-induced IBS rat model to provide transcriptome and methylome profiling. Most DEGs were associated with Notch signaling and focal adhesion, and only a few were altered by promoter methylation. The present results demonstrated that psychological stress could influence the integrity of the intestinal mucosa barrier and regulate inflammatory response.
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Affiliation(s)
- Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Qingdong Guo
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Hengcun Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Yang Yu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Ye Zong
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Liyong Wang
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100050, P.R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Junchao Gu
- Beijing Tropical Medicine Research Institute, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
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40
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Abstract
Approximately one-sixth of the worlds' population is infected with helminths and this class of parasite takes a major toll on domestic livestock. The majority of species of parasitic helminth that infect mammals live in the gut (the only niche for tapeworms) where they contact the hosts' epithelial cells. Here, the helminth-intestinal epithelial interface is reviewed in terms of the impact on, and regulation of epithelial barrier function, both intrinsic (epithelial permeability) and extrinsic (mucin, bacterial peptides, commensal bacteria) elements of the barrier. The data available on direct effects of helminths on epithelial permeability are scant, fragmentary and pales in comparison with knowledge of mobilization of immune reactions and effector cells in response to helminth parasites and how these impact intestinal barrier function. The interaction of helminth-host and helminth-host-bacteria is an important determinant of gut form and function and precisely defining these interactions will radically alter our understanding of normal gut physiology and pathophysiological reactions, revealing new approaches to infection with parasitic helminths, bacterial pathogens and idiopathic auto-inflammatory disease.
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Affiliation(s)
- Derek M McKay
- a Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology , Snyder Institute of Chronic Disease, Cumming School of Medicine, University of Calgary , Calgary , Alberta , Canada
| | - Adam Shute
- a Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology , Snyder Institute of Chronic Disease, Cumming School of Medicine, University of Calgary , Calgary , Alberta , Canada
| | - Fernando Lopes
- a Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology , Snyder Institute of Chronic Disease, Cumming School of Medicine, University of Calgary , Calgary , Alberta , Canada
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41
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Henriksen M, Høivik ML, Jelsness-Jørgensen LP, Moum B. Irritable Bowel-like Symptoms in Ulcerative Colitis are as Common in Patients in Deep Remission as in Inflammation: Results From a Population-based Study [the IBSEN Study]. J Crohns Colitis 2018; 12:389-393. [PMID: 29186372 DOI: 10.1093/ecco-jcc/jjx152] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 11/26/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS An increased prevalence of irritable bowel syndrome [IBS]-like symptoms has been reported in patients with ulcerative colitis [UC]. Whether ongoing inflammation increases the prevalence of such symptoms is unknown. The aims of this study were to determine the prevalence of IBS-like symptoms in a population-based cohort of UC patients 20 years after diagnosis, and to assess the possible association between such symptoms and ongoing inflammation. METHODS Patients diagnosed with UC between 1990 and 1994, in a geographically well-defined area, were included in a prospective follow-up study, and IBS symptoms according to Rome III criteria were recorded 20 years after diagnosis. The patients underwent colonoscopy with biopsies and/or the level of faecal calprotectin was analysed. RESULTS A total of 260 patients answered the Rome III questionnaire. The overall prevalence of IBS-like symptoms was 27%. In patients who had no signs of inflammation in colonic biopsies [n = 96] [deep remission], the prevalence was 29%. No difference in prevalence of IBS-like symptoms was found between patients with ongoing inflammation and patients in deep remission. CONCLUSIONS IBS-like symptoms in UC patients are frequent after 20 years of disease. Deep remission did not change the frequency of IBS-like symptoms.
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Affiliation(s)
- Magne Henriksen
- Østfold Hospital Trust, Department of Gastroenterology, Grålum, Norway
| | - Marte Lie Høivik
- Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
| | - Lars-Petter Jelsness-Jørgensen
- Østfold Hospital Trust, Department of Gastroenterology, Grålum, Norway.,Østfold University College, Department of Health Science, Halden, Norway
| | - Bjørn Moum
- Department of Gastroenterology, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Mroz MS, Lajczak NK, Goggins BJ, Keely S, Keely SJ. The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing. Am J Physiol Gastrointest Liver Physiol 2018; 314:G378-G387. [PMID: 29351391 DOI: 10.1152/ajpgi.00435.2016] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T84 cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl- channels, whereas inhibition of CFTR activity with either CFTR-inh-172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes wound healing, suggesting it may provide an alternative approach to prevent the losses of barrier function that are associated with mucosal inflammation in IBD patients.
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Affiliation(s)
- Magdalena S Mroz
- Department of Molecular Medicine, Royal College of Surgeons in Ireland , Dublin , Ireland
| | - Natalia K Lajczak
- Department of Molecular Medicine, Royal College of Surgeons in Ireland , Dublin , Ireland
| | - Bridie J Goggins
- School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, and Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Simon Keely
- School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, and Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
| | - Stephen J Keely
- Department of Molecular Medicine, Royal College of Surgeons in Ireland , Dublin , Ireland
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Boyer J, Saint-Paul MC, Dadone B, Patouraux S, Vivinus MH, Ouvrier D, Michiels JF, Piche T, Tulic MK. Inflammatory cell distribution in colon mucosa as a new tool for diagnosis of irritable bowel syndrome: A promising pilot study. Neurogastroenterol Motil 2018; 30. [PMID: 28975689 DOI: 10.1111/nmo.13223] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 09/07/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Currently, there are no histological criteria to diagnose irritable bowel syndrome (IBS). Our aims were (i) to examine the distribution of inflammatory cells in the colon of healthy and IBS subjects and (ii) to find histological diagnosis criteria for IBS. METHODS Colonic biopsies were taken from four distinct regions of the colon from 20 controls (HC) and 11 patients with IBS (4 with constipation (IBS-C) and 7 with diarrhea (IBS-D) and embedded in paraffin. Macrophages, mast cells, eosinophils, and T lymphocytes were immunostained and positive cells counted. KEY RESULTS In both HC and IBS patients, global cellularity decreased from the cecum to the rectum (P < .01) which is attributed to reduced number of macrophages (P < .05) and eosinophils (P < .001) but not T cells. Mast cells were reduced in IBS (P < .05) but not in HC, particularly in IBS-D (P < .05). Results showed higher number of macrophages in the left colon of IBS subjects than HC (P < .05). CONCLUSION & INFERENCES Here we report a decreasing gradient of immune cells from the cecum to the rectum of the human colon. Although global cellularity cannot be used to distinguish between IBS and HC, closer analysis of macrophages and mast cells may be useful markers to confirm IBS histologically and to differentiate between IBS-C and IBS-D when clinical presentation alternates between constipation and diarrhoea. This pilot study remains to be confirmed with greater number of patients.
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Affiliation(s)
- J Boyer
- Laboratoire d'anatomopathologie (LCAP) CHU de Nice Hôpital Pasteur, Nice, France
| | - M-C Saint-Paul
- Laboratoire d'anatomopathologie (LCAP) CHU de Nice Hôpital Pasteur, Nice, France
| | - B Dadone
- Laboratoire d'anatomopathologie (LCAP) CHU de Nice Hôpital Pasteur, Nice, France
| | - S Patouraux
- Laboratoire d'anatomopathologie (LCAP) CHU de Nice Hôpital Pasteur, Nice, France
| | - M-H Vivinus
- Laboratoire d'Immunologie CHU de Nice Hôpital de l'Archet 1, Nice, France
| | - D Ouvrier
- Service de Gastroentérologie, CHU de Nice, Hôpital de l'Archet 2, Nice, France
| | - J-F Michiels
- Laboratoire d'anatomopathologie (LCAP) CHU de Nice Hôpital Pasteur, Nice, France
| | - T Piche
- Service de Gastroentérologie, CHU de Nice, Hôpital de l'Archet 2, Nice, France
| | - M K Tulic
- Centre Méditerranéen de Médecine Moléculaire (C3M Team 12), INSERM U1065, Nice, France
- International Inflammation Network (in-FLAME) of the World Universities Network
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Katsumata R, Shiotani A, Murao T, Ishii M, Fujita M, Matsumoto H, Haruma K. Gender Differences in Serotonin Signaling in Patients with Diarrhea-predominant Irritable Bowel Syndrome. Intern Med 2017; 56:993-999. [PMID: 28458330 PMCID: PMC5478557 DOI: 10.2169/internalmedicine.56.7674] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 09/01/2016] [Indexed: 12/12/2022] Open
Abstract
Objective Gender differences, including differences in the prevalence, subtypes and the effectiveness of treatment, are generally recognized in irritable bowel syndrome (IBS). Although serotonin type 3 receptor (5-HT3R) antagonists appear to be more effective in women with diarrhea predominant IBS (IBS-D) than they are in men, the mechanisms underlying these effects remain unclear. The aim of the present was to investigate the gender differences in 5-HT signaling. Methods The subjects were selected from outpatients with IBS-D and healthy controls. Their rectal mucosal S100A, tryptophan hydroxylase (TPH) and 5-HT transporter (5-HTT, SERT, SLC6A4) mRNA expression levels were measured. Clinical symptoms were evaluated using the gastrointestinal symptom rating scale (GSRS) and the self-rating depression scale (SDS). Results The study population of 100 subjects included 47 IBS-D patients and 53 age- and gender-matched healthy controls. The S100A9 (5.20 vs. 1.90, p=0.001) and SLC6A4 (2.00 vs. 1.00, p=0.019) mRNA levels in the rectal mucosa of women with IBS-D were significantly higher than those in men. Among the healthy controls, the S100A10 expression levels in men were higher than those in women (1.33 vs. 0.82, p=0.005). The S100A8 and S100A10 expression levels in women with IBS-D were positively correlated with their diarrhea scores (r=0.55 and 0.58, p<0.05). Conclusion 5-HT signaling might be a major contributor to the symptoms of IBS in men, and the differences may be associated with the effectiveness of 5-HT3R antagonists.
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Affiliation(s)
- Ryo Katsumata
- Division of Gastroenterology, Department of Internal medicine, Kawasaki Medical School, Japan
| | - Akiko Shiotani
- Division of Gastroenterology, Department of Internal medicine, Kawasaki Medical School, Japan
| | - Takahisa Murao
- Division of Gastroenterology, Department of Internal medicine, Kawasaki Medical School, Japan
| | - Manabu Ishii
- Division of Gastroenterology, Department of Internal medicine, Kawasaki Medical School, Japan
| | - Minoru Fujita
- Division of Gastroenterology, Department of Internal medicine, Kawasaki Medical School, Japan
| | - Hiroshi Matsumoto
- Division of Gastroenterology, Department of Internal medicine, Kawasaki Medical School, Japan
| | - Ken Haruma
- Department of General Internal medicine 2, Kawasaki Medical School, Japan
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Undseth R, Berstad A, Valeur J. Systemic symptoms in irritable bowel syndrome: An investigative study on the role of enterocyte disintegrity, endotoxemia and inflammation. Mol Med Rep 2016; 14:5072-5076. [PMID: 27779674 PMCID: PMC5355706 DOI: 10.3892/mmr.2016.5878] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 08/30/2016] [Indexed: 12/13/2022] Open
Abstract
Irritable bowel syndrome (IBS) is often accompanied by extra-intestinal symptoms, including fatigue and musculoskeletal pain. The present study aimed to investigate whether these symptoms were associated with markers of enterocyte disintegrity, endotoxemia and inflammation. Patients with IBS were recruited consecutively from our outpatient clinic (n=94) and compared with a group of healthy controls (n=20). Habitual symptoms were assessed using the IBS Severity Scoring System, the Fatigue Impact Scale and Visual Analogue Scales for measuring musculoskeletal pain. A lactulose challenge test was performed to induce post-prandial symptoms, and blood samples were obtained prior to and 90 min following lactulose ingestion to determine levels of intestinal fatty acid binding protein (iFABP), lipopolysaccharide (LPS), the LPS co-receptor soluble cluster of differentiation (sCD) 14, monocyte chemoattractant protein-1 (MCP-1) and calprotectin. Habitual symptom scores were high among the included patients, and lactulose ingestion induced significantly more symptoms in the patient group compared with the healthy control group (P=0.0001). Serum levels of iFABP were reduced in IBS patients compared with healthy controls, prior to and following lactulose ingestion (P=0.0002 and P=0.0001, respectively). Following lactulose ingestion, iFABP levels decreased in IBS patients (P=0.0001) and in healthy controls (P=0.02). Fasting levels of LPS, sCD14, MCP-1 and calprotectin were not significantly different between IBS patients and healthy controls. However, following lactulose ingestion, LPS levels increased in healthy controls (P=0.03), whereas MCP-1 levels decreased in IBS patients (P=0.008). Intestinal and extra-intestinal symptom severities were not correlated with levels of circulating biomarkers. No assessed biomarker in the present study appeared to be associated with symptom development in IBS patients. However, the implications of the low levels of iFABP observed require further investigation.
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Affiliation(s)
- Ragnhild Undseth
- Department of Radiology, Lovisenberg Diaconal Hospital, NO‑0440 Oslo, Norway
| | - Arnold Berstad
- Unger‑Vetlesen Institute, Lovisenberg Diaconal Hospital, NO‑0440 Oslo, Norway
| | - Jørgen Valeur
- Unger‑Vetlesen Institute, Lovisenberg Diaconal Hospital, NO‑0440 Oslo, Norway
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