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      Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified

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          Abstract

          Proton pump inhibitors (PPIs) are common medications within the practice of gastroenterology. These drugs, which act through the irreversible inhibition of the hydrogen/potassium pump (H+/K+-ATPase pump) in the gastric parietal cells, are used in the treatment of several acid-related disorders. PPIs are generally well tolerated but, through the long-term reduction of gastric acid secretion, can increase the risk of an imbalance in gut microbiota composition ( i.e., dysbiosis). The gut microbiota is a complex ecosystem in which microbes coexist and interact with the human host. Indeed, the resident gut bacteria are needed for multiple vital functions, such as nutrient and drug metabolism, the production of energy, defense against pathogens, the modulation of the immune system and support of the integrity of the gut mucosal barrier. The bacteria are collected in communities that vary in density and composition within each segment of the gastrointestinal (GI) tract. Therefore, every change in the gut ecosystem has been connected to an increased susceptibility or exacerbation of various GI disorders. The aim of this review is to summarize the recently available data on PPI-related microbiota alterations in each segment of the GI tract and to analyze the possible involvement of PPIs in the pathogenesis of several specific GI diseases.

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          The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems

          The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent advances in research have described the importance of gut microbiota in influencing these interactions. This interaction between microbiota and GBA appears to be bidirectional, namely through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved. Most of the data have been acquired using technical strategies consisting in germ-free animal models, probiotics, antibiotics, and infection studies. In clinical practice, evidence of microbiota-GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety-depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel syndrome can be considered an example of the disruption of these complex relationships, and a better understanding of these alterations might provide new targeted therapies.
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            Comparative Analysis of Human Gut Microbiota by Barcoded Pyrosequencing

            Humans host complex microbial communities believed to contribute to health maintenance and, when in imbalance, to the development of diseases. Determining the microbial composition in patients and healthy controls may thus provide novel therapeutic targets. For this purpose, high-throughput, cost-effective methods for microbiota characterization are needed. We have employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing. In silico modeling demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level. Here we applied the technique to analyze microbial communities in throat, stomach and fecal samples. Our results demonstrate the applicability of barcoded pyrosequencing as a high-throughput method for comparative microbial ecology.
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              The gut microbiota and inflammatory bowel disease

              Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut. Although the precise cause of IBD remains unknown, the most accepted hypothesis of IBD pathogenesis to date is that an aberrant immune response against the gut microbiota is triggered by environmental factors in a genetically susceptible host. The advancement of next-generation sequencing technology has enabled identification of various alterations of the gut microbiota composition in IBD. While some results related to dysbiosis in IBD are different between studies owing to variations of sample type, method of investigation, patient profiles, and medication, the most consistent observation in IBD is reduced bacterial diversity, a decrease of Firmicutes, and an increase of Proteobacteria. It has not yet been established how dysbiosis contributes to intestinal inflammation. Many of the known IBD susceptibility genes are associated with recognition and processing of bacteria, which is consistent with a role of the gut microbiota in the pathogenesis of IBD. A number of trials have shown that therapies correcting dysbiosis, including fecal microbiota transplantation and probiotics, are promising in IBD.
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                Author and article information

                Contributors
                Journal
                World J Gastroenterol
                World J. Gastroenterol
                WJG
                World Journal of Gastroenterology
                Baishideng Publishing Group Inc
                1007-9327
                2219-2840
                14 June 2019
                14 June 2019
                : 25
                : 22
                : 2706-2719
                Affiliations
                Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
                Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
                Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
                Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
                Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy
                Department of Cardio-Thoracic, Vascular Surgery and Transplants, Sapienza University of Rome, Rome 00161, Italy
                Department of Surgical Sciences, Sapienza University of Rome, Rome 00161, Italy. stefano.pontone@ 123456uniroma1.it
                Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
                Author notes

                Author contributions: Bruno G, Zaccari P and Rocco G performed the literature search and wrote the manuscript; Porowska B critically revised the manuscript; Scalese G and Panetta C designed and created the figures; Pontone S and Severi C provided scientific guidance and equally contributed to the manuscript as senior authors; all authors revised and approved the final version of this article.

                Corresponding author: Stefano Pontone, MD, PhD, Research Assistant Professor, Department of Surgical Sciences, Sapienza University of Rome, V.le Regina Elena 324, Rome 00161, Italy. stefano.pontone@ 123456uniroma1.it

                Telephone: +39-06-49975503

                Article
                jWJG.v25.i22.pg2706
                10.3748/wjg.v25.i22.2706
                6580352
                31235994
                1c62800e-93bb-46d9-960a-d9633d0d8c5b
                ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 12 March 2019
                : 2 April 2019
                : 19 April 2019
                Categories
                Review

                proton pump inhibitors,hypochloridria,gut microbiota,dysbiosis,gastrointestinal tract,cancer,helicobacter pylori,gastrointestinal infections

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