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      Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanisms and Therapy

      , , *

      Nutrients

      MDPI

      gut microbiota, obesity, insulin resistance, NAFLD, probiotic, prebiotic, symbiotic

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          Abstract

          The gut microbiota plays critical roles in development of obese-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes(T2D), and insulin resistance(IR), highlighting the potential of gut microbiota-targeted therapies in these diseases. There are various ways that gut microbiota can be manipulated, including through use of probiotics, prebiotics, synbiotics, antibiotics, and some active components from herbal medicines. In this review, we review the main roles of gut microbiota in mediating the development of NAFLD, and the advances in gut microbiota-targeted therapies for NAFLD in both the experimental and clinical studies, as well as the conclusions on the prospect of gut microbiota-targeted therapies in the future.

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          Most cited references 108

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          Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.

          Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor alpha (TNF-alpha). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the intestine or inhibiting TNF-alpha improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-alpha activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet + VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-alpha messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNF-regulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor kappaB (NF-kappaB), the target of IKKbeta, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid beta-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions.
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            Prebiotics: The Concept Revisited

            The Journal of Nutrition, 137(3), 830S-837S
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              Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency.

              Nonalcoholic fatty liver disease affects up to 30% of the US population, but the mechanisms underlying this condition are incompletely understood. We investigated how diet standardization and choline deficiency influence the composition of the microbial community in the human gastrointestinal tract and the development of fatty liver under conditions of choline deficiency. We performed a 2-month inpatient study of 15 female subjects who were placed on well-controlled diets in which choline levels were manipulated. We used 454-FLX pyrosequencing of 16S ribosomal RNA bacterial genes to characterize microbiota in stool samples collected over the course of the study. The compositions of the gastrointestinal microbial communities changed with choline levels of diets; each individual's microbiome remained distinct for the duration of the experiment, even though all subjects were fed identical diets. Variations between subjects in levels of Gammaproteobacteria and Erysipelotrichi were directly associated with changes in liver fat in each subject during choline depletion. Levels of these bacteria, change in amount of liver fat, and a single nucleotide polymorphism that affects choline were combined into a model that accurately predicted the degree to which subjects developed fatty liver on a choline-deficient diet. Host factors and gastrointestinal bacteria each respond to dietary choline deficiency, although the gut microbiota remains distinct in each individual. We identified bacterial biomarkers of fatty liver that result from choline deficiency, adding to the accumulating evidence that gastrointestinal microbes have a role in metabolic disorders. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                16 October 2017
                October 2017
                : 9
                : 10
                Affiliations
                Center for Traditional Chinese Medicine and Systems Biology, Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; flyingwalnuts@ 123456163.com (J.M.); 15221368273@ 123456163.com (Q.Z.)
                Author notes
                [* ]Correspondence: houkai1976@ 123456126.com ; Tel.: +86-21-5132-2729
                Article
                nutrients-09-01124
                10.3390/nu9101124
                5691740
                29035308
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Review

                Nutrition & Dietetics

                gut microbiota, obesity, insulin resistance, nafld, probiotic, prebiotic, symbiotic

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