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Kim MJ, Lee YJ, Hussain Z, Park H. Effect of Probiotics on Improving Intestinal Mucosal Permeability and Inflammation after Surgery. Gut Liver 2025; 19:207-218. [PMID: 39327843 PMCID: PMC11907258 DOI: 10.5009/gnl240170] [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: 04/18/2024] [Revised: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 09/28/2024] Open
Abstract
Background/Aims We explored the mechanisms underlying the improvement of postoperative ileus (POI) following probiotic pretreatment. We assessed intestinal permeability, inflammation, tight junction (TJ) protein expression in the gut epithelium, and plasma interleukin (IL)-17 levels in a guinea pig model of POI. Methods Guinea pigs were divided into control, POI, and probiotic groups. The POI and probiotic groups underwent surgery, but the probiotic group received probiotics before the procedure. The ileum and proximal colon were harvested. Intestinal permeability was measured via horseradish peroxidase permeability. Inflammation was evaluated via leukocyte count in the intestinal wall muscle layer, and calprotectin expression in each intestinal wall layer was analyzed immunohistochemically. TJ proteins were analyzed using immunohistochemical staining, and plasma IL-17 levels were measured using an enzyme-linked immunosorbent assay. Results The POI group exhibited increased intestinal permeability and inflammation, whereas probiotic pretreatment reduced the extent of these POI-induced changes. Probiotics restored the expression of TJ proteins occludin and zonula occludens-1 in the proximal colon, which were increased in the POI group. Calprotectin expression significantly increased in the muscle layer of the POI group and was downregulated in the probiotic group; however, no distinct differences were observed between the mucosal and submucosal layers. Plasma IL-17 levels did not significantly differ among the groups. Conclusions Probiotic pretreatment may relieve POI by reducing intestinal permeability and inflammation and TJ protein expression in the gut epithelium. These findings suggest a potential therapeutic approach for POI management.
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Affiliation(s)
- Min-Jae Kim
- Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Ju Lee
- Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Zahid Hussain
- Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyojin Park
- Division of Gastroenterology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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2
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Ihara E, Manabe N, Ohkubo H, Ogasawara N, Ogino H, Kakimoto K, Kanazawa M, Kawahara H, Kusano C, Kuribayashi S, Sawada A, Takagi T, Takano S, Tomita T, Noake T, Hojo M, Hokari R, Masaoka T, Machida T, Misawa N, Mishima Y, Yajima H, Yamamoto S, Yamawaki H, Abe T, Araki Y, Kasugai K, Kamiya T, Torii A, Nakajima A, Nakada K, Fukudo S, Fujiwara Y, Miwa H, Kataoka H, Nagahara A, Higuchi K. Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023. Digestion 2024; 105:480-497. [PMID: 39197422 PMCID: PMC11633876 DOI: 10.1159/000541121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/22/2024] [Indexed: 09/01/2024]
Abstract
The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and anti-diarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogs, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide.
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Affiliation(s)
- Eikichi Ihara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noriaki Manabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hidenori Ohkubo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Naotaka Ogasawara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Haruei Ogino
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kazuki Kakimoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Motoyori Kanazawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hidejiro Kawahara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Chika Kusano
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shiko Kuribayashi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akinari Sawada
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tomohisa Takagi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shota Takano
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Toshihiko Tomita
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Toshihiro Noake
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Mariko Hojo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Ryota Hokari
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tatsuhiro Masaoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tomohiko Machida
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Noboru Misawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yoshiyuki Mishima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroshi Yajima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Sayuri Yamamoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroshi Yamawaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Tatsuya Abe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yasumi Araki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kunio Kasugai
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Takeshi Kamiya
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akira Torii
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Atsushi Nakajima
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Koji Nakada
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Shin Fukudo
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Yasuhiro Fujiwara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Hiromi Kataoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Akihito Nagahara
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
| | - Kazuhide Higuchi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Guidelines for Chronic Diarrhea 2023”, The Japanese Gastroenterological Association, Bunkyo-ku, Japan
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Mosgoeller W, Muss C, Eisenwagen S, Jagsch R, Vogelsang H. PMA - Zeolite (Clinoptilolite) in the Management of Irritable Bowel Syndrome - a Non-Interventional Study. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:379-387. [PMID: 38224685 PMCID: PMC10914565 DOI: 10.1055/a-2223-3963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/27/2023] [Indexed: 01/17/2024]
Abstract
In clinical practice, the treatment of patients with irritable bowel syndrome (IBS) can be very challenging. The aims of the present non-interventional study (NIS) were to investigate the tolerability and efficacy of PMA-zeolite under everyday conditions in patients with diarrheic IBS type (IBS-D) or constipated type (IBS-C) or mixed type (IBS-M). METHODS To document prospective data on tolerability and symptom frequency in the frame of a nationwide NIS, we recruited 204 IBS patients. The study focused on the IBS-related quality of life (measured by the SF-36 questionnaire) and improvements of IBS-related symptoms according to specific ROM-III criteria and stool consistency (Bristol stool scale). The participants documented their abdominal pain, bloating, number of bowel movements, and stool consistency through a web-based internet platform (initial and exit questionnaires) and daily diary entries over the period of intake (8 weeks). RESULTS A total of 82.2% of the recruited patients had filled in the questionnaires before and after the 8-week treatment with PMA-zeolite. Seven of the eight subscales of the SF-36 improved significantly (p<0,001); the reduction in abdominal pain was especially significant (p<0,001). The diary entries confirmed the reduction in abdominal pain and revealed a significant reduction in days with bloating (p<0,001). The Bristol-stool-scale analysis showed improvements; particularly, patients with IBS-D benefited from the treatment (p<0,001). CONCLUSION The treatment duration of 8 weeks was well tolerated by most patients. Under everyday life conditions, PMA-zeolite alleviated the global IBS-related symptoms and raised the quality of life (QOL). The PMA-zeolite, thus, may represent a good adjuvant therapeutic option for patients with irritable bowel syndrome.
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Affiliation(s)
- Wilhelm Mosgoeller
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Claus Muss
- St. Elisabeth University, Bratislava, Slovakia
| | - Sandra Eisenwagen
- Research, Panaceo International GmbH, Villach/Gödersdorf, Austria, Villach, Austria
| | - Reinhold Jagsch
- Department of Clinical and Health Psychology, University of Vienna, Vienna, Austria
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Elsasser TH, Faulkenberg S. Physiology of Gut Water Balance and Pathomechanics of Diarrhea. PRODUCTION DISEASES IN FARM ANIMALS 2024:179-209. [DOI: 10.1007/978-3-031-51788-4_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Korsten SGPJ, Vromans H, Garssen J, Willemsen LEM. Butyrate Protects Barrier Integrity and Suppresses Immune Activation in a Caco-2/PBMC Co-Culture Model While HDAC Inhibition Mimics Butyrate in Restoring Cytokine-Induced Barrier Disruption. Nutrients 2023; 15:2760. [PMID: 37375664 DOI: 10.3390/nu15122760] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Low-grade inflammation and barrier disruption are increasingly acknowledged for their association with non-communicable diseases (NCDs). Short chain fatty acids (SCFAs), especially butyrate, could be a potential treatment because of their combined anti-inflammatory and barrier- protective capacities, but more insight into their mechanism of action is needed. In the present study, non-activated, lipopolysaccharide-activated and αCD3/CD28-activated peripheral blood mononuclear cells (PBMCs) with and without intestinal epithelial cells (IEC) Caco-2 were used to study the effect of butyrate on barrier function, cytokine release and immune cell phenotype. A Caco-2 model was used to compare the capacities of butyrate, propionate and acetate and study their mechanism of action, while investigating the contribution of lipoxygenase (LOX), cyclooxygenase (COX) and histone deacetylase (HDAC) inhibition. Butyrate protected against inflammatory-induced barrier disruption while modulating inflammatory cytokine release by activated PBMCs (interleukin-1 beta↑, tumor necrosis factor alpha↓, interleukin-17a↓, interferon gamma↓, interleukin-10↓) and immune cell phenotype (regulatory T-cells↓, T helper 17 cells↓, T helper 1 cells↓) in the PBMC/Caco-2 co-culture model. Similar suppression of immune activation was shown in absence of IEC. Butyrate, propionate and acetate reduced inflammatory cytokine-induced IEC activation and, in particular, butyrate was capable of fully protecting against cytokine-induced epithelial permeability for a prolonged period. Different HDAC inhibitors could mimic this barrier-protective effect, showing HDAC might be involved in the mechanism of action of butyrate, whereas LOX and COX did not show involvement. These results show the importance of sufficient butyrate levels to maintain intestinal homeostasis.
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Affiliation(s)
- Sandra G P J Korsten
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Tiofarma B.V., 3261 ME Oud-Beijerland, The Netherlands
| | - Herman Vromans
- Tiofarma B.V., 3261 ME Oud-Beijerland, The Netherlands
- Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Danone/Nutricia Research B.V., 3584 CT Utrecht, The Netherlands
| | - Linette E M Willemsen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
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6
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Liu S, Huang Q, Huang Q, Wang Y, Li S, Wang J, Wu Q. The protective effects of electroacupuncture on intestinal barrier lesions in IBS and UC model. Sci Rep 2023; 13:7276. [PMID: 37142764 PMCID: PMC10160055 DOI: 10.1038/s41598-023-34182-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 04/25/2023] [Indexed: 05/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) and ulcerative colitis (UC) are two intestinal diseases with different pathological changes. Electroacupuncture (EA) at Zusanli (ST36) on both IBS and UC is widely used in clinic practice. But it is unclear whether acupuncture at one acupoint can treat two different intestinal diseases at different layers of intestinal barrier. To address this question, we explored three intestinal barrier lesions in IBS and UC mice with the aid of transcriptome data analysis and studied the efficacy of EA at ST36 on them. The transcriptome data analysis showed that both UC and IBS had disrupted intestinal barrier in various layers. And both UC and IBS had epithelial barrier lesions with reduction of ZO-1, Occludin and Claudin-1, while UC rather than IBS had the destruction of the mucus barrier with less MUC2 expression. As to the vascular barrier, UC showed a higher CD31 level and mesenteric blood flow reduction, while IBS showed a lower PV-1 level. EA at ST36 can significantly improve the above lesions of intestinal barrier of IBS and UC. Our results gave more details about the comprehensive protective effect of EA for UC and IBS. We guess the effect of acupuncture may be a kind of homeostasis regulation.
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Affiliation(s)
- Shuqing Liu
- Acupuncture and Moxibustion School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, People's Republic of China
| | - Qin Huang
- Acupuncture and Moxibustion School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, People's Republic of China
| | - Qianhui Huang
- Acupuncture and Moxibustion School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, People's Republic of China
| | - Yuemei Wang
- Acupuncture and Moxibustion School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, People's Republic of China
| | - Sihui Li
- Acupuncture and Moxibustion School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, People's Republic of China
| | - Junmeng Wang
- Acupuncture and Moxibustion School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, People's Republic of China
| | - Qiaofeng Wu
- Acupuncture and Moxibustion School, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, Sichuan, People's Republic of China.
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Marchix J, Quénéhervé L, Bordron P, Aubert P, Durand T, Oullier T, Blondeau C, Ait Abdellah S, Bruley des Varannes S, Chaffron S, Coron E, Neunlist M. Could the Microbiota Be a Predictive Factor for the Clinical Response to Probiotic Supplementation in IBS-D? A Cohort Study. Microorganisms 2023; 11:277. [PMID: 36838241 PMCID: PMC9964083 DOI: 10.3390/microorganisms11020277] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/16/2023] [Accepted: 01/16/2023] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Increasing evidence suggests the beneficial effects of probiotics in irritable bowel syndrome (IBS), but little is known about how they can impact the gut microbiota. Our objective was to evaluate the effects of a multistrain probiotic on IBS symptoms, gut permeability and gut microbiota in patients with diarrhoea-predominant IBS (IBS-D). METHODS Adults with IBS-D were enrolled in an open-label trial to receive a multistrain probiotic for 4 weeks. Abdominal pain, stool frequency, quality of life, gut permeability, and the luminal and adherent microbiota from colonic biopsies were evaluated before and after supplementation. RESULTS Probiotics significantly improved symptoms and quality of life, despite having no impact on permeability in the global population. In the population stratified by the response, the diarrhoea responders displayed reduced colonic permeability after supplementation. The luminal and adherent microbiota were specifically altered depending on the patients' clinical responses regarding pain and diarrhoea. Interestingly, we identified a microbial signature in IBS-D patients that could predict a response or lack of response to supplementation. CONCLUSIONS The multistrain probiotic improved the symptoms of IBS-D patients and induced distinct effects on the gut microbiota according to the patient's clinical response and initial microbiota composition. Our study further supports the need to develop individualised probiotic-based approaches regarding IBS.
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Affiliation(s)
- Justine Marchix
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
| | - Lucille Quénéhervé
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
- Gastroenterology Department, University Hospital of Brest, 29200 Brest, France
| | - Philippe Bordron
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
| | - Philippe Aubert
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
| | - Tony Durand
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
| | - Thibauld Oullier
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
| | - Claude Blondeau
- PiLeJe Laboratoire, 31-35 rue de la Fédération, 75015 Paris, France
| | | | - Stanislas Bruley des Varannes
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
- Nantes Université, CHU Nantes, INSERM, Département de Gastroentérologie, CIC 1413, IMAD, F-44000 Nantes, France
| | - Samuel Chaffron
- Nantes Université, École Centrale Nantes, CNRS, LS2N, UMR 6004, F-44000 Nantes, France
| | - Emmanuel Coron
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
- Nantes Université, CHU Nantes, INSERM, Département de Gastroentérologie, CIC 1413, IMAD, F-44000 Nantes, France
- Gastroenterology and Hepatology Department, University Hospital of Geneva (HUG), 1211 Geneva, Switzerland
| | - Michel Neunlist
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Diseases, IMAD, F-44000 Nantes, France
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Li X, Ren K, Hong X, Guo S, Yu S, Yang S. Ameliorating effects of electroacupuncture on the low-grade intestinal inflammation in rat model of diarrhea-predominant irritable bowel syndrome. J Gastroenterol Hepatol 2022; 37:1963-1974. [PMID: 35959628 DOI: 10.1111/jgh.15981] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 07/06/2022] [Accepted: 08/09/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM We aim to investigate the effects and mechanisms of electroacupuncture (EA) at ST25 and ST37 on the intestinal low-grade inflammation (LGI) in rat model of Diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS IBS-D model rats were established by acetic acid enema combined with restraint and tail clamping. Before EA intervention, they were divided into three groups: blank 1 group, blank 2 group, and IBS-D model group. Diarrhea symptoms and visceral pain sensitivity were evaluated. After constructed the model successfully, the remaining IBS-D model group rats were randomly divided into model group and EA group. Local intestinal inflammation (HE staining), changes of intestinal mucosa (occludin protein and microvascular diameter) were evaluated. Differences between two groups were compared using t-test or Mann-Whitney U-test. Differences among more than two groups were compared using one-way ANOVA or Kruskal-Wallis test. RESULTS After modeling, the results of HE staining in intestinal tract of IBS-D model rats showed LGI. Compared with the model group, 4 h fecal moisture content (diarrhea index) and the AWR score were decreased in the EA group. The results of HE in EA group showed that the infiltration of intestinal inflammatory cells were alleviated. Additionally, EA significantly upregulated the expression of occludin protein and partially dilated the intestinal microvascular diameter. Pearson correlation analysis showed that the symptoms of IBS-D rats were correlated with the changes of intestinal mucosa. CONCLUSION EA may treat intestinal LGI in IBS-D rats by upregulating the expression of occludin protein and dilating the intestinal microvascular diameter.
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Affiliation(s)
- Xuemei Li
- Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kuiyu Ren
- Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaojuan Hong
- Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China
| | - Sha Guo
- Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuguang Yu
- Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China
| | - Sha Yang
- Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China
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9
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Ait Abdellah S, Gal C, Laterza L, Velenza V, Settanni CR, Napoli M, Schiavoni E, Mora V, Petito V, Gasbarrini A. Effect of a Multistrain Probiotic on Leaky Gut in Patients with Diarrhea-Predominant Irritable Bowel Syndrome: A Pilot Study. Dig Dis 2022; 41:489-499. [PMID: 36007493 PMCID: PMC10906476 DOI: 10.1159/000526712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 08/12/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND A probiotic mixture prevented epithelial barrier impairment in various experimental models. The objective was to evaluate its effects in patients suffering from IBS with diarrhea (IBS-D) with confirmed leaky gut. METHODS IBS-D patients with increased intestinal permeability measured by radionuclide tracers were enrolled in this pilot, open-label, prospective, interventional, single-center, Phase IV study. Patients received two capsules of a multistrain probiotic a day for 30 days and were evaluated by repeated intestinal permeability tests, the Bristol Stool Scale, and patient-perceived quality of life and satisfaction. RESULTS Of the 30 enrolled patients (mean age: 42.1 [SD: 13.1] years; female: 60%), 27 completed the study (full analysis set [FAS]), and 18 had no major protocol violation (per protocol set [PPS]). On D30, an improvement of intestinal permeability was observed in 81.5% of patients in FAS, normalization being observed in 37% of the participants (44% in PPS). The mean intestinal permeability was significantly decreased: baseline minus D30, 3.4 (95% CI: 1.7, 5.2); the IBS-QOL total score was significantly increased: D30 minus baseline, 8.0 (95% CI: 3.0, 12.9); and stool consistency was significantly improved. On D15 and D30, 96.3% of patients claimed that their IBS symptoms had been satisfactory alleviated, and a significant improvement was reported for the following VAS-IBS items: abdominal pain, diarrhea, and impact of gastrointestinal problems in daily life. Compliance and tolerance were satisfactory. CONCLUSION The multistrain probiotic tested may reduce intestinal permeability in a considerable proportion of patients and may improve abdominal pain, stool consistency, and quality of life. These results pave the way for larger, placebo-controlled clinical studies.
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Affiliation(s)
| | | | - Lucrezia Laterza
- CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Venanzio Velenza
- Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Carlo Romano Settanni
- CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Marco Napoli
- CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Elisa Schiavoni
- CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Vincenzina Mora
- CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Valentina Petito
- CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Antonio Gasbarrini
- CEMAD, Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
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10
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Arjomand Fard N, Armstrong H, Perry T, Wine E. Appendix and Ulcerative Colitis: a Key to Explaining the Pathogenesis and Directing Novel Therapies? Inflamm Bowel Dis 2022; 29:151-160. [PMID: 35749298 PMCID: PMC9825289 DOI: 10.1093/ibd/izac106] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Indexed: 02/05/2023]
Abstract
The vermiform appendix is generally considered a redundant organ, but recent evidence suggests that the appendix could contribute to the pathogenesis of inflammatory bowel diseases, in particular ulcerative colitis (UC), and may even have a therapeutic role; however, mechanisms of the appendix involvement remain unclear. Here, we highlight current evidence on the link between the appendix and UC and consider plausible therapeutic implications. A literature search was conducted using PubMed and PubMed Central from inception to Nov 2021 using the terms "Appendix", "UC", "Appendix & UC," "Appendectomy", and "Peri-appendicular patch," including only articles published in English. Reference lists from the selected studies were manually searched and reviewed to gather additional related reports. Inflammation around the appendix ("peri-appendicular patch") has been frequently observed in UC patients without other cecal involvement, and this inflammation can even precede the onset of UC. Epidemiologic studies propose that appendectomy reduces the risk of developing UC or even the risk of flare after UC is diagnosed, although this remains controversial. We reviewed studies showing altered host-microbe interactions in the appendix in UC, which suggest that the appendix could act as a priming site for disease via alterations in the immune response and changes in microbiota carried distally to the colon. In summary, recent literature suggests a possible role for microbes and immune cells within the appendix; however, the role of the appendix in the pathogenesis of UC remains unclear. Further research could clarify the therapeutic potential related to this organ.
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Affiliation(s)
- Nazanin Arjomand Fard
- Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, T6G 2X8, Canada,Department of Physiology, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Heather Armstrong
- Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, T6G 2X8, Canada,Department of Pediatrics, University of Alberta, Edmonton Clinic Health Academy, Room 4-577, 11405 87th Ave, Edmonton, AB T6G 1C9, Canada,Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Troy Perry
- Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, T6G 2X8, Canada,Department of Surgery, University of Alberta, Edmonton, AB T6G 1C9, Canada
| | - Eytan Wine
- Address correspondence to: Dr. Eytan Wine, Department of Pediatrics, University of Alberta, Edmonton Clinic Health Academy, Room 4-577, 11405 87th Ave, Edmonton, AB T6G 1C9, Canada ()
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11
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Preventing Bacterial Translocation in Patients with Leaky Gut Syndrome: Nutrition and Pharmacological Treatment Options. Int J Mol Sci 2022; 23:ijms23063204. [PMID: 35328624 PMCID: PMC8949204 DOI: 10.3390/ijms23063204] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/14/2022] [Accepted: 03/14/2022] [Indexed: 12/11/2022] Open
Abstract
Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation.
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12
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Ojo BA, VanDussen KL, Rosen MJ. The Promise of Patient-Derived Colon Organoids to Model Ulcerative Colitis. Inflamm Bowel Dis 2022; 28:299-308. [PMID: 34251431 PMCID: PMC8804507 DOI: 10.1093/ibd/izab161] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Indexed: 12/11/2022]
Abstract
Physiologic, molecular, and genetic findings all point to impaired intestinal epithelial function as a key element in the multifactorial pathogenesis of ulcerative colitis (UC). The lack of epithelial-directed therapies is a conspicuous weakness of our UC therapeutic armamentarium. However, a critical barrier to new drug discovery is the lack of preclinical human models of UC. Patient tissue-derived colon epithelial organoids (colonoids) are primary epithelial stem cell-derived in vitro structures capable of self-organization and self-renewal that hold great promise as a human preclinical model for UC drug development. Several single and multi-tissue systems for colonoid culture have been developed, including 3-dimensional colonoids grown in a gelatinous extracellular matrix, 2-dimensional polarized monolayers, and colonoids on a chip that model luminal and blood flow and nutrient delivery. A small number of pioneering studies suggest that colonoids derived from UC patients retain some disease-related transcriptional and epigenetic changes, but they also raise questions regarding the persistence of inflammatory transcriptional programs in culture over time. Additional research is needed to fully characterize the extent to which and under what conditions colonoids accurately model disease-associated epithelial molecular and functional aberrations. With further advancement and standardization of colonoid culture methodology, colonoids will likely become an important tool for realizing precision medicine in UC.
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Affiliation(s)
- Babajide A Ojo
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
| | - Kelli L VanDussen
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Michael J Rosen
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
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13
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Grover M, Berumen A, Peters S, Wei T, Breen-Lyles M, Harmsen WS, Busciglio I, Burton D, Vazquez Roque M, DeVault KR, Camilleri M, Wallace M, Dasari S, Neumann H, Houghton LA. Intestinal chemosensitivity in irritable bowel syndrome associates with small intestinal TRPV channel expression. Aliment Pharmacol Ther 2021; 54:1179-1192. [PMID: 34472640 DOI: 10.1111/apt.16591] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/26/2021] [Accepted: 08/17/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) patients often experience meal-associated symptoms. However, the underlying mechanisms are unclear. AIM To determine small intestinal mechanisms of lipid-induced symptoms and rectal hypersensitivity in IBS METHODS: We recruited 26 IBS patients (12 IBS-C, 14 IBS-D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe-based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics. RESULTS Following lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS-C and IBS-D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Post-lipid, pCLE scores were higher than pre-lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS-D, and TRPV3 in IBS-C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = -0.48, FDR = 0.01) and pain (r = -0.41, FDR = 0.02) thresholds. CONCLUSION Lipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPV-mediated small intestinal chemosensitivity may mediate post-meal symptoms in IBS.
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Affiliation(s)
- Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Antonio Berumen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Stephanie Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ting Wei
- Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Margaret Breen-Lyles
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - William S Harmsen
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Irene Busciglio
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Duane Burton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Maria Vazquez Roque
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Kenneth R DeVault
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Wallace
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Surendra Dasari
- Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Helmut Neumann
- Department of Medicine I, University Medical Center Mainz, Mainz, Germany.,GastroZentrum Lippe, Bad Salzuflen, Germany
| | - Lesley A Houghton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA.,Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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Kimono DA. Gastrointestinal problems, mechanisms and possible therapeutic directions in Gulf war illness: a mini review. Mil Med Res 2021; 8:50. [PMID: 34503577 PMCID: PMC8431926 DOI: 10.1186/s40779-021-00341-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 08/19/2021] [Indexed: 11/25/2022] Open
Abstract
By its nature, Gulf war illness (GWI) is multisymptomatic and affects several organ systems in the body. Along with other symptoms, veterans who suffer from GWI commonly report chronic gastrointestinal issues such as constipation, pain, indigestion, etc. However, until recently, most attention has been focused on neurological disturbances such as cognitive impairments, chronic fatigue, and chronic pain among affected veterans. With such high prevalence of gastrointestinal problems among Gulf war (GW) veterans, it is surprising that there is little research to investigate the mechanisms behind these issues. This review summarizes all the available works on the mechanisms behind gastrointestinal problems in GWI that have been published to date in various databases. Generally, these studies, which were done in rodent models, in vitro and human cohorts propose that an altered microbiome, a reactive enteric nervous system or a leaky gut among other possible mechanisms are the major drivers of gastrointestinal problems reported in GWI. This review aims to draw attention to the gastrointestinal tract as an important player in GWI disease pathology and a potential therapeutic target.
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15
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Meira de-Faria F, Bednarska O, Ström M, Söderholm JD, Walter SA, Keita ÅV. Colonic paracellular permeability and circulating zonulin-related proteins. Scand J Gastroenterol 2021; 56:424-431. [PMID: 33535002 DOI: 10.1080/00365521.2021.1879247] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/14/2021] [Accepted: 01/16/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Irritable bowel syndrome (IBS) is a gut-brain disorder associated with increased gut permeability. Zonulin has been suggested to regulate the gut barrier and claimed to be pre-haptoglobin 2 (pre-HP2) and circulating zonulin is often used as a proxy for gastrointestinal permeability. This study investigated the correlation between colonic paracellular permeability and levels of circulating zonulin and pre-HP2. MATERIALS AND METHODS Colonic biopsies from 32 patients with IBS and 15 healthy controls (HC) were used to measure permeability in Ussing chambers and levels of zonulin (Cusabio ELISA). Zonulin was also measured in blood samples from 40 HC, 78 patients with IBS and 20 patients with celiac disease (CeD), before and after a gluten-free diet. In addition, we verified HP genotype and circulating pre-HP2 using a monoclonal pre-HP2 antibody (Bio-Rad) by ELISA. RESULTS Increased colonic paracellular permeability correlated positively with zonulin levels in IBS biopsies, but negatively with plasma zonulin. We found no agreement between circulating zonulin and pre-HP2. Genotyping revealed non-specificity of the zonulin kit, as all pre-HP2 non-producers presented detectable levels. Patients with CeD displayed higher pre-HP2 and zonulin levels compared to HC. A gluten-free diet in patients with CeD led to lower serum zonulin and pre-HP2 concentrations. CONCLUSIONS Our study suggests that neither circulating zonulin nor pre-HP2 mirror colonic permeability. Our data corroborate previous reports showing the inability of the Cusabio zonulin kit to target zonulin and highlights that the results of studies using this kit must be re-examined with caution.
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Affiliation(s)
- Felipe Meira de-Faria
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Olga Bednarska
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Gastroenterology, Linköping University, Linköping, Sweden
| | - Magnus Ström
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Gastroenterology, Linköping University, Linköping, Sweden
| | - Johan D Söderholm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Linköping University, Linköping, Sweden
| | - Susanna A Walter
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Gastroenterology, Linköping University, Linköping, Sweden
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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16
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The Functional Properties of Lactobacillus casei HY2782 Are Affected by the Fermentation Time. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11062481] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Maintaining probiotic effectiveness represents the most important task for the development of functional foods. Gastrointestinal stability and intestinal adhesion properties comprise one criterion for probiotic selection. Here, we investigated the benefits of milk fermented with Lactobacillus casei HY2782 at different fermentation times. The probiotic strain used was L. casei HY2782 and the reference strain was L. casei ATCC393 for comparisons. The samples were fermented for 7 days at 30 °C. We determined the pH, CFU/mL, survival rate during simulated gastrointestinal digestion, adhesion ability to HT-29 cells, and gene expression of tight-junction proteins known to regulate intestinal permeability in Caco-2 cells. L. casei HY2782 exhibited significantly higher survival rates in simulated gastrointestinal digestion during long-term fermentation than L. casei ATCC393. The adhesion ability to HT-29 cells was significantly increased with L. casei HY2782 (3.3% to 8.7%) after 7 days of fermentation; however, only a slight increase was observed for L. casei ATCC393 (3.1% to 4.7%). In addition, L. casei HY2782 can significantly increase the expression of genes encoding tight-junction proteins during long-term fermentation of milk. In conclusion, we confirmed that long-term fermentation could be a novel manufacturing process for fermented milk containing L. casei HY2782 and showed the beneficial effects.
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Hanning N, Edwinson AL, Ceuleers H, Peters SA, De Man JG, Hassett LC, De Winter BY, Grover M. Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review. Therap Adv Gastroenterol 2021; 14:1756284821993586. [PMID: 33717210 PMCID: PMC7925957 DOI: 10.1177/1756284821993586] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 01/19/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIM Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life. METHODS A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both in vivo and in vitro studies were considered. RESULTS We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17-50%), IBS-D (37-62%) and IBS-C (4-25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies). CONCLUSIONS Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.
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Affiliation(s)
- Nikita Hanning
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | - Adam L. Edwinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Hannah Ceuleers
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | - Stephanie A. Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Joris G. De Man
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | | | - Benedicte Y. De Winter
- Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, Universiteitsplein 1, Antwerp, 2610, Belgium
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium
| | - Madhusudan Grover
- Department of Medicine and Physiology, Enteric NeuroScience Program, 200 First St SW, Rochester, MN 55905, USA
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Muehler A, Slizgi JR, Kohlhof H, Groeppel M, Peelen E, Vitt D. Clinical relevance of intestinal barrier dysfunction in common gastrointestinal diseases. World J Gastrointest Pathophysiol 2020; 11:114-130. [PMID: 33362939 PMCID: PMC7739114 DOI: 10.4291/wjgp.v11.i6.114] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/07/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023] Open
Abstract
The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall. In this review, we focus on the intestinal barrier’s relationship with the host’s immune system interaction and the external environment, specifically the microbiome. The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens, luminal antigens, or other pro-inflammatory factors. Control over barrier function and the luminal milieu is maintained at the biochemical, cellular, and immunological level. However, disruption to this highly regulated environment can cause disease. Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology. There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences. The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases. This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.
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Ford AC, Sperber AD, Corsetti M, Camilleri M. Irritable bowel syndrome. Lancet 2020; 396:1675-1688. [PMID: 33049223 DOI: 10.1016/s0140-6736(20)31548-8] [Citation(s) in RCA: 438] [Impact Index Per Article: 87.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 06/26/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome is a functional gastrointestinal disorder with symptoms including abdominal pain associated with a change in stool form or frequency. The condition affects between 5% and 10% of otherwise healthy individuals at any one point in time and, in most people, runs a relapsing and remitting course. The best described risk factor is acute enteric infection, but irritable bowel syndrome is also more common in people with psychological comorbidity and in young adult women than in the rest of the general population. The pathophysiology of irritable bowel syndrome is incompletely understood, but it is well established that there is disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and altered CNS processing. Other less reproducible mechanisms might include genetic associations, alterations in gastrointestinal microbiota, and disturbances in mucosal and immune function. In most people, diagnosis can be made on the basis of clinical history with limited and judicious use of investigations, unless alarm symptoms such as weight loss or rectal bleeding are present, or there is a family history of inflammatory bowel disease or coeliac disease. Once the diagnosis is made, an empathetic approach is key and can improve quality of life and symptoms, and reduce health-care expenditure. The mainstays of treatment include patient education about the condition, dietary changes, soluble fibre, and antispasmodic drugs. Other treatments tend to be reserved for people with severe symptoms and include central neuromodulators, intestinal secretagogues, drugs acting on opioid or 5-HT receptors, or minimally absorbed antibiotics (all of which are selected according to predominant bowel habit), as well as psychological therapies. Increased understanding of the pathophysiology of irritable bowel syndrome in the past 10 years has led to a healthy pipeline of novel drugs in development.
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Affiliation(s)
- Alexander C Ford
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK.
| | - Ami D Sperber
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Maura Corsetti
- National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN, USA
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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: 27] [Impact Index Per Article: 5.4] [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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Ouabbou S, He Y, Butler K, Tsuang M. Inflammation in Mental Disorders: Is the Microbiota the Missing Link? Neurosci Bull 2020; 36:1071-1084. [PMID: 32592144 PMCID: PMC7475155 DOI: 10.1007/s12264-020-00535-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 03/18/2020] [Indexed: 01/15/2023] Open
Abstract
Research suggests that inflammation is important in the pathophysiology of mental disorders. In addition, a growing body of evidence has led to the concept of the microbiota-gut-brain axis. To understand the potential interactions, we begin by exploring the liaison between the immune system and mental disorders, then we describe the evidence that the microbiota impact the immune response in the developing brain. Next, we review the literature that has documented microbiome alterations in major mental disorders. We end with a summary of therapeutic applications, ranging from psycho-biotics to immunomodulatory drugs that could affect the microbiota-gut-brain axis, and potential treatments to alleviate the adverse effects of antipsychotics. We conclude that there is promising evidence to support the position that the microbiota plays an important role in the immunological pathophysiology of mental disorders with an emphasis on psychotic disorders and mood disorders. However, more research is needed to elucidate the mechanisms.
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Affiliation(s)
- Sophie Ouabbou
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, and Hunan Key Laboratory of Psychiatry and Mental Health, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, 00290, Helsinki, Finland
- Cellular and Molecular Biology Research Centre, University of Costa Rica, San José, 11501, Costa Rica
| | - Ying He
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, and Hunan Key Laboratory of Psychiatry and Mental Health, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
- Center for Behavioral Genomics, Department of Psychiatry, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
| | - Keith Butler
- Center for Behavioral Genomics, Department of Psychiatry, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Ming Tsuang
- Center for Behavioral Genomics, Department of Psychiatry, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard School of Public Health, Boston, MA, 02115, USA
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22
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Katinios G, Casado-Bedmar M, Walter SA, Vicario M, González-Castro AM, Bednarska O, Söderholm JD, Hjortswang H, Keita ÅV. Increased Colonic Epithelial Permeability and Mucosal Eosinophilia in Ulcerative Colitis in Remission Compared With Irritable Bowel Syndrome and Health. Inflamm Bowel Dis 2020; 26:974-984. [PMID: 31944236 PMCID: PMC7301402 DOI: 10.1093/ibd/izz328] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Barrier dysfunction is recognized as a pathogenic factor in ulcerative colitis (UC) and irritable bowel syndrome (IBS), but it is unclear to what extent the factors related to barrier dysfunction are disease-specific. The aim of this study was to compare these aspects in UC patients in remission, IBS patients, and healthy controls (HCs). METHODS Colonic biopsies were collected from 13 patients with UC in remission, 15 patients with IBS-mixed, and 15 HCs. Ulcerative colitis patients had recently been treated for relapse, and biopsies were taken from earlier inflamed areas. Biopsies were mounted in Ussing chambers for measurements of intestinal paracellular permeability to 51chromium (Cr)-ethylenediaminetetraacetic acid (EDTA). In addition, biopsies were analyzed for mast cells and eosinophils by histological procedures, and plasma tumor necrosis factor (TNF)-α was assessed by ELISA. RESULTS Ussing chamber experiments revealed an increased 51Cr-EDTA permeability in UC and IBS (P < 0.05). The 51Cr-EDTA permeability was higher in UC compared with IBS (P < 0.005). There were increased numbers of mucosal mast cells and eosinophils in UC and IBS and more eosinophils in UC compared with IBS (P < 0.05). Also, increased extracellular granule content was found in UC compared with HCs (P < 0.05). The 51Cr-EDTA permeability correlated significantly with eosinophils in all groups. Plasma TNF-α concentration was higher in UC compared with IBS and HCs (P < 0.0005). CONCLUSIONS Results indicate a more permeable intestinal epithelium in inactive UC and IBS compared with HCs. Ulcerative colitis patients, even during remission, demonstrate a leakier barrier compared with IBS. Both eosinophil numbers and activation state might be involved in the increased barrier function seen in UC patients in remission.
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Affiliation(s)
- Georgios Katinios
- Department of Gastroenterology, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Maite Casado-Bedmar
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Susanna A Walter
- Department of Gastroenterology, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Maria Vicario
- Laboratory of Translational Mucosal Immunology, Digestive Diseases Research Unit. Vall d’Hebron Institut de Recerca, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ana M González-Castro
- Laboratory of Translational Mucosal Immunology, Digestive Diseases Research Unit. Vall d’Hebron Institut de Recerca, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Olga Bednarska
- Department of Gastroenterology, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Johan D Söderholm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Linköping, Linköping University,Sweden
| | - Henrik Hjortswang
- Department of Gastroenterology, Linköping University, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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23
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Shaikh MF, Lee CY, Chen WN, Shaikh FA. The Gut-Brain-Axis on the Manifestation of Depressive Symptoms in Epilepsy: An Evidence-Driven Hypothesis. Front Pharmacol 2020; 11:465. [PMID: 32322213 PMCID: PMC7156621 DOI: 10.3389/fphar.2020.00465] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/25/2020] [Indexed: 12/15/2022] Open
Abstract
Epilepsy is a severe neurological disorder involving 70 million people around the globe. Epilepsy-related neuropsychiatric comorbidities such as depression, which is the most common, is an additional factor that negatively impacts the living quality of epilepsy patients. There are many theories and complexities associated with both epilepsy and associated comorbidities, one of which is the gut-brain-axis influence. The gut microbiome is hypothesized to be linked with many neurological disorders; however, little conclusive evidence is available in this area. Thus, highlighting the role will create interest in researchers to conduct detailed research in comprehending the influence of gut-brain-axis in the manifestation of depressive symptoms in epilepsy. The hypothesis which is explored in this review is that the gut-brain-axis do play an important role in the genesis of epilepsy and associated depression. The correction of this dysbiosis might be beneficial in treating both epilepsy and related depression. This hypothesis is illustrated through extensive literature discussion, proposed experimental models, and its applicability in the field. There is indirect evidence which revealed some specific bacterial strains that might cause depression in epilepsy.
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Affiliation(s)
- Mohd Farooq Shaikh
- Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia.,Global Asia in 21st Century (GA21) Multidisciplinary Platform, Monash University Malaysia, Bandar Sunway, Malaysia.,Tropical Medicine & Biology Multidisciplinary Platform (TMB), Monash University Malaysia, Bandar Sunway, Malaysia
| | - Chooi Yeng Lee
- School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Win Ning Chen
- Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Faiz Ahmed Shaikh
- School of Pharmacy, Management and Science University, Shah Alam, Malaysia
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24
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Sheptulin AA, Vinogradskaya KE. Inflammatory Bowel Diseases and Irritable Bowel Syndrome: Overlap of Two Nosological Forms or Two Variants of the Same Disease? ACTA ACUST UNITED AC 2019. [DOI: 10.22416/1382-4376-2019-29-5-43-48] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Aim. To review available literature data on the relationship between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).Key findings. Current publications on IBD and IBS present different viewpoints on their relationship. Thus, researchers have noted a high incidence of IBD against the background of IBS, frequent persistence of IBS-like symptoms after achieving IBD remission, as well as the possibility of overlapping the diseases. According to literature data, IBD and IBS should be treated as different forms of the same disease. An opinion is expressed that IBS-like complaints in patients with IBD remission should be considered as a separate disease referred to as “irritated inflammatory intestinal syndrome”. Treatment of IBS-like symptoms in patients with IBD remission has thus far not been developed.Conclusion. The problem of the relationship between IBD and IBS is currently controversial, thus requiring further clarification.
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Affiliation(s)
- A. A. Sheptulin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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25
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Liu F, Lee SA, Riordan SM, Zhang L, Zhu L. Effects of Anti-Cytokine Antibodies on Gut Barrier Function. Mediators Inflamm 2019; 2019:7028253. [PMID: 31780866 PMCID: PMC6875247 DOI: 10.1155/2019/7028253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/10/2019] [Indexed: 12/14/2022] Open
Abstract
Anti-cytokine antibodies are used in treating chronic inflammatory diseases and autoimmune diseases such as inflammatory bowel disease and rheumatic diseases. Patients with these diseases often have a compromised gut barrier function, suggesting that anti-cytokine antibodies may contribute to the re-establishment of gut barrier integrity, in addition to their immunomodulatory effects. This paper reviews the effects of anti-cytokine antibodies on gut barrier function and their mechanisms.
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Affiliation(s)
- Fang Liu
- Department of General Surgery and Central Lab, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Seul A. Lee
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Stephen M. Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia
| | - Li Zhang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Lixin Zhu
- Department of General Surgery and Central Lab, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
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26
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Camilleri M, Lyle BJ, Madsen KL, Sonnenburg J, Verbeke K, Wu GD. Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations. Am J Physiol Gastrointest Liver Physiol 2019; 317:G17-G39. [PMID: 31125257 PMCID: PMC6689735 DOI: 10.1152/ajpgi.00063.2019] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public.
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Affiliation(s)
- Michael Camilleri
- 1Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Barbara J. Lyle
- 2International Life Sciences Institute North America, Washington, DC,3School of Professional Studies, Northwestern University, Evanston, Illinois
| | - Karen L. Madsen
- 4Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Justin Sonnenburg
- 5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California
| | - Kristin Verbeke
- 6Translational Research in Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Gary D. Wu
- 7Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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27
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Zhu HM, Li L, Li SY, Yan Q, Li F. Effect of water extract from Berberis heteropoda Schrenk roots on diarrhea-predominant irritable bowel syndrome by adjusting intestinal flora. JOURNAL OF ETHNOPHARMACOLOGY 2019; 237:182-191. [PMID: 30902748 DOI: 10.1016/j.jep.2019.03.045] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/23/2019] [Accepted: 03/17/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND The aim of the present study was to investigate the antidiarrheal effect of Berberis heteropoda Schrenk roots (BHS), which are used by Chinese minorities to treat diarrhea, through regulation of intestinal flora and related signaling pathways. METHODS Wistar rats were randomly divided into 6 groups: Control group (Con), Model group (Mod), three BHS groups (BHS-L (0.65 g/kg), BHS-M (1.955 g/kg), BHS-H (5.86 g/kg) and Bifidobacterium group (Bif). The model of diarrhea-based irritable bowel syndrome (D-IBS) was induced by intragastric administration combined with restraint stress. The CRD method was used to determine the AWR score and the Bristol fecal score. Quantification of the intestinal bacteria groups in feces was performed using colony counting on plates. The mRNA expression levels of Gpr41, Gpr43, TLR2, TLR4, and nuclear protein κB were determined by qRT-PCR, and the relative abundances of intestinal flora in the intestinal contents were determined by high-throughput gene sequencing ratios. RESULTS Oral administration of BHS (L, M and H) significantly reduced the AWR score and the Bristol fecal score, significantly relieved diarrhea in D-IBS rats, reduced the number of Enterococci and Enterobacteria in feces, increased the number of Bifidobacteria and Lactobacilli, and upregulated the expression of SCFA in plasma. qRT-PCR analysis showed that the expression of TLR2, TLR4, Gpr41, Gpr43 and NF-κB in the BHS groups was downregulated. D-IBS rats reduced the abundance and diversity of intestinal flora and BHS (L, M and H) regulated the abundance and diversity of their intestinal flora. CONCLUSION The above data suggest that BHS potentially alleviates diarrhea, intestinal flora disorder and intestinal inflammation in D-IBS rats by regulating the immunological pathways. BHS is a promising agent in the treatment of D-IBS.
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Affiliation(s)
- Hui-Min Zhu
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
| | - Li Li
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China.
| | - Song-Ya Li
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
| | - Qi Yan
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
| | - Fei Li
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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28
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Yang ZJ, Zhu MJ, Wang FF, Di ZS, Wang YX, Li LS, Xu JD. Progress in understanding relationship between bile acid metabolic disorder and gut diseases. Shijie Huaren Xiaohua Zazhi 2019; 27:183-189. [DOI: 10.11569/wcjd.v27.i3.183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
There are a large number of microorganisms in the human intestine, which rely on the nutrition in the digestive tract to survive. At the same time, they affect the intestinal neuro-immune function through the metabolism substances produced by themselves. The enteric neuro-immune system regulates the functions of digestion and absorption so as to maintain the homeostasis in the intestine. Intestinal bile acid metabolism disorder might induce gut dysfunction or intestinal immune imbalance. This review describes the effect of intestinal microbes on the enteric nervous system or other signal molecules of the bile acid pathway linked to some intestinal disorders, with an aim to provide a theoretical basis for clinical treatment of the related diseases.
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Affiliation(s)
- Ze-Jun Yang
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Min-Jia Zhu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Fei-Fei Wang
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Zhi-Shan Di
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Yue-Xiu Wang
- International College, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- School of Basic Medicine, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
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29
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Singh P, Silvester J, Chen X, Xu H, Sawhney V, Rangan V, Iturrino J, Nee J, Duerksen DR, Lembo A. Serum zonulin is elevated in IBS and correlates with stool frequency in IBS-D. United European Gastroenterol J 2019; 7:709-715. [PMID: 31210949 DOI: 10.1177/2050640619826419] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 12/15/2018] [Indexed: 12/21/2022] Open
Abstract
Background Studies have shown increased intestinal permeability in irritable bowel syndrome. Validating serum biomarkers for altered intestinal permeability in irritable bowel syndrome will facilitate research and pathophysiology-based therapy. Objective To measure serum zonulin and intestinal fatty acid binding protein levels in diarrhea-predominant irritable bowel syndrome and constipation-predominant irritable bowel syndrome and compare with healthy controls and celiac disease. Methods Serum zonulin and intestinal fatty acid binding protein levels were measured using enzyme-linked immunosorbent assays in constipation-predominant irritable bowel syndrome (n = 50), diarrhea-predominant irritable bowel syndrome (n = 50), celiac disease (n = 53) and healthy controls (n = 42). Irritable bowel syndrome symptom severity was measured using the irritable bowel syndrome-symptom severity scale. Results Patients with constipation-predominant irritable bowel syndrome and diarrhea-predominant irritable bowel syndrome had higher zonulin levels compared with healthy controls (p = 0.006 and 0.009 respectively), which was comparable to those with active celiac disease. Although zonulin levels did not correlate with the overall irritable bowel syndrome symptom severity scale, it positively correlated with stool frequency per week (p = 0.03) and dissatisfaction with bowel habits (p = 0.007) in diarrhea-predominant irritable bowel syndrome. Patients with diarrhea-predominant irritable bowel syndrome and constipation-predominant irritable bowel syndrome had lower intestinal fatty acid binding protein levels compared with celiac patients (p = 0.005 and p = 0.047 respectively). Conclusion Serum zonulin is upregulated in irritable bowel syndrome and the levels are comparable to those in celiac disease. Zonulin levels correlated with severity of bowel habits in diarrhea-predominant irritable bowel syndrome. Intestinal fatty acid binding protein levels in irritable bowel syndrome patients were not increased suggesting no significant increase in enterocyte death.
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Affiliation(s)
- Prashant Singh
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Jocelyn Silvester
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America.,Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, United States of America
| | - Xinhua Chen
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Hua Xu
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Veer Sawhney
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Vikram Rangan
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Johanna Iturrino
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Judy Nee
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
| | - Donald R Duerksen
- Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
| | - Anthony Lembo
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, United States of America
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30
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Soldi S, Tagliacarne SC, Valsecchi C, Perna S, Rondanelli M, Ziviani L, Milleri S, Annoni A, Castellazzi A. Effect of a multistrain probiotic (Lactoflorene ® Plus) on inflammatory parameters and microbiota composition in subjects with stress-related symptoms. Neurobiol Stress 2018; 10:100138. [PMID: 30937345 PMCID: PMC6430185 DOI: 10.1016/j.ynstr.2018.11.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 09/17/2018] [Accepted: 11/03/2018] [Indexed: 12/14/2022] Open
Abstract
Stress affects the immune system and intestinal microbiota composition and can lead to imbalance between pro- and anti-inflammatory cytokines or to uncontrolled production of cytokines. The effect of emotional stress on secretory IgA levels also indicates that stress decreases mucosal integrity. Our aim was to evaluate whether a probiotic product (Lactoflorene® Plus) can prevent alterations in the immune response associated with self-reported stress and microbiota composition. Healthy adult volunteers who self-reported psychological stress were enrolled and randomised into a placebo and a probiotic group. Salivary stress markers (α-amylase, cortisol, chromogranin A) and immunological parameters (sIgA, NK cell activity, IL-8, IL-10, TNF-α) in feces and the composition of intestinal microbiota were evaluated. Administration of the product did not exert a direct effect on the salivary stress markers or NK cell activity but did reduce abdominal pain and increase faecal IgA and IL-10 levels. The probiotic product induced a moderate increase in Bifidobacterium and Lactobacillus spp., as expected, and in Faecalibacterium spp., and decreased the size of the Dialister spp. and Escherichia and Shigella populations. Administration of the product helped protect the mucosal barrier by supporting the number of short-chain fatty acid producers and decreasing the load of potentially harmful bacteria, thus reducing intestinal inflammation and abdominal discomfort. ClinicalTrials.gov NCT03234452.
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Affiliation(s)
- Sara Soldi
- AAT – Advanced Analytical Technologies Srl, via P. Majavacca 12, 29017, Fiorenzuola d’Arda, Pc, Italy
- Corresponding author.
| | - Sara Carlotta Tagliacarne
- Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, P.le Golgi 2, 27100, Pavia, Italy
| | - Chiara Valsecchi
- Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy
| | - Simone Perna
- Department of Biology, College of Science, University of Bahrain, Sakhir Campus, P. O. Box 32038, Bahrain
| | - Mariangela Rondanelli
- Department of Public Health, Experimental and Forensic Medicine, School of Medicine, Endocrinology and Nutrition Unit, University of Pavia, Pavia, Italy
- IRCCS Mondino Foundation, Pavia, Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, University of Pavia, Italy
| | - Luigi Ziviani
- Centro Ricerche Cliniche di Verona Srl, P.le L.A. Scuro 10, 37134, Verona, Vr, Italy
| | - Stefano Milleri
- Centro Ricerche Cliniche di Verona Srl, P.le L.A. Scuro 10, 37134, Verona, Vr, Italy
| | - Ariella Annoni
- Montefarmaco OTC, via IV Novembre 92, 20021, Bollate, Mi, Italy
| | - Annamaria Castellazzi
- Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, P.le Golgi 2, 27100, Pavia, Italy
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31
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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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Pham VT, Seifert N, Richard N, Raederstorff D, Steinert RE, Prudence K, Mohajeri MH. The effects of fermentation products of prebiotic fibres on gut barrier and immune functions in vitro. PeerJ 2018; 6:e5288. [PMID: 30128177 PMCID: PMC6089210 DOI: 10.7717/peerj.5288] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 07/02/2018] [Indexed: 12/18/2022] Open
Abstract
The beneficial effects of prebiotic fibres on human health have been related to their capacities to alter the gut microbiota and modify the growth of beneficial microorganisms. It is long appreciated that bacterial metabolites affect the host’s physiology. The inner lining of the intestinal tract is the first level of interaction between the host and bacteria and their metabolites. Therefore, we set out to test the effects of five common dietary fibres (oat β-glucan 28%; oat β-glucan 94%; dried chicory root containing inulin 75%; xylo-oligosaccharide; inulin 90%) and maltodextrin, after fermentation by human gut microbiota in vitro, on measures of gut barrier integrity using a Caco-2/HT29-MTX co-culture as well as mucus production and immune parameters using HT29-MTX and HT29 cell models, respectively. Our data show that all fibres, fermentation products increased the tightness of the gut barrier with oat β-glucan 28% having the largest effect. Fermentation supernatants were tested also in models of the compromised gut barrier (leaky gut). After the addition of ethanol as basolateral stressor, only fermentation supernatant of oat β-glucan 28%, oat β-glucan 94% and maltodextrin improved the gut barrier integrity, while oat β-glucan 28% and dried chicory root containing inulin 75% significantly improved the gut barrier integrity after addition of rhamnolipids as apical stressor. Using the Luminex Technology, we demonstrated an important role of oat β-glucan fermentation products in modulating cytokine and chemokine productions. Furthermore, treating the goblet cells with effluent from xylo-oligosaccharide fermentation significantly increased mucus production. In summary, our data emphasize the potential positive effects of fermentation supernatant of dietary fibres on gut-related physiological outcomes and show that prebiotic fibres may have promising potential to induce specific gut health benefits.
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Affiliation(s)
- Van T Pham
- R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
| | - Nicole Seifert
- R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
| | - Nathalie Richard
- R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
| | - Daniel Raederstorff
- R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
| | - Robert E Steinert
- R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
| | - Kevin Prudence
- R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
| | - M Hasan Mohajeri
- R&D Human Nutrition and Health, DSM Nutritional Products Ltd., Basel, Switzerland
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Puzan M, Hosic S, Ghio C, Koppes A. Enteric Nervous System Regulation of Intestinal Stem Cell Differentiation and Epithelial Monolayer Function. Sci Rep 2018; 8:6313. [PMID: 29679034 PMCID: PMC5910425 DOI: 10.1038/s41598-018-24768-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 04/10/2018] [Indexed: 12/15/2022] Open
Abstract
The Enteric Nervous System (ENS) is a complex network of neurons and glia, which regulates sensorimotor function throughout the gastroinestinal tract (GI). Here we investigated the role of the ENS and intestinal myofibroblasts in the maintenance of a primary intestinal epithelial barrier through regulation of monolayer permeability, cytokine production, and differentiation of intestinal stem cells. Utilizing a novel, in vitro, transwell-based coculture system, murine small intestinal stem cells were isolated and cultured with ENS neurons and glia or subepithelial myofibroblasts. Results show that the ENS contributes to regulation of intestinal stem cell fate, promoting differentiation into chemosensory enteroendocrine cells, with 0.9% of cells expressing chromogranin A when cultured with ENS versus 0.6% in cocultures with myofibroblasts and 0.3% in epithelial cultures alone. Additionally, enteric neurons and myofibroblasts differentially release cytokines Macrophage Inflammatory Protein 2 (MIP-2), Transforming Growth Factor beta 1 (TGF-β1), and Interleukin 10 (IL-10) when cultured with intestinal epithelial cells, with a 1.5 fold increase of IL-10 and a 3 fold increase in MIP-2 in ENS cocultures compared to coculture with myofibroblasts. These results indicate the importance of enteric populations in the regulation of intestinal barrier function.
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Affiliation(s)
- Marissa Puzan
- Department of Chemical Engineering, Northeastern University, Boston, MA, 02115, USA
| | - Sanjin Hosic
- Department of Chemical Engineering, Northeastern University, Boston, MA, 02115, USA
| | - Caroline Ghio
- Department of Chemical Engineering, Northeastern University, Boston, MA, 02115, USA
| | - Abigail Koppes
- Department of Chemical Engineering, Northeastern University, Boston, MA, 02115, USA.
- Department of Biology, Northeastern University, Boston, MA, 02115, USA.
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Buhner S, Hahne H, Hartwig K, Li Q, Vignali S, Ostertag D, Meng C, Hörmannsperger G, Braak B, Pehl C, Frieling T, Barbara G, De Giorgio R, Demir IE, Ceyhan GO, Zeller F, Boeckxstaens G, Haller D, Kuster B, Schemann M. Protease signaling through protease activated receptor 1 mediate nerve activation by mucosal supernatants from irritable bowel syndrome but not from ulcerative colitis patients. PLoS One 2018. [PMID: 29529042 PMCID: PMC5846775 DOI: 10.1371/journal.pone.0193943] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background & aims The causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC). Method Effects of supernatants from 7 healthy controls (HC), 20 IBS and 12 UC patients on human and guinea pig submucous neurons were studied with neuroimaging techniques. We identify differentially expressed proteins with proteome analysis. Results Nerve activation by IBS supernatants was prevented by the protease activated receptor 1 (PAR1) antagonist SCHE79797. UC supernatants also activated enteric neurons through protease dependent mechanisms but without PAR1 involvement. Proteome analysis of the supernatants identified 204 proteins, among them 17 proteases as differentially expressed between IBS, UC and HC. Of those the four proteases elastase 3a, chymotrypsin C, proteasome subunit type beta-2 and an unspecified isoform of complement C3 were significantly more abundant in IBS compared to HC and UC supernatants. Of eight proteases, which were upregulated in IBS, the combination of elastase 3a, cathepsin L and proteasome alpha subunit-4 showed the highest prediction accuracy of 98% to discriminate between IBS and HC groups. Elastase synergistically potentiated the effects of histamine and serotonin–the two other main neuroactive substances in the IBS supernatants. A serine protease inhibitor isolated from the probiotic Bifidobacterium longum NCC2705 (SERPINBL), known to inhibit elastase-like proteases, prevented nerve activation by IBS supernatants. Conclusion Proteases in IBS and UC supernatants were responsible for nerve activation. Our data demonstrate that proteases, particularly those signalling through neuronal PAR1, are biomarker candidates for IBS, and protease profiling may be used to characterise IBS.
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Affiliation(s)
- Sabine Buhner
- Human Biology, Technische Universität München, Freising, Germany
| | - Hannes Hahne
- Proteomics and Bioanalytics, Technische Universität München, Freising, Germany
| | - Kerstin Hartwig
- Human Biology, Technische Universität München, Freising, Germany
| | - Qin Li
- Human Biology, Technische Universität München, Freising, Germany
- Department of Physiology, Shangdong University, Shangdong, China
| | - Sheila Vignali
- Human Biology, Technische Universität München, Freising, Germany
| | - Daniela Ostertag
- Human Biology, Technische Universität München, Freising, Germany
| | - Chen Meng
- Proteomics and Bioanalytics, Technische Universität München, Freising, Germany
| | | | - Breg Braak
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | | | | | - Giovanni Barbara
- Department of Medical and Surgical Sciences, St. Orsola Hospital, Bologna, Italy
| | - Roberto De Giorgio
- Department of Clinical Sciences, Nuovo Arcispedale S. Anna, University of Ferrara, Ferrara, Italy
| | - Ihsan Ekin Demir
- Department of General Surgery, University Hospital Rechts der Isar, Technische Universität München, Germany
| | - Güralp Onur Ceyhan
- Department of General Surgery, University Hospital Rechts der Isar, Technische Universität München, Germany
| | | | - Guy Boeckxstaens
- Translational Research Centre for Gastrointestinal Disorders, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - Dirk Haller
- Nutrition and Immunology, Technische Universität München, Freising, Germany
| | - Bernhard Kuster
- Proteomics and Bioanalytics, Technische Universität München, Freising, Germany
| | - Michael Schemann
- Human Biology, Technische Universität München, Freising, Germany
- * E-mail:
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Navy and black bean supplementation attenuates colitis-associated inflammation and colonic epithelial damage. J Nutr Biochem 2018; 56:215-223. [PMID: 29631142 DOI: 10.1016/j.jnutbio.2018.02.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 01/15/2018] [Accepted: 02/21/2018] [Indexed: 12/15/2022]
Abstract
The enriched levels of nondigestible fermentable carbohydrates and phenolic compounds found in common beans can exert immunomodulatory effects within the colon that improve gut health and mitigate the severity of colitis-associated inflammatory pathology. Prior to acute colitis onset, C57Bl/6 mice were prefed isocaloric 20% cooked navy bean (NB) or black bean (BB) diets for 3 weeks and switched to control basal diet (BD) 24 h prior to colitis induction via 5-day exposure to dextran sodium sulfate (2% w/v in drinking water)+3 days of fresh water. The severity of the acute colitis phenotype was attenuated by bean prefeeding, evidenced by reduced colon tissue inflammatory transcription factor activation (NFκB, STAT3) and inflammatory mediator levels in the colon (IL-1β, IL-6, IL-18 and MCP-1) and serum (TNFα, IL-6, IL-1β, MCP-1) versus BD (P≤.05). Additionally, biomarkers of enhanced wound repair responses were increased by bean prefeeding including colon tissue protein levels of IL-22, IL-27 and activated (i.e., GTP-bound) Cdc42 and Rac1 versus BD (P≤.05). mRNA expressions of genes involved in normal colonic epithelial function and the promotion of epithelial barrier integrity, defense and/or restitution and wound closure including MUC1, RELMβ, IgA and REG3γ were all increased in NB and BB prefed mice versus BD (P≤.05). Collectively, bean supplementation prior to colitis induction (i.e., mimicking disease relapse) primes the colonic microenvironment to attenuate the severity of the colitis inflammatory phenotype and maintain aspects of epithelial barrier function.
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Blomberg J, Gottfries CG, Elfaitouri A, Rizwan M, Rosén A. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Front Immunol 2018; 9:229. [PMID: 29497420 PMCID: PMC5818468 DOI: 10.3389/fimmu.2018.00229] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 01/26/2018] [Indexed: 12/13/2022] Open
Abstract
Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.
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Affiliation(s)
- Jonas Blomberg
- Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
| | | | - Amal Elfaitouri
- Department of Infectious Disease and Tropical Medicine, Faculty of Public Health, Benghazi University, Benghazi, Libya
| | - Muhammad Rizwan
- Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
| | - Anders Rosén
- Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Linköping, Sweden
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van der Beek CM, Dejong CHC, Troost FJ, Masclee AAM, Lenaerts K. Role of short-chain fatty acids in colonic inflammation, carcinogenesis, and mucosal protection and healing. Nutr Rev 2017; 75:286-305. [PMID: 28402523 DOI: 10.1093/nutrit/nuw067] [Citation(s) in RCA: 243] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Short-chain fatty acids (SCFAs), mainly acetate, propionate, and butyrate, produced by microbial fermentation of undigested food substances are believed to play a beneficial role in human gut health. Short-chain fatty acids influence colonic health through various mechanisms. In vitro and ex vivo studies show that SCFAs have anti-inflammatory and anticarcinogenic effects, play an important role in maintaining metabolic homeostasis in colonocytes, and protect colonocytes from external harm. Animal studies have found substantial positive effects of SCFAs or dietary fiber on colonic disease, but convincing evidence in humans is lacking. Most human intervention trials have been conducted in the context of inflammatory bowel disease. Only a limited number of those trials are of high quality, showing little or no favorable effect of SCFA treatment over placebo. Opportunities for future research include exploring the use of combination therapies with anti-inflammatory drugs, prebiotics, or probiotics; the use of prodrugs in the setting of carcinogenesis; or the direct application of SCFAs to improve mucosal healing after colonic surgery.
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Affiliation(s)
- Christina M van der Beek
- C.M. van der Beek, C.H.C. Dejong, F.J. Troost, A.A.M. Masclee, and K. Lenaerts are with Top Institute Food and Nutrition, Wageningen, the Netherlands. C.M. van der Beek, C.H.C. Dejong, and K. Lenaerts are with the Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands. C.H.C. Dejong is with the School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht, the Netherlands. F.J. Troost and A.A.M. Masclee are with the Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Cornelis H C Dejong
- C.M. van der Beek, C.H.C. Dejong, F.J. Troost, A.A.M. Masclee, and K. Lenaerts are with Top Institute Food and Nutrition, Wageningen, the Netherlands. C.M. van der Beek, C.H.C. Dejong, and K. Lenaerts are with the Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands. C.H.C. Dejong is with the School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht, the Netherlands. F.J. Troost and A.A.M. Masclee are with the Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Freddy J Troost
- C.M. van der Beek, C.H.C. Dejong, F.J. Troost, A.A.M. Masclee, and K. Lenaerts are with Top Institute Food and Nutrition, Wageningen, the Netherlands. C.M. van der Beek, C.H.C. Dejong, and K. Lenaerts are with the Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands. C.H.C. Dejong is with the School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht, the Netherlands. F.J. Troost and A.A.M. Masclee are with the Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Ad A M Masclee
- C.M. van der Beek, C.H.C. Dejong, F.J. Troost, A.A.M. Masclee, and K. Lenaerts are with Top Institute Food and Nutrition, Wageningen, the Netherlands. C.M. van der Beek, C.H.C. Dejong, and K. Lenaerts are with the Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands. C.H.C. Dejong is with the School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht, the Netherlands. F.J. Troost and A.A.M. Masclee are with the Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Kaatje Lenaerts
- C.M. van der Beek, C.H.C. Dejong, F.J. Troost, A.A.M. Masclee, and K. Lenaerts are with Top Institute Food and Nutrition, Wageningen, the Netherlands. C.M. van der Beek, C.H.C. Dejong, and K. Lenaerts are with the Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands. C.H.C. Dejong is with the School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht, the Netherlands. F.J. Troost and A.A.M. Masclee are with the Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
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Pohl CS, Medland JE, Mackey E, Edwards LL, Bagley KD, DeWilde MP, Williams KJ, Moeser AJ. Early weaning stress induces chronic functional diarrhea, intestinal barrier defects, and increased mast cell activity in a porcine model of early life adversity. Neurogastroenterol Motil 2017; 29:10.1111/nmo.13118. [PMID: 28573751 PMCID: PMC5650513 DOI: 10.1111/nmo.13118] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/27/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Early life adversity (ELA) is a risk factor for development of gastrointestinal disorders later in life. The underlying mechanisms through which ELA and sex interact to influence disease susceptibility remains poorly understood. METHODS Utilizing a porcine early weaning stress (EWS) model to mimic ELA, we investigated the long-term effects of EWS on functional diarrhea, ileal permeability, mast cell activity and mast cell relationship with enteric ganglia. KEY RESULTS Juvenile and adult EWS pigs exhibited chronic, functional diarrhea (EWS 43.6% vs late wean control(LWC) 4.8%, P<.0001), increased intestinal permeability (2 fold increase EWS vs LWC, P<.0001), and mast cell numbers (at 7 weeks and 20 weeks ~1.6 fold increase EWS vs LWC, P<.05). Compared with EWS male castrates (Male-C), females EWS pigs exhibited more frequent diarrhea (58.8% vs 29.9%, P=.0016), and increased intestinal permeability (1-2 fold higher in EWS females, P<.001). Increased mast cell numbers and their enhanced co-localization with neuronal ganglia were observed in both Male-C and female EWS pigs; however, female pigs exhibited greater release of mast cell tryptase upon activation with c48/80 (~1.5 fold increase, P<.05), compared with Male-C pigs. CONCLUSIONS AND INFERENCES These data demonstrate that pigs exposed to ELA exhibit increased vulnerability to functional diarrhea, intestinal permeability and mast cell activity. Further, these studies also showed that EWS female and Male-C pigs exhibited dimorphic responses to EWS with female piglets exhibited greater susceptibility and severity of diarrhea, intestinal permeability and mast cell tryptase release. Together, these findings mimic some of the key pathophysiologic findings in human functional GI disorders functional gastrointestinal disorders (FGIDs) suggesting that the EWS porcine model could be a valuable preclinical translational model for FGID research associated with ELA.
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Affiliation(s)
- Calvin S. Pohl
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America,Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, Michigan, United States of America
| | - Julia E. Medland
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States of America
| | - Emily Mackey
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America,Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, Michigan, United States of America,Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States of America
| | - Laura L. Edwards
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States of America
| | - Kristen D. Bagley
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States of America
| | - Morgan P. DeWilde
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America,Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, Michigan, United States of America
| | - Kurt J. Williams
- Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America
| | - Adam J. Moeser
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America,Gastrointestinal Stress Biology Laboratory, Michigan State University, East Lansing, Michigan, United States of America,Neuroscience Program, Michigan State University, East Lansing, Michigan, United States of America,Department of Physiology, Michigan State University, East Lansing, Michigan, United States of America,Corresponding Author: Adam J. Moeser, , Veterinary Medical Center, 784 Wilson Rd, Room G326, East Lansing, MI 48824, Phone: +1 1-517-353-5978
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Kwak DS, Lee OY, Lee KN, Jun DW, Lee HL, Yoon BC, Choi HS. The Effect of DA-6034 on Intestinal Permeability in an Indomethacin-Induced Small Intestinal Injury Model. Gut Liver 2017; 10:406-11. [PMID: 27114435 PMCID: PMC4849694 DOI: 10.5009/gnl15251] [Citation(s) in RCA: 5] [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] [Indexed: 01/22/2023] Open
Abstract
Background/Aims DA-6034 has anti-inflammatory activities and exhibits cytoprotective effects in acute gastric injury models. However, explanations for the protective effects of DA-6034 on intestinal permeability are limited. This study sought to investigate the effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model and its protective effect against small intestinal injury. Methods Rats in the treatment group received DA-6034 from days 0 to 2 and indomethacin from days 1 to 2. Rats in the control group received indomethacin from days 1 to 2. On the fourth day, the small intestines were examined to compare the severity of inflammation. Intestinal permeability was evaluated by using fluorescein isothiocyanate-labeled dextran. Western blotting was performed to confirm the association between DA-6034 and the extracellular signal-regulated kinase (ERK) pathway. Results The inflammation scores in the treatment group were lower than those in the control group, but the difference was statistically insignificant. Hemorrhagic lesions in the treatment group were broader than those in the control group, but the difference was statistically insignificant. Intestinal permeability was lower in the treatment group than in the control group. DA-6034 enhanced extracellular signal-regulated kinase expression, and intestinal permeability was negatively correlated with ERK expression. Conclusions DA-6034 may decrease intestinal permeability in an indomethacin-induced intestinal injury model via the ERK pathway.
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Affiliation(s)
- Dong Shin Kwak
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Hang Lak Lee
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Byung Chul Yoon
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
| | - Ho Soon Choi
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, Korea
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Peters S, Edogawa S, Sundt W, Dyer R, Dalenberg D, Mazzone A, Singh R, Moses N, Weber C, Linden DR, MacNaughton WK, Turner JR, Camilleri M, Katzka D, Farrugia G, Grover M, Grover M. Constipation-Predominant Irritable Bowel Syndrome Females Have Normal Colonic Barrier and Secretory Function. Am J Gastroenterol 2017; 112:913-923. [PMID: 28323272 PMCID: PMC5502210 DOI: 10.1038/ajg.2017.48] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 01/02/2017] [Indexed: 02/08/2023]
Abstract
OBJECTIVES The objective of this study was to determine whether constipation-predominant irritable bowel syndrome (IBS-C) is associated with changes in intestinal barrier and secretory function. METHODS A total of 19 IBS-C patients and 18 healthy volunteers (all females) underwent saccharide excretion assay (0.1 g 13C mannitol and 1 g lactulose), measurements of duodenal and colonic mucosal barrier (transmucosal resistance (TMR), macromolecular and Escherichia coli Bio-Particle translocation), mucosal secretion (basal and acetylcholine (Ach)-evoked short-circuit current (Isc)), in vivo duodenal mucosal impedance, circulating endotoxins, and colonic tight junction gene expression. RESULTS There were no differences in the in vivo measurements of barrier function between IBS-C patients and healthy controls: cumulative excretion of 13C mannitol (0-2 h mean (s.e.m.); IBS-C: 12.1 (0.9) mg vs. healthy: 13.2 (0.8) mg) and lactulose (8-24 h; IBS-C: 0.9 (0.5) mg vs. healthy: 0.5 (0.2) mg); duodenal impedance IBS-C: 729 (65) Ω vs. healthy: 706 (43) Ω; plasma mean endotoxin activity level IBS-C: 0.36 (0.03) vs. healthy: 0.35 (0.02); and in colonic mRNA expression of occludin, zonula occludens (ZO) 1-3, and claudins 1-12 and 14-19. The ex vivo findings were consistent, with no group differences: duodenal TMR (IBS-C: 28.2 (1.9) Ω cm2 vs. healthy: 29.8 (1.9) Ω cm2) and colonic TMR (IBS-C: 19.1 (1.1) Ω cm2 vs. healthy: 17.6 (1.7) Ω cm2); fluorescein isothiocyanate (FITC)-dextran (4 kDa) and E. coli Bio-Particle flux. Colonic basal Isc was similar, but duodenal basal Isc was lower in IBS-C (43.5 (4.5) μA cm-2) vs. healthy (56.9 (4.9) μA cm-2), P=0.05. Ach-evoked ΔIsc was similar. CONCLUSIONS Females with IBS-C have normal colonic barrier and secretory function. Basal duodenal secretion is decreased in IBS-C.
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Affiliation(s)
- S Peters
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - S Edogawa
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - W Sundt
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - R Dyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - D Dalenberg
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - A Mazzone
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - R Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - N Moses
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - C Weber
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - DR Linden
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - WK MacNaughton
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - JR Turner
- Departments of Pathology and Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - M Camilleri
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - D Katzka
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - G Farrugia
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - M Grover
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Ishimoto H, Oshima T, Sei H, Yamasaki T, Kondo T, Tozawa K, Tomita T, Ohda Y, Fukui H, Watari J, Miwa H. Claudin-2 expression is upregulated in the ileum of diarrhea predominant irritable bowel syndrome patients. J Clin Biochem Nutr 2017; 60:146-150. [PMID: 28366996 PMCID: PMC5370533 DOI: 10.3164/jcbn.16-92] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 10/13/2016] [Indexed: 12/12/2022] Open
Abstract
Intestinal epithelial barrier function is impaired in irritable bowel syndrome patients. Claudins are highly expressed in cells with tight junctions and are involved in the intestinal epithelial barrier function. The expression pattern of tight junction proteins in diarrhea-predominant irritable bowel syndrome have not been fully elucidated. We therefore recruited 17 diarrhea-predominant irritable bowel syndrome patients and 20 healthy controls. The expression of the tight junction-related proteins was examined in the ileal, cecal, and rectal mucosa of diarrhea-predominant irritable bowel syndrome patients using real-time PCR and immunofluorescence. Claudin-2 expression was high in the ileum of diarrhea-predominant irritable bowel syndrome patients. Claudin-2 expression was the same in cecum and rectal mucosa of control and diarrhea-predominant irritable bowel syndrome patients. Similarly, the expression of clauidn-1, claudin-7, JAM-A, occludin, and ZO-1 in the ileal, cecal, and rectal mucosa did not change between control and diarrhea-predominant irritable bowel syndrome samples. Infiltration of eosinophil and mast cells in the mucosa of ileum, cecum and rectum was evaluated using immunohistochemical staining and was not affected by diarrhea-predominant irritable bowel syndrome. Claudin-2 was expressed on the apical side of villi and crypts of ileal mucosal epithelial cells. Clauidn-2 expression is upregulated in diarrhea-predominant irritable bowel syndrome patients and may contribute to the pathogenesis of this condition.
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Affiliation(s)
- Haruka Ishimoto
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Hiroo Sei
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Takahisa Yamasaki
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Takashi Kondo
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Katsuyuki Tozawa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Yoshio Ohda
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Jiro Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
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Abstract
The gastrointestinal mucosal barrier plays an essential role in the separation of the inside of the body from the outside environment. Tight junctions (TJs) are the most important component for construction of a constitutive barrier of epithelial cells, and they regulate the permeability of the barrier by tightly sealing the cell-cell junctions. TJ proteins are represented by claudins, occludin, junctional adhesion molecules, and scaffold protein zonula occludens. Among these TJ proteins, claudins are the major components of TJs and are responsible for the barrier and the polarity of the epithelial cells. Gastrointestinal diseases including reflux esophagitis, inflammatory bowel disease, functional gastrointestinal disorders, and cancers may be regulated by these molecules, and disruption of their functions leads to chronic inflammatory conditions and chronic or progressive disease. Therefore, regulation of the barrier function of epithelial cells by regulating the expression and localization of TJ proteins is a potential new target for the treatment of these diseases. Treatment strategies for these diseases might thus be largely altered if symptom generation and/or immune dysfunction could be regulated through improvement of mucosal barrier function. Since TJ proteins may also modify tumor infiltration and metastasis, other important goals include finding a good TJ biomarker of cancer progression and patient prognosis, and developing TJ protein-targeted therapies that can modify patient prognosis. This review summarizes current understanding of gastrointestinal barrier function, TJ protein expression, and the mechanisms underlying epithelial barrier dysregulation in gastrointestinal diseases.
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Li L, Xiong L, Yao J, Zhuang X, Zhang S, Yu Q, Xiao Y, Cui Y, Chen M. Increased small intestinal permeability and RNA expression profiles of mucosa from terminal ileum in patients with diarrhoea-predominant irritable bowel syndrome. Dig Liver Dis 2016; 48:880-7. [PMID: 27246797 DOI: 10.1016/j.dld.2016.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 04/15/2016] [Accepted: 05/02/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Altered intestinal permeability in diarrhoea-predominant irritable bowel syndrome (IBS-D) has been reported in some studies. AIMS The study aimed to investigate the altered intestinal permeability and its associated clinical characteristics and RNA expression profiles in IBS-D. METHODS We stratified IBS-D patients into two groups according to the P95 value of the permeability in controls. The clinical characteristics of the two groups were evaluated, and two biopsy cases from each of the two groups were selected for the RNA-seq analysis. RESULTS IBS-D patients had a significant increase in the small intestinal permeability compared with controls [0.0245 (0.0229) median (interquartile range)] versus 0.0156 (0.0098), P=0.010), but no significant difference was found in the colonic permeability [23.286 (10.470) versus 21.650 (6.650), P=0.574]. The IBS-D patients with increased small intestinal permeability had worse psychological effects (P=0.027) and quality of life (P=0.044). Analysis of RNA-seq data revealed 185 genes differentially expressed, many of which were related to mucosal inflammation and immunity. CONCLUSIONS Small intestinal permeability, but not colonic permeability, is increased in IBS-D patients. IBS-D patients with increased small intestinal permeability tend to be more severely impaired in terms of psychological effects and quality of life, and analysis of RNA-seq data reveals that increased small intestinal permeability is related to mucosal inflammation and immunity.
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Affiliation(s)
- Li Li
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Lishou Xiong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
| | - Junhua Yao
- Instrumental Analysis and Research Centre, Sun Yat-Sen University, Guangzhou, China
| | - Xiaojun Zhuang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Shenghong Zhang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qiao Yu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yinglian Xiao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yi Cui
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Teruel C, Garrido E, Mesonero F. Diagnosis and management of functional symptoms in inflammatory bowel disease in remission. World J Gastrointest Pharmacol Ther 2016; 7:78-90. [PMID: 26855814 PMCID: PMC4734957 DOI: 10.4292/wjgpt.v7.i1.78] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/03/2015] [Accepted: 10/27/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) patients in remission may suffer from gastrointestinal symptoms that resemble irritable bowel syndrome (IBS). Knowledge on this issue has increased considerably in the last decade, and it is our intention to review and summarize it in the present work. We describe a problematic that comprises physiopathological uncertainties, diagnostic difficulties, as IBS-like symptoms are very similar to those produced by an inflammatory flare, and the necessity of appropriate management of these patients, who, although in remission, have impaired quality of life. Ultimately, from almost a philosophical point of view, the presence of IBS-like symptoms in IBD patients in remission supposes a challenge to the traditional functional-organic dichotomy, suggesting the need for a change of paradigm.
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Daguet D, Pinheiro I, Verhelst A, Possemiers S, Marzorati M. Arabinogalactan and fructooligosaccharides improve the gut barrier function in distinct areas of the colon in the Simulator of the Human Intestinal Microbial Ecosystem. J Funct Foods 2016. [DOI: 10.1016/j.jff.2015.11.005] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Dlugosz A, Nowak P, D'Amato M, Mohammadian Kermani G, Nyström J, Abdurahman S, Lindberg G. Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil 2015; 27:1747-54. [PMID: 26387872 DOI: 10.1111/nmo.12670] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 08/11/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Innate immune responses to conserved microbial products such as lipopolysaccharide (LPS) and flagellin are likely important in microbial-host interactions and intestinal homeostasis. We hypothesized that bacterial translocation and activation of mucosal immunity against common microbial antigens might be involved in the development of irritable bowel syndrome (IBS). We therefore compared serum levels of LPS, soluble CD14 (sCD14), and flagellin antibodies between patients with different subtypes of IBS and healthy controls. METHODS We analyzed serum obtained from 88 patients (74 females) aged 19(43)-73 years and 106 healthy volunteers (77 females) aged 19(38)-62 years. Diarrhea-predominant IBS (D-IBS) was present in 32 patients (36%), 23 patients (26%) had constipation-predominant IBS (C-IBS), and 33 patients (38%) had A-IBS. We used ELISA for sCD14 and antiflagellin immunoglobulin G and limulus amebocyte assay for LPS. Abdominal symptoms and psychiatric comorbidities were assessed using validated questionnaires. KEY RESULTS We found a significantly higher serum level of LPS in patients with D-IBS compared to controls (p = 0.0155). The level of antibodies to flagellin was higher in patients with IBS than in controls (mainly driven by higher levels in D-IBS, p = 0.0018). The levels of sCD14 were lower in D-IBS patients compared to controls (p = 0.0498). We found a weak, but significant correlation between the levels of antiflagellin antibodies and anxiety among IBS patients (ρ = 0.38; p = 0.0045). CONCLUSIONS & INFERENCES Our results support the concept that immune reactivity to luminal antigens may have a role in the development of D-IBS. The serum level of antiflagellin antibodies was found to correlate with patients' self-reported anxiety score.
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Affiliation(s)
- A Dlugosz
- Karolinska Institutet, Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - P Nowak
- Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - M D'Amato
- Karolinska Institutet, Department of Biosciences and Nutrition, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - G Mohammadian Kermani
- Karolinska Institutet, Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - J Nyström
- Karolinska Institutet, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - S Abdurahman
- Department of Science and Technology, Örebro Life Science Center, Örebro University, Örebro, Sweden
| | - G Lindberg
- Karolinska Institutet, Department of Medicine and Center for Digestive Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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Monk JM, Lepp D, Zhang CP, Wu W, Zarepoor L, Lu JT, Pauls KP, Tsao R, Wood GA, Robinson LE, Power KA. Diets enriched with cranberry beans alter the microbiota and mitigate colitis severity and associated inflammation. J Nutr Biochem 2015; 28:129-39. [PMID: 26878790 DOI: 10.1016/j.jnutbio.2015.10.014] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 09/23/2015] [Accepted: 10/16/2015] [Indexed: 12/19/2022]
Abstract
Common beans are rich in phenolic compounds and nondigestible fermentable components, which may help alleviate intestinal diseases. We assessed the gut health priming effect of a 20% cranberry bean flour diet from two bean varieties with differing profiles of phenolic compounds [darkening (DC) and nondarkening (NDC) cranberry beans vs. basal diet control (BD)] on critical aspects of gut health in unchallenged mice, and during dextran sodium sulfate (DSS)-induced colitis (2% DSS wt/vol, 7 days). In unchallenged mice, NDC and DC increased (i) cecal short-chain fatty acids, (ii) colon crypt height, (iii) crypt goblet cell number and mucus content and (iv) Muc1, Klf4, Relmβ and Reg3γ gene expression vs. BD, indicative of enhanced microbial activity and gut barrier function. Fecal 16S rRNA sequencing determined that beans reduced abundance of the Lactobacillaceae (Ruminococcus gnavus), Clostridiaceae (Clostridium perfringens), Peptococcaceae, Peptostreptococcaceae, Rikenellaceae and Pophyromonadaceae families, and increased abundance of S24-7 and Prevotellaceae. During colitis, beans reduced (i) disease severity and colonic histological damage, (ii) increased gene expression of barrier function promoting genes (Muc1-3, Relmβ, and Reg3γ) and (iii) reduced colonic and circulating inflammatory cytokines (IL-1β, IL-6, IFNγ and TNFα). Therefore, prior to disease induction, bean supplementation enhanced multiple concurrent gut health promoting parameters that translated into reduced colitis severity. Moreover, both bean diets exerted similar effects, indicating that differing phenolic content did not influence the endpoints assessed. These data demonstrate a proof-of-concept regarding the gut-priming potential of beans in colitis, which could be extended to mitigate the severity of other gut barrier-associated pathologies.
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Affiliation(s)
- Jennifer M Monk
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - Dion Lepp
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9
| | - Claire P Zhang
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - Wenqing Wu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9
| | - Leila Zarepoor
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - Jenifer T Lu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - K Peter Pauls
- Department of Plant Agriculture, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - Rong Tsao
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9
| | - Geoffrey A Wood
- Department of Pathobiology, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - Lindsay E Robinson
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1
| | - Krista A Power
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
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Claudin-related intestinal diseases. Semin Cell Dev Biol 2015; 42:30-8. [PMID: 25999319 DOI: 10.1016/j.semcdb.2015.05.006] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Revised: 05/09/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023]
Abstract
With up to 200 m(2) the human intestine is the organ with the largest absorptive surface of the body. It is lined by a single layer of epithelial cells that separates the host from the environment. The intestinal epithelium provides both, selective absorption of nutrients, ions, and water but also a highly effective barrier function which includes the first line of defense against environmental antigens. The paracellular part of this barrier function is provided by tight junction (TJ) proteins, especially the large family of claudins. Changes in abundance or molecular structure of claudins can generally result in three typical effects, (i) decreased absorptive passage, (ii) increased secretory passage of small solutes and water causing leak flux diarrhea and (iii) increased absorptive passage of macromolecules which may induce inflammatory processes. Several intestinal diseases are associated with such changes that can result in intestinal inflammation and symptoms like weight loss, abdominal pain or diarrhea. This review summarizes our current knowledge on barrier dysfunction and claudin dysregulation in several intestinal diseases gastroenterologists are often faced with, like inflammatory bowel disease, microscopic colitis, celiac disease, irritable bowel syndrome, gallstones and infectious diseases like HIV enteropathy, Campylobacter jejuni and Clostridium perfringens infection.
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Monk JM, Zhang CP, Wu W, Zarepoor L, Lu JT, Liu R, Pauls KP, Wood GA, Tsao R, Robinson LE, Power KA. White and dark kidney beans reduce colonic mucosal damage and inflammation in response to dextran sodium sulfate. J Nutr Biochem 2015; 26:752-60. [PMID: 25841250 DOI: 10.1016/j.jnutbio.2015.02.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 12/17/2014] [Accepted: 02/06/2015] [Indexed: 02/08/2023]
Abstract
Common beans are a rich source of nondigestible fermentable components and phenolic compounds that have anti-inflammatory effects. We assessed the gut-health-promoting potential of kidney beans in healthy mice and their ability to attenuate colonic inflammation following dextran sodium sulphate (DSS) exposure (via drinking water, 2% DSS w/v, 7 days). C57BL/6 mice were fed one of three isocaloric diets: basal diet control (BD), or BD supplemented with 20% cooked white (WK) or dark red kidney (DK) bean flour for 3 weeks. In healthy mice, anti-inflammatory microbial-derived cecal short chain fatty acid (SCFA) levels (acetate, butyrate and propionate), colon crypt height and colonic Mucin 1 (MUC1) and Resistin-like Molecule beta (Relmβ) mRNA expression all increased in WK- and DK-fed mice compared to BD, indicative of enhanced microbial activity, gut barrier integrity and antimicrobial defense response. During colitis, both bean diets reduced (a) disease severity, (b) colonic histological damage and (c) increased mRNA expression of antimicrobial and barrier integrity-promoting genes (Toll-like Receptor 4 (TLR4), MUC1-3, Relmβ and Trefoil Factor 3 (TFF3)) and reduced proinflammatory mediator expression [interleukin (IL)-1β, IL-6, interferon (IFN)γ, tumor necrosis factor (TNF)α and monocyte chemoattractant protein-1], which correlated with reduced colon tissue protein levels. Further, bean diets exerted a systemic anti-inflammatory effect during colitis by reducing serum levels of IL-17A, IFNγ, TNFα, IL-1β and IL-6. In conclusion, both WK and DK bean-supplemented diets enhanced microbial-derived SCFA metabolite production, gut barrier integrity and the microbial defensive response in the healthy colon, which supported an anti-inflammatory phenotype during colitis. Collectively, these data demonstrate a beneficial colon-function priming effect of bean consumption that mitigates colitis severity.
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Affiliation(s)
- Jennifer M Monk
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada, N1G 2W1
| | - Claire P Zhang
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada, N1G 2W1
| | - Wenqing Wu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9
| | - Leila Zarepoor
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada, N1G 2W1
| | - Jenifer T Lu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada, N1G 2W1
| | - Ronghua Liu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9
| | - K Peter Pauls
- Department of Plant Agriculture, University of Guelph, Guelph ON, Canada, N1G 2W1
| | - Geoffrey A Wood
- Department of Pathobiology, University of Guelph, Guelph ON, Canada, N1G 2W1
| | - Rong Tsao
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9
| | - Lindsay E Robinson
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada, N1G 2W1
| | - Krista A Power
- Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph ON, Canada, N1G 5C9; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada, N1G 2W1.
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Fehér J, Kovács I, Pacella E, Radák Z. [Correlation of the microbiota and intestinal mucosa in the pathophysiology and treatment of irritable bowel, irritable eye, and irritable mind syndrome]. Orv Hetil 2014; 155:1454-60. [PMID: 25194867 DOI: 10.1556/oh.2014.29987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Accumulating clinical evidence supports co-morbidity of irritable bowel, irritable eye and irritable mind symptoms. Furthermore, perturbation of the microbiota-host symbiosis (dysbiosis) is considered a common pathogenic mechanism connecting gastrointestinal, ocular and neuropsychiatric symptoms. Consequently, maintaining or restoring microbiota-host symbiosis represents a new approach to treat these symptoms or to prevent their relapses. Current treatment approach assigned a primary role to live probiotics alone or in combination with prebiotics to enhance colonization of beneficial bacteria and to strengthen the symbiosis. However, several papers showed major benefits of heat-killed probiotics as compared to their live counterparts on both intestinal and systemic symptoms. Recently, in addition to killing probiotics, in a proof of concept study lysates (fragments) of probiotics in combination with vitamins A, B, D and omega 3 fatty acids were successfully tested. These findings suggested a conceptual change in the approach addressed to both the microbiota and host as targets for intervention.
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Affiliation(s)
- János Fehér
- Nutripharma Hungaria Kft. Ophthalmic Neuroscience Program Budapest Sapienza Tudományegyetem Szemklinika via Sardegna 139 00187 Róma Olaszország
| | - Illés Kovács
- Semmelweis Egyetem, Általános Orvostudományi Kar Szemészeti Klinika Budapest
| | - Elena Pacella
- Sapienza Tudományegyetem Szemklinika via Sardegna 139 00187 Róma Olaszország
| | - Zsolt Radák
- Semmelweis Egyetem, Testnevelési és Sporttudományi Kar Sporttudományi Kutatóintézet Budapest
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