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Jeon JH, Lee J, Baek YJ, Lim KJ, Kim JD, Park JS, Choi MK, Song IS. Restoration of intestinal barrier function by fexuprazan, a potassium-competitive acid blocker, in Caco-2 cells and its higher gastrointestinal distribution in rats. Biomed Pharmacother 2025; 188:118185. [PMID: 40412363 DOI: 10.1016/j.biopha.2025.118185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 05/12/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025] Open
Abstract
This study aimed to investigate the efficacy of fexuprazan in restoring intestinal barrier function in comparison with other potassium-competitive acid blockers (P-CABs) and esomeprazole. The effect of fexuprazan on trans-epithelial electrical resistance (TEER) value, mRNA and protein expression of tight junction genes, and cell morphology was investigated using a dextran sulfate sodium (DSS)-induced ulcerative colitis Caco-2 cell model. Treatment with fexuprazan, esomeprazole, tegoprazan, and vonoprazan significantly increased TEER values in a 3 % DSS-induced ulcerative colitis Caco-2 cells in a concentration-dependent manner. The TEER value-concentration profile showed sigmoidal shape curves and yielded half maximal effective concentration of 0.983 - 1.17 μg/mL for P-CABs and 3.27 μg/mL for esomeprazole. Among these drugs, fexuprazan showed the highest activity in the restoring intestinal barrier function. Fexuprazan also increased the expression of tight junction genes including zonula occludens-1, claudin 1, occludin, and mucin 1, and also thickened the epithelial cell membrane after treatment with 20 μg/mL fexuprazan. Fexuprazan showed a particularly high distribution in the liver and gastrointestinal tract in rats following oral administration of 2 mg/kg fexuprazan, which appears to be a positive characteristic of fexuprazan's effect on ulcerative colitis and gastric acid-related diseases although in vivo therapeutic efficacy of fexuprazan for ulcerative colitis requires further validation in both animal and human. In conclusion, fexuprazan can potentially restore intestinal barrier function by increasing the expression of tight junction genes and by strengthening the cell membrane integrity in DSS-induced colitis model.
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Affiliation(s)
- Ji-Hyeon Jeon
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Jihoon Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea; Vessel‑Organ Interaction Research Center (VOICE) and BK21 FOUR Community‑Based Intelligent Novel Drug Discovery Education Unit, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Yeon-Ju Baek
- College of Pharmacy, Dankook University, Cheon‑an 31116, Republic of Korea
| | - Kwon-Jo Lim
- Life Science Institute, Daewoong Pharmaceutical, Yongin, Gyeonggido 17028, Republic of Korea
| | - Ji Duck Kim
- Life Science Institute, Daewoong Pharmaceutical, Yongin, Gyeonggido 17028, Republic of Korea
| | - Joon Seok Park
- Life Science Institute, Daewoong Pharmaceutical, Yongin, Gyeonggido 17028, Republic of Korea
| | - Min-Koo Choi
- College of Pharmacy, Dankook University, Cheon‑an 31116, Republic of Korea
| | - Im-Sook Song
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea; Vessel‑Organ Interaction Research Center (VOICE) and BK21 FOUR Community‑Based Intelligent Novel Drug Discovery Education Unit, Kyungpook National University, Daegu 41566, Republic of Korea.
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Tischler-Strasser V, Burdiladze I, Cabral G, Ekizoglu E, Grodzka O, Pardo K, Sochan P, Zaunandra L, MaassenVanDenBrink A, Lampl C. Effects of proton pump inhibitor (PPI) use on migraine - a critical review. J Headache Pain 2025; 26:20. [PMID: 39885408 PMCID: PMC11783727 DOI: 10.1186/s10194-025-01954-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/13/2025] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND Proton pump inhibitor (PPI) drugs are widely used and are among the most significant achievements of modern pharmacology. Their primary purpose is treating and preventing gastric acid-related disorders. Migraine and PPI intake are prevalent, and many people are affected by both. In the last few years, a potential link between PPI intake and the development of headaches-especially migraine-has come to increased attention. In this review, we critically examine the scientific data concerning the co-occurrence of these two entities. FINDINGS There seems to be a possible link between the use of PPIs and the occurrence of headache, especially migraine, suggesting a pathophysiological connection on several levels. Moreover, PPI use is only partially without side effects, even if these may not occur immediately. Whether the relation is causative or merely co-existential is currently not yet clear. The influence of genetics, environment, gut microbiome, medication intake and evolution of headache is multidirectional. CONCLUSION A relation between the prevalence of migraine and the use of PPIs on a population and personal level seems likely. Although PPIs have many advantages, they should be prescribed with caution, especially in patients who suffer from headaches and migraine. In this narrative review, we aim to critically evaluate existing data and offer a potential approach to accurately identify any connections and interactions, leading to a better understanding of how these conditions may influence each other.
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Affiliation(s)
- Viktoria Tischler-Strasser
- Department of Neurology, Koventhospital Barmherzige Brüder, Linz, Austria
- Headache Medical Center Linz, Seilerstätte 2, Linz, Austria
| | - Irma Burdiladze
- Department of Neurology, Tbilisi Central Hospital, Tbilisi, Georgia
| | - Goncalo Cabral
- Neurology Department, Hospital de Egas Moniz, Rua da Junqueira, Lisbon, Portugal
| | - Esme Ekizoglu
- Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Olga Grodzka
- Department of Neurology, Faculty of Medicine and Dentistry, Medical University of Warsaw, Warsaw, Poland
| | - Keshet Pardo
- Department of Neurology, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel
| | - Patryk Sochan
- Department of Neurology, Faculty of Medicine and Dentistry, Medical University, Bielanski Hospital, Warsaw, Poland
| | - Laura Zaunandra
- Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antoinette MaassenVanDenBrink
- Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Christian Lampl
- Department of Neurology, Koventhospital Barmherzige Brüder, Linz, Austria.
- Headache Medical Center Linz, Seilerstätte 2, Linz, Austria.
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Kim JH, Min JH, Jo YW, Kwon JW, Her Y. Association between acid-suppressive drugs and risk of psoriasis: retrospective study using Korean National Health Insurance Service-National Sample Cohort. Korean J Intern Med 2025; 40:57-64. [PMID: 39778526 PMCID: PMC11725478 DOI: 10.3904/kjim.2024.096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/08/2024] [Accepted: 08/19/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/AIMS Psoriasis is a common inflammatory skin disorder following non-specific triggers. Involvement of immune system is widely accepted for pathogenesis studies have demonstrated importance of gut microbiota in pathogenesis of inflammatory skin diseases. Proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) are acid-suppressive drugs widely used for acid related gastrointestinal diseases, and prolonged use has been associated with altered gut microbiota. This study aimed to investigate association between psoriasis and acid suppressing drugs in Korean population. METHODS This study was conducted with 3,662 patients diagnosed with psoriasis between 2002 and 2013 in NHIS-NSC. A total of 14,648 controls were matched at 1:4 based on sex, age, and gastrointestinal disease. ORs were estimated to determine the association between acid suppressing drug use and psoriasis. RESULTS Our study found a statistically significant association between the prolonged use of acid-suppressive drugs and the development of psoriasis in the Korean population. Specifically, patients with gastrointestinal diseases who used histamine-2 receptor antagonists (H2RA) or proton pump inhibitors (PPI) for extended periods exhibited a higher risk of developing psoriasis. The adjusted odds ratio for psoriasis was 1.89 (95% CI, 1.66-2.17) with long-term use, indicating a clear dose-response relationship. CONCLUSION Results from our study indicate that prolonged use of H2RA or PPI is associated with the risk of psoriasis among patients with gastrointestinal diseases in Korean population. The risk was increased in dose-response trend after adjusting for confounding variables. Clinicians should be aware of risks associated with prolonged use of acid suppressing drugs.
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Affiliation(s)
- Ji Hyun Kim
- Department of Gastroenterology and Hepatology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon,
Korea
| | - Joon-hong Min
- Department of Dermatology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon,
Korea
| | - Young Woo Jo
- Department of Dermatology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon,
Korea
| | - Jae Woo Kwon
- Department of Allergy and Clinical Immunology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon,
Korea
| | - Young Her
- Department of Dermatology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon,
Korea
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Hu L, Peng Y. Are histamine-2 receptor antagonists a reasonable comparator: comparing apples and apples? Gut 2024:gutjnl-2024-334496. [PMID: 39715671 DOI: 10.1136/gutjnl-2024-334496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/08/2024] [Indexed: 12/25/2024]
Affiliation(s)
- Lizhi Hu
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yu Peng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha, Hunan, China
- Research Center for Geriatric Disorder, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Zhang Q, Lou D, Zhang Y, Xu A, Fang Y, Zhou X. A Meta-Analysis of Proton Pump Inhibitor Exposure and the Risk of Adverse Outcomes in Patients with Inflammatory Bowel Disease. Dig Dis 2024; 43:28-35. [PMID: 39571562 DOI: 10.1159/000542729] [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: 09/01/2024] [Accepted: 11/18/2024] [Indexed: 12/19/2024]
Abstract
INTRODUCTION This study aimed to investigate the association between proton pump inhibitors (PPIs) exposure and adverse outcomes in patients with inflammatory bowel disease (IBD). METHODS According to the guidelines outlined in the PRISMA and Meta-analysis of Observational Studies in Epidemiology (MOOSE), we conducted a comprehensive search of PubMed, Web of Science, Embase, and the Cochrane Library databases for relevant cohort and case-control studies comparing the incidence of adverse outcomes between IBD patients exposed to PPIs and those not exposed, from the inception of the databases to April 2024. The primary adverse outcomes analyzed included hospitalization and surgery. RESULTS Five studies, encompassing nearly 100,000 subjects, were included in this meta-analysis. The findings indicated that IBD patients exposed to PPIs had a significantly higher incidence of adverse outcomes compared to those not exposed (odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.07-1.44, p = 0.004), although it was low-quality evidence. This increased risk was observed in both ulcerative colitis (OR = 1.38, 95% CI = 1.04-1.83, p = 0.025) and Crohn's disease (OR = 1.14, 95% CI = 1.02-1.29, p = 0.025). Additionally, the incidence of surgery was higher in IBD patients with PPI exposure (OR = 1.31, 95% CI = 1.02-1.68). However, the OR for hospitalization did not show a statistically significant difference (OR = 1.43, p = 0.244). Moreover, the use of glucocorticoids was more frequent among patients exposed to PPIs (OR = 1.16, 95% CI = 1.06-1.28, p = 0.001). CONCLUSION PPI exposure may be associated with an increased risk of adverse outcomes in IBD patients, particularly a higher rate of surgery. Limited by various factors, the evidence is considered low quality.
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Affiliation(s)
- Qiufeng Zhang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Dandi Lou
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yueming Zhang
- Intensive Care Unit, Hospital of Zhejiang People's Armed Police, Hangzhou, China
| | - Anyi Xu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yingying Fang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Xiaoshuai Zhou
- Department of Anus and Intestine Surgery, Ningbo Yinzhou No. 2 Hospital, Ningbo, China
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Zhang X, Li Q, Xia S, He Y, Liu Y, Yang J, Xiao X. Proton Pump Inhibitors and Oral-Gut Microbiota: From Mechanism to Clinical Significance. Biomedicines 2024; 12:2271. [PMID: 39457584 PMCID: PMC11504961 DOI: 10.3390/biomedicines12102271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/13/2024] [Accepted: 09/19/2024] [Indexed: 10/28/2024] Open
Abstract
Proton pump inhibitors (PPIs) are some of the most commonly prescribed drugs worldwide, but there are increasing concerns about digestive complications linked to PPIs. Next-generation sequencing studies have suggested that PPIs can significantly affect the composition of the gut microbiota, which in turn may substantially contribute to the development of these complications. Recently, emerging evidence has suggested that the translocation of oral microbes into the gut may be the primary mechanism underlying the alterations in the gut microbiota induced by PPIs in the presence of gastric acid suppression and impaired oral-gut barrier function. Moreover, the significance of oral-gut microbial translocation in health and disease conditions has gained increasing recognition. Consequently, it is imperative to enhance our understanding of the functions of the oral-gut microbiota axis in digestive disorders associated with PPI therapies. This review aims to summarize current research findings and further elucidate the contribution of the oral-gut microbiota to the pathogenesis of PPI-related digestive diseases. We aim to provide a theoretical foundation for future therapeutic and preventive strategies targeting PPI-related digestive complications through modulation of the oral-gut microbiota.
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Affiliation(s)
- Xian Zhang
- Department of Pathology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Qing Li
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (Q.L.); (S.X.); (Y.L.); (J.Y.)
| | - Siyuan Xia
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (Q.L.); (S.X.); (Y.L.); (J.Y.)
| | - Yan He
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (Q.L.); (S.X.); (Y.L.); (J.Y.)
| | - Yuqiang Liu
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (Q.L.); (S.X.); (Y.L.); (J.Y.)
| | - Jinlin Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (Q.L.); (S.X.); (Y.L.); (J.Y.)
| | - Xue Xiao
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China; (Q.L.); (S.X.); (Y.L.); (J.Y.)
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Shah AR, Aliyev N, Khan ZH, Ali R, Bilal M. Gastric Acid Suppression Is Associated With Higher Rates of Colectomy in Patients With Inflammatory Bowel Disease. GASTRO HEP ADVANCES 2024; 4:100553. [PMID: 39866722 PMCID: PMC11762160 DOI: 10.1016/j.gastha.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 09/14/2024] [Indexed: 01/28/2025]
Affiliation(s)
- Aun R. Shah
- Division of Gastroenterology and Hepatology, Creighton University Medical Center, Omaha, Nebraska
| | - Nurlan Aliyev
- Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Zarak H. Khan
- Division of Gastroenterology and Hepatology, Eastern Carolina University Health Medical Center, Greenville, North Carolina
| | - Rubab Ali
- Clarkson Family Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Mohammad Bilal
- Division of Gastroenterology and Hepatology, University of Minnesota/Minneapolis VA Medical Center, Minneapolis, Minnesota
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Liang Y, Meng Z, Ding XL, Jiang M. Effects of proton pump inhibitors on inflammatory bowel disease: An updated review. World J Gastroenterol 2024; 30:2751-2762. [PMID: 38899331 PMCID: PMC11185295 DOI: 10.3748/wjg.v30.i21.2751] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/26/2024] [Accepted: 05/15/2024] [Indexed: 06/03/2024] Open
Abstract
Inflammatory bowel disease (IBD) is believed to be caused by various factors, including abnormalities in disease susceptibility genes, environmental factors, immune factors, and intestinal bacteria. Proton pump inhibitors (PPIs) are the primary drugs used to treat acid-related diseases. They are also commonly prescribed to patients with IBD. Recent studies have suggested a potential association between the use of certain medications, such as PPIs, and the occurrence and progression of IBD. In this review, we summarize the potential impact of PPIs on IBD and analyze the underlying mechanisms. Our findings may provide insights for conducting further investigations into the effects of PPIs on IBD and serve as an important reminder for physicians to exercise caution when prescribing PPIs to patients with IBD.
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Affiliation(s)
- Yu Liang
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Zhen Meng
- Department of Intervention, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Xue-Li Ding
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Man Jiang
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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9
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Kong L, Chen S, Huang S, Zheng A, Gao S, Ye J, Hua C. Challenges and opportunities in inflammatory bowel disease: from current therapeutic strategies to organoid-based models. Inflamm Res 2024; 73:541-562. [PMID: 38345635 DOI: 10.1007/s00011-024-01854-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 01/20/2024] [Accepted: 01/24/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is an increasingly prevalent global health concern that has garnered substantial attention. However, the underlying mechanisms are still unclear and the current treatments have significant limitations. Intestinal organoids provide an in vitro model to explore the pathogenesis, test the therapeutic effects, and develop regenerative treatments as well as offer the potential to transform drug discovery of IBD. METHODS To advance our understanding of the whole story of IBD spanning from the pathogenesis to the current therapeutic strategies and latest advancements, a comprehensive search of major databases including PubMed, Scopus, and Web of Science was conducted to retrieve original articles and reviews related to IBD, organoids, pathogenesis and therapy. RESULTS This review deciphers the etiopathogenesis and the current therapeutic approaches in the treatment of IBD. Notably, critical aspects of intestinal organoids in IBD, such as their potential applications, viability, cell renewal ability, and barrier functionality are highlighted. We also discuss the advances, limitations, and prospects of intestinal organoids for precision medicine. CONCLUSION The latest strides made in research about intestinal organoids help elucidate intricate aspects of IBD pathogenesis, and pave the prospective avenues for novel therapeutic interventions.
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Affiliation(s)
- Lingjie Kong
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Siyan Chen
- School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Shenghao Huang
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Anzhe Zheng
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Jianzhong Ye
- Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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Capobianco I, Di Vincenzo F, Puca P, Becherucci G, Mentella MC, Petito V, Scaldaferri F. Adverse Food Reactions in Inflammatory Bowel Disease: State of the Art and Future Perspectives. Nutrients 2024; 16:351. [PMID: 38337636 PMCID: PMC10857040 DOI: 10.3390/nu16030351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Limited knowledge is available about the relationship between food allergies or intolerances and inflammatory bowel disease (IBD). Clinicians frequently encounter patients who report food allergies or intolerances, and gastroenterologists struggle distinguishing between patients with organic disorders and those with functional disorders, which the patients themselves may associate with specific dietary components. This task becomes even more arduous when managing patients with significant underlying organic conditions, like IBD. The aim of this review is to summarize and emphasize any actual associations between food allergies and intolerances and inflammatory diseases, such as ulcerative colitis and Crohn's disease. Through a narrative disceptation of the current literature, we highlight the increased prevalence of various food intolerances, including lactose, fructose, histamine, nickel, and non-celiac gluten sensitivity, in individuals with IBD. Additionally, we explore the association between increased epithelial barrier permeability in IBD and the development of food sensitization. By doing so, we aim to enhance clinicians' awareness of the nutritional management of patients with IBD when facing complaints or evidence of food allergies or intolerances.
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Affiliation(s)
- Ivan Capobianco
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (F.D.V.); (P.P.); (F.S.)
| | - Federica Di Vincenzo
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (F.D.V.); (P.P.); (F.S.)
| | - Pierluigi Puca
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (F.D.V.); (P.P.); (F.S.)
| | - Guia Becherucci
- UOC Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (G.B.); (M.C.M.)
| | - Maria Chiara Mentella
- UOC Nutrizione Clinica, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (G.B.); (M.C.M.)
| | - Valentina Petito
- IBD Unit, UOC CEMAD Centro Malattie dell’Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Franco Scaldaferri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (F.D.V.); (P.P.); (F.S.)
- IBD Unit, UOC CEMAD Centro Malattie dell’Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
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Szemes K, Farkas N, Sipos Z, Bor R, Fabian A, Szepes Z, Farkas K, Molnar T, Schafer E, Szamosi T, Salamon A, Vincze A, Sarlos P. Co-Administration of Proton Pump Inhibitors May Negatively Affect the Outcome in Inflammatory Bowel Disease Treated with Vedolizumab. Biomedicines 2024; 12:158. [PMID: 38255263 PMCID: PMC10813460 DOI: 10.3390/biomedicines12010158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/31/2023] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Concomitant medications may alter the effect of biological therapy in inflammatory bowel disease. The aim was to investigate the effect of proton pump inhibitors on remission rates in patients with inflammatory bowel disease treated with the gut-selective vedolizumab. Patients from the Hungarian nationwide, multicenter vedolizumab cohort were selected for post hoc analysis. Primary outcomes were the assessment of clinical response and endoscopic and clinical remission at weeks 14 and 54. Secondary outcomes were the evaluation of the combined effect of concomitant steroid therapy and other factors, such as smoking, on remission. A total of 108 patients were identified with proton pump inhibitor data from 240 patients in the original cohort. Patients on steroids without proton pump inhibitors were more likely to have a clinical response at week 14 than patients on concomitant PPI (95% vs. 67%, p = 0.005). Non-smokers with IBD treated with VDZ were more likely to develop a clinical response at week 14 than smokers, particularly those not receiving PPI compared with patients on co-administered PPI therapy (81% vs. 53%, p = 0.041, and 92% vs. 74%, p = 0.029, respectively). We found that the use of PPIs in patients treated with VDZ may impair the achievement of response in certain subgroups. Unnecessary PPI prescriptions should be avoided.
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Affiliation(s)
- Kata Szemes
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, 13 Ifjúság Street, 7624 Pecs, Hungary
| | - Nelli Farkas
- Institute of Bioanalysis, Medical School, University of Pécs, 7624 Pecs, Hungary
| | - Zoltan Sipos
- Institute of Bioanalysis, Medical School, University of Pécs, 7624 Pecs, Hungary
| | - Renata Bor
- First Department of Medicine, University of Szeged, 6720 Szeged, Hungary
| | - Anna Fabian
- First Department of Medicine, University of Szeged, 6720 Szeged, Hungary
| | - Zoltan Szepes
- First Department of Medicine, University of Szeged, 6720 Szeged, Hungary
| | - Klaudia Farkas
- First Department of Medicine, University of Szeged, 6720 Szeged, Hungary
| | - Tamas Molnar
- First Department of Medicine, University of Szeged, 6720 Szeged, Hungary
| | - Eszter Schafer
- Department of Gastroenterology, Hungarian Defence Forces Military Hospital, 1134 Budapest, Hungary
| | - Tamas Szamosi
- Department of Gastroenterology, Hungarian Defence Forces Military Hospital, 1134 Budapest, Hungary
| | | | - Aron Vincze
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, 13 Ifjúság Street, 7624 Pecs, Hungary
| | - Patricia Sarlos
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, 13 Ifjúság Street, 7624 Pecs, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pecs, Hungary
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12
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Varma S, Trudeau SJ, Li J, Freedberg DE. Proton pump Inhibitors and Risk of Enteric Infection in Inflammatory Bowel Disease: A Self-controlled Case Series. Inflamm Bowel Dis 2024; 30:38-44. [PMID: 36917215 PMCID: PMC11491639 DOI: 10.1093/ibd/izad035] [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: 07/17/2022] [Indexed: 03/16/2023]
Abstract
BACKGROUND We tested whether proton pump inhibitors (PPIs) are associated with enteric infections among those with inflammatory bowel disease (IBD), after adequately accounting for baseline differences between PPI users and nonusers. METHODS This was a self-controlled case series, with each patient serving as their own control. Ambulatory patients with IBD were included if they were tested for enteric infection by multiplex polymerase chain reaction testing panel (GIPCR) and/or Clostridoides difficile toxin PCR from 2015 to 2019 and received PPIs for some but not all of this period. Rates of enteric infections were compared between the PPI-exposed period vs pre- and post-PPI periods identical in duration to the exposed period. Conditional Poisson regression was used to adjust for time-varying factors. RESULTS Two hundred twenty-one IBD patients were included (49% ulcerative colitis, 46% Crohn's disease, and 5% indeterminate colitis). The median PPI duration was 7 months (interquartile range 4 to 11 months). A total of 25 (11%) patients had a positive GIPCR or C. difficile test in the PPI period, 9 (4%) in the pre-PPI period, and 8 (4%) in the post-PPI period. Observed incidence rates for enteric infections were 2.5, 7.4, and 2.2 per 100 person years for the pre-PPI, PPI, and post-PPI periods, respectively (adjusted incidence rate ratios, 2.8; 95% confidence interval [CI] 1.3-6.0) for PPI vs pre-PPI and 2.9 (95% CI, 1.3-6.4) for PPI vs post-PPI). The adjusted absolute excess risk associated with PPIs was 4.9 infections per 100 person years. CONCLUSIONS Proton pump inhibitors were associated with a 3-fold increased risk for enteric infection among those with IBD but had a modest absolute risk.
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Affiliation(s)
- Sanskriti Varma
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Stephen J Trudeau
- Columbia Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Jianhua Li
- Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA
| | - Daniel E Freedberg
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
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13
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Fossmark R, Lirhus SS, Høivik ML. The impact of proton pump inhibitors on the course of ulcerative colitis: a cohort study of over 10,000 newly diagnosed patients in Norway. Scand J Gastroenterol 2024; 59:46-51. [PMID: 37681998 DOI: 10.1080/00365521.2023.2255710] [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: 06/16/2023] [Accepted: 08/31/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND AND AIMS Proton pump inhibitors (PPI) affect the gastrointestinal microbiota, which is thought to play a role in the pathogenesis of ulcerative colitis (UC). Previous studies suggest an association between PPI use and risk of incident UC as well as disease course. The aim of the study was to examine if PPI exposure is associated with disease course in UC patients. METHODS A national cohort consisting of all newly diagnosed UC patients from 2010 to 2020 was defined combining data from Norwegian registries. PPI exposure was included as a time dependent variable with a 30 day time lag from starting the drug. Outcomes were starting advanced therapies including anti-TNF, systemic glucocorticoids, any additional systemic anti-inflammatory medication and undergoing colectomy during follow-up. Time-dependent Cox regressions included the variables PPI use, first systemic glucocorticoid prescription, first UC hospitalization, age-groups and sex. RESULTS The study cohort consisted of 10,149 patients with median age 40 years (IQR 27-56) and 56% males. PPI use independently increased the risk of starting advanced therapies (HR 1.54, 95% CI 1.36-1.73, p < 0.005), starting systemic glucocorticoids (HR 1.20, 95% CI 1.07-1.34, p < 0.005), starting any additional anti-inflammatory treatment (HR 1.18, 95%CI 1.05-1.32, p < 0.01) and undergoing colectomy (HR 1.52, 95%CI 1.17-1.98, p < 0.005). CONCLUSIONS PPI use was associated with unfavorable outcomes including advanced therapy initiation, additional anti-inflammatory medications and undergoing colectomy. Although further studies are needed, the evidence suggests that PPIs could affect the course of UC and should be used cautiously in UC patients.
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Affiliation(s)
- Reidar Fossmark
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Gastroenterology and Hepatology, St. Olav's University Hospital, Trondheim, Norway
| | - Sandre Svatun Lirhus
- Department of Health Management and Health Economics, University of Oslo, Oslo, Norway
| | - Marte Lie Høivik
- Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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14
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Singh N, Nugent Z, Singh H, Shaffer SR, Bernstein CN. Proton Pump Inhibitor Use Before and After a Diagnosis of Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:1871-1878. [PMID: 36790051 DOI: 10.1093/ibd/izad017] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Indexed: 02/16/2023]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) have an impact on the gut microbiome. We investigated whether increased use of PPIs was associated with a diagnosis of inflammatory bowel disease (IBD). METHODS The University of Manitoba IBD Epidemiology Database includes all Manitobans diagnosed with IBD between 1984 and 2018 with age-, sex-, and geography-matched control subjects and comprehensive prescription drug data from April 1995. Subjects were considered to be users if they received 2 PPI prescriptions. We assessed PPI prescriptions prediagnosis and for 3 years postdiagnosis of IBD. The absolute and relative rates were calculated and compared for PPI use pre- and post-IBD diagnosis. RESULTS A total of 5920 subjects were diagnosed with IBD after April 1996. Rates of PPI use in control subjects increased gradually from 1.5% to 6.5% over 15 years. Persons with IBD had a higher rate of PPI use, peaking up to 17% within 1 year of IBD diagnosis with a rate ratio (RR) of 3.1 (95% confidence interval [CI], 2.9-3.3). Furthermore, persons with Crohn's disease (RR, 4.2; 95% CI, 3.7-4.6) were more likely to have been PPI users prediagnosis than persons with ulcerative colitis (RR, 2.4; 95% CI, 2.2-2.7). Important predictors of increased PPI use were older age, year of data collection, and Crohn's disease diagnosis. CONCLUSIONS Persons with IBD have higher PPI use preceding their diagnosis. Possibly, the use of a PPI alters the gut microbiome, increasing the risk for IBD diagnosis; or persons with IBD have increased rates of dyspepsia, warranting PPI use; or some IBD symptoms are treated with PPIs whether warranted or not.
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Affiliation(s)
- Noreen Singh
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Zoann Nugent
- University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
| | - Harminder Singh
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
- CancerCare Manitoba, Winnipeg, MB, Canada
| | - Seth R Shaffer
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
| | - Charles N Bernstein
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, MB, Canada
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15
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Kitamoto S, Kamada N. The oral-gut axis: a missing piece in the IBD puzzle. Inflamm Regen 2023; 43:54. [PMID: 37932859 PMCID: PMC10626704 DOI: 10.1186/s41232-023-00304-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 10/17/2023] [Indexed: 11/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a multifactorial intractable intestinal disease. Focusing on only one facet of the pathogenesis of IBD is insufficient to fully capture the complexity of the disease, and results in limited advance in clinical management. Therefore, it is critical to dissect the interactions amongst the multifarious contributors to the pathogenesis to comprehensively understand its pathology and subsequently improve clinical outcomes. In this context, the systemic interactions between organs, particularly the oral-gut axis mediated by host immune cells and resident microorganisms, have garnered significant attention in IBD research. More specifically, periodontal disease such as periodontitis has been implicated in augmenting intestinal inflammation beyond the confines of the oral cavity. There is mounting evidence suggesting that potentially harmful oral resident bacteria, termed pathobionts, and pro-inflammatory immune cells from the oral mucosa can migrate to the gastrointestinal tract, thereby potentiating intestinal inflammation. This article aims to provide a holistic overview of the causal relationship between periodontal disease and intestinal inflammation. Furthermore, we will discuss potential determinants that facilitate the translocation of oral pathobionts into the gut, a key event underpinning the oral-gut axis. Unraveling the complex dynamics of microbiota and immunity in the oral-gut continuum will lead to a better understanding of the pathophysiology inherent in both oral and intestinal diseases and the development of prospective therapeutic strategies.
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Affiliation(s)
- Sho Kitamoto
- The World Premier International Research Center (WPI) Immunology Frontier Research Center (IFReC), 1012 IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Nobuhiko Kamada
- The World Premier International Research Center (WPI) Immunology Frontier Research Center (IFReC), 1012 IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
- Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
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16
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Zhai C, Lu F, Du X, Zhang M, Zhang Y, Ma Y, Zhao Y, Huang H, Kang Z. Green carbon dots derived from Atractylodes macrocephala: A potential nanodrug for treating alcoholic gastric ulcer. Colloids Surf B Biointerfaces 2023; 230:113492. [PMID: 37556883 DOI: 10.1016/j.colsurfb.2023.113492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/18/2023] [Accepted: 08/02/2023] [Indexed: 08/11/2023]
Abstract
Alcoholic gastric ulcer is a common acute gastric injury disease. The drugs currently used in clinical practice not only cannot fundamentally treat gastric injury, but also have serious side effects. There is an urgent demand for the discovery of a mild drug to treat alcoholic gastric ulcers. Herein, the green carbon dots derived from charred Atractylodes macrocephala (CAM-CDs) were acquired and have been proven to be safe and effective in alleviating alcoholic gastric ulcers at an inhibition rate up to 60%. CAM-CDs can markedly attenuate the gastric mucosa damage such as mucosal defect, bleeding and inflammatory cell infiltration by histopathological examination. Serum and tissue inflammatory cytokine measurements, as well as immunohistochemistry results, indicate that its mechanism of gastric mucosal protection may involve the reduction of IL-1β and TNF-α by regulating inflammatory signaling pathway of the NF-κB/NLRP3 axis, as well as elevation of IL-10 levels. CAM-CDs also can reduce oxidative stress markers (MDA), increase PGE2 and mucin secretion (MUC5AC), and it simultaneously exerts slight inhibition of hydrogen potassium ATPase and pepsin activity to protect gastric mucosa, as well as increases the microbial diversity and regulates species composition of gut microbiota in rats with gastric ulcer. Our work provides a new perspective on utilizing carbon-based nanomaterials in the development of new mild drugs.
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Affiliation(s)
- Changming Zhai
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Fang Lu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xin Du
- Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, Jiangsu, China
| | - Mengling Zhang
- Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, Jiangsu, China; Macao Institute of Materials Science and Engineering (MIMSE), MUST-SUDA Joint Research Center for Advanced Functional Materials, Macau University of Science and Technology, Taipa 999078, Macao, China
| | - Yue Zhang
- Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, Jiangsu, China
| | - Yurong Ma
- Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, Jiangsu, China
| | - Yan Zhao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Hui Huang
- Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, Jiangsu, China.
| | - Zhenhui Kang
- Institute of Functional Nano and Soft Materials Laboratory (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, Jiangsu, China; Macao Institute of Materials Science and Engineering (MIMSE), MUST-SUDA Joint Research Center for Advanced Functional Materials, Macau University of Science and Technology, Taipa 999078, Macao, China.
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17
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Dvornikova KA, Platonova ON, Bystrova EY. Inflammatory Bowel Disease: Crosstalk between Histamine, Immunity, and Disease. Int J Mol Sci 2023; 24:9937. [PMID: 37373085 DOI: 10.3390/ijms24129937] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel disease (IBD) is increasingly recognized as a serious, worldwide public health concern. It is generally acknowledged that a variety of factors play a role in the pathogenesis of this group of chronic inflammatory diseases. The diversity of molecular actors involved in IBD does not allow us to fully assess the causal relationships existing in such interactions. Given the high immunomodulatory activity of histamine and the complex immune-mediated nature of inflammatory bowel disease, the role of histamine and its receptors in the gut may be significant. This paper has been prepared to provide a schematic of the most important and possible molecular signaling pathways related to histamine and its receptors and to assess their relevance for the development of therapeutic approaches.
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Affiliation(s)
| | - Olga N Platonova
- I.P. Pavlov Institute of Physiology RAS, St. Petersburg 199034, Russia
| | - Elena Y Bystrova
- I.P. Pavlov Institute of Physiology RAS, St. Petersburg 199034, Russia
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18
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Nighot M, Liao PL, Morris N, McCarthy D, Dharmaprakash V, Ullah Khan I, Dalessio S, Saha K, Ganapathy AS, Wang A, Ding W, Yochum G, Koltun W, Nighot P, Ma T. Long-Term Use of Proton Pump Inhibitors Disrupts Intestinal Tight Junction Barrier and Exaggerates Experimental Colitis. J Crohns Colitis 2023; 17:565-579. [PMID: 36322638 PMCID: PMC10115233 DOI: 10.1093/ecco-jcc/jjac168] [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: 04/19/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Proton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier. TJ barrier dysfunction is an important pathogenic factor in inflammatory bowel disease [IBD]. Recent studies suggest that PPIs may promote disease flares in IBD patients. The role of PPIs in intestinal permeability is not clear. AIM The aim of the present study was to study the effect of PPIs on the intestinal TJ barrier function. METHODS Human intestinal epithelial cell culture and organoid models and mouse IBD models of dextran sodium sulphate [DSS] and spontaneous enterocolitis in IL-10-/- mice were used to study the role of PPIs in intestinal permeability. RESULTS PPIs increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase [MLCK] activity and expression, in a p38 MAPK-dependent manner. The PPI-induced increase in extracellular pH caused MLCK activation via p38 MAPK. Long-term PPI administration in mice exaggerated the increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10-/- enterocolitis. The TJ barrier disruption by PPIs was prevented in MLCK-/- mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients. CONCLUSIONS Our results suggest that long-term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via an increase in MLCK expression and activity.
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Affiliation(s)
- Meghali Nighot
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Pei-Luan Liao
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Nathan Morris
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Dennis McCarthy
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Viszwapriya Dharmaprakash
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Inam Ullah Khan
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Shannon Dalessio
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Kushal Saha
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | | | - Alexandra Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Wei Ding
- Division of Colon and Rectal Surgery, Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Gregory Yochum
- Division of Colon and Rectal Surgery, Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Walter Koltun
- Division of Colon and Rectal Surgery, Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Prashant Nighot
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
| | - Thomas Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
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19
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Feng L, A L, Li H, Mu X, Ta N, Bai L, Fu M, Chen Y. Pharmacological Mechanism of Aucklandiae Radix against Gastric Ulcer Based on Network Pharmacology and In Vivo Experiment. Medicina (B Aires) 2023; 59:medicina59040666. [PMID: 37109624 PMCID: PMC10140907 DOI: 10.3390/medicina59040666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/13/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Background and Objectives: Aucklandiae Radix is a well-known medicinal herb that is often used to treat gastric ulcer, but its molecular mechanism of anti-ulcer action is poorly understood. This research aimed to reveal the potential active components, core targets, and mechanisms of Aucklandiae Radix in treating gastric ulcer by combining network pharmacology and animal experimentation. Materials and Methods: First, a network pharmacology strategy was used to predict the main components, candidate targets, and potential signaling pathways. Molecular docking was then used to confirm the binding affinity between the main components and primary targets. Finally, rats were treated with indomethacin 30 mg/kg to establish a gastric ulcer model. Aucklandiae Radix extract (0.15, 0.3, and 0.6 g/kg) was pre-treated in rats by oral gavage for 14 days, and the protective effect and candidate targets of network pharmacology were validated through morphological observation, pathological staining, and biochemical index detection. Results: A total of eight potential active components and 331 predicted targets were screened from Aucklandiae Radix, 37 of which were common targets with gastric ulcer. According to the component–target network and protein-protein interaction (PPI) network, stigmasterol, mairin, sitosterol, and dehydrocostus lactone were identified as the key components, and RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), interleukin 1 beta (IL1B), caspase-3 (CASP3), and CASP8 were selected as the core targets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment results revealed the pharmacological mechanism of Aucklandiae Radix against gastric ulcer related to many biological processes and pathways, including antibacterial, anti-inflammatory, prostaglandin receptor response, and apoptosis. Molecular docking verification showed that the key components and core targets had good binding affinities. In the in vivo experiments, Aucklandiae Radix notably relieved the gastric ulcer by reducing the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and myeloperoxidase (MPO) while improving the gastric histopathological features. Conclusion: The overall findings suggest that Aucklandiae Radix treats gastric ulcer with a multi-component, multi-target, and multi-mechanism model.
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Affiliation(s)
- Lan Feng
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China
| | - Lisha A
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China
| | - Huifang Li
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Xiyele Mu
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Na Ta
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Laxinamujila Bai
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Minghai Fu
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China
- Correspondence: (M.F.); (Y.C.)
| | - Yongsheng Chen
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Mongolian Medicine), School of Mongolian Medicine, Inner Mongolia Minzu University, Tongliao 028000, China
- Correspondence: (M.F.); (Y.C.)
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20
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Malick A, Shen B. Endoscopic Treatment of Postoperative Bleeding, Bezoars, and Foreign Bodies. Gastrointest Endosc Clin N Am 2022; 32:829-843. [PMID: 36202519 DOI: 10.1016/j.giec.2022.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Altered gastrointestinal anatomy is common in patients with inflammatory bowel disease, particularly in those who underwent bowel surgery. Commonly performed surgeries are bowel resection and anastomosis and strictureplasty for Crohn's disease; and restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. The area of anastomosis and suture line is at the greatest risk for the development of postoperative bleeding. Altered bowel anatomy, especially the presence of strictures, strictureplasty, or structural or functional pouch outlet obstruction, puts these patients at risk for bezoar formation and foreign body retention, including video endoscopy capsule. This article will focus on postoperative bleeding, bezoar formation, and video capsule retention in patients with inflammatory bowel disease. Endoscopic management of these conditions is useful and is becoming an increasingly popular alternative to surgery.
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Affiliation(s)
- Alyyah Malick
- Department of Medicine, Columbia University Irving Medical Center-New York Presbyterian Hospital, 622 W 168th St, New York, NY 10032, USA.
| | - Bo Shen
- Center for Inflammatory Bowel Disease, Columbia University Irving Medical Center-NewYork Presbyterian Hospital, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA
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21
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Kitamoto S, Kamada N. Untangling the oral-gut axis in the pathogenesis of intestinal inflammation. Int Immunol 2022; 34:485-490. [PMID: 35716367 DOI: 10.1093/intimm/dxac027] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/16/2022] [Indexed: 11/12/2022] Open
Abstract
An increasing body of literature reveals that host-microbe networks are well-coordinated and impact human health and disease. Recently, it has become evident that an abnormal alteration in bacterial configuration in the oral cavity, namely oral dysbiosis, caused by periodontal inflammation, is associated with various distant inflammatory diseases, including inflammatory bowel disease. However, the extent to which the relationships between oral and distant disorders are merely an association or are causally triggered by oral microorganisms remains debated. In this mini-review, we highlight mechanisms in inter-related organ system diseases , particularly the one between oral and gut inflammation. Further, we discuss clinical perspectives and propose a novel concept of a multi-hit hypothesis in the pathogenesis of gut inflammation, based on our updated knowledge of shared microbiological and immunological pathways between the oral and gut mucosae.
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Affiliation(s)
- Sho Kitamoto
- The World Premier International Research Center (WPI) Immunology Frontier Research Center (IFReC), 1012 IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Nobuhiko Kamada
- The World Premier International Research Center (WPI) Immunology Frontier Research Center (IFReC), 1012 IFReC Research Building, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA
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22
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Kitamoto S, Kamada N. Periodontal connection with intestinal inflammation: Microbiological and immunological mechanisms. Periodontol 2000 2022; 89:142-153. [PMID: 35244953 PMCID: PMC9018512 DOI: 10.1111/prd.12424] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Humans have coevolved with the trillions of resident microbes that populate every nook and cranny of the body. At each site, the resident microbiota creates a unique ecosystem specialized to its environment, benefiting the development and maintenance of human physiology through harmonious symbiotic relationships with the host. However, when the resident microbiota is perturbed, significant complications may arise with disastrous consequences that affect the local and distant ecosystems. In this context, periodontal disease results in inflammation beyond the oral cavity, such as in the gastrointestinal tract. Accumulating evidence indicates that potentially harmful oral resident bacteria (referred to as pathobionts) and pathogenic immune cells in the oral mucosa can migrate to the lower gastrointestinal tract and contribute to intestinal inflammation. We will review the most recent advances concerning the periodontal connection with intestinal inflammation from microbiological and immunological perspectives. Potential therapeutic approaches that target the connection between the mouth and the gut to treat gastrointestinal diseases, such as inflammatory bowel disease, will be examined. Deciphering the complex interplay between microbes and immunity along the mouth-gut axis will provide a better understanding of the pathogenesis of both oral and gut pathologies and present therapeutic opportunities.
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Affiliation(s)
- Sho Kitamoto
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Nobuhiko Kamada
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
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23
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Yin J, Elias R, Peng L, Levonyak N, Asokan A, Christie A, Kubiliun N, Brugarolas J, Hammers HJ. Chronic Use of Proton Pump Inhibitors Is Associated With an Increased Risk of Immune Checkpoint Inhibitor Colitis in Renal Cell Carcinoma. Clin Genitourin Cancer 2022; 20:260-269. [PMID: 35277350 PMCID: PMC9701615 DOI: 10.1016/j.clgc.2022.01.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 12/20/2021] [Accepted: 01/25/2022] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) have become a standard of care in metastatic renal cell carcinoma (mRCC) but are associated with immune-related adverse events (irAEs) including colitis. Growing evidence suggests proton pump inhibitors (PPIs) increase the risk of inflammatory bowel disease (IBD). Given the pathophysiological overlap between IBD and ICI colitis, we sought to evaluate the relationship between PPI use and ICI colitis in mRCC patients. PATIENTS AND METHODS We performed a retrospective study of adult patients who received ICI therapy for mRCC between 2015 and 2018 at University of Texas Southwestern Medical Center affiliated hospitals. Clinical characteristics, oncological outcomes, ICI colitis details, and PPI use details were collected by manual chart review. The diagnosis of ICI colitis was made via biopsy when available, or by clinical criteria (symptoms and response to immunosuppressive therapy) when biopsy specimens were unavailable or inconclusive. Univariable and multivariable logistic regression analyses were conducted to assess the potential contribution of PPIs to ICI colitis. RESULTS A total of 176 patients received ICI therapy for mRCC, of which 16 (9.1%) were diagnosed with ICI colitis. Patients with ICI colitis presented with elevated stool lactoferritin and calprotectin and a wide range of endoscopic and histologic findings. There were no significant differences between patients with and without ICI colitis in age, gender, medical comorbidities, RCC history, and overall survival. However, exposure to ipilimumab and PPI use were more frequently observed in patients with ICI colitis than those without. In univariable and multivariable logistic regression analyses, exposure to ipilimumab and chronic use of PPIs > 8 weeks were significantly associated with ICI colitis. CONCLUSION In addition to ipilimumab use, chronic use of PPIs may be associated with ICI colitis in patients with mRCC.
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Affiliation(s)
- Jianyi Yin
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - Roy Elias
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390,Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - Lan Peng
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - Nicholas Levonyak
- Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - Annapoorani Asokan
- University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - Alana Christie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - Nisa Kubiliun
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - James Brugarolas
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390,Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390
| | - Hans J Hammers
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
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24
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Son M, Park IS, Kim S, Ma HW, Kim JH, Kim TI, Kim WH, Han J, Kim SW, Cheon JH. Novel Potassium-Competitive Acid Blocker, Tegoprazan, Protects Against Colitis by Improving Gut Barrier Function. Front Immunol 2022; 13:870817. [PMID: 35693794 PMCID: PMC9174989 DOI: 10.3389/fimmu.2022.870817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by prolonged inflammation of the gastrointestinal tract. IBD can result from gut barrier dysfunction, altered gut microbiota, and abnormal intestinal immunity induced by environmental factors in genetically susceptible individuals. Proton pump inhibitors (PPIs) such as rabeprazole are frequently employed for gastric acid inhibition. However, long-term PPI administration can alter the intestinal microbiome composition, possibly worsening IBD severity. The present study revealed that tegoprazan, a potassium-competitive acid blocker, significantly improved colitis in mice and enhanced the intestinal epithelial barrier function. Tegoprazan alleviated gut microbiota dysbiosis and enhanced the growth of Bacteroides vulgatus. In turn, B. vulgatus alleviated intestinal inflammation by inhibiting epithelial adhesion of pathogenic bacteria. Unlike rabeprazole, tegoprazan did not induce gut dysbiosis. Our findings provide novel insights into the potential role of tegoprazan as an intestinal protectant for IBD and as a therapeutic agent for gastric acid-related diseases.
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Affiliation(s)
- Mijeong Son
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - I Seul Park
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Soochan Kim
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyun Woo Ma
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Ji Hyung Kim
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
| | - Jaeyong Han
- Department of Internal Medicine, Cha Ilsan Medical Center, CHA University, Goyang, South Korea
| | - Seung Won Kim
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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25
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D’sa FF, Fernandes EZ, Kesarkar SV, Swaminathan L, Kunhikatta V, Rashid M, Thunga G, Chandran VP, Nair S. Use of histamine‐2 receptor antagonists and risk of inflammatory bowel diseases: A systematic review and meta‐analysis of observational studies. J Clin Pharm Ther 2022; 47:1103-1111. [DOI: 10.1111/jcpt.13662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/09/2022] [Accepted: 03/21/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Freya Felicia D’sa
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Elaine Zourra Fernandes
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Srushti Vaibhav Kesarkar
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Lavanya Swaminathan
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Vijayanarayana Kunhikatta
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Muhammed Rashid
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Girish Thunga
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Viji Pulikkel Chandran
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
| | - Sreedharan Nair
- Department of Pharmacy Practice Manipal College of Pharmaceutical Sciences Manipal Academy of Higher Education Manipal India
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26
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Wellens J, Sabino J, Vermeire S. PPIs and anti-TNF in patients with IBD: a forbidden combination? Gut 2021; 70:2397-2398. [PMID: 33514599 DOI: 10.1136/gutjnl-2021-324040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/08/2022]
Affiliation(s)
- Judith Wellens
- Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Flanders, Belgium .,Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium
| | - João Sabino
- Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Flanders, Belgium.,Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium.,Department of Chronic Diseases Metabolism and Ageing, KU Leuven University Hospitals Leuven Campus Gasthuisberg, Leuven, Flanders, Belgium
| | - Séverine Vermeire
- Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Flanders, Belgium.,Department of Chronic Diseases Metabolism and Ageing, KU Leuven University Hospitals Leuven Campus Gasthuisberg, Leuven, Flanders, Belgium
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27
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Xia B, Yang M, Nguyen LH, He Q, Zhen J, Yu Y, Di M, Qin X, Lu K, Kuo ZC, He Y, Zhang C, Meng W, Yuan J. Regular Use of Proton Pump Inhibitor and the Risk of Inflammatory Bowel Disease: Pooled Analysis of 3 Prospective Cohorts. Gastroenterology 2021; 161:1842-1852.e10. [PMID: 34389338 DOI: 10.1053/j.gastro.2021.08.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Proton pump inhibitors (PPIs) have a major impact on gut microbiome and immune function, which in turn, may increase the risk of inflammatory bowel disease (IBD). Our aim in this study was to evaluate PPI use and subsequent risk of IBD and subtypes (ie, Crohn's disease and ulcerative colitis). METHODS This was a pooled analysis of the Nurses' Health Study (NHS, n = 82,869), NHS II (n = 95,141), and UK Biobank (n = 469,397). We included participants with information on personal use of PPIs and free of IBD or cancer at baseline. We evaluated hazard ratios and 95% confidence intervals (CIs) with Cox regression adjusting for lifestyle factors, PPI indications, comorbidities, and other medications. RESULTS We documented 271 cases of IBD (median follow-up, 12 years) in the pooled NHS cohorts and 1419 cases (median follow-up, 8.1 years) in the UK Biobank. For both pooled NHS cohorts and UK Biobank, regular use of PPIs consistently showed a significantly positive association with IBD, Crohn's disease, and ulcerative colitis risk. Combined analyses of 3 cohorts showed that regular PPI users had an increased risk of IBD as compared with nonusers (hazard ratio, 1.42; 95% CI, 1.22-1.65; number needed to harm, 3770; 95% CI, 3668-4369). Direct comparison with H2 receptor antagonist, a less potent acid suppressor, showed that PPI use was also associated with higher IBD risk (hazard ratio, 1.38; 95% CI, 1.16-1.65). CONCLUSIONS Regular use of PPIs was associated with an increased risk of IBD and its subtypes. The findings should be interpreted with caution because the absolute risk was low and the clinical benefits of PPIs are substantial.
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Affiliation(s)
- Bin Xia
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Man Yang
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long H Nguyen
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Qiangsheng He
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jie Zhen
- MRC Integrative Epidemiology Unit, Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, United Kingdom
| | - Yuanyuan Yu
- Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Mengyang Di
- Department of Hematology and Medical Oncology, Yale New Haven Hospital, Yale School of Medicine, New Haven, Connecticut
| | - Xiwen Qin
- Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Science, Monash University, Melbourne, Australia; Victorian Heart Institute, Monash University, Melbourne, Australia; School of Population and Global Health, Faculty of Medicine, Density and Health Sciences, University of Western Australia, Perth, Australia
| | - Kuiqing Lu
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Zi Chong Kuo
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yulong He
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Changhua Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China; Guangdong Provincial Key Laboratory of Gastroenterology, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
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28
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Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in Mice. Cell Mol Gastroenterol Hepatol 2021; 13:717-737. [PMID: 34781022 PMCID: PMC8783126 DOI: 10.1016/j.jcmgh.2021.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS We previously showed that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells. METHODS Analyses using online databases of single-cell RNA sequencing of intestinal epithelial cells in mice and RNA sequencing of mouse immune cells were performed to determine the relative abundances of 4 histamine receptors among different cell types. Mouse neutrophils, which expressed greater amounts of H2R, were collected from the peritoneum of wild-type and H2R-deficient mice, of which low-density and high-density neutrophils were extracted by centrifugation and were subjected to RNA sequencing. The effects of H2R activation on neutrophil differentiation and its functions in colitis and inflammation-associated colon tumors were investigated in a mouse model of dextran sulfate sodium-induced colitis. RESULTS Data analysis of RNA sequencing and quantitative reverse-transcription polymerase chain reaction showed that Hrh2 is highly expressed in neutrophils, but barely detectable in intestinal epithelial cells. In mice, the absence of H2R activation promoted infiltration of neutrophils into both sites of inflammation and colonic tumors. H2R-deficient high-density neutrophils yielded proinflammatory features via nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and suppressed T-cell proliferation. On the other hand, low-density neutrophils, which totally lack H2R activation, showed an immature phenotype compared with wild-type low-density neutrophils, with enhanced MYC pathway signaling and reduced expression of the maturation marker Toll-like receptor 4. CONCLUSIONS Blocking H2R signaling enhanced proinflammatory responses of mature neutrophils and suppressed neutrophil maturation, leading to accelerated progression of inflammation-associated colonic tumorigenesis.
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29
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Lu TX, Dapas M, Lin E, Peters T, Sakuraba A. The influence of proton pump inhibitor therapy on the outcome of infliximab therapy in inflammatory bowel disease: a patient-level meta-analysis of randomised controlled studies. Gut 2021; 70:2076-2084. [PMID: 33334900 DOI: 10.1136/gutjnl-2020-321609] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE In treating patients with inflammatory bowel disease (IBD), how concomitant medications influence the response to infliximab is largely unexplored. We aim to evaluate whether proton pump inhibitors (PPIs) affect the response to infliximab therapy in patients with IBD. DESIGN Patient-level data of adult patients with moderate-to-severe IBD treated with infliximab were obtained from the Yale Open Data Access Framework. Multivariable analysis and propensity score-matched analysis were performed to assess week 30 remission rates, week 54 remission rates and hospitalisation rates in patients on infliximab therapy with and without PPI exposure. RESULTS Among the five randomised controlled studies, there were 147 and 889 patients on infliximab with and without PPI therapy, respectively. Patients on PPI were older, more likely to be Caucasian and were less likely to be on immunomodulator therapy. Patients on PPI were significantly less likely to achieve week 30 remission on multivariable analysis (OR 0.45, p<0.001). Following propensity score matching adjusting for baseline difference in patient characteristics, the week 30 remission rates were 30% and 49% in patients with and without PPI therapy, respectively (p<0.001). Analysing separately for disease, the findings remained statistically significant in Crohn's disease but did not reach significance in UC. Similar results were seen with week 54 remission rates. Patients on PPI were also more likely to be hospitalised (15% vs 8%, p=0.007). Rates of adverse events such as gastroenteritis were not different between the two groups. CONCLUSION In this patient-level meta-analysis of randomised controlled studies, we found that patients with IBD taking PPI were less likely to achieve remission while on infliximab therapy. The results of our study warrant further investigation into the effect of PPI on IBD outcomes and therapies.
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Affiliation(s)
- Thomas X Lu
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
- Indiana University Health Southern Indiana Physicians, Bloomington, IN, USA
- The Graham School of Continuing Liberal and Professional Studies, University of Chicago, Chicago, IL, USA
| | - Matthew Dapas
- The Graham School of Continuing Liberal and Professional Studies, University of Chicago, Chicago, IL, USA
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
| | - Erika Lin
- The Graham School of Continuing Liberal and Professional Studies, University of Chicago, Chicago, IL, USA
| | - Trevor Peters
- The Graham School of Continuing Liberal and Professional Studies, University of Chicago, Chicago, IL, USA
| | - Atsushi Sakuraba
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
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30
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Read E, Curtis MA, Neves JF. The role of oral bacteria in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2021; 18:731-742. [PMID: 34400822 DOI: 10.1038/s41575-021-00488-4] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/23/2021] [Indexed: 02/06/2023]
Abstract
Over the past two decades, the importance of the microbiota in health and disease has become evident. Pathological changes to the oral bacterial microbiota, such as those occurring during periodontal disease, are associated with multiple inflammatory conditions, including inflammatory bowel disease. However, the degree to which this association is a consequence of elevated oral inflammation or because oral bacteria can directly drive inflammation at distal sites remains under debate. In this Perspective, we propose that in inflammatory bowel disease, oral disease-associated bacteria translocate to the intestine and directly exacerbate disease. We propose a multistage model that involves pathological changes to the microbial and immune compartments of both the oral cavity and intestine. The evidence to support this hypothesis is critically evaluated and the relevance to other diseases in which oral bacteria have been implicated (including colorectal cancer and liver disease) are discussed.
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Affiliation(s)
- Emily Read
- Centre for Host-Microbiome Interactions, King's College London, London, UK.,Wellcome Trust Cell Therapies and Regenerative Medicine PhD Programme, King's College London, London, UK
| | - Michael A Curtis
- Centre for Host-Microbiome Interactions, King's College London, London, UK
| | - Joana F Neves
- Centre for Host-Microbiome Interactions, King's College London, London, UK.
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31
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Rameau A, Andreadis K, Bayoumi A, Kaufman M, Belafsky P. Side Effects of Proton Pump Inhibitors: What are Patients’ Concerns? J Voice 2021; 35:809.e15-809.e20. [DOI: 10.1016/j.jvoice.2020.01.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 02/06/2023]
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Upper gastrointestinal tract involvement in Crohn's disease: A case report. Int J Surg Case Rep 2021; 81:105810. [PMID: 33887830 PMCID: PMC8041720 DOI: 10.1016/j.ijscr.2021.105810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 03/20/2021] [Indexed: 01/25/2023] Open
Abstract
Upper gastrointestinal tract manifestations of Crohn’s disease are unusual. There is limited literature guiding management decisions in affected patients. This case report highlights surgical management in this aspect of Crohn’s disease. Background Crohn’s disease (CD) is an inflammatory bowel disease that typically affects the distal part of the gastrointestinal tract (GI) such as the terminal ileum and colon. However, it can affect the upper GI tract, potentially resulting in complications such as strictures, but discussion of the management of such effects is limited in the surgical literature. Case presentation A 39 year old male was referred to our department with stricturing upper GI disease 20 years after CD diagnosis. He had a history of intermittent abdominal pain, nausea, frequent vomiting and weight loss. Imaging demonstrated a long stricture in the duodenum with proximal dilatation. There was no evidence of acute inflammatory Crohn’s disease. A Roux-en-Y bypass was performed to successfully relieve the obstructive symptoms. Discussion Proximal obstructive gastrointestinal manifestations of CD are a rare entity and require a full diagnostic workup and treatment in a specialist centre. A variety of systemic treatments, endoscopic procedures and surgical techniques are addressed in this paper. Conclusion Evidence for the optimal treatment of obstructive upper gastrointestinal CD is limited, but careful consideration of the extent of the disease, thorough preoperative planning and weighing up the benefits and risks can lead to a positive outcome for these patients.
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Effinger A, O'Driscoll CM, McAllister M, Fotaki N. Predicting budesonide performance in healthy subjects and patients with Crohn's disease using biorelevant in vitro dissolution testing and PBPK modeling. Eur J Pharm Sci 2021; 157:105617. [PMID: 33164838 DOI: 10.1016/j.ejps.2020.105617] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 10/02/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Drug product performance might be affected in Crohn's disease (CD) patients compared to healthy subjects due to pathophysiological changes. Since a low number of clinical studies is performed in this patient population, physiologically-based pharmacokinetic (PBPK) models with integrated results from biorelevant in vitro dissolution studies could be used to assess differences in the bioavailability of drugs. Using this approach, budesonide was used as model drug and its performance in healthy subjects and CD patients was predicted and compared against observed pharmacokinetic data. The in vitro release tests, under healthy versus CD conditions, revealed a similar extent of drug release from a controlled-release budesonide formulation in the fasted state, whereas in the fed state a lower extent was observed with CD. Differences in the physiology of CD patients were identified in literature and their impact on budesonide performance was investigated with a PBPK model, revealing the highest impact on the simulated bioavailability for the reduced hepatic CYP3A4 enzyme abundance and lower human serum albumin concentration. For CD patients, a higher budesonide exposure compared to healthy subjects was predicted with a PBPK population adapted to CD physiology and in agreement with observed pharmacokinetic data. Budesonide performance in the fasted and fed state was successfully predicted in healthy subjects and CD patients using PBPK modeling and in vitro release testing. Following this approach, predictions of the direction and magnitude of changes in bioavailability due to CD could be made for other drugs and guide prescribers to adjust dosage regimens for CD patients accordingly.
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Affiliation(s)
- Angela Effinger
- Department of Pharmacy and Pharmacology, University of Bath, Bath, UK
| | | | | | - Nikoletta Fotaki
- Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
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Histamine H 2-Receptor Antagonists Improve Non-Steroidal Anti-Inflammatory Drug-Induced Intestinal Dysbiosis. Int J Mol Sci 2020; 21:ijms21218166. [PMID: 33142910 PMCID: PMC7662336 DOI: 10.3390/ijms21218166] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/19/2022] Open
Abstract
Dysbiosis, an imbalance of intestinal flora, can cause serious conditions such as obesity, cancer, and psychoneurological disorders. One cause of dysbiosis is inflammation. Ulcerative enteritis is a side effect of non-steroidal anti-inflammatory drugs (NSAIDs). To counteract this side effect, we proposed the concurrent use of histamine H2 receptor antagonists (H2RA), and we examined the effect on the intestinal flora. We generated a murine model of NSAID-induced intestinal mucosal injury, and we administered oral H2RA to the mice. We collected stool samples, compared the composition of intestinal flora using terminal restriction fragment length polymorphism, and performed organic acid analysis using high-performance liquid chromatography. The intestinal flora analysis revealed that NSAID [indomethacin (IDM)] administration increased Erysipelotrichaceae and decreased Clostridiales but that both had improved with the concurrent administration of H2RA. Fecal levels of acetic, propionic, and n-butyric acids increased with IDM administration and decreased with the concurrent administration of H2RA. Although in NSAID-induced gastroenteritis the proportion of intestinal microorganisms changes, leading to the deterioration of the intestinal environment, concurrent administration of H2RA can normalize the intestinal flora.
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Scarpignato C, Hongo M, Wu JCY, Lottrup C, Lazarescu A, Stein E, Hunt RH. Pharmacologic treatment of GERD: Where we are now, and where are we going? Ann N Y Acad Sci 2020; 1482:193-212. [PMID: 32935346 DOI: 10.1111/nyas.14473] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/20/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023]
Abstract
The introduction of acid inhibition in clinical practice has revolutionized the management of acid-related diseases, leading to the virtual abolition of elective surgery for ulcer disease and relegating antireflux surgery to patients with gastroesophageal reflux disease (GERD) not adequately managed by medical therapy. Proton pump inhibitors (PPIs) are the antisecretory drugs of choice for the treatment of reflux disease. However, these drugs still leave some unmet clinical needs in GERD. PPI-refractoriness is common, and persistent symptoms are observed in up to 40-55% of daily PPI users. Potassium-competitive acid blockers (P-CABs) clearly overcome many of the drawbacks and limitations of PPIs, achieving rapid, potent, and prolonged acid suppression, offering the opportunity to address many of the unmet needs. In recent years, it has been increasingly recognized that impaired mucosal integrity is involved in the pathogenesis of GERD. As a consequence, esophageal mucosal protection has emerged as a new, promising therapeutic avenue. When P-CABS are used as add-on medications to standard treatment, a growing body of evidence suggests a significant additional benefit, especially in the relief of symptoms not responding to PPI therapy. On the contrary, reflux inhibitors are considered a promise unfulfilled, and prokinetic agents should only be used on a case-by-case basis.
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Affiliation(s)
- Carmelo Scarpignato
- Department of Health Sciences, United Campus of Malta, Msida, Malta.,Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
| | - Michio Hongo
- Department of Comprehensive Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Justin C Y Wu
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong, China
| | - Christian Lottrup
- Department of Medicine, Aalborg University Hospital, Hobro, Denmark.,Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmak
| | - Adriana Lazarescu
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Ellen Stein
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Richard H Hunt
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Grover S, Dougan M, Tyan K, Giobbie-Hurder A, Blum SM, Ishizuka J, Qazi T, Elias R, Vora KB, Ruan AB, Martin-Doyle W, Manos M, Eastman L, Davis M, Gargano M, Haq R, Buchbinder EI, Sullivan RJ, Ott PA, Hodi FS, Rahma OE. Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis. Cancer 2020; 126:3758-3767. [PMID: 32567084 DOI: 10.1002/cncr.32966] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.
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Affiliation(s)
- Shilpa Grover
- Harvard Medical School, Boston, Massachusetts.,Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael Dougan
- Harvard Medical School, Boston, Massachusetts.,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Kevin Tyan
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Anita Giobbie-Hurder
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Steven M Blum
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Broad Institute at MIT and Harvard, Cambridge, Massachusetts.,Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Jeffrey Ishizuka
- Departments of Medicine and Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Taha Qazi
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.,Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Rawad Elias
- Hartford HealthCare Cancer Institute, Hartford, Connecticut
| | | | - Alex B Ruan
- Harvard Medical School, Boston, Massachusetts
| | - William Martin-Doyle
- Harvard Medical School, Boston, Massachusetts.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael Manos
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Lauren Eastman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Meredith Davis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Maria Gargano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Rizwan Haq
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Elizabeth I Buchbinder
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Ryan J Sullivan
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Patrick A Ott
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Broad Institute at MIT and Harvard, Cambridge, Massachusetts.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - F Stephen Hodi
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Osama E Rahma
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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Kitamoto S, Nagao-Kitamoto H, Jiao Y, Gillilland MG, Hayashi A, Imai J, Sugihara K, Miyoshi M, Brazil JC, Kuffa P, Hill BD, Rizvi SM, Wen F, Bishu S, Inohara N, Eaton KA, Nusrat A, Lei YL, Giannobile WV, Kamada N. The Intermucosal Connection between the Mouth and Gut in Commensal Pathobiont-Driven Colitis. Cell 2020; 182:447-462.e14. [PMID: 32758418 DOI: 10.1016/j.cell.2020.05.048] [Citation(s) in RCA: 401] [Impact Index Per Article: 80.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 04/22/2020] [Accepted: 05/26/2020] [Indexed: 12/19/2022]
Abstract
The precise mechanism by which oral infection contributes to the pathogenesis of extra-oral diseases remains unclear. Here, we report that periodontal inflammation exacerbates gut inflammation in vivo. Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation. In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut. When in the gut, Th17 cells of oral origin can be activated by translocated oral pathobionts and cause development of colitis, but they are not activated by gut-resident microbes. Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells.
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Affiliation(s)
- Sho Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Hiroko Nagao-Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Yizu Jiao
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Merritt G Gillilland
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Atsushi Hayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Research Laboratory, Miyarisan Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Jin Imai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Kohei Sugihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mao Miyoshi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | - Peter Kuffa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Brett D Hill
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Syed M Rizvi
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Fei Wen
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Shrinivas Bishu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Naohiro Inohara
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Kathryn A Eaton
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Asma Nusrat
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Yu L Lei
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - William V Giannobile
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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Sohn J, Sun Y, Genco RJ, Kirkwood KL. The Periodontal Microenvironment: a Potential Reservoir for Intestinal Pathobionts in Crohn’s Disease. CURRENT ORAL HEALTH REPORTS 2020; 7:37-44. [DOI: 10.1007/s40496-020-00251-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Schwartz NRM, Hutfless S, Herrinton LJ, Amsden LB, Fevrier HB, Giefer M, Lee D, Suskind DL, Delaney JAC, Phipps AI. Proton Pump Inhibitors, H 2 Blocker Use, and Risk of Inflammatory Bowel Disease in Children. J Pediatr Pharmacol Ther 2019; 24:489-496. [PMID: 31719810 DOI: 10.5863/1551-6776-24.6.489] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Evidence suggests use of proton pump inhibitors (PPIs) and H2 blockers may provoke disease flares in individuals with established inflammatory bowel disease (IBD); however, there are no studies investigating the relationship of these medications with risk of developing pediatric IBD. The hypothesis was that use of acid suppression therapy in children might be associated with development of pediatric IBD. METHODS This was a nested case-control study of 285 Kaiser Permanente Northern California members, age ≤21 years diagnosed with IBD from 1996 to 2016. Four controls without IBD were matched to each case on age, race, and membership status at the case's index date. Disease risk scores (DRS) were computed for each subject. Odds ratios and 95% confidence intervals were calculated by using conditional logistic regression models adjusted for DRS. RESULTS The children's mean age was 15.1 ± 2.6 years and 49.5% were female. Six cases (n = 3 Crohn's disease [CD], n = 3 ulcerative colitis [UC]) and 6 controls were prescribed PPIs and 10 cases (n = 7 CD, n = 3 UC) and 28 controls were prescribed H2 blockers. The OR for the association of at least 1 PPI or H2 blocker prescription with subsequent IBD was 3.6 (95% CI, 1.1-11.7) for PPIs and 1.6 (95% CI, 0.7-3.7) for H2 blockers. CONCLUSIONS Early-life PPI use appears to be associated with subsequent IBD risk. These findings have implications for clinical treatment of children with gastrointestinal symptoms and warrant further investigation in a larger cohort.
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Segregur D, Flanagan T, Mann J, Moir A, Karlsson EM, Hoch M, Carlile D, Sayah-Jeanne S, Dressman J. Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Tests to Reflect These Changes. J Pharm Sci 2019; 108:3461-3477. [PMID: 31265846 DOI: 10.1016/j.xphs.2019.06.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/25/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023]
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Bruno G, Zaccari P, Rocco G, Scalese G, Panetta C, Porowska B, Pontone S, Severi C. Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified. World J Gastroenterol 2019; 25:2706-2719. [PMID: 31235994 PMCID: PMC6580352 DOI: 10.3748/wjg.v25.i22.2706] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/02/2019] [Accepted: 04/19/2019] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors (PPIs) are common medications within the practice of gastroenterology. These drugs, which act through the irreversible inhibition of the hydrogen/potassium pump (H+/K+-ATPase pump) in the gastric parietal cells, are used in the treatment of several acid-related disorders. PPIs are generally well tolerated but, through the long-term reduction of gastric acid secretion, can increase the risk of an imbalance in gut microbiota composition (i.e., dysbiosis). The gut microbiota is a complex ecosystem in which microbes coexist and interact with the human host. Indeed, the resident gut bacteria are needed for multiple vital functions, such as nutrient and drug metabolism, the production of energy, defense against pathogens, the modulation of the immune system and support of the integrity of the gut mucosal barrier. The bacteria are collected in communities that vary in density and composition within each segment of the gastrointestinal (GI) tract. Therefore, every change in the gut ecosystem has been connected to an increased susceptibility or exacerbation of various GI disorders. The aim of this review is to summarize the recently available data on PPI-related microbiota alterations in each segment of the GI tract and to analyze the possible involvement of PPIs in the pathogenesis of several specific GI diseases.
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Affiliation(s)
- Giovanni Bruno
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Piera Zaccari
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Giulia Rocco
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Giulia Scalese
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Cristina Panetta
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Barbara Porowska
- Department of Cardio-Thoracic, Vascular Surgery and Transplants, Sapienza University of Rome, Rome 00161, Italy
| | - Stefano Pontone
- Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
| | - Carola Severi
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
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Sonnenberg A, Turner KO, Genta RM. Decreased risk for microscopic colitis and inflammatory bowel disease among patients with reflux disease. Colorectal Dis 2018; 20:813-820. [PMID: 29603881 DOI: 10.1111/codi.14114] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 03/20/2018] [Indexed: 02/08/2023]
Abstract
AIM Previous studies have found an increased risk for microscopic colitis (MC) associated with proton pump inhibitors. In patients with ulcerative colitis (UC) or Crohn's disease (CD), proton pump inhibitors have been associated with an increased risk for IBD flares and impaired outcomes. The aim of this study was to test the epidemiological associations between gastro-oesophageal reflux disease (GERD) and MC, UC or CD in a large database. METHOD The Miraca Life Sciences Database is a national electronic repository of histopathological records of patients distributed throughout the entire USA. A case-control study evaluated whether the presence of Barrett's metaplasia, erosive oesophagitis on endoscopy or histological signs of reflux oesophagitis, clinical diagnosis of GERD or any GERD type affected the occurrence of MC, UC or CD among 228 506 subjects undergoing bidirectional endoscopy. Multivariate logistic regression analyses were used to calculate ORs and their 95% CI for the risk of MC, UC or CD associated with various types of GERD and were adjusted for age, sex and presence of Helicobacter pylori. RESULTS The analysis revealed an inverse relationship between GERD and different types of inflammatory bowel disease. The inverse relationships applied similarly to MC (mean = 0.62, 95% CI: 0.58-0.66), UC (mean = 0.89, 95% CI: 0.81-0.97) and CD (mean = 0.76, 95% CI: 0.69-0.85). It also applied to different forms of GERD, with a trend towards more pronounced inverse relationships associated with Barrett's metaplasia or erosive oesophagitis than clinical diagnosis of GERD. CONCLUSION Gastro-oesophageal reflux disease is inversely associated with all forms of inflammatory bowel disease, such as MC, UC, or CD.
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Affiliation(s)
- A Sonnenberg
- Division of Gastroenterology, Portland VA Medical Center and Oregon Health & Science University, Portland, OR, USA
| | | | - R M Genta
- Miraca Life Sciences, Irving, TX, USA.,Baylor College of Medicine, Houston, TX, USA
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Naito Y, Kashiwagi K, Takagi T, Andoh A, Inoue R. Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use. Digestion 2018; 97:195-204. [PMID: 29316555 DOI: 10.1159/000481813] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gut dysbiosis associated with the use of proton-pump inhibitors (PPIs) has been found to lead to the occurrence of infectious and inflammatory adverse events. A longitudinal observational cohort study has demonstrated the heightened risk of death associated with PPI use. SUMMARY We evaluated meta-analyses to determine the association between PPI use and infectious and inflammatory diseases. Meta-analyses showed that PPI use is a potential risk for the development of enteric infections caused by Clostridium difficile, as well as small intestinal bacterial overgrowth, spontaneous bacterial peritonitis, community-acquired pneumonia, hepatic encephalopathy, and adverse outcomes in inflammatory bowel disease. We also examined changes in the composition and function of the gut microbiota with the use of PPIs. PPI use significantly increased the presence of Streptococcaceae and Enterococcaceae, which are risk factors for C. difficile infection, and decreased that of Faecalibacterium, a commensal anti-inflammatory microorganism. Key Message: High-throughput, microbial 16S rRNA gene sequencing has allowed us to investigate the association between the gut microbiome and PPI use. Future prospective comparison studies are necessary to confirm this association, and to develop new strategies to prevent complications of PPI use.
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Affiliation(s)
- Yuji Naito
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Microbial Metabolism in the Mammalian Gut: Molecular Mechanisms and Clinical Implications. J Pediatr Gastroenterol Nutr 2018; 66 Suppl 3:S72-S79. [PMID: 29762384 DOI: 10.1097/mpg.0000000000001857] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Human intestinal microbes participate actively at the interface of diet, nutrition, and overall health status. These biodiverse communities of microorganisms have a broader metabolic repertoire compared with their host, and they are able to synthesize and degrade substrates that would be otherwise unavailable. In recent years, we have recognized that healthy microbial communities are important for energy harvest and the regulation of body systems outside the digestive tract. Microbial dysbiosis, however, has been implicated in a number of human disorders, including obesity and inflammation. This dichotomy highlights the need to understand the factors that determine the composition and metabolic output of our resident and transient microbes. Throughout the human lifespan, we know that diet plays a major role in shaping gut microbial communities, as well as directing the types and amounts of metabolites produced. Understanding the factors that affect microbial metabolic output within the host may help identify the roles of microbes in health, as well as new targets for treatment in disease. In this article, we review facets of the assembly and activities of the healthy human intestinal microbiome, as well as ways that the microbiota has been shown to influence the host via metabolism of two dietary macronutrients: carbohydrates and amino acids.
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Su T, Lai S, Lee A, He X, Chen S. Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. J Gastroenterol 2018; 53:27-36. [PMID: 28770351 DOI: 10.1007/s00535-017-1371-9] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 07/15/2017] [Indexed: 02/06/2023]
Abstract
The use of proton pump inhibitors (PPIs) may potentially predispose to the development of small intestinal bacterial overgrowth (SIBO), but this association is controversial due to conflicting results from studies conducted to date. The aim of this meta-analysis was to evaluate the association between the use of PPIs and the risk of SIBO. We systematically searched the online PubMed, Embase, and Cochrane Library databases and Web of Science for relevant articles published up to November 2016. Two researchers identified and extracted data independent of each other. The pooled analysis was performed using the generic inverse-variance random-effects model. Subgroup and sensitivity analysis were conducted to assess the stability and heterogeneity of the pooled results. The risk of publication bias was evaluated by assessing for funnel plot asymmetry and by Egger's test and Begg's test. A total of 19 articles met the eligibility criteria for the meta-analysis, reporting on 7055 subjects. The pooled odds ratio (OR) showed a statistically significant association between increased risk of SIBO and PPI use (OR 1.71, 95% confidence interval 1.20-2.43). Subgroup analyses demonstrated an association between SIBO and PPI use in studies that employed small bowel aspirates culture and glucose hydrogen breath tests (GHBT) as diagnostic tests for SIBO. Our meta-analysis suggests that the use of PPI moderately increases the risk of SIBO, thereby highlighting the need for appropriate prescribing of PPIs.
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Affiliation(s)
- Tingting Su
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Sanchuan Lai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Allen Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Hospital, Ann Arbor, MI, USA.
| | - Xingkang He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China.,Institute of Gastroenterology, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Shujie Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China. .,Institute of Gastroenterology, Zhejiang University, Hangzhou, 310016, Zhejiang, China.
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Wallace JL, Ianaro A, de Nucci G. Gaseous Mediators in Gastrointestinal Mucosal Defense and Injury. Dig Dis Sci 2017; 62:2223-2230. [PMID: 28733867 DOI: 10.1007/s10620-017-4681-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 07/11/2017] [Indexed: 12/26/2022]
Abstract
Of the numerous gaseous substances that can act as signaling molecules, the best characterized are nitric oxide, carbon monoxide and hydrogen sulfide. Contributions of each of these low molecular weight substances, alone or in combination, to maintenance of gastrointestinal mucosal integrity have been established. There is considerable overlap in the actions of these gases in modulating mucosal defense and responses to injury, and in some instances they act in a cooperative manner. Each also play important roles in regulating inflammatory and repair processes throughout the gastrointestinal tract. In recent years, significant progress has been made in the development of novel anti-inflammatory and cytoprotective drugs that exploit the beneficial activities of one or more of these gaseous mediators.
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Affiliation(s)
- John L Wallace
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. .,Department of Medicine, Universidade Camilo Castelo Branco, Fernandopolis, SP, Brazil.
| | - Angela Ianaro
- Department of Experimental Pharmacology, University of Naples, Naples, Italy
| | - Gilberto de Nucci
- Department of Medicine, Universidade Camilo Castelo Branco, Fernandopolis, SP, Brazil
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