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Brusselaers N, Gudnadottir U, Engstrand L, Lilja HE. Trends in Proton Pump Inhibitor Use in Sweden by Sex and Age: A Drug Utilisation Study. Drug Saf 2025; 48:389-400. [PMID: 39645619 PMCID: PMC11903566 DOI: 10.1007/s40264-024-01502-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are among the most popular drugs worldwide. Yet, there are concerns on long-term safety and poor adherence to prescription guidelines. Off-label use in children and increasing maintenance use in older adults may be particularly worrisome. OBJECTIVES To assess differences in PPI use by age, sex calendar year and PPI type, and to explore potential underlying indications (ulcerogenic drugs, and indications) in Sweden. METHODS Proton pump inhibitor drug utilisation study based on the Swedish nationwide prescribed drug (2006-2023) and patient registries (2006-2022). RESULTS Proton pump inhibitors were used by 14.4% (women) and 10.5% (men) of adults; and 1.0-1.5% of children and adolescents (aged < 20 years). Proton pump inhibitor use was higher in women in all age-groups except small children (aged < 5 years). Proton pump inhibitor use has increased in all age groups, especially in young children (aged < 10 years) and the oldest groups (aged > 65 years). Proton pump inhibitor users aged > 85 years filled most prescriptions with an annual average of 9.5 (men), 11.6 (women) prescriptions. Most prescriptions were for omeprazole and esomeprazole: 63.7% and 23.5% in adults; 23.5% and 44.7% in children (2023). Prescriptions for other drugs for peptic ulcers/reflux became rare, with 99% of prescriptions in this category being PPIs by 2023. Gastro-intestinal diagnoses were predominantly recorded in men, became less prevalent and only explained part of PPI use, while ulcerogenic drugs were common (particularly in women), suggesting PPIs are regularly used for gastroprotection. CONCLUSION Proton pump inhibitor use has doubled in children and increased 50% in adults over the study period, in both sexes, while recorded gastrointestinal indications decreased. Alternative therapies were rarely prescribed in Sweden.
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Affiliation(s)
- Nele Brusselaers
- Department of Women's and Children's Health, Karolinska Institutet, Tomtebodavägen 18A, 17177, Stockholm, Sweden.
- Department of Microbiology, Tumour and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institutet, Stockholm, Sweden.
- Department of Family Medicine and Primary Care, Global Health Institute, University of Antwerp, Antwerp, Belgium.
- Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
| | - Unnur Gudnadottir
- Department of Microbiology, Tumour and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institutet, Stockholm, Sweden
| | - Lars Engstrand
- Department of Microbiology, Tumour and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institutet, Stockholm, Sweden
| | - Helene E Lilja
- Department of Women's and Children's Health, Karolinska Institutet, Tomtebodavägen 18A, 17177, Stockholm, Sweden
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Wen S, Zhao X, Lin X, Fu Z, Qin S, Pan Q, Liu F, He W, Liu T. Acupoint catgut embedding advantage in treating gastro-oesophageal reflux disease (ACE-GERD): study protocol for a randomised controlled trial. BMJ Open 2024; 14:e081059. [PMID: 39419622 PMCID: PMC11488128 DOI: 10.1136/bmjopen-2023-081059] [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: 10/17/2023] [Accepted: 10/02/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Gastro-oesophageal reflux disease (GERD) is a highly prevalent disorder worldwide and developing effective treatment strategies for GERD is a clinical priority. GERD is associated with anxiety and depression. Several approaches have been developed to improve GERD, although effectiveness is limited. Acupoint catgut embedding (ACE) is an established technique in traditional Chinese medicine for the treatment of anxiety and depression. This study will investigate the effects of ACE on anxiety, depression, acid reflux and heartburn in patients with GERD. METHODS The ACE-GERD trial is a single-centre, prospective randomised controlled trial. 62 patients will be randomly assigned equally to the experimental and control groups. Patients will be treated with ACE or sham ACE. In the experimental group, absorbable polyglycolic acid sutures will be implanted at the acupoints using sterile disposable injection needles. The sham ACE treatment will exhibit similar surface characteristics but lack absorbable polyglycolic acid sutures. Treatments will be administered every 2 weeks for a period of 10 weeks. The main outcome measure is the Reflux Disease Questionnaire symptom score. Secondary outcomes are the endoscopic assessment, 24-hour pH/impedance monitoring test, oesophageal high-resolution manometer, Gastro-oesophageal Reflux Disease Questionnaire score, Gastro-oesophageal Reflux Disease Health-related Quality of Life, Self-rating Anxiety Scale and Self-rating Depression Scale scores. DISCUSSION The ACE-GERD trial aims to evaluate the efficacy of ACE treatment as a therapeutic tool for improving anxiety, depression, acid reflux and heartburn in patients with GERD and to provide the evidence base for future clinical studies. ETHICS AND DISSEMINATION The trial has been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (ethics no. BF2023-113-01). Results will be published in peer-reviewed journals and presented at scientific conferences and meetings. TRIAL REGISTRATION NUMBER ChiCTR2300074643.
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Affiliation(s)
- Shuting Wen
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
China
| | - Xiying Zhao
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
China
| | - Xiaofeng Lin
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
China
| | - Zhaoli Fu
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
China
| | - Shumin Qin
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
China
| | - Qimou Pan
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
China
| | - Fengbin Liu
- Department of
Gastroenterology, Guangzhou University of Traditional Chinese
Medicine First Affiliated Hospital, Guangzhou, Guangdong,
China
| | - Wenfang He
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
China
| | - Tianwen Liu
- Department of
Gastroenterology, The Second Affiliated Hospital of Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong,
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] [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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Mohamed ME, Saqr A, Staley C, Onyeaghala G, Teigen L, Dorr CR, Remmel RP, Guan W, Oetting WS, Matas AJ, Israni AK, Jacobson PA. Pharmacomicrobiomics: Immunosuppressive Drugs and Microbiome Interactions in Transplantation. Transplantation 2024; 108:1895-1910. [PMID: 38361239 PMCID: PMC11327386 DOI: 10.1097/tp.0000000000004926] [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] [Indexed: 02/17/2024]
Abstract
The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high.
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Affiliation(s)
- Moataz E Mohamed
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Abdelrahman Saqr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | | | - Guillaume Onyeaghala
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Levi Teigen
- Department of Food Science and Nutrition, University of Minnesota, St Paul, MN
| | - Casey R Dorr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, University of Minnesota, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
| | - Rory P Remmel
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN
| | - William S Oetting
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, MN
| | - Ajay K Israni
- Hennepin Healthcare Research Institute, Minneapolis, MN
- Department of Medicine, Hennepin Healthcare, Minneapolis, MN
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN
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Zhang YJ, Connearney S, Hester L, Du M, Catacora A, Akkara A, Wen A, Bry L, Alm EJ, Rosen R. Longitudinal Microbiome Changes in Children Exposed to Proton Pump Inhibitors. Clin Transl Gastroenterol 2024; 15:e1. [PMID: 38624107 PMCID: PMC11421719 DOI: 10.14309/ctg.0000000000000703] [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: 01/10/2024] [Accepted: 03/30/2024] [Indexed: 04/17/2024] Open
Abstract
INTRODUCTION Proton pump inhibitor (PPI) use has been associated with an increased risk of gastrointestinal and upper respiratory infections in children. There are limited longitudinal data on the effect of PPI in children. The goal of this prospective observational study was to compare the stool and oropharyngeal microbiome of children before and after starting PPIs. METHODS We prospectively recruited participants from a gastroenterology clinic. Consented participants provided stool samples and oropharyngeal swabs at baseline and after 8 weeks of PPI therapy. Microbiome changes were measured by analyzing 16S sequencing from both body sites at both time points. RESULTS Thirty-four participants completed the study and provided samples both at baseline and after 8 weeks on PPI therapy. Of those, 24 participants had sufficient sequencing from both stool and oropharyngeal samples at both time points. There were no differences between the pre-PPI and post-PPI samples using beta-diversity metrics in either the oropharynx or stool. There were, however, significant changes in specific taxa. There was an enrichment of Streptococcus in the stool after PPI use and a reduction in the relative abundance of Bifidobacterium , Peptostreptococcus , and Turicibacter ( P -values < 0.01). Furthermore, there was an increase in the relative abundance of oropharyngeal bacteria in the stool after PPI therapy. This enrichment of oropharyngeal bacteria in the stool was most prominent in younger participants. DISCUSSION Further investigation is needed to determine the clinical and microbial factors that predispose or protect against microbiome changes due to PPI use and why young children are more susceptible to this PPI effect.
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Affiliation(s)
- Yanjia Jason Zhang
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
- Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sarah Connearney
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Lisa Hester
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Maritha Du
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Andrea Catacora
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Anna Akkara
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Anna Wen
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Lynn Bry
- Massachusetts Host-Microbiome Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Clinical Microbiology Laboratory, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Eric J. Alm
- Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Rachel Rosen
- Gastroenterology/Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
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Xiao X, Zhang X, Wang J, Liu Y, Yan H, Xing X, Yang J. Proton pump inhibitors alter gut microbiota by promoting oral microbiota translocation: a prospective interventional study. Gut 2024; 73:1098-1109. [PMID: 38267200 DOI: 10.1136/gutjnl-2023-330883] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 01/08/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND The mechanism by which proton pump inhibitors (PPIs) alter gut microbiota remains to be elucidated. We aimed to learn whether PPI induced gut microbiota alterations by promoting oral microbial translocation. METHODS Healthy adult volunteers were randomly assigned: PP group (n=8, 40 mg esomeprazole daily for seven days) and PM group (n=8, 40 mg esomeprazole along with chlorhexidine mouthwash after each meal for seven days). Fecal and saliva samples were analysed using 16S ribosomal RNA sequencing. Mouse models were introduced to confirm the findings in vivo, while the effect of pH on oral bacteria proliferation activity was investigated in vitro. RESULTS Taxon-based analysis indicated that PPI administration increased Streptococcus abundance in gut microbiota (P<0.001), and the increased species of Streptococcus were found to be from the oral site or oral/nasal sites, in which Streptococcus anginosus was identified as the significantly changed species (P<0.004). Microbial source tracker revealed that PPI significantly increased the contribution of oral bacteria to gut microbiota (P=0.026), and no significant difference was found in PM group (P=0.467). Compared to the baseline, there was a 42-fold increase in gut abundance of Streptococcus anginosus in PP group (P=0.002), and the times decreased to 16-fold in PM group (P=0.029). Mouse models showed that combination of PPI and Streptococcus anginosus significantly increased the gut abundance of Streptococcus anginosus compared with using PPI or Streptococcus anginosus only. Furthermore, Streptococcus anginosus cannot survive in vitro at a pH lower than 5. CONCLUSIONS PPIs altered gut microbiota by promoting oral-originated Streptococcus translocation into gut.
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Affiliation(s)
- Xue Xiao
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xian Zhang
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jin Wang
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yuqiang Liu
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hailin Yan
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xiaocun Xing
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jinlin Yang
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Hashimoto H, Takagi T, Asaeda K, Yasuda T, Kajiwara M, Sugaya T, Mizushima K, Inoue K, Uchiyama K, Kamada K, Higashimura Y, Inoue R, Naito Y, Itoh Y. D-alanine Inhibits Murine Intestinal Inflammation by Suppressing IL-12 and IL-23 Production in Macrophages. J Crohns Colitis 2024; 18:908-919. [PMID: 38165390 DOI: 10.1093/ecco-jcc/jjad217] [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: 01/19/2023] [Revised: 11/21/2023] [Accepted: 12/30/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND AND AIMS Free D-amino acids, which have different functions from L-amino acids, have recently been discovered in various tissues. However, studies on the potential interactions between intestinal inflammation and D-amino acids are limited. We examined the inhibitory effects of D-alanine on the pathogenesis of intestinal inflammation. METHODS We investigated serum D-amino acid levels in 40 patients with ulcerative colitis and 34 healthy volunteers. For 7 days [d], acute colitis was induced using dextran sulphate sodium in C57BL/6J mice. Plasma D-amino acid levels were quantified in mice with dextran sulphate sodium-induced colitis, and these animals were administered D-alanine via intraperitoneal injection. IFN-γ, IL-12p35, IL-17A, and IL-23p19 mRNA expression in the colonic mucosa was measured using real-time polymerase chain reaction [PCR]. In vitro proliferation assays were performed to assess naïve CD4+ T cell activation under Th-skewing conditions. Bone marrow cells were stimulated with mouse macrophage-colony stimulating factor to generate mouse bone marrow-derived macrophages. RESULTS Serum D-alanine levels were significantly lower in patients with ulcerative colitis than in healthy volunteers. Dextran sulphate sodium-treated mice had significantly lower plasma D-alanine levels than control mice. D-alanine-treated mice had significantly lower disease activity index than control mice. IFN-γ, IL-12p35, IL-17A, and IL-23p19 mRNA expression levels were significantly lower in D-alanine-administered mice than in control mice. D-alanine suppressed naïve T cell differentiation into Th1 cells in vitro, and inhibited the production of IL-12p35 and IL-23p19 in bone marrow-derived macrophages. CONCLUSIONS Our results suggest that D-alanine prevents dextran sulphate sodium-induced colitis in mice and suppresses IL-12p35 and IL-23p19 production in macrophages.
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Affiliation(s)
- Hikaru Hashimoto
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Tomohisa Takagi
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
- Department for Medical Innovation and Translational Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kohei Asaeda
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Takeshi Yasuda
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Mariko Kajiwara
- Department of Gastroenterology, Fukuchiyama City Hospital, Fukuchiyama, Japan
| | - Takeshi Sugaya
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Katsura Mizushima
- Department of Human Immunology and Nutrition Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ken Inoue
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Kazuhiko Uchiyama
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Kazuhiro Kamada
- Department of Gastroenterology, Matsushita Memorial Hospital, Moriguchi, Japan
| | - Yasuki Higashimura
- Department of Food Science, Ishikawa Prefectural University, Nonoichi, Japan
| | - Ryo Inoue
- Laboratory of Animal Science, Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University, Hirakata, Japan
| | - Yuji Naito
- Department of Human Immunology and Nutrition Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
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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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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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10
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Moaligou C, Dion M, Ishnaiwer M, Dailly É, Batard É, Javaudin F. Pantoprazole promotes sustained intestinal carriage of multidrug-resistant Escherichia coli in amoxicillin-treated mice. J Appl Microbiol 2023; 134:lxad223. [PMID: 37766396 DOI: 10.1093/jambio/lxad223] [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: 03/28/2023] [Revised: 07/19/2023] [Accepted: 09/26/2023] [Indexed: 09/29/2023]
Abstract
AIMS The main objective of this study was to compare extended-spectrum β-lactamase (ESBL) Escherichia coli fecal titers during 12 days between two groups: mice who received proton pump inhibitors (PPIs) and those that did not. METHODS AND RESULTS We tested three different in vivo models: model 1, high inoculum (106 CFU ml-1); model 2, low inoculum (102 CFU ml-1); and model 3, low inoculum and 2-day amoxicillin wash-out. There was no significant difference between the two groups in fecal ESBL E. coli titers in models 1 and 2. The fecal titers of ESBL E. coli were probably too high to show differences in colonization related to PPI treatment. By introducing a 2-day wash-out period after stopping amoxicillin (model 3), the fecal ESBL E. coli titers were higher in the PPI-treated mice during 12 days (3 log versus 11 log day CFU g-1; P < 0.05). This result highlighted that PPIs promote stable ESBL E. coli digestive carriage in mice. Fecal quantitative PCR showed that mice with low ESBL E. coli fecal titers had a much higher concentration of equol-producing bacteria, Muribaculum sp., and Adlercreutzia caecimuris. CONCLUSIONS Pantoprazole treatment promotes sustained digestive carriage of ESBL E. coli in amoxicillin-treated mice.
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Affiliation(s)
- Camille Moaligou
- Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, Nantes Université, Nantes 44000, France
| | - Michel Dion
- Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, Nantes Université, Nantes 44000, France
| | - Murad Ishnaiwer
- Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, Nantes Université, Nantes 44000, France
| | - Éric Dailly
- Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, Nantes Université, Nantes 44000, France
- Clinical Pharmacology Department, Nantes University Hospital, Nantes 44000, France
| | - Éric Batard
- Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, Nantes Université, Nantes 44000, France
- Emergency department, Nantes University Hospital, Nantes 44000, France
| | - François Javaudin
- Cibles et médicaments des infections et de l'immunité, IICiMed, UR 1155, Nantes Université, Nantes 44000, France
- Emergency department, Nantes University Hospital, Nantes 44000, France
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11
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Shi Y, Li J, Cai S, Zhao H, Zhao H, Sun G, Yang Y. Proton pump inhibitors induced fungal dysbiosis in patients with gastroesophageal reflux disease. Front Cell Infect Microbiol 2023; 13:1205348. [PMID: 37662013 PMCID: PMC10469693 DOI: 10.3389/fcimb.2023.1205348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/25/2023] [Indexed: 09/05/2023] Open
Abstract
Gut mycobiota inhabits human gastrointestinal lumen and plays a role in human health and disease. We investigated the influence of proton pump inhibitors (PPIs) on gastric mucosal and fecal mycobiota in patients with gastroesophageal reflux diseases (GERD) by using Internal Transcribed Spacer 1 sequencing. A total of 65 participants were included, consisting of the healthy control (HC) group, GERD patients who did not use PPIs (nt-GERD), and GERD patients who used PPIs, which were further divided into short-term (s-PPI) and long-term PPI user (l-PPI) groups based on the duration of PPI use. The alpha diversity and beta diversity of gastric mucosal mycobiota in GERD patients with PPI use were significantly different from HCs, but there were no differences between s-PPI and l-PPI groups. LEfSe analysis identified Candida at the genus level as a biomarker for the s-PPI group when compared to the nt-GERD group. Meanwhile, Candida, Nothojafnea, Rhizodermea, Ambispora, and Saccharicola were more abundant in the l-PPI group than in the nt-GERD group. Furthermore, colonization of Candida in gastric mucosa was significantly increased after PPI treatment. However, there was no significant difference in Candida colonization between patients with endoscopic esophageal mucosal breaks and those without. There were significant differences in the fecal mycobiota composition between HCs and GERD patients regardless whether or not they used PPI. As compared to nt-GERD patient samples, there was a high abundance of Alternaria, Aspergillus, Mycenella, Exserohilum, and Clitopilus in the s-PPI group. In addition, there was a significantly higher abundance of Alternaria, Aspergillus, Podospora, Phallus, and Monographella in the l-PPI group than nt-GERD patients. In conclusion, our study indicates that dysbiosis of mycobiota was presented in GERD patients in both gastric mucosal and fecal mycobiota. PPI treatment may increase the colonization of Candida in the gastric mucosa in GERD patients.
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Affiliation(s)
- Yichao Shi
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, China
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Jianfeng Li
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Shuntian Cai
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hong Zhao
- Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Huijun Zhao
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Gang Sun
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yunsheng Yang
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
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12
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Zhang J, Zhang C, Zhang Q, Yu L, Chen W, Xue Y, Zhai Q. Meta-analysis of the effects of proton pump inhibitors on the human gut microbiota. BMC Microbiol 2023; 23:171. [PMID: 37337143 DOI: 10.1186/s12866-023-02895-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 05/16/2023] [Indexed: 06/21/2023] Open
Abstract
Mounting evidence has linked changes in human gut microbiota to proton pump inhibitor (PPI) use. Accordingly, multiple studies have analyzed the gut microbiomes of PPI users, but PPI-microbe interactions are still understudied. Here, we performed a meta-analysis of four studies with available 16S rRNA gene amplicon sequencing data to uncover the potential changes in human gut microbes among PPI users. Despite some differences, we found common features of the PPI-specific microbiota, including a decrease in the Shannon diversity index and the depletion of bacteria from the Ruminococcaceae and Lachnospiraceae families, which are crucial short-chain fatty acid-producers. Through training based on multiple studies, using a random forest classification model, we further verified the representativeness of the six screened gut microbial genera and 20 functional genes as PPI-related biomarkers, with AUC values of 0.748 and 0.879, respectively. Functional analysis of the PPI-associated 16S rRNA microbiome revealed enriched carbohydrate- and energy-associated genes, mostly encoding fructose-1,6-bisphosphatase and pyruvate dehydrogenase, among others. In this study, we have demonstrated alterations in bacterial abundance and functional metabolic potential related to PPI use, as a basis for future studies on PPI-induced adverse effects.
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Affiliation(s)
- Jiayi Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Chengcheng Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Qingsong Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Leilei Yu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Yuzheng Xue
- Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Jiangsu Province, Wuxi, China.
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, People's Republic of China.
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China.
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13
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Saka Y, Naruse T, Chikamatsu T, Mitani K, Hayashi M, Matsumoto J, Yosizawa Y, Mimura T, Takahashi H, Watanabe Y. Long-Term Proton Pump Inhibitor Therapy Increases the Risk of Infection in Patients with Incident Hemodialysis. Nephron Clin Pract 2023; 147:608-615. [PMID: 37231855 DOI: 10.1159/000531028] [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: 12/26/2022] [Accepted: 04/12/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Infection is one of the most common causes of death in patients with chronic kidney disease (CKD). Proton pump inhibitors (PPIs) are not only widely used in patients with CKD but also represent a known risk factor for infection in the general population. Here, we investigated associations between PPIs and infection events in patients with incident hemodialysis. METHODS We analyzed data from 485 consecutive patients with CKD who started hemodialysis at our hospital between January 2013 and December 2019. We analyzed associations between infection events and long-term (≥6 months) PPI use before and after propensity score-matched analysis. RESULTS Of the 485 patients, PPIs were administered to 177 patients (36.5%). During 24 months of follow-up, infection events occurred in 53 patients (29.9%) with PPIs and 40 patients (13.0%) without PPIs (p < 0.001). Patients with PPIs had a significantly higher cumulative incidence rate of infection events than those without PPIs (hazard ratio [HR] 2.13, 95% confidence interval [CI]: 1.36-3.32; p < 0.001). Even after propensity score-matched analysis (132 patients matched in each), the rate of infection events was higher for patients with PPIs (28.8% vs. 12.1%, HR 2.88, 95% CI: 1.61-5.16; p < 0.001). Similar results were obtained for severe infection events in both unmatched (14.1% vs. 4.5%, HR 2.97, 95% CI: 1.47-6.00; p = 0.002) and propensity score-matched analyses (14.4% vs. 3.8%, HR 4.54, 95% CI: 1.85-11.13; p < 0.001). CONCLUSIONS In patients with incident hemodialysis, long-term PPI use increases the risk of infection. Clinicians should be wary of unnecessarily prolonging PPI therapy.
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Affiliation(s)
- Yosuke Saka
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Tomohiko Naruse
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Taiki Chikamatsu
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Kotaro Mitani
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Mako Hayashi
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Jun Matsumoto
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Yuka Yosizawa
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Tetsushi Mimura
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Hiroshi Takahashi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Yuzo Watanabe
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
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14
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Chen Y, Xia SY, Ru FX, Feng JJ, Tao J, Wei ZY, Li X, Qian C, Lin Q, Chen JH. Gastric juice microbiota in pediatric chronic gastritis that clinically tested positive and negative for Helicobacter pylori. Front Microbiol 2023; 14:1112709. [PMID: 37180270 PMCID: PMC10168005 DOI: 10.3389/fmicb.2023.1112709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/28/2023] [Indexed: 05/16/2023] Open
Abstract
Purpose Helicobacter pylori (HP) infection is an identified risk factor for pediatric chronic gastritis (PCG), but its impact on gastric juice microbiota (GJM) remains to be further elucidated in PCG. This study aimed to analyze and compare the microbial communities and microbial interactive networks of GJM in PCG that clinically tested positive and negative for HP (HP+ and HP-, respectively). Methods A total of 45 PCG patients aged from 6 to 16 years were recruited, including 20 HP+ and 25 HP- patients tested by culture and rapid urease test. Gastric juice samples were collected from these PCG patients and subjected to high-throughput amplicon sequencing and subsequent analysis of 16S rRNA genes. Results While no significant change in alpha diversity, significant differences in beta diversity were observed between HP+ and HP- PCG. At the genus level, Streptococcus, Helicobacter, and Granulicatella were significantly enriched in HP+ PCG, whereas Campylobacter and Absconditabacteriales (SR1) were significantly enriched in HP- PCG. Network analysis showed that Streptococcus was the only genus positively correlated with Helicobacter (r = 0.497) in the GJM network of overall PCG. Moreover, compared to HP- PCG, HP+ PCG showed a reduction in microbial network connectivity in GJM. Netshift analysis identified driver microbes including Streptococcus and other four genera, which substantially contributed to the GJM network transition from HP- PCG to HP+ PCG. Furthermore, Predicted GJM function analysis indicated up-regulated pathways related to the metabolism of nucleotides, carbohydrates, and L-Lysine, the urea cycle, as well as endotoxin peptidoglycan biosynthesis and maturation in HP+ PCG. Conclusion GJM in HP+ PCG exhibited dramatically altered beta diversity, taxonomic structure, and function, with reduced microbial network connectivity, which could be involved in the disease etiology.
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Affiliation(s)
- Ying Chen
- Department of Gastroenterology, Affiliated Children’s Hospital of Jiangnan University, Wuxi, China
| | - Shou-Yue Xia
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Fu-Xia Ru
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Jun-Jie Feng
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Ji Tao
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Zhi-Yuan Wei
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Xiu Li
- Laboratory Animal Center, Jiangnan University, Wuxi, Jiangsu, China
| | - Chengjia Qian
- Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Qiong Lin
- Department of Gastroenterology, Affiliated Children’s Hospital of Jiangnan University, Wuxi, China
| | - Jian-Huan Chen
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
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15
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Zhang X, Adebayo AS, Wang D, Raza Y, Tomlinson M, Dooley H, Bowyer RC, Small KS, Steves CJ, Spector TD, Duncan EL, Visconti A, Falchi M. PPI-Induced Changes in Plasma Metabolite Levels Influence Total Hip Bone Mineral Density in a UK Cohort. J Bone Miner Res 2023; 38:326-334. [PMID: 36458982 PMCID: PMC10108201 DOI: 10.1002/jbmr.4754] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/08/2022] [Accepted: 11/26/2022] [Indexed: 12/05/2022]
Abstract
Proton pump inhibitors (PPIs) are among the most used drugs in the UK. PPI use has been associated with decreased bone mineral density (BMD) and increased fracture risk, although these results have been inconsistent. We hypothesized that PPI could modulate BMD by altering gut and/or host systemic metabolic environments. Using data from more than 5000 British male and female individuals, we confirmed that PPI use is associated with decreased lumbar spine and total hip BMD. This effect was not mediated through the gut microbiome. We suggest here that PPI use may influence total hip BMD, both directly and indirectly, via plasma metabolites involved in the sex hormone pathway. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Xinyuan Zhang
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Adewale S. Adebayo
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
- Present address:
NIHR Leicester Biomedical Research Centre, Department of Cardiovascular SciencesUniversity of LeicesterLeicesterUK
| | - Dongmeng Wang
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Yasrab Raza
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Max Tomlinson
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Hannah Dooley
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Ruth C.E. Bowyer
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Kerrin S. Small
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Claire J. Steves
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Tim D. Spector
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Emma L. Duncan
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Alessia Visconti
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
| | - Mario Falchi
- Department of Twins Research & Genetics EpidemiologyKing's College LondonLondonUK
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16
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Sbeit W, Abukaes H, Said Ahmad H, Sbeit M, Kalisky I, Katz L, Mari A, Khoury T. The possible association of proton pump inhibitor use with acute cholangitis in patients with choledocholithiasis: a multi-center study. Scand J Gastroenterol 2023; 58:83-87. [PMID: 35930433 DOI: 10.1080/00365521.2022.2106150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gallstone disease is common worldwide and can lead to severe complications, including cholangitis; thus, it is important to identify modifiable risk factors for cholangitis. Proton pump inhibitors (PPIs) are commonly prescribed to treat gastroenterological disorders. We aimed to explore whether PPI use is associated with an increased risk of acute cholangitis in patients with gallstone disease. METHODS This retrospective multicenter study included all patients arriving to the hospital over a 10-year period with various presentations of choledocholithiasis. We compared active PPI use in two groups: those with cholangitis (group A) vs. without cholangitis (group B). RESULTS Overall, 811 patients were included, 161 in group A and 650 in group B. The average age ± standard deviation (SD) in groups A and B was 74.5 ± 20.6 vs. 61.6 ± 20.9 years, respectively. PPI use in group A was higher vs. group B (42.9% vs. 29.1%, p = 0.001). On univariate analysis, male gender (OR 1.47, 95% confidence interval (CI) 1.04-2.08), age (OR 1.04, 95% CI 1.03-1.05), ischemic heart disease (IHD) (OR 1.68, 95% CI 1.07-2.64), hyperlipidemia (OR 1.59, 95% CI 1.11-2.29), hypertension (OR 1.81, 95% CI 1.28-2.57) and PPI use (OR 1.83, 95% CI 1.28-2.61), all were associated with acute cholangitis. On multivariate analysis, only PPI use kept its association after adjustment for age (OR 1.64, 95% CI 1.2-3.7). CONCLUSIONS Active PPI use was associated with a higher rate of cholangitis among patients with choledocholithiasis. We advocate considering this risk before prescribing PPIs to patients with gallstones. TRIAL REGISTRATION NUMBER NHR-0263-20 received on 14/01/2021 date 'retrospectively registered'.
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Affiliation(s)
- Wisam Sbeit
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel.,Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Hani Abukaes
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel.,Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Helal Said Ahmad
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.,Gastroenterology and Endoscopy Unit, Nazareth Hospital, EMMS, Nazareth, Israel
| | - Moeen Sbeit
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Itai Kalisky
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.,Institute of Gastroenterology and Hepatology, Hadassah University Medical Center, Jerusalem, Israel
| | - Lior Katz
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.,Institute of Gastroenterology and Hepatology, Hadassah University Medical Center, Jerusalem, Israel
| | - Amir Mari
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.,Gastroenterology and Endoscopy Unit, Nazareth Hospital, EMMS, Nazareth, Israel
| | - Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel.,Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
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17
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Abstract
Gut microbiota and fecal bile acids were analyzed in 278 patients with α-synucleinopathies, which were comprised of 28 patients with dementia with Lewy bodies (DLB), 224 patients with Parkinson's disease (PD), and 26 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Similarly to PD, short-chain fatty acids-producing genera were decreased in DLB. Additionally, Ruminococcus torques and Collinsella were increased in DLB, which were not changed in PD. Random forest models to differentiate DLB and PD showed that high Ruminococcus torques and high Collinsella, which presumably increase intestinal permeability, as well as low Bifidobacterium, which are also observed in Alzheimer's disease, were predictive of DLB. As Ruminococcus torques and Collinsella are also major secondary bile acids-producing bacteria, we quantified fecal bile acids and found that the production of ursodeoxycholic acid (UDCA) was high in DLB. Increased UDCA in DLB may mitigate neuroinflammation at the substantia nigra, whereas neuroinflammation may not be critical at the neocortex. Theraeutic intervention to increase Bifidobacteirum and its metabolites may retard the development and progression of DLB.
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18
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Zhang Y, Li J, Chen Z, Liu L, Zhan X, Peng F, Zhou Q, Wu X, Zeng Y, Zhu L, Xie Y, Lai X, Wang Z, Wen Y, Feng X, Liang J. Proton pump inhibitor usage associates with higher risk of first episodes of pneumonia and peritonitis in peritoneal dialysis patients. Ren Fail 2022; 44:1623-1631. [PMID: 36195979 PMCID: PMC9542879 DOI: 10.1080/0886022x.2022.2129064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background A large number of studies have shown that proton pump inhibitors (PPIs) are associated with infection events. Therefore, we retrospectively evaluated the association of PPI therapy with the occurrence of first pneumonia and peritoneal dialysis(PD)-related peritonitis events in the maintenance PD patients. Methods We collected PD patients in two large hospitals from January 1, 2012 to December 31, 2016, and divided them into the PPI group and the non-PPI group. Multivariate Cox proportional hazards models were applied to evaluate the cumulative incidence and hazard ratios (HRs). Inverse probability of treatment weight (IPTW) method was used to adjust for covariate imbalance between the two groups and further confirm our findings. Results Finally, 656 PD patients were included for data analysis, and the results showed that PPI usage was associated with an increased risk of pneumonia [HR 1.71; 95% CI 1.06-2.76; p = 0.027] and peritonitis [HR 1.73; 95% CI 1.24-2.40; p = 0.001]. IPTW-adjusted HRs for the association of PPIs with pneumonia and peritonitis were 1.58 (95% CI:1.18-2.12; p = 0.002) and 2.33 (95% CI:1.91-2.85; p < 0.001), respectively. Moreover, the competitive risk model proved that under the conditions of competition for other events(including transfer to hemodialysis therapy, kidney transplant, transfer from our research center, loss to follow-up, and death), the differences in endpoints events between the two groups were still statistically significant (p = 0.009, p < 0.001, respectively). Conclusions PPIs was associated with an increased risk of first pneumonia and PD-related peritonitis events in PD patients, which reminds clinicians to be cautious when prescribing acid-suppressing drugs for PD patients.
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Affiliation(s)
- Yujing Zhang
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Jiao Li
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China.,Department of Cardiology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Zijun Chen
- Department of Nephrology, Affiliated Dongguan People's Hospital Southern Medical University, Guangdong, China
| | - Lingling Liu
- Department of General Medicine, The Third Affiliated Hospital Sun Yat-sen University, Guangzhou, China
| | - Xiaojiang Zhan
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fenfen Peng
- Department of Nephrology, Zhujiang Hospital Southern Medical University, Guangzhou, China
| | - Qian Zhou
- Department of Medical Statistics, Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xianfeng Wu
- Department of Nephrology, Affiliated Sixth People's Hospital Shanghai Jiao Tong University, Shanghai, China
| | - Yingsi Zeng
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Liya Zhu
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Yuxin Xie
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Xiaochun Lai
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Zebin Wang
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Yueqiang Wen
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
| | - Xiaoran Feng
- Department of Nephrology, Jiujiang NO.1 people's Hospital, Jiujiang, China
| | - Jianbo Liang
- Department of Nephrology, The Second Affiliated Hospital Guangzhou Medical University, Guangzhou, China
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LeBaron TW, Sharpe R, Ohno K. Electrolyzed-Reduced Water: Review II: Safety Concerns and Effectiveness as a Source of Hydrogen Water. Int J Mol Sci 2022; 23:14508. [PMID: 36498838 PMCID: PMC9736533 DOI: 10.3390/ijms232314508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
Many studies demonstrate the safety of alkaline-electrolyzed-reduced water (ERW); however, several animal studies have reported significant tissue damage and hyperkalemia after drinking ERW. The mechanism responsible for these results remains unknown but may be due to electrode degradation associated with the production of higher pH, in which platinum nanoparticles and other metals that have harmful effects may leach into the water. Clinical studies have reported that, when ERW exceeds pH 9.8, some people develop dangerous hyperkalemia. Accordingly, regulations on ERW mandate that the pH of ERW should not exceed 9.8. It is recommended that those with impaired kidney function refrain from using ERW without medical supervision. Other potential safety concerns include impaired growth, reduced mineral, vitamin, and nutrient absorption, harmful bacterial overgrowth, and damage to the mucosal lining causing excessive thirst. Since the concentration of H2 in ERW may be well below therapeutic levels, users are encouraged to frequently measure the H2 concentration with accurate methods, avoiding ORP or ORP-based H2 meters. Importantly, although, there have been many people that have used high-pH ERW without any issues, additional safety research on ERW is warranted, and ERW users should follow recommendations to not ingest ERW above 9.8 pH.
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Affiliation(s)
- Tyler W. LeBaron
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia
- Molecular Hydrogen Institute, Enoch, UT 84721, USA
- Department of Kinesiology and Outdoor Recreation, Southern Utah University, Cedar City, UT 84720, USA
| | | | - Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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20
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Alterations in the gut microbiome in patients with esophageal carcinoma in response to esophagectomy and neoadjuvant treatment. Surg Today 2022; 53:663-674. [DOI: 10.1007/s00595-022-02607-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 09/18/2022] [Indexed: 11/21/2022]
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Association of suicidal ideation and depression with the use of proton pump inhibitors in adults: a cross-sectional study. Sci Rep 2022; 12:19539. [PMID: 36376493 PMCID: PMC9663563 DOI: 10.1038/s41598-022-24244-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Proton pump inhibitors (PPIs) were found to be associated with depression. This study aimed to find the cross-sectional association between recent PPI use and suicidal ideation. Item 9 of Patient Health Questionnaire-9 (PHQ-9) of the US National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018 was used to categorize whether or not the participants had suicidal ideation. The secondary outcome of this study was depression and the scores of the PHQ-9 were used as the depression diagnostic instrument. The study population included 16,881 participants who were over 20 years old. The bivariate Rao-Scott χ2 test showed a significant association between PPI use and suicidal ideation (P < 0.001) and a stronger association was observed between PPIs and depression (P < 0.001). Multiple logistic regression analysis of the education, gender, race and age-adjusted model revealed that the PPI users had a 2.34 (95% CI 1.66-3.31) greater risk of having suicidal ideation than the non-PPI users. Middle-aged participants (40-49 years) showed the greatest number of differences in suicidal ideation between PPI and non-PPI users (P < 0.001). Future research should continue to consider the psychiatric effects of taking PPIs.
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22
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Proton Pump Inhibitor Pantoprazole Modulates Intestinal Microbiota and Induces TLR4 Signaling and Fibrosis in Mouse Liver. Int J Mol Sci 2022; 23:ijms232213766. [PMID: 36430244 PMCID: PMC9693486 DOI: 10.3390/ijms232213766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/21/2022] [Accepted: 11/02/2022] [Indexed: 11/12/2022] Open
Abstract
Proton pump inhibitors (PPIs) are one of the most prescribed drugs around the world. PPIs induce microbiota modulation such as obesity both in humans and in animal models. However, since PPIs can induce microbiota modulation despite the absence of a high-fat diet or weight gain, it is an interesting model to correlate microbiota modulation with the establishment of non-alcoholic fatty liver disease (NAFLD). We investigated the effect of pantoprazole treatment on TLR4 signaling and liver histology in C57BL/6J mice for 60 days, trying to correlate microbiota modulation with some aspects of liver injury. We performed glucose (GTT) and insulin (ITT) tolerance tests, serum lipopolysaccharide (LPS) dosage, liver histology, liver and intestine extraction for Western blot and qPCR. Fecal microbiota were investigated via metagenomics. Chronic treatment with pantoprazole induced microbiota modulation and impaired ileum barrier integrity, without an association with insulin resistance. Furthermore, increased circulating LPS and increased Toll-like receptor 4 (TLR4) and TGFβ downstream signaling may have an important role in the development of the observed liver microvesicular steatosis and fibrosis. Finally, this model of PPI-induced changes in microbiota might be useful to investigate liver microvesicular steatosis and fibrosis.
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Brown G, Hoedt EC, Keely S, Shah A, Walker MM, Holtmann G, Talley NJ. Role of the duodenal microbiota in functional dyspepsia. Neurogastroenterol Motil 2022; 34:e14372. [PMID: 35403776 PMCID: PMC9786680 DOI: 10.1111/nmo.14372] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/04/2022] [Accepted: 03/14/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND Functional dyspepsia (FD) is a common and debilitating gastrointestinal disorder attributed to altered gut-brain interactions. While the etiology of FD remains unknown, emerging research suggests the mechanisms are likely multifactorial and heterogenous among patient subgroups. Small bowel motor disturbances, visceral hypersensitivity, chronic microinflammation, and increased intestinal tract permeability have all been linked to the pathogenesis of FD. Recently, alterations to the gut microbiome have also been implicated to play an important role in the disease. Changes to the duodenal microbiota may either trigger or be a consequence of immune and neuronal disturbances observed in the disease, but the mechanisms of influence of small intestinal flora on gastrointestinal function and symptomatology are unknown. PURPOSE This review summarizes and synthesizes the literature on the link between the microbiota, low-grade inflammatory changes in the duodenum and FD. This review is not intended to provide a complete overview of FD or the small intestinal microbiota, but instead outline some of the key conceptual advances in understanding the interactions between altered gastrointestinal bacterial communities; dietary factors; host immune activation; and stimulation of the gut-brain axes in patients with FD versus controls. Current and emerging treatment approaches such as dietary interventions and antibiotic or probiotic use that have demonstrated symptom benefits for patients are reviewed, and their role in modulating the host-microbiota is discussed. Finally, suggested opportunities for diagnostic and therapeutic improvements for patients with this condition are presented.
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Affiliation(s)
- Georgia Brown
- School of Medicine and Public HealthUniversity of NewcastleNewcastleNew South WalesAustralia,AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia
| | - Emily C. Hoedt
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,School of Biomedical Sciences and PharmacyUniversity of NewcastleNewcastleNew South WalesAustralia,Hunter Medical Research InstituteNew Lambton HeightsNewcastleNew South WalesAustralia
| | - Simon Keely
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,School of Biomedical Sciences and PharmacyUniversity of NewcastleNewcastleNew South WalesAustralia,Hunter Medical Research InstituteNew Lambton HeightsNewcastleNew South WalesAustralia
| | - Ayesha Shah
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,Faculty of Medicine and Faculty of Health and Behavioural SciencesThe University of QueenslandSt. LuciaQueenslandAustralia
| | - Marjorie M. Walker
- School of Medicine and Public HealthUniversity of NewcastleNewcastleNew South WalesAustralia,AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia
| | - Gerald Holtmann
- AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,Faculty of Medicine and Faculty of Health and Behavioural SciencesThe University of QueenslandSt. LuciaQueenslandAustralia,Department of Gastroenterology & HepatologyPrincess Alexandra HospitalWoolloongabbaQueenslandAustralia
| | - Nicholas J. Talley
- School of Medicine and Public HealthUniversity of NewcastleNewcastleNew South WalesAustralia,AGIRA (Australian Gastrointestinal Research Alliance)NewcastleNew South WalesAustralia,NHMRC Centre of Research Excellence in Digestive HealthNewcastleNew South WalesAustralia,Hunter Medical Research InstituteNew Lambton HeightsNewcastleNew South WalesAustralia
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Saifon W, Sensorn I, Trachu N, Oranratnachai S, Charoenyingwattana A, Runcharoen C, Monnamo N, Sukkasem W, Inchareon P, Suwatanapongched T, Chansriwong P, Ativitavas T, Panvichian R, Chantratita W, Reungwetwattana T. Gastrointestinal microbiota profile and clinical correlations in advanced EGFR-WT and EGFR-mutant non-small cell lung cancer. BMC Cancer 2022; 22:963. [PMID: 36076157 PMCID: PMC9454126 DOI: 10.1186/s12885-022-10050-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/31/2022] [Indexed: 11/26/2022] Open
Abstract
Introduction Difference in clinical responses to cancer therapy in each patient is from several factors. Gastrointestinal microbiota is one of the reasons. However, this correlation remains unknown. This study aims to explore correlation between gastrointestinal microbiota profile and clinical outcomes in Thai advanced non-small cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) status. Methods We enrolled 13 patients with advanced EGFR–wild-type (WT) NSCLC who received chemotherapy and 15 patients with EGFR-mutant NSCLC who received EGFR tyrosine kinase inhibitors. We collected fecal samples at baseline and first disease evaluation and performed 16S rRNA gene sequencing by NGS to assess microbiota profile. The correlations between gastrointestinal microbiota and clinical variables were studied. Results The clinical characteristics were balanced between the cohorts, excluding significantly higher albumin levels in the EGFR-mutant group. Albumin was the only significant clinical factor affecting the treatment response in multivariate analysis (ORR 15.6%, P = 0.03). Proteobacteria counts were higher in the EGFR-WT group, whereas Bacteroidetes and Firmicutes counts were higher in the EGFR-mutant group. The alpha diversity of the gastrointestinal microbiome was significantly higher in the EGFR-mutant group (Shannon index: 3.82 vs. 3.25, P = 0.022). Following treatment, Proteobacteria counts were lower and Bacteroidetes and Firmicutes counts were higher in both cohorts; the changes were more prominent in the EGFR-WT cohort. No significant correlation between microbiota profile and treatment response were demonstrated in our study. However, beta diversity was significantly different according to severity of adverse events. Enrichment of Clostridia and Bacteroidia was associated with higher adverse event risk in the EGFR-WT cohort. Conclusions Proteobacteria was dominant in Thai lung cancer patients both EGFR-WT and EGFR-mutant, and this phylum maybe associate with lung cancer carcinogenesis. Chemotherapy altered the gastrointestinal microbiota, whereas EGFR-TKIs had less effects. Our findings highlight the potential predictive utility of the gastrointestinal microbiota for lung cancer carcinogenesis. Studies with larger cohorts and comparison with the healthy Thai population are ongoing to validate this pilot study. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10050-3.
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Affiliation(s)
- Woraseth Saifon
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Department of Medicine, Golden Jubilee Medical Center, Nakorn Pathom, Thailand
| | - Insee Sensorn
- Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Narumol Trachu
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Songporn Oranratnachai
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Sriphat Medical Center, Faculty of Medicine, Oncology Clinic, Chiang Mai University, Chiang Mai, Thailand
| | - Angkana Charoenyingwattana
- Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chakkaphan Runcharoen
- Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nanamon Monnamo
- Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Warawut Sukkasem
- Department of Diagnostic and Therapeutic Radiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Ramathibodi Lung Cancer Consortium, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Pimpin Inchareon
- Ramathibodi Lung Cancer Consortium, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Thitiporn Suwatanapongched
- Department of Diagnostic and Therapeutic Radiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Ramathibodi Lung Cancer Consortium, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Phichai Chansriwong
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Ramathibodi Lung Cancer Consortium, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Touch Ativitavas
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Ramathibodi Lung Cancer Consortium, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ravat Panvichian
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Ramathibodi Lung Cancer Consortium, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Wasun Chantratita
- Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Thanyanan Reungwetwattana
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. .,Ramathibodi Lung Cancer Consortium, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
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Lin CY, Cheng HT, Kuo CJ, Lee YS, Sung CM, Keidan M, Rao K, Kao JY, Hsieh SY. Proton Pump Inhibitor-Induced Gut Dysbiosis Increases Mortality Rates for Patients with Clostridioides difficile Infection. Microbiol Spectr 2022; 10:e0048622. [PMID: 35863023 PMCID: PMC9430933 DOI: 10.1128/spectrum.00486-22] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 06/14/2022] [Indexed: 11/24/2022] Open
Abstract
Clostridioides difficile infection (CDI) is associated with high mortality rates among patients with chronic illnesses. We aimed to identify avoidable risk factors to reduce the mortality rate in CDI patients. A total of 306 patients with diarrhea and clinical suspicion of CDI were enrolled, and fecal samples were gathered from 145 patients. CDI was diagnosed by fecal positivity for the C. difficile tcdB gene. Risk factors associated with death within 180 days were identified using Cox regression analysis. The fecal microbiota was determined through bacterial 16S rRNA gene sequencing. Of the patients with diarrhea, 240 (mean age, 69.1 years) were positive for CDI, and 91 died within 180 days. Multivariate analysis revealed that male sex, high Charlson Comorbidity Index and McCabe scores, high serum C-reactive protein levels, low hematocrit levels, low absolute eosinophil counts, high neutrophil/lymphocyte ratios, and daily use of proton pump inhibitors (PPIs) were independent risk factors for overall mortality. Cumulative analyses confirmed the association of duration-dependent PPI use with a high mortality rate. Fecal microbiota analyses showed associations of decreased relative abundance of Ruminococcus gnavus (P = 0.001) and Prevotella copri (P = 0.025) and increased relative abundance of Parabacteroides merdae (P = 0.001) and Clostridioides difficile (P = 0.040) with higher mortality rates in patients with CDI. Moreover, these microbiota changes were correlated with the duration of PPI use. IMPORTANCE This article demonstrates that daily PPI use was the only avoidable risk factor for death. With more extended PPI use, the mortality rate was higher in patients with CDI. Decreases in Prevotella copri and Ruminococcus gnavus and increases in Parabacteroides merdae and Clostridioides difficile in line with daily PPI use duration were significantly associated with the death of CDI patients. Our findings provide in-depth insights into the cautious use of PPIs in chronically ill patients with CDI.
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Affiliation(s)
- Cheng-Yu Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Hao-Tsai Cheng
- Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of Gastroenterology and Hepatology, Tu Cheng Hospital, New Taipei City, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yun-Shien Lee
- Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan
| | - Chang-Mu Sung
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Micah Keidan
- Department of Internal Medicine, Division of Infectious Diseases, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Krishna Rao
- Department of Internal Medicine, Division of Infectious Diseases, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - John Y. Kao
- Department of Internal Medicine, Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Sen-Yung Hsieh
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
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Lassmann Ł, Pollis M, Żółtowska A, Manfredini D. Gut Bless Your Pain—Roles of the Gut Microbiota, Sleep, and Melatonin in Chronic Orofacial Pain and Depression. Biomedicines 2022; 10:biomedicines10071528. [PMID: 35884835 PMCID: PMC9313154 DOI: 10.3390/biomedicines10071528] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 11/18/2022] Open
Abstract
Background. Increased attention has been paid to the gut–brain axis recently, but little is known so far regarding how this translates into pain susceptibility. Aim. The aim of this review is to determine whether gastroenterological disorders and sleep disorders (directly or indirectly) contribute to an increased susceptibility to depression and chronic orofacial pain. Method. A search was performed in the U.S. National Library of Medicine (PubMed) database in order to find studies published before 19 December 2021. We used the following terms: gut microbiome, OR sleep quality, OR melatonin, OR GERD, OR IBS, AND: depression OR chronic pain, in different configurations. Only papers in English were selected. Given the large number of papers retrieved in the search, their findings were described and organized narratively. Results. A link exists between sleep disorders and gastroenterological disorders, which, by adversely affecting the psyche and increasing inflammation, disturb the metabolism of tryptophan and cause excessive microglial activation, leading to increased susceptibility to pain sensation and depression. Conclusions. Pain therapists should pay close attention to sleep and gastrointestinal disorders in patients with chronic pain and depression.
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Affiliation(s)
- Łukasz Lassmann
- Dental Sense Medicover, 80-283 Gdańsk, Poland
- Correspondence:
| | - Matteo Pollis
- Department of Medical Biotechnology, School of Dentistry, University of Siena, 53100 Siena, Italy; (M.P.); (D.M.)
| | - Agata Żółtowska
- Department of Conservative Dentistry, Faculty of Medicine, Medical University of Gdańsk, 80-210 Gdańsk, Poland;
| | - Daniele Manfredini
- Department of Medical Biotechnology, School of Dentistry, University of Siena, 53100 Siena, Italy; (M.P.); (D.M.)
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Rashed R, Valcheva R, Dieleman LA. Manipulation of Gut Microbiota as a Key Target for Crohn's Disease. Front Med (Lausanne) 2022; 9:887044. [PMID: 35783604 PMCID: PMC9244564 DOI: 10.3389/fmed.2022.887044] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/19/2022] [Indexed: 12/12/2022] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease (IBD) sub-type characterized by transmural chronic inflammation of the gastrointestinal tract. Research indicates a complex CD etiology involving genetic predisposition and immune dysregulation in response to environmental triggers. The chronic mucosal inflammation has been associated with a dysregulated state, or dysbiosis, of the gut microbiome (bacteria), mycobiome (fungi), virome (bacteriophages and viruses), and archeaome (archaea) further affecting the interkingdom syntrophic relationships and host metabolism. Microbiota dysbiosis in CD is largely described by an increase in facultative anaerobic pathobionts at the expense of strict anaerobic Firmicutes, such as Faecalibacterium prausnitzii. In the mycobiome, reduced fungal diversity and fungal-bacteria interactions, along with a significantly increased abundance of Candida spp. and a decrease in Saccharomyces cerevisiae are well documented. Virome analysis also indicates a significant decrease in phage diversity, but an overall increase in phages infecting bacterial groups associated with intestinal inflammation. Finally, an increase in methanogenic archaea such as Methanosphaera stadtmanae exhibits high immunogenic potential and is associated with CD etiology. Common anti-inflammatory medications used in CD management (amino-salicylates, immunomodulators, and biologics) could also directly or indirectly affect the gut microbiome in CD. Other medications often used concomitantly in IBD, such as antibiotics, antidepressants, oral contraceptives, opioids, and proton pump inhibitors, have shown to alter the gut microbiota and account for increased susceptibility to disease onset or worsening of disease progression. In contrast, some environmental modifications through alternative therapies including fecal microbiota transplant (FMT), diet and dietary supplements with prebiotics, probiotics, and synbiotics have shown potential protective effects by reversing microbiota dysbiosis or by directly promoting beneficial microbes, together with minimal long-term adverse effects. In this review, we discuss the different approaches to modulating the global consortium of bacteria, fungi, viruses, and archaea in patients with CD through therapies that include antibiotics, probiotics, prebiotics, synbiotics, personalized diets, and FMT. We hope to provide evidence to encourage clinicians and researchers to incorporate these therapies into CD treatment options, along with making them aware of the limitations of these therapies, and indicate where more research is needed.
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Gommers LMM, Hoenderop JGJ, de Baaij JHF. Mechanisms of proton pump inhibitor-induced hypomagnesemia. Acta Physiol (Oxf) 2022; 235:e13846. [PMID: 35652564 PMCID: PMC9539870 DOI: 10.1111/apha.13846] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022]
Abstract
Proton pump inhibitors (PPIs) reliably suppress gastric acid secretion and are therefore the first-line treatment for gastric acid-related disorders. Hypomagnesemia (serum magnesium [Mg2+ ] <0.7 mmol/L) is a commonly reported side effect of PPIs. Clinical reports demonstrate that urinary Mg2+ excretion is low in PPI users with hypomagnesemia, suggesting a compensatory mechanism by the kidney for malabsorption of Mg2+ in the intestines. However, the exact mechanism by which PPIs cause impaired Mg2+ absorption is still unknown. In this review, we show that current experimental evidence points toward reduced Mg2+ solubility in the intestinal lumen. Moreover, the absorption pathways in both the small intestine and the colon may be reduced by changes in the expression and activity of key transporter proteins. Additionally, the gut microbiome may contribute to the development of PPI-induced hypomagnesemia, as PPI use affects the composition of the gut microbiome. In this review, we argue that the increase of the luminal pH during PPI treatment may contribute to several of these mechanisms. Considering the fact that bacterial fermentation of dietary fibers results in luminal acidification, we propose that targeting the gut microbiome using dietary intervention might be a promising treatment strategy to restore hypomagnesemia in PPI users.
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Affiliation(s)
- Lisanne M. M. Gommers
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
| | - Joost G. J. Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
| | - Jeroen H. F. de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
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Kitae H, Takagi T, Naito Y, Inoue R, Azuma Y, Torii T, Mizushima K, Doi T, Inoue K, Dohi O, Yoshida N, Kamada K, Uchiyama K, Ishikawa T, Konishi H, Itoh Y. Gut Microbiota Associated with Clinical Relapse in Patients with Quiescent Ulcerative Colitis. Microorganisms 2022; 10:microorganisms10051044. [PMID: 35630486 PMCID: PMC9144486 DOI: 10.3390/microorganisms10051044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/14/2022] [Accepted: 05/17/2022] [Indexed: 12/02/2022] Open
Abstract
The microbiota associated with relapse in patients with quiescent ulcerative colitis (qUC) remains unclear. Our objective was to analyze the fecal microbiota of Japanese patients with qUC and identify the relapse-associated microbiota. In this study, 59 patients with qUC and 59 healthy controls (HCs) were enrolled (UMIN 000019486), and their fecal microbiota was compared using 16S rRNA gene amplicon sequencing. We followed their clinical course up to 3.5 years and analyzed the relapse-associated microbiota. Potential functional changes in the fecal microbiota were evaluated using PICRUSt software and the Kyoto Encyclopedia of Genes and Genomes database. There were significant differences in fecal microbiota diversity between HC and qUC subjects, with 13 taxa characterizing each subject. Despite no significant difference in variation of microbiota in a single sample (α diversity) between patients in sustained remission and relapsed patients, the variation in microbial communities between samples (β diversity) was significantly different. Prevotella was more abundant in the sustained remission patients, whereas Faecalibacterium and Bifidobacterium were more abundant in the relapsed patients. We clustered the entire cohort into four clusters, and Kaplan–Meier analysis revealed the subsequent clinical course of each cluster was different. We identified 48 metabolic pathways associated with each cluster using linear discriminant analysis effect size. We confirmed the difference in microbiota between patients with qUC and HCs and identified three genera associated with relapse. We found that the clusters based on these genera had different subsequent clinical courses and activated different metabolic pathways.
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Affiliation(s)
- Hiroaki Kitae
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Tomohisa Takagi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
- Department for Medical Innovation and Translational Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Correspondence: ; Tel.: +81-75-251-5519
| | - Yuji Naito
- Department of Human Immunology and Nutrition Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan;
| | - Ryo Inoue
- Laboratory of Animal Science, Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University, Osaka 573-0101, Japan;
| | - Yuka Azuma
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Takashi Torii
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Katsura Mizushima
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Toshifumi Doi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Ken Inoue
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Osamu Dohi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Naohisa Yoshida
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Kazuhiro Kamada
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Kazuhiko Uchiyama
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Takeshi Ishikawa
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Hideyuki Konishi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.K.); (Y.A.); (T.T.); (K.M.); (T.D.); (K.I.); (O.D.); (N.Y.); (K.K.); (K.U.); (T.I.); (H.K.); (Y.I.)
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Liatsos C, Papaefthymiou A, Kyriakos N, Galanopoulos M, Doulberis M, Giakoumis M, Petridou E, Mavrogiannis C, Rokkas T, Kountouras J. Helicobacter pylori, gastric microbiota and gastric cancer relationship: Unrolling the tangle. World J Gastrointest Oncol 2022; 14:959-972. [PMID: 35646287 PMCID: PMC9124990 DOI: 10.4251/wjgo.v14.i5.959] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/12/2021] [Accepted: 04/09/2022] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori infection (Hp-I) represents a typical microbial agent intervening in the complex mechanisms of gastric homeostasis by disturbing the balance between the host gastric microbiota and mucosa-related factors, leading to inflammatory changes, dysbiosis and eventually gastric cancer. The normal gastric microbiota shows diversity, with Proteobacteria [Helicobacter pylori (H. pylori) belongs to this family], Firmicutes, Actinobacteria, Bacteroides and Fusobacteria being the most abundant phyla. Most studies indicate that H. pylori has inhibitory effects on the colonization of other bacteria, harboring a lower diversity of them in the stomach. When comparing the healthy with the diseased stomach, there is a change in the composition of the gastric microbiome with increasing abundance of H. pylori (where present) in the gastritis stage, while as the gastric carcinogenesis cascade progresses to gastric cancer, the oral and intestinal-type pathogenic microbial strains predominate. Hp-I creates a premalignant environment of atrophy and intestinal metaplasia and the subsequent alteration in gastric microbiota seems to play a crucial role in gastric tumorigenesis itself. Successful H. pylori eradication is suggested to restore gastric microbiota, at least in primary stages. It is more than clear that Hp-I, gastric microbiota and gastric cancer constitute a challenging tangle and the strong interaction between them makes it difficult to unroll. Future studies are considered of crucial importance to test the complex interaction on the modulation of the gastric microbiota by H. pylori as well as on the relationships between the gastric microbiota and gastric carcinogenesis.
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Affiliation(s)
- Christos Liatsos
- Department of Gastroenterology, 401 General Military Hospital of Athens, Athens 11525, Greece
| | - Apostolis Papaefthymiou
- Department of Gastroenterology, 401 General Military Hospital of Athens, Athens 11525, Greece
- Gastroenterology, University Hospital of Larissa, Larissa 41336, Greece
| | - Nikolaos Kyriakos
- Department of Gastroenterology, 401 General Military Hospital of Athens, Athens 11525, Greece
| | - Michail Galanopoulos
- Department of Gastroenterology, 401 General Military Hospital of Athens, Athens 11525, Greece
| | - Michael Doulberis
- Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau 1234, Switzerland
| | - Marios Giakoumis
- Department of Gastroenterology, 401 General Military Hospital of Athens, Athens 11525, Greece
| | - Evangelia Petridou
- Department of Microbiology, “Agia Sofia” Paediatric Hospital, Goudi, Athens 11527, Greece
| | - Christos Mavrogiannis
- Gastrointestinal and Liver Unit, Faculty of Nursing, Kifissia General and Oncology Hospital, Kaliftaki, N.Kifisia 14564, Greece
| | - Theodore Rokkas
- Gastroenterological Clinic, Henry Dunant Hospital, Athens 11525, Greece
| | - Jannis Kountouras
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki 41336, Macedonia, Greece
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Abstract
OBJECTIVES There is limited knowledge about the role of esophageal microbiome in pediatric esophageal eosinophilia (EE). We aimed to characterize the esophageal microbiome in pediatric patients with and without EE. METHODS In the present prospective study, esophageal mucosal biopsies were obtained from 41 children. Of these, 22 had normal esophageal mucosal biopsies ("healthy"), 6 children had reflux esophagitis (RE), 4 had proton pump inhibitor (PPi)-responsive esophageal eosinophilia (PPi-REE), and 9 had eosinophilic esophagitis (EoE). The microbiome composition was analyzed using 16S rRNA gene sequencing. The age median (range) in years for the healthy, RE, PPi-REE, and EoE group were 10 (1.5-18), 6 (2-15), 6.5 (5-15), and 9 (1.5-17), respectively. RESULTS The bacterial phylum Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria were the most predominant. The Epsilonproteobacteria, Betaproteobacteria, Flavobacteria, Fusobacteria, and Sphingobacteria class were underrepresented across groups. The Vibrionales was predominant in healthy and EoE group but lower in RE and PPi-REE groups. The genus Streptococcus, Rahnella, and Leptotrichia explained 29.65% of the variation in the data with an additional 10.86% variation in the data was explained by Microbacterium, Prevotella, and Vibrio genus. The healthy group had a higher diversity and richness index compared to other groups, but this was not statistically different. CONCLUSIONS The pediatric esophagus has an abundant and diverse microbiome, both in the healthy and diseased states. The healthy group had a higher, but not significantly different, diversity and richness index compared to other groups.
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Typing of the Gut Microbiota Community in Japanese Subjects. Microorganisms 2022; 10:microorganisms10030664. [PMID: 35336239 PMCID: PMC8954045 DOI: 10.3390/microorganisms10030664] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 12/11/2022] Open
Abstract
Gut microbiota are involved in both host health and disease and can be stratified based on bacteriological composition. However, gut microbiota clustering data are limited for Asians. In this study, fecal microbiota of 1803 Japanese subjects, including 283 healthy individuals, were analyzed by 16S rRNA sequencing and clustered using two models. The association of various diseases with each community type was also assessed. Five and fifteen communities were identified using partitioning around medoids (PAM) and the Dirichlet multinominal mixtures model, respectively. Bacteria exhibiting characteristically high abundance among the PAM-identified types were of the family Ruminococcaceae (Type A) and genera Bacteroides, Blautia, and Faecalibacterium (Type B); Bacteroides, Fusobacterium, and Proteus (Type C); and Bifidobacterium (Type D), and Prevotella (Type E). The most noteworthy community found in the Japanese subjects was the Bifidobacterium-rich community. The odds ratio based on type E, which had the largest population of healthy subjects, revealed that other types (especially types A, C, and D) were highly associated with various diseases, including inflammatory bowel disease, functional gastrointestinal disorder, and lifestyle-related diseases. Gut microbiota community typing reproducibly identified organisms that may represent enterotypes peculiar to Japanese individuals and that are partly different from those of indivuals from Western countries.
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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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Fan L, Lee JH. Enteral feeding and the microbiome in critically ill children: a narrative review. Transl Pediatr 2021; 10:2778-2791. [PMID: 34765500 PMCID: PMC8578772 DOI: 10.21037/tp-20-349] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 04/09/2021] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE This narrative review summarizes our current knowledge on the interplay between enteral nutrition (EN) and gut microbiota in critically ill children, using examples from two commonly encountered diagnoses in the pediatric intensive care unit (PICU): severe sepsis and acute respiratory distress syndrome (ARDS). This review will also highlight potential areas of therapeutic interventions that should be explored in future studies. BACKGROUND Critically ill children display extreme dysbiosis in their gut microbiome. Factors within the PICU that are often associated with dysbiosis include the use of broad-spectrum antibiotics, proton-pump inhibitors (PPIs), intravenous morphine, and fasting. Dysbiosis can potentially lead to adverse clinical outcomes (e.g., nosocomial infection, and prolonged hospitalization). EN may modulate dysbiosis. The gut microbiota is involved in the breaking down of macronutrients, mainly carbohydrates and proteins. Fermentation of undigestible carbohydrate (e.g., inulin and oligosaccharides), and amino acids by large intestine microbiota produces short chain fatty acids (SCFAs). SCFAs serve as the main fuel source for enterocytes and help to maintain healthy gut lining. Changes to selected components of macronutrients can result in alterations in gut microbiome and have potentially beneficial effects in patients in the PICU. METHODS A comprehensive search of the MEDLINE, Cochrane Library and Google Scholar databases was conducted using appropriate MESH terms and keywords. In this narrative review, we provide a summary of current knowledge on effect of EN on gut microbiota in pediatric studies, but also describes animal- and lab-based, as well as adult studies where relevant. CONCLUSIONS The gut microbiome can be altered by dietary modifications and common PICU practices and treatment. Although there are strong associations in restoring eubiosis and improvement in clinical outcomes, proving causality remains challenging. Further microbiome research is needed to provide mechanistic insights into the impact of the ever changing gut microbiome. In the future, new microbiota targeted therapies could potentially be the treatment of challenging PICU conditions and restore homeostasis in these children.
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Affiliation(s)
- Lijia Fan
- Division of Paediatric Critical Care, Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore, Singapore
| | - Jan Hau Lee
- Children's Intensive Care Unit, KK Women's and Children's Hospital, Singapore, Singapore.,Duke-NUS Medical School, Singapore, Singapore
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Bakulin IG, Oganezova IA, Skalinskaya MI, Skazyvaeva EV. Liver cirrosis and complication risk management. TERAPEVT ARKH 2021; 93:963-968. [DOI: 10.26442/00403660.2021.08.200917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 09/04/2021] [Indexed: 11/22/2022]
Abstract
Liver cirrhosis (LC) takes the main place in the structure of the pathology of the digestive system in terms of the frequency of mortality, as well as in the development of fatal and poorly controlled complications, which requires the search for effective methods for preventing the progression of the disease and the development of complications. The article provides updated information on the role of the intestinal microbiota, as well as endotoxemia and increased intestinal permeability syndromes in the pathophysiology of LC and its complications. The results of recent meta-analyses of the impact of dysbiotic disorders on the prognosis of the LC and the options for their correction are presented. Understanding of the significance of involvement of gut microbiota in the pathogenesis of LC has become one of the levers of management of the risks of complications of LC. In this case, the livergut axis can be considered to be the leading link to the formation of most of the main complications of LC.
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Baima DC, Carvalho NS, Barbuti RC, Navarro-Rodriguez T. ASSESSMENT OF THE INTESTINAL MICROBIOTA IN ADULTS WITH EROSIVE ESOPHAGITIS. ARQUIVOS DE GASTROENTEROLOGIA 2021; 58:168-174. [PMID: 34287529 DOI: 10.1590/s0004-2803.202100000-29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/07/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND The intestinal microbiota influences the appropriate function of the gastrointestinal tract. Intestinal dysbiosis may be associated with a higher risk of esophageal lesions, mainly due to changes in gastroesophageal motility patterns, elevation of intra-abdominal pressure, and increased frequency of transient relaxation of the lower esophageal sphincter. OBJECTIVE The aim of this study was to evaluate the intestinal microbiota in individuals with erosive esophagitis and in healthy individuals using metagenomics. METHODS A total of 22 fecal samples from adults aged between 18 and 60 years were included. Eleven individuals had esophagitis (eight men and three women) and 11 were healthy controls (10 men and one woman). The individuals were instructed to collect and store fecal material into a tube containing guanidine solution. The DNA of the microbiota was extracted from each fecal samples and PCR amplification was performed using primers for the V4 region of the 16S rRNA gene. The amplicons were sequenced using the Ion Torrent PGM platform and the data were analyzed using the QIIME™ software version 1.8. Statistical analyses were performed using the Mann-Whitney non-parametric test and the ANOSIM non-parametric method based on distance matrix. RESULTS The alpha-diversity and beta-diversity indices were similar between the two groups, without statistically significant differences. There was no statistically significant difference in the phylum level. However, a statistically significant difference was observed in the abundance of the family Clostridiaceae (0.3% vs 2.0%, P=0.032) and in the genus Faecaliumbacterium (10.5% vs 4.5%, P=0.045) between healthy controls and esophagitis patients. CONCLUSION The findings suggest that reduced abundance of the genus Faecaliumbacterium and greater abundance of the family Clostridiaceae may be risk factors for the development of erosive esophagitis. Intervention in the composition of the intestinal microbiota should be considered as an adjunct to current therapeutic strategies for this clinical condition.
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Affiliation(s)
- Diego Cardoso Baima
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Nayara Salgado Carvalho
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Ricardo Correa Barbuti
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Tomas Navarro-Rodriguez
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
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Uchida A, Yasuma T, Takeshita A, Toda M, Okano Y, Nishihama K, D'Alessandro-Gabazza CN, Fridman D'Alessandro V, Inoue C, Takagi T, Mukaiyama H, Takagi N, Shimizu K, Yano Y, Gabazza EC. Oral Limonite Supplement Ameliorates Glucose Intolerance in Diabetic and Obese Mice. J Inflamm Res 2021; 14:3089-3105. [PMID: 34276223 PMCID: PMC8277451 DOI: 10.2147/jir.s320451] [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: 05/19/2021] [Accepted: 06/18/2021] [Indexed: 12/20/2022] Open
Abstract
Introduction Diabetes mellitus is a serious threat to public health worldwide. It causes a substantial economic burden, mental and physical disabilities, poor quality of life, and high mortality. Limonite is formed when iron-rich materials from the underground emerge and oxidized on the ground surface. It is currently used to purify contaminated water, absorption of irritant gases, and improve livestock breeding. Limonite can change the composition of environmental microbial communities. In the present study, we evaluated whether limonite can ameliorate glucose metabolism abnormalities by remodeling the gut microbiome. Methods The investigation was performed using mouse models of streptozotocin-induced diabetes mellitus and high-calorie diet-induced metabolic syndrome. Results Oral limonite supplement was associated with significant body weight recovery, reduced glycemia with improved insulin secretion, increased number of regulatory T cells, and abundant beneficial gut microbial populations in mice with diabetes mellitus compared to control. Similarly, mice with obesity fed with limonite supplements had significantly reduced body weight, insulin resistance, steatohepatitis, and systemic inflammatory response with significant gut microbiome remodeling. Conclusion This study demonstrates that limonite supplement ameliorates abnormal glucose metabolism in diabetes mellitus and obesity. Gut microbiome remodeling, inhibition of inflammatory cytokines, and the host immune response regulation may explain the limonite’s beneficial activity under pathological conditions in vivo.
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Affiliation(s)
- Akihiro Uchida
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | - Taro Yasuma
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan.,Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | - Atsuro Takeshita
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan.,Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | - Masaaki Toda
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | - Yuko Okano
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan.,Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | - Kota Nishihama
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | | | | | - Chisa Inoue
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | | | | | | | | | - Yutaka Yano
- Department of Diabetes and Endocrinology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
| | - Esteban C Gabazza
- Department of Immunology, Mie University Faculty and Graduate School of Medicine, Tsu, Mie, Japan
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Abstract
Magnesium (Mg2+) plays an essential role in many biological processes. Mg2+ deficiency is therefore associated with a wide range of clinical effects including muscle cramps, fatigue, seizures and arrhythmias. To maintain sufficient Mg2+ levels, (re)absorption of Mg2+ in the intestine and kidney is tightly regulated. Genetic defects that disturb Mg2+ uptake pathways, as well as drugs interfering with Mg2+ (re)absorption cause hypomagnesemia. The aim of this review is to provide an overview of the molecular mechanisms underlying genetic and drug-induced Mg2+ deficiencies. This leads to the identification of four main mechanisms that are affected by hypomagnesemia-causing mutations or drugs: luminal transient receptor potential melastatin type 6/7-mediated Mg2+ uptake, paracellular Mg2+ reabsorption in the thick ascending limb of Henle's loop, structural integrity of the distal convoluted tubule and Na+-dependent Mg2+ extrusion driven by the Na+/K+-ATPase. Our analysis demonstrates that genetic and drug-induced causes of hypomagnesemia share common molecular mechanisms. Targeting these shared pathways can lead to novel treatment options for patients with hypomagnesemia.
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The alterations of microbiota and pathological conditions in the gut of patients with colorectal cancer undergoing chemotherapy. Anaerobe 2021; 68:102361. [PMID: 33781900 DOI: 10.1016/j.anaerobe.2021.102361] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/10/2021] [Accepted: 03/15/2021] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) has become a serious threat to human life and health. Most patients are diagnosed at the late stage of advanced CRC, resulting in losing their best opportunity for surgical treatment. Chemotherapy plays a crucial role in the control and treatment of advanced CRC. However, the cytotoxicity of chemotherapeutic drugs can easily cause the imbalance of gut flora, damage the barrier of the gastrointestinal mucosa, and mediate mucosal inflammation of the digestive tract, which is called "gastrointestinal mucositis." This mucositis can affect the quality of life of the host and even threaten their lives. Several studies reported the association between chemotherapy-mediated gastrointestinal mucositis in CRC and gut dysbiosis. However, the underlying mechanisms of this association are still unclear. The alternative or complementary treatments to reshape gut microbiota and slow down the side effects of chemotherapy have shown the improvement of gastrointestinal mucositis following chemotherapy in the CRC condition. This review will summarize and discuss the evidence of the association between chemotherapy-mediated gastrointestinal mucositis in CRC and altered gut microbiota from in vivo and clinical studies. The possible mechanisms of gastrointestinal mucositis, including the destruction of the gastrointestinal mucosal barrier, the induction of gut dysbiosis, and histopathological changes in the gut of CRC with chemotherapy will be illustrated. In addition, the nonpharmacological interventions and phytochemical extracts by using the manipulation of the microbial population for therapeutic purposes for relieving side effects of chemotherapy as well as a cancer treatment would be summarized and discussed in this review.
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Anti-Acid Drug Treatment Induces Changes in the Gut Microbiome Composition of Hemodialysis Patients. Microorganisms 2021; 9:microorganisms9020286. [PMID: 33573326 PMCID: PMC7910989 DOI: 10.3390/microorganisms9020286] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/15/2021] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
Anti-acid drugs, proton pump inhibitor (PPI) and histamine-2 blocker (H2-blocker), are commonly prescribed to treat gastrointestinal disorders. These anti-acid drugs alter gut microbiota in the general population, but their effects are not known in hemodialysis patients. Hence, we investigated the microbiota composition in hemodialysis patients treated with PPIs or H2-blocker. Among 193 hemodialysis patients, we identified 32 H2-blocker users, 23 PPI users, and 138 no anti-acid drug subjects. Fecal samples were obtained to analyze the gut microbiome using 16S RNA amplicon sequencing. Differences in the microbial composition of the H2-blocker users, PPI users, and controls were assessed using linear discriminant analysis effect size and the random forest algorithm. The species richness or evenness (α-diversity) was similar among the three groups, whereas the inter-individual diversity (β-diversity) was different between H2-blocker users, PPI users, and controls. Hemodialysis patients treated with H2-blocker and PPIs had a higher microbial dysbiosis index than the controls, with a significant increase in the genera Provetella 2, Phascolarctobacterium, Christensenellaceae R-7 group, and Eubacterium oxidoreducens group in H2-blocker users, and Streptococcus and Veillonella in PPI users. In addition, compared to the H2-blocker users, there was a significant enrichment of the genera Streptococcus in PPI users, as confirmed by the random forest analysis and the confounder-adjusted regression model. In conclusion, PPIs significantly changed the gut microbiota composition in hemodialysis patients compared to H2-blocker users or controls. Importantly, the Streptococcus genus was significantly increased in PPI treatment. These findings caution against the overuse of PPIs.
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Haran JP, McCormick BA. Aging, Frailty, and the Microbiome-How Dysbiosis Influences Human Aging and Disease. Gastroenterology 2021; 160:507-523. [PMID: 33307030 PMCID: PMC7856216 DOI: 10.1053/j.gastro.2020.09.060] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 09/08/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023]
Abstract
The human gut microbiome is a collection of bacteria, protozoa, fungi, and viruses that coexist in our bodies and are essential in protective, metabolic, and physiologic functions of human health. Gut dysbiosis has traditionally been linked to increased risk of infection, but imbalances within the intestinal microbial community structure that correlate with untoward inflammatory responses are increasingly recognized as being involved in disease processes that affect many organ systems in the body. Furthermore, it is becoming more apparent that the connection between gut dysbiosis and age-related diseases may lie in how the gut microbiome communicates with both the intestinal mucosa and the systemic immune system, given that these networks have a common interconnection to frailty. We therefore discuss recent advances in our understanding of the important role the microbiome plays in aging and how this knowledge opens the door for potential novel therapeutics aimed at shaping a less dysbiotic microbiome to prevent or treat age-related diseases.
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Affiliation(s)
- John P Haran
- Department of Emergency Medicine; Department of Microbiology and Physiological Systems; Center for Microbiome Research, University of Massachusetts Medical School, Worcester, Massachusetts.
| | - Beth A McCormick
- Department of Microbiology and Physiological Systems; Center for Microbiome Research, University of Massachusetts Medical School, Worcester, Massachusetts
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Chamniansawat S, Kampuang N, Suksridechacin N, Thongon N. Ultrastructural intestinal mucosa change after prolonged inhibition of gastric acid secretion by omeprazole in male rats. Anat Sci Int 2021; 96:142-156. [PMID: 32931001 DOI: 10.1007/s12565-020-00572-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023]
Abstract
Omeprazole is a potent inhibitor of gastric acid secretion. It was reported that omeprazole induced dramatic gastric mucosa morphologic changes from the resting state to the stimulated state. However, the effect of omeprazole administration on the ultrastructure and absorptive function of small intestines was largely unknown. Here, male Sprague-Dawley rats were daily treated with a single dose of omeprazole for 12 or 24 weeks. Ultrastructure intestinal mucosal change in duodenum, jejunum, and ileum was observed. We also determined small intestine inflammation, using intraepithelial lymphocytes activation. Finally, magnesium levels were measured in plasma, urine, feces, muscle, and bone to determine systemic magnesium balance. Omeprazole-treated rats had significantly decreased the width of tight junction, villous length, and absorptive area of duodenum, jejunum, and ileum compared to control rats. The small intestine of the omeprazole-treated group showed significantly higher intraepithelial lymphocytes activation levels compared with the control group. Lower secretory granules of Paneth cells at the base of the crypts were showed in omeprazole-treated rats. They also had significantly lower plasma, urinary, bone, and muscle Mg2+ contents indicating hypomagnesemia with systemic magnesium deficiency. In conclusion, prolonged omeprazole treatment-induced small intestinal inflammation and villous atrophy, which led to decrease small intestinal magnesium absorption in the condition of proton pump inhibitor-induced hypomagnesemia.
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Affiliation(s)
- Siriporn Chamniansawat
- Division of Anatomy, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd., Saensook, Muang, Chon Buri, 20131, Thailand
| | - Nattida Kampuang
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chon Buri, Thailand
| | - Nasisorn Suksridechacin
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chon Buri, Thailand
| | - Narongrit Thongon
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chon Buri, Thailand.
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Otani K, Watanabe T, Kosaka S, Matsumoto Y, Nakata A, Nadatani Y, Fukunaga S, Hosomi S, Tanaka F, Kamata N, Taira K, Nagami Y, Tanigawa T, Kimura T, Fukumoto S, Kawada N, Fujiwara Y. Utility of Kyoto Classification of Gastritis in subjects with a high-negative titer of anti- Helicobacter pylori antibody during a medical check-up. J Clin Biochem Nutr 2020; 67:317-322. [PMID: 33293774 PMCID: PMC7705079 DOI: 10.3164/jcbn.20-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 03/15/2020] [Indexed: 02/06/2023] Open
Abstract
Subjects with a high-negative titer (3-9.9 U/ml) of serum anti-Helicobacter pylori (H. pylori) antibody represent a heterogeneous group of currently H. pylori-infected, H. pylori-uninfected, and previously H. pylori-infected cases. We investigated the characteristics of subjects with a high-negative titer during a medical check-up and the utility of H. pylori infection score, the sum of scores of endoscopic findings based on the Kyoto Classification of Gastritis, for diagnosing H. pylori infection. Subjects with 13C-urea breath test-positive or H. pylori stool antigen test-positive were diagnosed as currently H. pylori-infected. Although around half of subjects with a high-negative titer were after eradication therapy (48.6%), currently H. pylori-infected were considerably confirmed (11.7%). H. pylori infection score showed a high value of area under the receiver operating characteristic curve [0.92; 95% confidence interval (CI), 0.84-1.00] with the most suitable cut-off value of 1.0 (sensitivity: 0.92; specificity: 0.90). Multivariate logistic regression analysis revealed that H. pylori infection score was an independent factor associated with increased prevalence of H. pylori infection (odds ratio, 9.53; 95% CI, 2.64-34.40; p<0.001). Currently H. pylori-infected subjects were considerably included among the subjects with a high-negative titer, and the Kyoto Classification of Gastritis was useful to predict current H. pylori infection.
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Affiliation(s)
- Koji Otani
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Toshio Watanabe
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Satoshi Kosaka
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Yuji Matsumoto
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Akinobu Nakata
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Yuji Nadatani
- Premier Preventive Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Shusei Fukunaga
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Shuhei Hosomi
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Fumio Tanaka
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Noriko Kamata
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Koichi Taira
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Yasuaki Nagami
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Tetsuya Tanigawa
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Tatsuo Kimura
- Premier Preventive Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Shinya Fukumoto
- Premier Preventive Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Norifumi Kawada
- Premier Preventive Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
| | - Yasuhiro Fujiwara
- Departments of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
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Fujimoto S, Tsuruoka N, Esaki M, Takamori A, Sakata Y, Shimoda R, Akutagawa T, Node K, Anzai K, Sugisaki N, Iwakiri R, Takagi K, Yamanouchi K, Fujimoto K. Decline incidence in upper gastrointestinal bleeding in several recent years: data of the Japan claims database of 13 million accumulated patients. J Clin Biochem Nutr 2020; 68:95-100. [PMID: 33536718 PMCID: PMC7844659 DOI: 10.3164/jcbn.20-153] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 09/27/2020] [Indexed: 12/27/2022] Open
Abstract
This study was to examine the recent trends in upper gastrointestinal bleeding in Japan using a large-scale real-world database. The incidence of upper gastrointestinal bleeding was evaluated in the Japan Medical Data Center claims database of 13,019,713 patients aged 20 to 74 years with traceability for 3 months from 2009 to 2014. The incidence was compared with peptic ulcers and gastroesophageal reflux disease. The prescription of medications was also evaluated. The incidence of bleeding was 0.137%, 0.121%, 0.113%, 0.106%, 0.099%, and 0.105% during 2009 to 2014 with a time-dependent decline (p<0.001). Peptic ulcers (>10 times higher than the incidence of bleeding) decreased with time (p<0.001), whereas gastroesophageal reflux disease increased (p = 0.006). Upper gastrointestinal bleeding was higher in male patients and older patients (60–74 years old) (p<0.001 respectively). The prescription rate of antithrombotic medications and proton pump inhibitors increased from 2009 to 2014 (p<0.001 respectively). The incidence of upper gastrointestinal bleeding decreased from 2009 to 2014 in this relatively large-scale real-world database in Japan, concomitant with the decrease in peptic ulcers. The decreased incidence might have been due to changes in the disease structure and therapeutic strategies over time.
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Affiliation(s)
- Shun Fujimoto
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Nanae Tsuruoka
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Motohiro Esaki
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Ayako Takamori
- Division of Clinical Research Center, Saga University Hospital, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Yasuhisa Sakata
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Ryo Shimoda
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Takashi Akutagawa
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Koichi Node
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Keizo Anzai
- Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Nobuyuki Sugisaki
- EA Pharma Co., Ltd., 1-1, Irifune 2-chome, Chuo-ku, Tokyo 104-0042, Japan
| | - Ryuichi Iwakiri
- Takeda Pharmaceutical Company, Ltd., 1-1, Nihonbashimotomachi 2-chome, Chuo-ku, Tokyo 103-8668, Japan
| | - Kuniaki Takagi
- Divison of Gastroenterology, Faculty of Medicine, International University of Health and Welfare, 137-1 Enokitsu, Okawa, Fukuoka 831-8501, Japan
| | - Kohei Yamanouchi
- Divison of Gastroenterology, Faculty of Medicine, International University of Health and Welfare, 137-1 Enokitsu, Okawa, Fukuoka 831-8501, Japan
| | - Kazuma Fujimoto
- Divison of Gastroenterology, Faculty of Medicine, International University of Health and Welfare, 137-1 Enokitsu, Okawa, Fukuoka 831-8501, Japan
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Fisher L, Fisher A, Smith PN. Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review). J Clin Med 2020; 9:E3253. [PMID: 33053671 PMCID: PMC7600664 DOI: 10.3390/jcm9103253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/28/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Osteoporosis (OP) and osteoporotic fractures (OFs) are common multifactorial and heterogenic disorders of increasing incidence. Helicobacter pylori (H.p.) colonizes the stomach approximately in half of the world's population, causes gastroduodenal diseases and is prevalent in numerous extra-digestive diseases known to be associated with OP/OF. The studies regarding relationship between H.p. infection (HPI) and OP/OFs are inconsistent. The current review summarizes the relevant literature on the potential role of HPI in OP, falls and OFs and highlights the reasons for controversies in the publications. In the first section, after a brief overview of HPI biological features, we analyze the studies evaluating the association of HPI and bone status. The second part includes data on the prevalence of OP/OFs in HPI-induced gastroduodenal diseases (peptic ulcer, chronic/atrophic gastritis and cancer) and the effects of acid-suppressive drugs. In the next section, we discuss the possible contribution of HPI-associated extra-digestive diseases and medications to OP/OF, focusing on conditions affecting both bone homeostasis and predisposing to falls. In the last section, we describe clinical implications of accumulated data on HPI as a co-factor of OP/OF and present a feasible five-step algorithm for OP/OF risk assessment and management in regard to HPI, emphasizing the importance of an integrative (but differentiated) holistic approach. Increased awareness about the consequences of HPI linked to OP/OF can aid early detection and management. Further research on the HPI-OP/OF relationship is needed to close current knowledge gaps and improve clinical management of both OP/OF and HPI-related disorders.
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Affiliation(s)
- Leon Fisher
- Department of Gastroenterology, Frankston Hospital, Peninsula Health, Melbourne 3199, Australia
| | - Alexander Fisher
- Department of Geriatric Medicine, The Canberra Hospital, ACT Health, Canberra 2605, Australia;
- Department of Orthopedic Surgery, The Canberra Hospital, ACT Health, Canberra 2605, Australia;
- Australian National University Medical School, Canberra 2605, Australia
| | - Paul N Smith
- Department of Orthopedic Surgery, The Canberra Hospital, ACT Health, Canberra 2605, Australia;
- Australian National University Medical School, Canberra 2605, Australia
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Changes in the Gut Microbiota are Associated with Hypertension, Hyperlipidemia, and Type 2 Diabetes Mellitus in Japanese Subjects. Nutrients 2020; 12:nu12102996. [PMID: 33007825 PMCID: PMC7601322 DOI: 10.3390/nu12102996] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 12/11/2022] Open
Abstract
The human gut microbiota is involved in host health and disease development. Therefore, lifestyle-related diseases such as hypertension (HT), hyperlipidemia (HL), and type 2 diabetes mellitus (T2D) may alter the composition of gut microbiota. Here, we investigated gut microbiota changes related to these diseases and their coexistence. This study involved 239 Japanese subjects, including healthy controls (HC). The fecal microbiota was analyzed through the isolation of bacterial genomic DNA obtained from fecal samples. Although there were no significant differences in the microbial structure between groups, there was a significant difference in the α-diversity between HC and the patients in whom two diseases coexisted. Moreover, Actinobacteria levels were significantly increased, whereas Bacteroidetes levels were significantly decreased in all disease groups. At the genus level, Bifidobacterium levels were significantly increased in the HL and T2D groups, as were those of Collinsella in all disease groups. In contrast, Alistipes levels were significantly lower in the HL group. Furthermore, metabolic enzyme families were significantly increased in all disease groups. Interestingly, the structure and function of the gut microbiota showed similar profiles in all the studied diseases. In conclusion, several changes in the structure of the gut microbiota are associated with T2D, HT, and HL in Japanese subjects.
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Sbeit W, Khoury T, Kadah A, Asadi W, Shahin A, Lubany A, Safadi M, Haddad H, Abu Ahmad R, Abu El Hija S, Abboud R, Mahamid M, Pellicano R, Mari A. Proton Pump Inhibitor Use May Increase the Risk of Diverticulitis but Not It's Severity among Patients with Colonic Diverticulosis: A Multicenter Study. J Clin Med 2020; 9:2966. [PMID: 32937926 PMCID: PMC7565510 DOI: 10.3390/jcm9092966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 12/12/2022] Open
Abstract
Colonic diverticular disease, especially diverticulitis constitutes a major cause of hospitalization and an economic burden in developed countries. Proton pump inhibitors (PPIs) are among the commonest drugs used to treat several diseases affecting the upper gastrointestinal tract. A few studies have reported that the use of Proton Pump Inhibitors PPIs caused dysbiosis. In this study, we searched for a relationship between PPI use and the onset and severity of diverticulitis in patients with colonic diverticulosis. In a retrospective study, patients who were hospitalized for documented diverticulitis were enrolled as cases and compared with a control group of patients with uncomplicated diverticulosis. Overall, 613 patients who had a diagnosis of diverticulosis were included in the study, 217 of whom had diverticulitis. After multivariate analysis, the non-modifiable risk factors associated with diverticulitis included: age (p < 0.0001), hypertension (p < 0.0001), chronic renal failure (p = 0.007), diabetes mellitus (p < 0.0001), and left colon location (p = 0.02). However, among the modifiable factors, only PPI use (p < 0.0001) showed a significant association. Advanced disease severity (according to Hinchey classification of diverticulitis stages II-IV) was associated with aspirin use (p = 0.0004) and pan-colonic location (p = 0.02). PPI use was the only modifiable factor significantly associated with diverticulitis, but not with its severity, among patients with diverticulosis. This observation should be confirmed in future multicenter prospective studies.
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Affiliation(s)
- Wisam Sbeit
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13100, Israel; (W.S.); (T.K.); (A.K.); (W.A.); (A.S.)
| | - Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13100, Israel; (W.S.); (T.K.); (A.K.); (W.A.); (A.S.)
| | - Anas Kadah
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13100, Israel; (W.S.); (T.K.); (A.K.); (W.A.); (A.S.)
| | - Waseem Asadi
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13100, Israel; (W.S.); (T.K.); (A.K.); (W.A.); (A.S.)
| | - Amir Shahin
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13100, Israel; (W.S.); (T.K.); (A.K.); (W.A.); (A.S.)
| | - Ahmad Lubany
- Surgery Department, The Nazareth Hospital, EMMS, Nazareth 1613101, Israel; (A.L.); (M.S.); (H.H.); (R.A.A.); (S.A.E.H.); (R.A.)
| | - Mohammed Safadi
- Surgery Department, The Nazareth Hospital, EMMS, Nazareth 1613101, Israel; (A.L.); (M.S.); (H.H.); (R.A.A.); (S.A.E.H.); (R.A.)
| | - Haya Haddad
- Surgery Department, The Nazareth Hospital, EMMS, Nazareth 1613101, Israel; (A.L.); (M.S.); (H.H.); (R.A.A.); (S.A.E.H.); (R.A.)
| | - Ruba Abu Ahmad
- Surgery Department, The Nazareth Hospital, EMMS, Nazareth 1613101, Israel; (A.L.); (M.S.); (H.H.); (R.A.A.); (S.A.E.H.); (R.A.)
| | - Sami Abu El Hija
- Surgery Department, The Nazareth Hospital, EMMS, Nazareth 1613101, Israel; (A.L.); (M.S.); (H.H.); (R.A.A.); (S.A.E.H.); (R.A.)
| | - Rand Abboud
- Surgery Department, The Nazareth Hospital, EMMS, Nazareth 1613101, Israel; (A.L.); (M.S.); (H.H.); (R.A.A.); (S.A.E.H.); (R.A.)
| | - Mahmud Mahamid
- Faculty of Medicine, Hebrew University of Jerusalem, Department of Gastroenterology and Liver Diseases, Shaare Zedek Medical Center, Jerusalem 9103401, Israel;
| | | | - Amir Mari
- Gastroenterology and Endoscopy United, The Nazareth Hospital, EMMS, Faculty of medicine, Bar-Ilan University, Nazareth 1613101, Israel
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Jang S, Lebwohl B, Abrams JA, Green PH, Freedberg DE, Alaedini A. Celiac disease serology and gut microbiome following proton pump inhibitor treatment. Medicine (Baltimore) 2020; 99:e21488. [PMID: 32871870 PMCID: PMC7458245 DOI: 10.1097/md.0000000000021488] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Celiac disease is an autoimmune enteropathy characterized by an aberrant immune response to ingested gluten in genetically predisposed individuals. Studies have pointed to a rising prevalence of celiac disease in recent decades. Changes in diet and use of medication that may impact the gut microbiome have been suggested as potential contributors. Exposure to proton pump inhibitors (PPIs) was recently found to be associated with an increased risk for subsequent diagnosis of celiac disease. We aimed to investigate potential mechanisms for this link by examining the relationship between PPI use and gluten-related immune responses in the context of changes in gut microbiome. METHODS We performed a post hoc analysis of blood and fecal samples from a recent randomized trial in order to assess the potential association between PPI use and development of celiac disease serology in conjunction with alterations in gastrointestinal microbial composition. The study included 12 healthy participants who were administered a PPI (Omeprazole; 40 mg twice daily) for 4 or 8 weeks. RESULTS The analysis did not reveal an overall significant change in levels of serologic markers of celiac disease for the study cohort in response to PPI treatment. However, one individual developed a marked increase in the celiac disease-specific autoantibody response to transglutaminase 2 in conjunction with enhanced immune reactivity to gluten during the trial. Genotyping revealed positivity for the celiac disease-associated HLA-DQ2 and -DQ8 alleles. Furthermore, the observed elevation in antibody responses was closely associated with a sharp increase in fecal abundance of bacteria of the order Actinomycetales. CONCLUSIONS The results of this exploratory analysis support further investigation of molecular mechanisms involved in the contribution of PPIs to celiac disease risk through the potential enhancement of gluten immunopathology and changes in gut microbial population.
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Affiliation(s)
- Sophie Jang
- Department of Medicine
- Institute of Human Nutrition
| | - Benjamin Lebwohl
- Department of Medicine
- Celiac Disease Center
- Department of Epidemiology, Columbia University Irving Medical Center
| | - Julian A. Abrams
- Department of Medicine
- Department of Epidemiology, Columbia University Irving Medical Center
| | | | | | - Armin Alaedini
- Department of Medicine
- Institute of Human Nutrition
- Celiac Disease Center
- Department of Medicine, New York Medical College, Valhalla, New York
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49
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Hashimoto Y, Hamaguchi M, Kaji A, Sakai R, Osaka T, Inoue R, Kashiwagi S, Mizushima K, Uchiyama K, Takagi T, Naito Y, Fukui M. Intake of sucrose affects gut dysbiosis in patients with type 2 diabetes. J Diabetes Investig 2020; 11:1623-1634. [PMID: 32412684 PMCID: PMC7610116 DOI: 10.1111/jdi.13293] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 05/07/2020] [Accepted: 05/08/2020] [Indexed: 12/14/2022] Open
Abstract
Aims/Introduction Gut dysbiosis is generally associated with type 2 diabetes mellitus. However, the effect of habitual dietary intake on gut dysbiosis in Japanese patients with type 2 diabetes mellitus has not yet been explicated. This study investigated whether alteration of the gut microbiota was influenced by dietary intake of sucrose in Japanese patients with type 2 diabetes mellitus. Materials and Methods In this cross‐sectional study, 97 patients with type 2 diabetes mellitus and 97 healthy individuals were matched by age and sex, and then, fecal samples were obtained. Next‐generation sequencing of the 16S ribosomal ribonucleic acid gene was carried out, and functional profiles for the gut microbiota were analyzed. We selected the top 30 gut microbial genera and top 20 functional profiles for the gut microbiota specified by the weighted average difference method. The association between gut microbial genera or functional profiles and habitual dietary intake was investigated by Spearman’s rank correlation coefficient, and then, clustering analysis was carried out to clarify the impact of habitual dietary intake. Results The Actinobacteria phylum was highly abundant in patients with type 2 diabetes mellitus, whereas the Bacteroidetes phylum was less abundant. Diabetic‐type gut microbes, specifically Bacteroides and Bifidobacterium, were altered by sucrose intake at the genus level. Furthermore, sucrose intake was associated with glycolysis/gluconeogenesis in the diabetic‐type functional profiles of the gut microbiota. Conclusions The gut microbiota and functional profiles for the gut microbiota in patients with type 2 diabetes mellitus were significantly different from those in healthy individuals. Furthermore, we showed that sucrose intake was closely associated with these differences.
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Affiliation(s)
- Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ayumi Kaji
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryosuke Sakai
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takafumi Osaka
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryo Inoue
- Laboratory of Animal Science, Kyoto Prefectural University, Kyoto, Japan.,Laboratory of Animal Science, Setsunan University, Hirakata, Japan
| | - Saori Kashiwagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.,Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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50
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Shah A, Talley NJ, Koloski N, Macdonald GA, Kendall BJ, Shanahan ER, Walker MM, Keely S, Jones MP, Morrison M, Holtmann GJ. Duodenal bacterial load as determined by quantitative polymerase chain reaction in asymptomatic controls, functional gastrointestinal disorders and inflammatory bowel disease. Aliment Pharmacol Ther 2020; 52:155-167. [PMID: 32412673 DOI: 10.1111/apt.15786] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 02/12/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Small intestinal bacterial overgrowth may play a role in gastrointestinal and non-gastrointestinal diseases. AIMS To use quantitative polymerase chain reaction (qPCR) to determine and compare bacterial loads of duodenal biopsies in asymptomatic controls, and patients with functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease (CD). To define effects of gastric acid inhibition on bacterial load, explore links of bacterial load and gastrointestinal symptoms in response to a standardised nutrient challenge and compare bacterial load with glucose breath test results. METHODS In 237 patients (63 controls, 84 FGID and 90 IBD), we collected mucosal samples under aseptic conditions during endoscopy extracted and total DNA. Bacterial load metric was calculated utilising qPCR measurements of the bacterial 16S rRNA gene, normalised to human beta-actin expression. Standard glucose breath test and nutrient challenge test were performed. RESULTS The duodenal microbial load was higher in patients with FGID (0.22 ± 0.03) than controls (0.07 ± 0.05; P = 0.007) and patients with UC (0.01 ± 0.05) or CD (0.02 ± 0.09), (P = 0.0001). While patients treated with proton pump inhibitors (PPI) had significantly higher bacterial loads than non-users (P < 0.05), this did not explain differences between patient groups and controls. Bacterial load was significantly (r = 0.21, P < 0.016) associated with the symptom response to standardised nutrient challenge test. Methane, but not hydrogen values on glucose breath test were associated with bacterial load measured utilising qPCR. CONCLUSIONS Utilising qPCR, a diagnosis of FGID and treatment with PPI were independently associated with increased bacterial loads. Increased bacterial loads are associated with an augmented symptom response to a standardised nutrient challenge.
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Affiliation(s)
- Ayesha Shah
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Faculty of Medicine and Faulty of Health and Behavioural Sciences, University of Queensland, Brisbane, Qld, Australia
| | - Nicholas J Talley
- Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Natasha Koloski
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Faculty of Medicine and Faulty of Health and Behavioural Sciences, University of Queensland, Brisbane, Qld, Australia
| | - Graeme A Macdonald
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Faculty of Medicine and Faulty of Health and Behavioural Sciences, University of Queensland, Brisbane, Qld, Australia
| | - Bradley J Kendall
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Faculty of Medicine and Faulty of Health and Behavioural Sciences, University of Queensland, Brisbane, Qld, Australia
| | - Erin R Shanahan
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Faculty of Medicine and Faulty of Health and Behavioural Sciences, University of Queensland, Brisbane, Qld, Australia
| | - Marjorie M Walker
- Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Simon Keely
- Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Michael P Jones
- Psychology Department, Macquarie University, Ryde, NSW, Australia
| | - Mark Morrison
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Diamantina Institute, University of Queensland, Brisbane, Qld, Australia
| | - Gerald J Holtmann
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld, Australia.,Faculty of Medicine and Faulty of Health and Behavioural Sciences, University of Queensland, Brisbane, Qld, Australia
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