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Huang Y, Cai Y, Chen Y, Zhu Q, Feng W, Jin L, Ma Y. Cholelithiasis and cholecystectomy increase the risk of gastroesophageal reflux disease and Barrett's esophagus. Front Med (Lausanne) 2024; 11:1420462. [PMID: 39091288 PMCID: PMC11292949 DOI: 10.3389/fmed.2024.1420462] [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: 04/20/2024] [Accepted: 06/20/2024] [Indexed: 08/04/2024] Open
Abstract
Background Cholelithiasis or cholecystectomy may contribute to the development of gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) through bile reflux; however, current observational studies yield inconsistent findings. We utilized a novel approach combining meta-analysis and Mendelian randomization (MR) analysis, to assess the association between them. Methods The literature search was done using PubMed, Web of Science, and Embase databases, up to 3 November 2023. A meta-analysis of observational studies assessing the correlations between cholelithiasis or cholecystectomy, and the risk factors for GERD, BE, and EACwas conducted. In addition, the MR analysis was employed to assess the causative impact of genetic pre-disposition for cholelithiasis or cholecystectomy on these esophageal diseases. Results The results of the meta-analysis indicated that cholelithiasis was significantly linked to an elevated risk in the incidence of BE (RR, 1.77; 95% CI, 1.37-2.29; p < 0.001) and cholecystectomy was a risk factor for GERD (RR, 1.37; 95%CI, 1.09-1.72; p = 0.008). We observed significant genetic associations between cholelithiasis and both GERD (OR, 1.06; 95% CI, 1.02-1.10; p < 0.001) and BE (OR, 1.21; 95% CI, 1.11-1.32; p < 0.001), and a correlation between cholecystectomy and both GERD (OR, 1.04; 95% CI, 1.02-1.06; p < 0.001) and BE (OR, 1.13; 95% CI, 1.06-1.19; p < 0.001). After adjusting for common risk factors, such as smoking, alcohol consumption, and BMI in multivariate analysis, the risk of GERD and BE still persisted. Conclusion Our study revealed that both cholelithiasis and cholecystectomy elevate the risk of GERD and BE. However, there is no observed increase in the risk of EAC, despite GERD and BE being the primary pathophysiological pathways leading to EAC. Therefore, patients with cholelithiasis and cholecystectomy should be vigilant regarding esophageal symptoms; however, invasive EAC cytology may not be necessary.
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Affiliation(s)
- Yu Huang
- Department of Cardiothoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, China
| | - Yicong Cai
- Department of Gastrointestinal Surgery, Third Xiangya Hospital of Central South University, Changsha, China
| | - Yingji Chen
- Department of Cardiothoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, China
| | - Qianjun Zhu
- Department of Cardiothoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, China
| | - Wei Feng
- Department of Cardiothoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, China
| | - Longyu Jin
- Department of Cardiothoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, China
| | - Yuchao Ma
- Department of Cardiothoracic Surgery, Third Xiangya Hospital of Central South University, Changsha, China
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Li Y, Duan Z. Updates in interaction of gastroesophageal reflux disease and extragastroesophageal digestive diseases. Expert Rev Gastroenterol Hepatol 2022; 16:1053-1063. [PMID: 35860994 DOI: 10.1080/17474124.2022.2056018] [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: 12/27/2022]
Abstract
INTRODUCTION Gastroesophageal reflux disease (GERD) is one of the common chronic diseases with prevalence increasing in the last decades. Because of its prevalence and chronicity, GERD affects the quality of life and increases health-care costs. Gastroesophageal diseases leading to GERD have been thoroughly studied, while extragastroesophageal digestive diseases (EGEDDs) may coexist with GERD and affect the occurrence and persistence of GERD symptoms and therapeutic effect. AREAS COVERED In this review, we aim to summarize the EGEDDs correlated with GERD and explore the potential mechanisms of this interaction. EXPERT OPINION Individuals with troublesome GERD symptoms may have some common gastroesophageal etiologies, but EGEDDs may also overlap and impact on the progression of GERD, which are often ignored in clinic. The lesions in the small intestine, colon, and hepatobiliary tract as well as functional bowel disorders had positive or negative associations with GERD through potential mechanisms. These diseases aggravate GERD symptoms, increase the esophageal acid burden, cause esophageal hypersensitivity, and finally affect the response to therapy in GERD patients. Therefore, it is necessary to clear the interaction between GERD and EGEDDs and their mechanisms.
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Affiliation(s)
- Yanqiu Li
- Second Gastroenterology Department, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Zhijun Duan
- Second Gastroenterology Department, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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Ushiroda C, Naito Y, Takagi T, Uchiyama K, Mizushima K, Higashimura Y, Yasukawa Z, Okubo T, Inoue R, Honda A, Matsuzaki Y, Itoh Y. Green tea polyphenol (epigallocatechin-3-gallate) improves gut dysbiosis and serum bile acids dysregulation in high-fat diet-fed mice. J Clin Biochem Nutr 2019; 65:34-46. [PMID: 31379412 PMCID: PMC6667385 DOI: 10.3164/jcbn.18-116] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 01/04/2019] [Indexed: 12/11/2022] Open
Abstract
Gut microbiota have profound effects on bile acid metabolism by promoting deconjugation, dehydrogenation, and dehydroxylation of primary bile acids in the distal small intestine and colon. High-fat diet-induced dysbiosis of gut microbiota and bile acid dysregulation may be involved in the pathology of steatosis in patients with non-alcoholic fatty liver disease. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenolic catechin in green tea, has been widely investigated for its inhibitory or preventive effects against fatty liver. The aim of the present study was to investigate the effects of EGCG on the abundance of gut microbiota and the composition of serum bile acids in high-fat diet-fed mice and determine the specific bacterial genera that can improve the serum bile acid dysregulation associated with EGCG anti-hepatic steatosis action. Male C57BL/6N mice were fed with the control diet, high-fat diet, or high-fat diet + EGCG at a concentration of 0.32% for 8 weeks. EGCG significantly inhibited the increases in weight, the area of fatty lesions, and the triglyceride content in the liver induced by the high-fat diet. Principal coordinate analysis revealed significant differences in microbial structure among the groups. At the genus level, EGCG induced changes in the microbiota composition in high-fat diet-fed mice, showing a significantly higher abundance of Adlercreutzia, Akkermansia, Allobaculum and a significantly lower abundance of Desulfovibrionaceae. EGCG significantly reversed the decreased population of serum primary cholic acid and β-muricholic acid as well as the increased population of taurine-conjugated cholic acid, β-muricholic acid and deoxycholic acid in high-fat diet-fed mice. Finally, the correlation analysis between bile acid profiles and gut microbiota demonstrated the contribution of Akkermansia and Desulfovibrionaceae in the improvement of bile acid dysregulation in high-fat diet-fed mice by treatment with EGCG. In conclusion, the present study suggests that EGCG could alter bile acid metabolism, especially taurine deconjugation, and suppress fatty liver disease by improving the intestinal luminal environment.
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Affiliation(s)
- Chihiro Ushiroda
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yuji Naito
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kazuhiko Uchiyama
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Katsura Mizushima
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yasuki Higashimura
- Department of Food Science, Ishikawa Prefectural University, 1-308 Suematsu, Nonoichi, Ishikawa 921-8836, Japan
| | - Zenta Yasukawa
- Nutrition Division, Taiyo Kagaku Co. Ltd., 1-3 Takaramachi, Yokkaichi, Mie 510-0844, Japan
| | - Tsutomu Okubo
- Nutrition Division, Taiyo Kagaku Co. Ltd., 1-3 Takaramachi, Yokkaichi, Mie 510-0844, Japan
| | - Ryo Inoue
- Laboratory of Animal Science, Department of Agricultural and Life Sciences, Kyoto Prefectural University, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-8522, Japan
| | - Akira Honda
- Gastroenterology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Ami-machi Chuo, Inashiki-gun, Ibaraki 300-0395, Japan
| | - Yasushi Matsuzaki
- Gastroenterology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Ami-machi Chuo, Inashiki-gun, Ibaraki 300-0395, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
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Matsuzaki J, Suzuki H. Circulating microRNAs as potential biomarkers to detect transformation of Barrett's oesophagus to oesophageal adenocarcinoma. BMJ Open Gastroenterol 2017; 4:e000160. [PMID: 29177063 PMCID: PMC5689485 DOI: 10.1136/bmjgast-2017-000160] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 07/05/2017] [Accepted: 07/07/2017] [Indexed: 12/19/2022] Open
Abstract
Objective Circulating microRNAs (miRNAs) are promising biomarkers for the early detection of cancers. This study aimed to address potential circulating miRNAs to monitor the progression from Barrett’s oesophagus (BO) to oesophageal adenocarcinoma (OAC). Design We comprehensively analysed tissue and serum miRNA expression profiles of BO mice model (L2-interleukin-1β (IL-1β) mice) using microarray analysis. To validate the data from mice, a published dataset of human plasma miRNAs, consisting of eight patients with OAC, eight with BO and six healthy controls, was used (GSE51410). Results We identified 20 upregulated miRNAs and 44 downregulated miRNAs both in tissues and in sera of 46-week-old mice compared with 28-week-old mice. Two of the 20 miRNAs (miR-128-3 p and miR-328-3 p) were upregulated, and five of the 44 miRNAs (miR-143-3 p, miR-144-3 p, miR-15a-5p, miR-1-3 p and miR-133b) were downregulated in plasma of patients with OAC compared with plasma of patients with BO. Receiver operating characteristic curve analysis revealed that a prediction index calculated by the above-mentioned seven miRNAs could discriminate between patients with OAC and those without OAC with the area under the curve of 0.91, sensitivity of 1 and specificity of 0.75. Conclusions Levels of the seven circulating miRNAs may represent the tissue miRNA levels and could be promising non-invasive biomarkers to evaluate the carcinogenic process of BO.
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Affiliation(s)
- Juntaro Matsuzaki
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hidekazu Suzuki
- Medical Education Center, Keio University School of Medicine, Tokyo, Japan
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Shah Gilani SN, Bass GA, Kharytaniuk N, Downes MR, Caffrey EF, Tobbia I, Walsh TN. Gastroesophageal Mucosal Injury after Cholecystectomy: An Indication for Surveillance? J Am Coll Surg 2016; 224:319-326. [PMID: 27993699 DOI: 10.1016/j.jamcollsurg.2016.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/03/2016] [Accepted: 12/05/2016] [Indexed: 11/18/2022]
Abstract
BACKGROUND Cholecystectomy alters bile release dynamics from pulsatile meal-stimulated to continuous, and results in retrograde duodeno-gastric bile reflux (DGR). Bile is implicated in mucosal injury after gastric surgery, but whether cholecystectomy causes esophagogastric mucosal inflammation, therefore increasing the risk of metaplasia, is unclear. STUDY DESIGN This study examined whether cholecystectomy-induced DGR promotes chronic inflammatory mucosal changes of the stomach and/or the esophagogastric junction (EGJ). Four groups of patients were studied and compared with controls. A group of patients was studied before and 1 year after cholecystectomy; 2 further groups were studied long-term post-cholecystectomy (LTPC) at 5 to 10 years and 10 to 20 years. All underwent abdominal ultrasound and upper gastrointestinal endoscopy with gastric antral and EGJ biopsies, noting the presence of gastric bile pooling. Biopsy specimens were stained for Ki67 and p53 overexpression, and the bile reflux index (BRI) was calculated. RESULTS At endoscopy, bile pooling was observed in 9 of 26 (34.6%) controls, in 8 of 25 (32%) patients pre-cholecystectomy, in 15 of 25 (60%) 1 year post-cholecystectomy patients (p = 0.047), and 23 of 29 (79.3%) LTPC patients (p = 0.001). Bile reflux index positivity at the EGJ increased from 19% of controls through 41% of LTPC patients (p = 0.032). Ki67 was overexpressed at the EGJ in 19% of controls, but in 62% of LTPC patients (p = 0.044); p53 was overexpressed at the EGJ in 19% of controls compared with 66% of LTPC patients (p = 0.001). CONCLUSIONS Duodeno-gastric bile reflux was more common in patients with gallstones than in controls, and its incidence doubled after cholecystectomy. This was associated with inflammatory changes in the gastric antrum and the EGJ, evident in most LTPC patients. Ki67 and p53 overexpression at the EGJ suggests cellular damage attributable to chronic bile exposure post-cholecystectomy, increasing the likelihood of dysplasia. Further studies are required to determine whether DGR-mediated esophageal mucosal injury is reversible or avoidable, and whether surveillance endoscopy is indicated after cholecystectomy.
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Affiliation(s)
- Syeda Nadia Shah Gilani
- Department of Surgery, Connolly Hospital, Blanchardstown, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Gary Alan Bass
- Department of Surgery, Connolly Hospital, Blanchardstown, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | | | | | - Iqbal Tobbia
- Department of Pathology, Connolly Hospital, Blanchardstown, Dublin, Ireland
| | - Thomas Noel Walsh
- Department of Surgery, Connolly Hospital, Blanchardstown, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland.
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Sallum RAA, Padrão EMH, Szachnowicz S, Seguro FCBC, Bianchi ET, Cecconello I. Prevalence of gallstones in 1,229 patients submitted to surgical laparoscopic treatment of GERD and esophageal achalasia: associated cholecystectomy was a safe procedure. ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2016; 28:113-6. [PMID: 26176247 PMCID: PMC4737332 DOI: 10.1590/s0102-67202015000200007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 01/08/2015] [Indexed: 12/23/2022]
Abstract
Background Association between esophageal achalasia/ gastroesophageal reflux disease (GERD)
and cholelithiasis is not clear. Epidemiological data are controversial due to
different methodologies applied, the regional differences and the number of
patients involved. Results of concomitant cholecistectomy associated to surgical
treatment of both diseases regarding safety is poorly understood. Aim To analyze the prevalence of cholelithiasis in patients with esophageal achalasia
and gastroesophageal reflux submitted to cardiomyotomy or fundoplication. Also, to
evaluate the safety of concomitant cholecistectomy. Methods Retrospective analysis of 1410 patients operated from 2000 to 2013. They were
divided into two groups: patients with GERD submitted to laparocopic hiatoplasty
plus Nissen fundoplication and patients with esophageal achalasia to laparoscopic
cardiomyotomy plus partial fundoplication. It was collected epidemiological data,
specific diagnosis and subgroups, the presence or absence of gallstones, surgical
procedure, operative and clinical complications and mortality. All
groups/subgroups were compared. Results From 1,229 patients with GERD or esophageal achalasia, submitted to laparoscopic
cardiomyotomy or fundoplication, 138 (11.43%) had cholelitiasis, occurring more in
females (2.38:1) with mean age of 50,27 years old. In 604 patients with GERD, 79
(13,08%) had cholelitiasis. Lower prevalence occurred in Barrett's esophagus
patients 7/105 (6.67%) (p=0.037). In 625 with esophageal achalasia, 59 (9.44%) had
cholelitiasis, with no difference between chagasic and idiopathic forms (p=0.677).
Complications of patients with or without cholecystectomy were similar in
fundoplication and cardiomyotomy (p=0.78 and p=1.00).There was no mortality or
complications related to cholecystectomy in this series. Conclusions Prevalence of cholelithiasis was higher in patients submitted to fundoplication
(GERD). Patients with chagasic or idiopatic forms of achalasia had the same
prevalence of cholelithiasis. Gallstones occurred more in GERD patients without
Barrett's esophagus. Simultaneous laparoscopic cholecystectomy was proved
safe.
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Affiliation(s)
| | | | - Sergio Szachnowicz
- Hospital das Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | | | - Edno Tales Bianchi
- Hospital das Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
| | - Ivan Cecconello
- Hospital das Clínicas, Medical School, University of São Paulo, São Paulo, SP, Brazil
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Ireland CJ, Thompson SK, Laws TA, Esterman A. Risk factors for Barrett's esophagus: a scoping review. Cancer Causes Control 2016; 27:301-23. [PMID: 26847374 DOI: 10.1007/s10552-015-0710-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 12/22/2015] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Cancer of the esophagus is a highly lethal disease with many patients presenting with metastatic spread of their tumor at diagnosis; a consequence of this late presentation is the 5-year survival rate of <20 %. Barrett's esophagus (BE), a premalignant condition of the distal esophagus, is the main risk factor for adenocarcinoma of the esophagus. The development of a risk prediction tool that could assist healthcare professionals in identifying people at increased risk of developing BE would be advantageous. Understanding the factors that influence the risk of developing BE is the first stage of developing a risk prediction tool. METHODS A scoping review was undertaken to address the following question 'what factors influence the risk of developing Barrett's esophagus?' Forty-six articles were included in this review. RESULTS The majority of articles reviewed were case-control or cohort studies. Samples sizes ranged from 68 to 84,606. Risk factors reported to be statistically significant were divided into three categories: demographic, lifestyle and clinical factors. Strongest risk factors identified include: male gender, increasing age, white race, smoking, obesity and gastro-esophageal reflux disease symptoms, while some aspects of a person's diet appear to act as a protective measure. CONCLUSION Risk factors for BE are complex and need to be considered by healthcare professionals when identifying patients that could benefit from endoscopic eradication. These results provide a stepping stone for the future development of a risk prediction model.
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Affiliation(s)
- Colin J Ireland
- School of Nursing and Midwifery, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia.
| | - Sarah K Thompson
- Discipline of Surgery, University of Adelaide, Level 5, Eleanor Harrold Building, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia
| | - Thomas A Laws
- School of Nursing and Midwifery, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia
| | - Adrian Esterman
- Sansom Institute of Health Service Research and School of Nursing and Midwifery, University of South Australia, GPO Box 2471, Adelaide, SA, 5001, Australia
- Centre for Chronic Disease Prevention, James Cook University, PO Box 6811, Cairns, QLD, 4870, Australia
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Matsuzaki J, Suzuki H. MicroRNAs in Barrett's esophagus: future prospects. Front Genet 2014; 5:69. [PMID: 24765103 PMCID: PMC3982049 DOI: 10.3389/fgene.2014.00069] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 03/17/2014] [Indexed: 01/10/2023] Open
Affiliation(s)
- Juntaro Matsuzaki
- Center for Preventive Medicine, Keio University Hospital Tokyo, Japan ; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine Tokyo, Japan
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine Tokyo, Japan
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Masaoka T, Suzuki H. Does Bile Reflux Influence the Progression of Barrett's Esophagus to Adenocarcinoma? (Gastroenterology 2013;145:1300-1311). J Neurogastroenterol Motil 2013; 20:124-6. [PMID: 24466454 PMCID: PMC3895599 DOI: 10.5056/jnm.2014.20.1.124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/19/2013] [Accepted: 11/28/2013] [Indexed: 12/17/2022] Open
Affiliation(s)
- Tatsuhiro Masaoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Matsuzaki J, Suzuki H, Tsugawa H, Watanabe M, Hossain S, Arai E, Saito Y, Sekine S, Akaike T, Kanai Y, Mukaisho KI, Auwerx J, Hibi T. Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. Gastroenterology 2013; 145:1300-11. [PMID: 23933602 DOI: 10.1053/j.gastro.2013.08.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 08/03/2013] [Accepted: 08/05/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3'-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2; levels of CDX2 have been reported to decrease during progression of BE to EAC. METHODS We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rγ(null) mice. RESULTS Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2; this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rγ(null) mice. CONCLUSIONS We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC.
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Affiliation(s)
- Juntaro Matsuzaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan
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Andrici J, Cox MR, Eslick GD. Cigarette smoking and the risk of Barrett's esophagus: a systematic review and meta-analysis. J Gastroenterol Hepatol 2013; 28:1258-1273. [PMID: 23611750 DOI: 10.1111/jgh.12230] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Barrett's esophagus (BE) is a premalignant condition to esophageal adenocarcinoma. It is currently not clear whether cigarette smoking increases the risk of developing BE, and no meta-analysis has been performed on the topic. We conducted a systematic review and meta-analysis, providing a quantitative estimate of the increased risk of BE associated with cigarette smoking, to help clarify whether a relationship exists between smoking and BE. METHODS Four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) were searched to May 17, 2013, for observational studies of BE patients. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using a random effects model for the association of smoking with BE. BE patients were compared with non-gastroesophageal reflux disease (GERD) controls as well as with population-based and GERD controls. RESULTS Thirty-nine studies comprising 7069 BE patients were included in the meta-analysis. Having ever-smoked was associated with an increased risk of BE compared with non-GERD controls (OR 1.44; 95% CI 1.20-1.74), population-based controls (OR 1.42; 95% CI 1.15-1.76), but not GERD controls (OR 1.18; 95% CI 0.75-1.86). The meta-analyses of the studies reporting the lowest and highest number of pack-years smoked showed an increased risk of BE (OR 1.41; 95% CI 1.22-1.63) and (OR 1.53; 95% CI 1.27-1.84), respectively. CONCLUSION Cigarette smoking was associated with an increased risk of BE. Being an ever-smoker was associated with an increased risk of BE in all control groups. A greater number of pack-years smoked was associated with a greater risk of BE.
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Affiliation(s)
- Juliana Andrici
- The Whiteley-Martin Research Centre, The Discipline of Surgery, The University of Sydney, Sydney Medical School, Penrith, New South Wales, Australia
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Etiological difference between ultrashort- and short-segment Barrett's esophagus. J Gastroenterol 2011; 46:332-8. [PMID: 21132333 DOI: 10.1007/s00535-010-0353-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 11/08/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND Barrett's esophagus has been divided into three categories based on the extent of the metaplasia: long-segment (LSBE), short-segment (SSBE), and ultrashort-segment Barrett's esophagus (USBE). While both LSBE and SSBE are thought to be induced by gastroesophageal reflux, the etiology of USBE is still unclear. METHODS We conducted a case-control study to identify the differences in the pathogenesis between SSBE and USBE in a hospital-based population. The endoscopic findings and clinical factors of 199 patients with short-segment endoscopically suspected esophageal metaplasia (SS-ESEM) and 317 patients with ultrashort-segment ESEM (US-ESEM) were compared with those of 199 and 317 age- and gender-matched patients without ESEM. RESULTS The severity of gastric mucosal atrophy was marginally associated with the presence of US-ESEM [odds ratio (OR) 1.20, 95% confidence interval (CI) 0.98-1.46, p = 0.08], but not with that of SS-ESEM. On the other hand, the presence of gallstones and that of severe reflux esophagitis were associated with the presence of SS-ESEM (OR 2.19, 95% CI 1.21-3.98; OR 1.72, 95% CI 1.08-2.75), but not with that of US-ESEM. Presence of gastric corpus atrophy without gallstones was associated with the presence of US-ESEM, but not with that of SS-ESEM. CONCLUSIONS Presence of gastric corpus atrophy was associated with an increased likelihood of the presence of US-ESEM, whereas the presence of gallstones was associated with an increased likelihood of the presence of SS-ESEM, suggesting difference in etiology between US- and SS-ESEM.
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Ghoshal UC, Chourasia D. Gastroesophageal Reflux Disease and Helicobacter pylori: What May Be the Relationship? J Neurogastroenterol Motil 2010; 16:243-50. [PMID: 20680162 PMCID: PMC2912116 DOI: 10.5056/jnm.2010.16.3.243] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2010] [Revised: 07/01/2010] [Accepted: 07/02/2010] [Indexed: 12/12/2022] Open
Abstract
Relationship between Helicobacter pylori (H. pylori) and gastroesophageal reflux disease (GERD) is controversial. We aimed to review the possible relationship between H. pylori infection and GERD. Epidemiological data indicate an inverse relationship between frequency of H. pylori infection and prevalence of GERD and its complications like Barrett's esophagus and esophageal adenocarcinoma. H. pylori eradication in patients with peptic ulcer disease may be associated with increased risk of development of GERD compared with untreated patients. Infection with cagA bearing strains of H. pylori was associated with less severe GERD including endoscopic esophagitis, possibly due to pangastritis leading to hypochlorhydria. Recent studies on inflammatory markers (IL-1β and IL-1RN) suggest pro-inflammatory genotypes to be protective against development of severe GERD, especially in patients with H. pylori infection. Identification of candidate genes playing an important role in gastric acid secretion and visceral hypersensitivity to the esophageal epithelium might help in early detection of individuals susceptible to develop GERD. Interplay between H. pylori and host factors play an important role in the pathogenesis of GERD.
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Affiliation(s)
- Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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