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      Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity

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          Abstract

          AIM

          To determine the efficacy of rifaximin for hepatic encephalopathy (HE) with the linkage of gut microbiome in decompensated cirrhotic patients.

          METHODS

          Twenty patients (12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis (Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test (NCT)-A. Changes in whole blood endotoxin activity (EA) was analyzed by endotoxin activity assay. Fecal microbiome was assessed by 16S ribosome RNA (rRNA) gene sequencing.

          RESULTS

          Treatment with rifaximin for 4 wk improved hyperammonemia (from 90.6 ± 23.9 μg/dL to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT (from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced (from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels ( r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator (Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups (3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were lowered.

          CONCLUSION

          Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.

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          Most cited references26

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          Linkage of gut microbiome with cognition in hepatic encephalopathy.

          Hepatic encephalopathy (HE) has been related to gut bacteria and inflammation in the setting of intestinal barrier dysfunction. We aimed to link the gut microbiome with cognition and inflammation in HE using a systems biology approach. Multitag pyrosequencing (MTPS) was performed on stool of cirrhotics and age-matched controls. Cirrhotics with/without HE underwent cognitive testing, inflammatory cytokines, and endotoxin analysis. Patients with HE were compared with those without HE using a correlation-network analysis. A select group of patients with HE (n = 7) on lactulose underwent stool MTPS before and after lactulose withdrawal over 14 days. Twenty-five patients [17 HE (all on lactulose, 6 also on rifaximin) and 8 without HE, age 56 ± 6 yr, model for end-stage liver disease score 16 ± 6] and ten controls were included. Fecal microbiota in cirrhotics were significantly different (higher Enterobacteriaceae, Alcaligeneceae, and Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae) compared with controls. We found altered flora (higher Veillonellaceae), poor cognition, endotoxemia, and inflammation (IL-6, TNF-α, IL-2, and IL-13) in HE compared with cirrhotics without HE. In the cirrhosis group, Alcaligeneceae and Porphyromonadaceae were positively correlated with cognitive impairment. Fusobacteriaceae, Veillonellaceae, and Enterobacteriaceae were positively and Ruminococcaceae negatively related to inflammation. Network-analysis comparison showed robust correlations (all P < 1E-5) only in the HE group between the microbiome, cognition, and IL-23, IL-2, and IL-13. Lactulose withdrawal did not change the microbiome significantly beyond Fecalibacterium reduction. We concluded that cirrhosis, especially when complicated with HE, is associated with significant alterations in the stool microbiome compared with healthy individuals. Specific bacterial families (Alcaligeneceae, Porphyromonadaceae, Enterobacteriaceae) are strongly associated with cognition and inflammation in HE.
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            Modulation of the Metabiome by Rifaximin in Patients with Cirrhosis and Minimal Hepatic Encephalopathy

            Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. Methods Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. Results There was a significant improvement in cognition(six of seven tests improved,p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. Conclusions Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. Trial Registration ClinicalTrials.gov NCT01069133
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              Mechanisms, diagnosis and management of hepatic encephalopathy.

              Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic liver disease. Symptoms of HE can include confusion, disorientation and poor coordination. A general consensus exists that the synergistic effects of excess ammonia and inflammation cause astrocyte swelling and cerebral edema; however, the precise molecular mechanisms that lead to these morphological changes in the brain are unclear. Cerebral edema occurs to some degree in all patients with HE, regardless of its grade, and could underlie the pathogenesis of this disorder. The different grades of HE can be diagnosed by a number of investigations, including neuropsychometric tests (such as the psychometric hepatic encephalopathy score), brain imaging and clinical scales (such as the West Haven criteria). HE is best managed by excluding other possible causes of encephalopathy alongside identifying and the precipitating cause, and confirming the diagnosis by a positive response to empiric treatment. Empiric therapy for HE is largely based on the principle of reducing the production and absorption of ammonia in the gut through administration of pharmacological agents such as rifaximin and lactulose, which are approved by the FDA for the treatment of HE.
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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
                21 December 2017
                21 December 2017
                : 23
                : 47
                : 8355-8366
                Affiliations
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan. kajik@ 123456naramed-u.ac.jp
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
                Author notes

                Author contributions: Kaji K collected and analyzed the data, and drafted the manuscript; Takaya H also collected and analyzed the data; Saikawa S, Furukawa M, Sato S, Kawaratani H, Kitade M, Moriya K, Namisaki T, Akahane T and Mitoro A offered the technical or material support; Yoshiji H designed and supervised the study; all authors have read and approved the final version to be published.

                Correspondence to: Kosuke Kaji, MD, PhD, Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. kajik@ 123456naramed-u.ac.jp

                Telephone: +81-744-22-3051 Fax: +81-744-24-7122

                Article
                jWJG.v23.i47.pg8355
                10.3748/wjg.v23.i47.8355
                5743506
                29307995
                d19550b0-15df-48f3-8d28-69d980640bdb
                ©The Author(s) 2017. 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
                : 4 October 2017
                : 30 October 2017
                : 14 November 2017
                Categories
                Case Control Study

                gut microbiome,hepatic encephalopathy,liver cirrhosis,endotoxin,rifaximin

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