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      Influence of Microbiota on NSAID Enteropathy: A Systematic Review of Current Knowledge and the Role of Probiotics

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          Abstract

          Microbiota are increasingly studied, providing more precise information on their important role in physiologic processes. They also influence some pathologic processes, such as NSAID-induced enteropathy. This side effect is much more diffuse than it has been described in the past. It derives mainly from the local action of the medicines and is caused by the local binding of gram-negative bacterial lipopolysaccharides and infiltration of neutrophils into the intestinal mucosa. The initial interest in the interaction between these damages and microbiota is very old, but new and interesting data are available. This review aims to focus on recent studies on NSAID-induced enteropathy, an often-underestimated medical condition, and on the influence of microbiota on this condition. Apart from the broadly investigated use of antibiotics and other mucosal protective solutions, this systematic review focuses mostly on the use of probiotics, which directly influence intestinal microflora. Other important factors influencing NSAID-induced enteropathy, such as sex, advanced age, infection and use of proton pump inhibitors, are also discussed.

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          Most cited references40

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          Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial.

          Pouchitis is the major long-term complication after ileal pouch-anal anastomosis for ulcerative colitis. Most patients have relapsing disease, and no maintenance treatment study has been performed. We evaluated the efficacy of a probiotic preparation (VSL#3) containing 5 x 10(11) per gram of viable lyophilized bacteria of 4 strains of lactobacilli, 3 strains of bifidobacteria, and 1 strain of Streptococcus salivarius subsp. thermophilus compared with placebo in maintenance of remission of chronic pouchitis. Forty patients in clinical and endoscopic remission were randomized to receive either VSL#3, 6 g/day, or an identical placebo for 9 months. Patients were assessed clinically every month and endoscopically and histologically every 2 months or in the case of a relapse. Fecal samples were collected for stool culture before and after antibiotic treatment and each month during maintenance treatment. Three patients (15%) in the VSL#3 group had relapses within the 9-month follow-up period, compared with 20 (100%) in the placebo group (P < 0.001). Fecal concentration of lactobacilli, bifidobacteria, and S. thermophilus increased significantly from baseline levels only in the VSL#3-treated group (P < 0.01). These results suggest that oral administration of this new probiotic preparation is effective in preventing flare-ups of chronic pouchitis.
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            The influence of non-steroidal anti-inflammatory drugs on the gut microbiome.

            The composition of the gut microbiome with the use of non-steroidal anti-inflammatory drugs (NSAIDs) has not been fully characterized. Drug use within the past 30 days was ascertained in 155 adults, and stool specimens were submitted for analysis. Area under the receiver operating characteristic curve (AUC) was calculated in logit models to distinguish the relative abundance of operational taxonomic units (OTUs) by medication class. The type of medication had a greater influence on the gut microbiome than the number of medications. NSAIDs were particularly associated with distinct microbial populations. Four OTUs (Prevotella species, Bacteroides species, family Ruminococcaceae, and Barnesiella species) discriminated aspirin users from those using no medication (AUC = 0.96; 95% CI 0.84-1.00). The microbiome profile of celecoxib users was similar to that of ibuprofen users, with both showing enrichment of Acidaminococcaceae and Enterobacteriaceae. Bacteria from families Propionibacteriaceae, Pseudomonadaceae, Puniceicoccaceae and Rikenellaceae were more abundant in ibuprofen users than in controls or naproxen users. Bacteroides species and Erysipelotrichaceae species discriminated individuals using NSAIDs plus proton-pump inhibitors from those using NSAIDs alone (AUC = 0.96; 95% CI 0.87-1.00). Bacteroides species and a bacterium of family Ruminococcaceae discriminated individuals using NSAIDs in combination with antidepressants and laxatives from those using NSAIDs alone (AUC = 0.98; 95% CI 0.93-1.00). In conclusion, bacteria in the gastrointestinal tract reflect the combinations of medications that people ingest. The bacterial composition of the gut varied with the type of NSAID ingested.
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              Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis.

              Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used classes of drugs, with the former frequently coprescribed to reduce gastroduodenal injury caused by the latter. However, suppression of gastric acid secretion by PPIs is unlikely to provide any protection against the damage caused by NSAIDs in the more distal small intestine. Rats were treated with antisecretory doses of omeprazole or lanzoprazole for 9 days, with concomitant treatment with anti-inflammatory doses of naproxen or celecoxib on the final 4 days. Small intestinal damage was blindly scored, and changes in hematocrit were measured. Changes in small intestinal microflora were evaluated by denaturing gradient gel electrophoresis and reverse-transcription polymerase chain reaction. Both PPIs significantly exacerbated naproxen- and celecoxib-induced intestinal ulceration and bleeding in the rat. Omeprazole treatment did not result in mucosal injury or inflammation; however, there were marked shifts in numbers and types of enteric bacteria, including a significant reduction (∼80%) of jejunal Actinobacteria and Bifidobacteria spp. Restoration of small intestinal Actinobacteria numbers through administration of selected (Bifidobacteria enriched) commensal bacteria during treatment with omeprazole and naproxen prevented intestinal ulceration/bleeding. Colonization of germ-free mice with jejunal bacteria from PPI-treated rats increased the severity of NSAID-induced intestinal injury, as compared with mice colonized with bacteria from vehicle-treated rats. PPIs exacerbate NSAID-induced intestinal damage at least in part because of significant shifts in enteric microbial populations. Prevention or reversal of this dysbiosis may be a viable option for reducing the incidence and severity of NSAID enteropathy. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                giuvarr@gmail.com
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                10 April 2020
                10 April 2020
                2020
                : 37
                : 5
                : 1933-1945
                Affiliations
                [1 ]GRID grid.439257.e, ISNI 0000 0000 8726 5837, Anaesthetic Department, , Moorfields Eye Hospital, ; London, UK
                [2 ]GRID grid.158820.6, ISNI 0000 0004 1757 2611, Department of Life, Health and Environmental Sciences, , University of L’Aquila, ; Building Delta 6, 67100 L’Aquila, Italy
                [3 ]GRID grid.459798.e, NEMA Research Group, Inc, ; Naples, FL USA
                [4 ]Paolo Procacci Foundation, Via Tacito 7, 00193 Rome, Italy
                [5 ]World Institute of Pain, Winston Salem, NC USA
                Article
                1338
                10.1007/s12325-020-01338-6
                7467482
                32291647
                302d4dd0-12bc-47db-b0db-c19246f96dcf
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 11 March 2020
                Categories
                Review
                Custom metadata
                © Springer Healthcare Ltd., part of Springer Nature 2020

                enteropathy,gut microbiota,nsaids,probiotics
                enteropathy, gut microbiota, nsaids, probiotics

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