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1
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Horvath A, Zukauskaite K, Hazia O, Balazs I, Stadlbauer V. Human gut microbiome: Therapeutic opportunities for metabolic syndrome-Hype or hope? Endocrinol Diabetes Metab 2024; 7:e436. [PMID: 37771199 PMCID: PMC10781898 DOI: 10.1002/edm2.436] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/01/2023] [Accepted: 06/11/2023] [Indexed: 09/30/2023] Open
Abstract
Shifts in gut microbiome composition and metabolic disorders are associated with one another. Clinical studies and experimental data suggest a causal relationship, making the gut microbiome an attractive therapeutic goal. Diet, intake of probiotics or prebiotics and faecal microbiome transplantation (FMT) are methods to alter a person's microbiome composition. Although FMT may allow establishing a proof of concept to use microbiome modulation to treat metabolic disorders, studies show mixed results regarding the effects on metabolic parameters as well as on the composition of the microbiome. This review summarizes the current knowledge on diet, probiotics, prebiotics and FMT to treat metabolic diseases, focusing on studies that also report alterations in microbiome composition. Furthermore, clinical trial results on the effects of common drugs used to treat metabolic diseases are synopsized to highlight the bidirectional relationship between the microbiome and metabolic diseases. In conclusion, there is clear evidence that microbiome modulation has the potential to influence metabolic diseases; however, it is not possible to distinguish which intervention is the most successful. In addition, a clear commitment from all stakeholders is necessary to move forward in the direction of developing targeted interventions for microbiome modulation.
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Affiliation(s)
- Angela Horvath
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Kristina Zukauskaite
- Medical University of GrazGrazAustria
- Life Sciences CentreVilnius UniversityVilniusLithuania
| | - Olha Hazia
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Irina Balazs
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Vanessa Stadlbauer
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
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2
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Wang JS, Liu JC. Intestinal microbiota in the treatment of metabolically associated fatty liver disease. World J Clin Cases 2022; 10:11240-11251. [PMID: 36387806 PMCID: PMC9649557 DOI: 10.12998/wjcc.v10.i31.11240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/07/2022] [Accepted: 09/27/2022] [Indexed: 02/05/2023] Open
Abstract
Metabolically associated fatty liver disease (MAFLD) is a common cause of chronic liver disease, the hepatic manifestation of metabolic syndrome. Despite the increasing incidence of MAFLD, no effective treatment is available. Recent research indicates a link between the intestinal microbiota and liver diseases such as MAFLD. The composition and characteristics of the intestinal microbiota and therapeutic perspectives of MAFLD are reviewed in the current study. An imbalance in the intestinal microbiota increases intestinal permeability and exposure of the liver to adipokines. Furthermore, we focused on reviewing the latest "gut-liver axis" targeted therapy.
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Affiliation(s)
- Ji-Shuai Wang
- Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Jin-Chun Liu
- Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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3
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Hernandez GV, Smith VA, Melnyk M, Burd MA, Sprayberry KA, Edwards MS, Peterson DG, Bennet DC, Fanter RK, Columbus DA, Steibel JP, Glanz H, Immoos C, Rice MS, Santiago-Rodriguez TM, Blank J, VanderKelen JJ, Kitts CL, Piccolo BD, La Frano MR, Burrin DG, Maj M, Manjarin R. Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH. Am J Physiol Gastrointest Liver Physiol 2020; 318:G582-G609. [PMID: 32003601 PMCID: PMC7099491 DOI: 10.1152/ajpgi.00344.2019] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/21/2020] [Accepted: 01/25/2020] [Indexed: 02/08/2023]
Abstract
To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a "Western-style diet" [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine-N-oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver.NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine-N-oxide in the liver.
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Affiliation(s)
- Gabriella V Hernandez
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Victoria A Smith
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Megan Melnyk
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
| | - Matthew A Burd
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Kimberly A Sprayberry
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Mark S Edwards
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Daniel G Peterson
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Darin C Bennet
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Rob K Fanter
- Center for Health Research, California Polytechnic State University, San Luis Obispo, California
| | | | - Juan P Steibel
- Department of Animal Science and Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan
| | - Hunter Glanz
- Department of Statistics, California Polytechnic State University, San Luis Obispo, California
| | - Chad Immoos
- Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California
| | - Margaret S Rice
- Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California
| | | | - Jason Blank
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
| | - Jennifer J VanderKelen
- Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, California
| | - Christopher L Kitts
- Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, California
| | - Brian D Piccolo
- United States Department of Agriculture-Agricultural Research Services, Arkansas Children's Nutrition Center, Little Rock, Arkansas
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Michael R La Frano
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, California
- Center for Health Research, California Polytechnic State University, San Luis Obispo, California
| | - Douglas G Burrin
- United States Department of Agriculture-Agricultural Research Services, Children's Nutrition Research Center, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Magdalena Maj
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
- Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, California
| | - Rodrigo Manjarin
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
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Horvath A, Leber B, Feldbacher N, Tripolt N, Rainer F, Blesl A, Trieb M, Marsche G, Sourij H, Stadlbauer V. Effects of a multispecies synbiotic on glucose metabolism, lipid marker, gut microbiome composition, gut permeability, and quality of life in diabesity: a randomized, double-blind, placebo-controlled pilot study. Eur J Nutr 2019; 59:2969-2983. [PMID: 31729622 PMCID: PMC7501130 DOI: 10.1007/s00394-019-02135-w] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/04/2019] [Indexed: 01/08/2023]
Abstract
Purpose Diabesity, the combination of obesity and type 2 diabetes, is an ever-growing global health burden. Diabesity-associated dysbiosis of the intestinal microbiome has gained attention as a potential driver of disease and, therefore, a possible therapeutic target by means of pro- or prebiotic supplementation. This study tested the effects of a multispecies synbiotic (i.e. a combination of probiotics and prebiotics) on glucose metabolism, gut microbiota, gut permeability, neutrophil function and quality of life in treatment-experienced diabesity patients. Methods A randomized, double-blind, placebo-controlled pilot study with 26 diabesity patients was conducted in which patients received a daily dose of a multispecies probiotic and a prebiotic (or a placebo) for 6 months. Results There were no changes in glucose metabolism or mixed meal tolerance test responses throughout the study. The analysis of secondary outcomes revealed beneficial effects on hip circumference [− 1 (95% CI − 4; 3) vs +3 (− 1; 8) cm, synbiotics vs. placebo, respectively, p = 0.04], serum zonulin [− 0.04 (− 0.2; 0.1) vs +0.3 (− 0.05; 0.6) ng/ml, p = 0.004)] and the physical role item of the SF36 quality of life assessment [+ 5.4 (− 1.7; 12.5) vs − 5.0 (− 10.1; 0.2) points, p = 0.02] after 3 months of intervention, and lipoprotein (a) [− 2.1 (− 5.7; 1.6) vs +3.4 (− 0.9; 7.9) mg/dl, p = 0.02] after 6 months. There were no significant differences in alpha or beta diversity of the microbiome between groups or time points. Conclusions Glucose metabolism as the primary outcome was unchanged during the intervention with a multispecies synbiotic in patients with diabesity. Nevertheless, synbiotics improved some symptoms and biomarkers of type 2 diabetes and aspects of quality of life suggesting a potential role as adjuvant tool in the management of diabesity. Graphic abstract ![]()
Electronic supplementary material The online version of this article (10.1007/s00394-019-02135-w) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Angela Horvath
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria. .,Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria.
| | - Bettina Leber
- Division of Transplantation Surgery, Medical University of Graz, Auenbruggerplatz 29, 8036, Graz, Austria
| | - Nicole Feldbacher
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria
| | - Norbert Tripolt
- Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Florian Rainer
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Andreas Blesl
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Markus Trieb
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria
| | - Gunther Marsche
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria
| | - Harald Sourij
- Center for Biomarker Research in Medicine (CBmed), Stiftingtalstrasse 5, 8010, Graz, Austria.,Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.,Zayed Center for Health Sciences (ZCHS), UAE University, Al-Ain, UAE
| | - Vanessa Stadlbauer
- Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
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5
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Koopman N, Molinaro A, Nieuwdorp M, Holleboom AG. Review article: can bugs be drugs? The potential of probiotics and prebiotics as treatment for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2019; 50:628-639. [PMID: 31373710 DOI: 10.1111/apt.15416] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 05/06/2019] [Accepted: 06/23/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver condition. A major current research effort is ongoing to find potential strategies to treat NAFLD-non-alcoholic steatohepatitis (NASH), with special attention to the gut microbiota. Multiple animal studies and pilot clinical trials are assessing different gut microbiota modulating strategies such as faecal microbiota transplantation, antibiotics, probiotics, prebiotics and synbiotics. AIM To review the role of microbiota in NAFLD-NASH and determine whether pro- and prebiotics have potential as treatment METHODS: Information was obtained from critically reviewing literature on PubMed on targeting the gut microbiota in NAFLD. Search terms included NAFLD, NASH, non-alcoholic fatty liver disease, steatohepatitis; combined with microbiome, microbiota, gut bacteria, probiotics and prebiotics. RESULTS Animal studies and the first emerging studies in humans show promising results for both the common probiotics Lactobacillus, Bifidobacterium and Streptococci as for short chain fatty acid (SCFA) butyrate-producing bacteria. Also, prebiotics have positive effects on different mechanisms underlying NAFLD-NASH. CONCLUSIONS The most promising strategies thus far developed to alter the microbiome in NAFLD-NASH are probiotics and prebiotics. However, pre- and probiotic treatment of NAFLD-NASH is relatively new and still under development. Actual understanding of the involved mechanisms is lacking and changes in the intestinal microbiota composition after treatment are rarely measured. Furthermore, large clinical trials with comparative endpoints are unavailable. Personalised treatment based on metagenomics gut microbiota analysis will probably be part of the future diagnosis and treatment of NAFLD-NASH.
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Affiliation(s)
- Nienke Koopman
- Department of Molecular Biology and Microbial Food Safety, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Antonio Molinaro
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Max Nieuwdorp
- Vascular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Adriaan G Holleboom
- Vascular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
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Zhou R, Fan X, Schnabl B. Role of the intestinal microbiome in liver fibrosis development and new treatment strategies. Transl Res 2019; 209:22-38. [PMID: 30853445 DOI: 10.1016/j.trsl.2019.02.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 01/26/2019] [Accepted: 02/14/2019] [Indexed: 02/06/2023]
Abstract
Liver cirrhosis is a major cause of morbidity and mortality worldwide. The most common chronic liver diseases in western countries are alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Although these diseases have different causes, liver fibrosis develops via shared mechanisms. The liver and intestinal microbiome are linked by the portal vein and have bidirectional interactions. Changes in the intestinal microbiome contribute to the pathogenesis and progression of liver diseases including ALD, NAFLD, viral hepatitis and cholestatic disorders, based on studies in patients and animal models. Intestinal microbial dysbiosis has been associated with liver cirrhosis and its complications. We review the mechanisms by which alterations in the microbiome contribute to liver fibrosis and discuss microbiome-based treatment approaches.
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Affiliation(s)
- Rongrong Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, and Key Laboratory of Viral Hepatitis, Changsha, Hunan, China; Department of Medicine, University of California San Diego, La Jolla, California
| | - Xuegong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, and Key Laboratory of Viral Hepatitis, Changsha, Hunan, China
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.
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7
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Abstract
Liver cancer is the sixth most common cancer worldwide, and the third most common cause of cancer-related death. Hepatocellular carcinoma (HCC), which accounts for more than 90% of primary liver cancers, is an important public health problem. In addition to cirrhosis caused by hepatitis B viral (HBV) or hepatitis C viral (HCV) infection, non-alcoholic fatty liver disease (NAFLD) is becoming a major risk factor for liver cancer because of the prevalence of obesity. Non-alcoholic steatohepatitis (NASH) will likely become the leading indication for liver transplantation in the future. It is well recognized that gut microbiota is a key environmental factor in the pathogenesis of liver disease and cancer. The interplay between gut microbiota and liver disease has been investigated in animal and clinical studies. In this article, we summarize the roles of gut microbiota in the development of liver disease as well as gut microbiota-targeted therapies.
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Affiliation(s)
- Lijun Wang
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA,The College of Life Science, Yangtze University, Jingzhou, Hubei, China
| | - Yu-Jui Yvonne Wan
- Department of Medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA,Corresponding author. Department of medical Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA. (Y.-J.Y. Wan)
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8
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Dornas W, Lagente V. Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis. Pharmacol Res 2019; 141:418-428. [PMID: 30658094 DOI: 10.1016/j.phrs.2019.01.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/12/2019] [Accepted: 01/14/2019] [Indexed: 02/08/2023]
Abstract
Fatty livers are susceptible to factors that cause inflammation and fibrosis, but fat deposition and the inflammatory response can be dissociated. While nonalcoholic fatty liver disease (NAFLD), caused by pathologic fat accumulation inside the liver, can remain stable for several years, in other cases NAFLD progresses to nonalcoholic steatohepatitis (NASH), which is characterized by fat accumulation and inflammation and is not a benign condition. In this review, we discuss the NASH host cells and microbial mechanisms that stimulate inflammation and predispose the liver to hepatocyte injury and fibrotic stages via increased lipid deposition. We highlight the interactions between intestine-derived bacterial products, such as lipopolysaccharide, and nutritional models of NAFLD and/or obese individuals. The results of modulating enteric microbiota suggest that gut-derived endotoxins may be essential determinants of fibrotic progression and regression in NASH.
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Affiliation(s)
- Waleska Dornas
- NuMeCan Institute (Nutrition, Metabolism and Cancer), Université de Rennes, INSERM, INRA, F-35000 Rennes, France.
| | - Vincent Lagente
- NuMeCan Institute (Nutrition, Metabolism and Cancer), Université de Rennes, INSERM, INRA, F-35000 Rennes, France.
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9
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Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD. Int J Mol Sci 2018; 20:ijms20010001. [PMID: 30577415 PMCID: PMC6337295 DOI: 10.3390/ijms20010001] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/04/2018] [Accepted: 12/15/2018] [Indexed: 12/21/2022] Open
Abstract
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr−/−.Leiden mice received one of three different energy-dense (ED)-diets (n = 15/group) for 15 weeks. All of the ED diets induced obesity and metabolic risk factors, altered short-chain fatty acids (SCFA), and increased gut permeability and NAFLD to various extents. ED diets reduced the diversity of high-abundant bacteria and increased the diversity of low-abundant bacteria in all of the gut compartments. The ED groups showed highly variable, partially overlapping microbiota compositions that differed significantly from chow. Correlation analyses demonstrated that (1) specific groups of bacteria correlate with metabolic risk factors, organ dysfunction, and NAFLD endpoints, (2) colon mucosa had greater predictive value than other compartments, (3) correlating bacteria differed per compartment, and (4) some bacteria correlated with plasma SCFA levels. In conclusion, this comprehensive microbiota analysis demonstrates correlations between the microbiota and dysfunctions of gut, adipose tissue, and liver, independent of a specific disease-inducing diet.
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10
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Aitbaev KA, Murkamilov IT, Fomin VV. [Liver diseases: The pathogenetic role of the gut microbiome and the potential of treatment for its modulation]. TERAPEVT ARKH 2017; 89:120-128. [PMID: 28914862 DOI: 10.17116/terarkh2017898120-128] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The paper gives an update on the role of the gut microbiome (GM) in the development of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver cirrhosis (LC), and its complications, such as hepatic encephalopathy (HE) and hepatocellular carcinoma (HCC), and discusses the possibilities of its correction with prebiotics, probiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). The pathophysiology of the liver diseases in question demonstrates some common features that are characterized by pathogenic changes in the composition of the gastrointestinal tract microflora, by intestinal barrier impairments, by development of endotoxemia, by increased liver expression of proinflammatory factors, and by development of liver inflammation. In progressive liver disease, the above changes are more pronounced, which contributes to the development of LC, HE, and HCC. GM modulation using prebiotics, probiotics, synbiotics, antibiotics, and FMT diminishes dysbacteriosis, strengthens the intestinal mucosal barrier, reduces endotoxemia and liver damage, and positively affects the clinical manifestations of HE. Further investigations are needed, especially in humans, firstly, to assess a relationship of GM to the development of liver diseases in more detail and, secondly, to obtain evidence indicating the therapeutic efficacy of GM-modulating agents in large-scale, well-designed, randomized, controlled, multicenter studies.
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Affiliation(s)
- K A Aitbaev
- Research Institute of Molecular Biology and Medicine, National Center of Cardiology and Therapy, Ministry of Health of the Kyrgyz Republic, Bishkek, Kyrgyz Republic
| | - I T Murkamilov
- I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyz Republic
| | - V V Fomin
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
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Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanisms and Therapy. Nutrients 2017; 9:nu9101124. [PMID: 29035308 PMCID: PMC5691740 DOI: 10.3390/nu9101124] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/06/2017] [Accepted: 10/10/2017] [Indexed: 12/13/2022] Open
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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12
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Greuter T, Malhi H, Gores GJ, Shah VH. Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. JCI Insight 2017; 2:95354. [PMID: 28878132 DOI: 10.1172/jci.insight.95354] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are among the most frequent causes of chronic liver disease in the United States. Although the two entities are triggered by different etiologies - chronic alcohol consumption (ASH) and obesity-associated lipotoxicity (NASH) - they share overlapping histological and clinical features owing to common pathogenic mechanisms. These pathogenic processes include altered hepatocyte lipid metabolism, organelle dysfunction (i.e., ER stress), hepatocyte apoptosis, innate immune system activation, and hepatic stellate cell activation. Nonetheless, there are several disease-specific molecular signaling pathways, such as differential pathway activation downstream of TLR4 (MyD88-dependence in NASH versus MyD88-independence in ASH), inflammasome activation and IL-1β signaling in ASH, insulin resistance and lipotoxicity in NASH, and dysregulation of different microRNAs, which clearly highlight that ASH and NASH are two distinct biological entities. Both pathogenic similarities and differences have therapeutic implications. In this Review, we discuss these pathogenic mechanisms and their therapeutic implications for each disease, focusing on both shared and distinct targets.
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Affiliation(s)
- Thomas Greuter
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gregory J Gores
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vijay H Shah
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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13
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Gut-Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease. CHILDREN-BASEL 2017; 4:children4080066. [PMID: 28767077 PMCID: PMC5575588 DOI: 10.3390/children4080066] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/18/2017] [Accepted: 07/21/2017] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A “multiple-hit” hypothesis has been invoked to explain its pathogenesis. The “first hit” is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as “second hits” implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut–liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising.
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Mintziori G, Polyzos SA. Emerging and future therapies for nonalcoholic steatohepatitis in adults. Expert Opin Pharmacother 2016; 17:1937-46. [DOI: 10.1080/14656566.2016.1225727] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Ferolla SM, Couto CA, Costa-Silva L, Armiliato GNA, Pereira CAS, Martins FS, Ferrari MDLA, Vilela EG, Torres HOG, Cunha AS, Ferrari TCA. Beneficial Effect of Synbiotic Supplementation on Hepatic Steatosis and Anthropometric Parameters, But Not on Gut Permeability in a Population with Nonalcoholic Steatohepatitis. Nutrients 2016; 8:nu8070397. [PMID: 27367724 PMCID: PMC4963873 DOI: 10.3390/nu8070397] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 06/10/2016] [Accepted: 06/20/2016] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease is the most prevalent chronic liver disease in Western countries; it can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocarcinoma. The importance of gut-liver-adipose tissue axis has become evident and treatments targeting gut microbiota may improve inflammatory and metabolic parameters in NASH patients. In a randomized, controlled clinical trial, involving 50 biopsy-proven NASH patients, we investigated the effects of synbiotic supplementation on metabolic parameters, hepatic steatosis, intestinal permeability, small intestinal bacterial overgrowth (SIBO) and lipopolysaccharide (LPS) serum levels. Patients were separated into two groups receiving Lactobacillus reuteri with guar gum and inulin for three months and healthy balanced nutritional counseling versus nutritional counseling alone. Before and after the intervention we assessed steatosis by magnetic resonance imaging, intestinal permeability by lactulose/mannitol urinary excretion and SIBO by glucose breath testing. NASH patients presented high gut permeability, but low prevalence of SIBO. After the intervention, only the synbiotic group presented a reduction in steatosis, lost weight, diminished BMI and waist circumference measurement. Synbiotic did not improve intestinal permeability or LPS levels. We concluded that synbiotic supplementation associated with nutritional counseling seems superior to nutritional counseling alone for NASH treatment as it attenuates steatosis and may help to achieve weight loss.
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Affiliation(s)
- Silvia M Ferolla
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Cláudia A Couto
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Luciana Costa-Silva
- Departamento de Anatomia e Imagem, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Geyza N A Armiliato
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Cristiano A S Pereira
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Flaviano S Martins
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte31270-901, Brazil.
| | - Maria de Lourdes A Ferrari
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Eduardo G Vilela
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Henrique O G Torres
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Aloísio S Cunha
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
| | - Teresa C A Ferrari
- Departamento de ClínicaMédica, Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil.
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16
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A Comprehensive Updated Review of Pharmaceutical and Nonpharmaceutical Treatment for NAFLD. Gastroenterol Res Pract 2016; 2016:7109270. [PMID: 27006654 PMCID: PMC4781972 DOI: 10.1155/2016/7109270] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 01/27/2016] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with prevalence of 20–33%. NAFLD comprises a pathological spectrum. Nonalcoholic fatty liver (NAFL) is at one end and consists of simple hepatic steatosis. On the contrary, nonalcoholic steatohepatitis (NASH) consists of steatosis, inflammation, and ballooning degeneration and can progress to cirrhosis. Despite the rising incidence, definitive treatment for NAFLD, specifically NASH, has not yet been established. Lifestyle modification with dietary changes combined with regular aerobic exercise, along with multidisciplinary approach including cognitive behavior therapy, has been shown to be an effective therapeutic option, even without a significant weight loss. Pioglitazone and vitamin E have shown to be most effective in NASH patients. Surgery and weight loss medication are effective means of weight loss but can potentially worsen NASH related fibrosis. Other agents such as n-3 polyunsaturated fatty acids, probiotics, and pentoxifylline along with herbal agent such as milk thistle as well as daily intake of coffee have shown potential benefits, but further well organized studies are definitely warranted. This review focuses on the available evidence on pharmaceutical and nonpharmaceutical therapy in the treatment and the prevention of NAFLD, primarily NASH.
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Abstract
The gut microbiome is composed of a vast number of microbes in the gastrointestinal tract, which benefit host metabolism, aid in digestion, and contribute to normal immune function. Alterations in microbial composition can result in intestinal dysbiosis, which has been implicated in several diseases including obesity, inflammatory bowel disease, and liver diseases. Over the past several years, significant interactions between the intestinal microbiota and liver have been discovered, with possible mechanisms for the development as well as progression of liver disease and promising therapeutic targets to either prevent or halt the progression of liver disease. In this review the authors examine mechanisms of dysbiosis-induced liver disease; highlight current knowledge regarding the role of dysbiosis in nonalcoholic liver disease, alcoholic liver disease, and cirrhosis; and discuss potential therapeutic targets.
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Affiliation(s)
- Gobind Anand
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California
| | - Amir Zarrinpar
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California
| | - Rohit Loomba
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California,NAFLD Translational Research Unit, Department of Medicine, University of California at San Diego, La Jolla, California
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18
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Probiotics in Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Cirrhosis. J Clin Gastroenterol 2015; 49 Suppl 1:S28-32. [PMID: 26447961 DOI: 10.1097/mcg.0000000000000347] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
With the growing epidemic of obesity, the incidence of both nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH) is increasing. The intestinal microbiota differs between individuals who are obese or have normal body mass indices. Animal studies have shown increased intestinal permeability in NAFL, NASH, and cirrhosis. This increases the risk of oxidative and inflammatory injury to the liver from intestinal microbacteria. It may also increase the risk of fatty acid injury and fatty deposition. Bacterial translocation is associated with increased portal hypertension and hepatic encephalopathy in cirrhosis. By preventing bacterial adhesion and translocation, probiotics may have a role in the management of patients with NAFL, NASH, and cirrhosis. Multiple small studies have suggested that probiotics improve some of the clinical markers of activity in patients with NAFL and NASH. Controlled studies have also shown improved outcomes in patients with cirrhosis who were treated with probiotics.
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Fallucca F, Fontana L, Fallucca S, Pianesi M. Gut microbiota and Ma-Pi 2 macrobiotic diet in the treatment of type 2 diabetes. World J Diabetes 2015; 6:403-11. [PMID: 25897351 PMCID: PMC4398897 DOI: 10.4239/wjd.v6.i3.403] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 01/10/2015] [Accepted: 01/30/2015] [Indexed: 02/05/2023] Open
Abstract
In the past 10 years the prevalence of type 2 diabetes mellitus (T2DM) has increased hugely worldwide, driven by a rise in the numbers of overweight and obese individuals. A number of diets have been shown to be effective for the management of T2DM: the Mediterranean diet, the vegetarian diet and the low-calorie diet. Results of studies clearly indicate, however, that the efficacy of these diets is not solely related to the biochemical structure of the individual nutrients they contain. This review discusses this point with reference to the potential role of the intestinal microbiota in diabetes. The macrobiotic Ma-Pi 2 diet is rich in carbohydrates, whole grains and vegetables, with no animal fat or protein or added sugar. In short- and medium-term trials conducted in patients with T2DM, the Ma-Pi 2 diet has been found to significantly improve indicators of metabolic control, including fasting blood glucose, glycosylated hemoglobin, the serum lipid profile, body mass index, body weight and blood pressure. The diet may also alter the gut microbiota composition, which could additionally affect glycemic control. As a result, the Ma-Pi 2 diet could be considered a valid additional short- to medium-term treatment for T2DM.
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20
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Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2015; 21:3777-3785. [PMID: 25852263 PMCID: PMC4385525 DOI: 10.3748/wjg.v21.i13.3777] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/08/2015] [Accepted: 02/05/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.
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21
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Ferolla SM, Armiliato GNDA, Couto CA, Ferrari TCA. Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease. World J Hepatol 2015; 7:559-565. [PMID: 25848479 PMCID: PMC4381178 DOI: 10.4254/wjh.v7.i3.559] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 10/30/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently recognized as one of the most common causes of chronic liver disease. It involves a spectrum of conditions that include pure steatosis without inflammation, steatohepatitis, fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes and, thus, oxidative stress, which is followed by inflammatory response. However, NAFLD pathogenesis is still largely unknown and has been extensively investigated. Although life style modification with the aim of losing weight has been advocated to treat this disorder, its effectiveness is limited; additionally, there is no specific pharmacologic treatment until nowadays. Recent evidence suggests that the gut microbiota may play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. Differences in gut microbiota between NAFLD patients and lean individuals as well as presence of small intestinal bacterial overgrowth in NAFLD subjects have been demonstrated. Furthermore, some data indicate that the immunoregulatory effects of probiotics may be beneficial in NAFLD treatment as they modulate the intestinal microbiota; improve epithelial barrier function and strengthen the intestinal wall decreasing its permeability; reduce bacterial translocation and endotoxemia; improve intestinal inflammation; and reduce oxidative and inflammatory liver damage. In this article, we review the clinical trials on the use of probiotics in the treatment of NAFLD and discuss the effects of these agents and their efficacy as an emerging therapeutic resource to treat NAFLD patients.
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22
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Alisi A, Nobili V. Editorial: probiotics in NASH - more studies are needed; authors' reply. Aliment Pharmacol Ther 2014; 40:212. [PMID: 24946063 DOI: 10.1111/apt.12816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 05/12/2014] [Indexed: 12/08/2022]
Affiliation(s)
- A Alisi
- Hepato-Metabolic Disease Unit and Liver Research Unit, "Bambino Gesù" Children's Hospital, IRCCS, Rome, Italy.
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23
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Ong JP, Younossi ZM. Editorial: probiotics in NASH - more studies are needed. Aliment Pharmacol Ther 2014; 40:211-2. [PMID: 24946062 DOI: 10.1111/apt.12812] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 05/07/2014] [Indexed: 12/21/2022]
Affiliation(s)
- J P Ong
- Section of Gastroenterology, Department of Medicine, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines.
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24
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Núñez IN, Galdeano CM, de LeBlanc ADM, Perdigón G. Evaluation of immune response, microbiota, and blood markers after probiotic bacteria administration in obese mice induced by a high-fat diet. Nutrition 2014; 30:1423-32. [PMID: 25280423 DOI: 10.1016/j.nut.2014.03.025] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 03/28/2014] [Accepted: 03/30/2014] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Obesity is associated with alterations in intestinal microbiota and immunity. The aim of this study was to determine the effect of probiotic Lactobacillus casei CRL 431 administration on intestinal and humoral immune response, clinical parameters, and gut microbiota was evaluated using a high-fat diet to induce obesity in a mouse model. METHODS Adult mice received a conventional balanced diet or a high-fat diet supplemented with milk, milk fermented by Lactobacillus casei (FM), L. casei as suspension, or water over 60 d. Histology of liver and small intestine (SI), immunoglobulin A-positive cells and macrophages in SI, phagocytic activity of spleen and peritoneal macrophages, and humoral immune response to ovalbumin were studied. Clinical parameters in serum and gut microbiota were also analyzed. RESULTS FM was the most effective supplement for decreasing body weight and clinical parameters in serum. The histology of liver and SI was also improved in obese mice given FM. These animals had increased numbers of immunoglobulin A-positive cells and macrophages in SI. The gut microbiota showed that obese mice given probiotics had increased Bacteroides and bifidobacteria. Administration of FM or L. casei as suspension enhanced the phagocytic activity of macrophages. The anti-ovalbumin specific immune response was not increased by any supplement assayed. CONCLUSION Administration of probiotics to obese hosts improved the gut microbiota and the mucosal immunity altered by obesity, down-regulated some biochemical parameters in blood associated with metabolic syndrome, and decreased liver steatosis. These results demonstrate the potential use of probiotics in obese individuals to decrease the body weight and to improve the biochemical and immunologic parameters altered by obesity.
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Affiliation(s)
- Ivanna Novotny Núñez
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina
| | - Carolina Maldonado Galdeano
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina; Cátedra de Inmunología. Instituto de Microbiología, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina
| | | | - Gabriela Perdigón
- Centro de Referencia para Lactobacilos (CERELA-CONICET), San Miguel de Tucumán, Tucumán, Argentina; Cátedra de Inmunología. Instituto de Microbiología, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina.
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25
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Fallucca F, Porrata C, Fallucca S, Pianesi M. Influence of diet on gut microbiota, inflammation and type 2 diabetes mellitus. First experience with macrobiotic Ma-Pi 2 diet. Diabetes Metab Res Rev 2014; 30 Suppl 1:48-54. [PMID: 24532292 DOI: 10.1002/dmrr.2518] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 12/19/2013] [Indexed: 12/17/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a complex disorder influenced by both genetic and environmental factors. Recent studies have suggested that an imbalance of the intestinal microbiota may be involved in the development of several human diseases, including obesity and T2DM. The main regulators of the intestinal microbiota are age, ethnicity, the immune system and diet. A high-fat diet may induce dysbiosis, which can result in a low-grade inflammatory state, obesity and other metabolic disorders. Adding prebiotics to the diet may reduce inflammation, endotoxaemia and cytokine levels as well as improving insulin resistance and glucose tolerance. The administration of prebiotics such as fermentable dietary fibres, promotes glucagon-like peptide 1 and peptide YY (anorexigenic) and decreases ghrelin (orexigenic). In a recent 21-day, intervention study in patients with T2DM, the effect of using the macrobiotic Ma-Pi 2 diet was investigated. Results suggested that it could induce a significant improvement in fasting blood glucose, plasma lipid fractions, plasma insulin and homeostasis. It is therefore possible that a diet rich in prebiotics and probiotics can play a role in T2DM management, probably due to positive intestinal microbiota modulation. However, this must be demonstrated by larger studies including randomized controlled trials that measure indicators of inflammation.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients.
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Affiliation(s)
- Katherine J P Schwenger
- Katherine JP Schwenger, Institute of Medical Science, University of Toronto, 1 King's Circle, Toronto M5S 1A8, Canada
| | - Johane P Allard
- Katherine JP Schwenger, Institute of Medical Science, University of Toronto, 1 King's Circle, Toronto M5S 1A8, Canada
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27
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Schwenger KJP, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20:1712-1723. [PMID: 24587650 PMCID: PMC3930971 DOI: 10.3748/wjg.v20.i7.1712] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/05/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients.
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28
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Abstract
The rationale for specific pharmacologic therapy in nonalcoholic steatohepatitis (NASH) is determined by the potential for disease progression and the difficulties, in many patients, to successfully implement diet and lifestyle changes in the long term. Because they correct insulin resistance, insulin-sensitizing agents are attractive candidates for the treatment of NASH. However, two randomized studies have shown that vitamin E, despite having no effect on insulin sensitivity, achieves interesting histological and biochemical efficacy. This review provides an insight into the therapeutic efficacy and safety issues of different pharmacological agents tested in human NASH.
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Affiliation(s)
- Maeva Guillaume
- Service d'Hépatologie et Gastro-entérologie, INSERM 1048 and Université Paul Sabatier, Hôpital Purpan, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. .,Service d'Hépatologie et Gastro-entérologie, Hôpital Purpan, Pavillon Dieulafoy, 4ème étage, Place du Docteur Baylac, TSA 40031, 31059, Toulouse Cedex 9, France.
| | - Vlad Ratziu
- INSERM U938, Hospital Pitié Salpêtrière, CdR Saint-Antoine and Université Pierre et Marie Curie, Paris, France. .,Service d'Hépatologie et Gastro-entérologie, Hôpital Pitié-Salpêtrière, 47-83, Boulevard de l'hôpital, 75651, Paris Cedex 13, France.
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29
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Vajro P, Mandato C, D’Aniello R. More on current evidences on probiotics as a novel treatment for non-alcoholic Fatty liver disease. HEPATITIS MONTHLY 2013; 13:e13780. [PMID: 24130602 PMCID: PMC3796194 DOI: 10.5812/hepatmon.13780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 07/27/2013] [Accepted: 08/13/2013] [Indexed: 02/06/2023]
Affiliation(s)
- Pietro Vajro
- Department of Medicine and Surgery, University of Salerno, Baronissi-Salerno, Italy
- Corresponding author: Pietro Vajro, Department of Medicine and Surgery, University of Salerno, Baronissi-Salerno, Italy. Tel: +39-89965016, Fax: +39-3392361008, E-mail:
| | | | - Roberta D’Aniello
- Department of Medicine and Surgery, University of Salerno, Baronissi-Salerno, Italy
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30
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Kelishadi R, Farajian S, Mirlohi M. Probiotics as a novel treatment for non-alcoholic Fatty liver disease; a systematic review on the current evidences. HEPATITIS MONTHLY 2013; 13:e7233. [PMID: 23885277 PMCID: PMC3719124 DOI: 10.5812/hepatmon.7233] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 08/01/2012] [Accepted: 08/22/2012] [Indexed: 12/11/2022]
Abstract
CONTEXT Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with 5-10% of liver having extra fat. Increase in its prevalence in all age groups is linked with obesity and Type II diabetes. The treatment of NAFLD remains controversial. A growing body of evidence suggests a relation between overgrowth of gut microbiota with NAFLD and non-alcoholic steatohepatitis (NASH). The objective of this review is to provide an overview on experimental and clinical studies assessing all positive and negative effects of probiotics. EVIDENCE ACQUISITION We made a critical appraisal on various types of documents published from 1999 to March 2012 in journals, electronic books, seminars, and symposium contexts including Medline, PubMed, and Cochrane Central Register of Controlled Trials databases. We used the key words: "non-alcoholic fatty liver disease, probiotics, non-alcoholic steatohepatitis, liver disease, and fatty liver". RESULTS Probiotics, as biological factors, control the gut microbiota and result in its progression. It is in this sense that they are suggestive of a new and a natural way of promoting liver function. Correspondingly, limited evidence suggests that probiotics could be considered as a new way of treatment for NAFLD. CONCLUSIONS Various experimental studies and clinical trials revealed promising effects of probiotics in improving NAFLD; however given the limited experience in this field, generalization of probiotics as treatment of NAFLD needs substantiation through more trials with a larger sample sizes and with longer-term follow up.
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Affiliation(s)
- Roya Kelishadi
- Faculty of Medicine and Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran
| | - Sanam Farajian
- Faculty of Nutrition and Food Sciences, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran
- Corresponding author: Sanam Farajian, Faculty of Nutrition and Food Sciences, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran. Tel.: +98-3117923060, Fax: +98-31187898, E-mail:
| | - Maryam Mirlohi
- Faculty of Nutrition and Food Sciences, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, IR Iran
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Imani Fooladi AA, Mahmoodzadeh Hosseini H, Nourani MR, Khani S, Alavian SM. Probiotic as a novel treatment strategy against liver disease. HEPATITIS MONTHLY 2013; 13:e7521. [PMID: 23610585 PMCID: PMC3631524 DOI: 10.5812/hepatmon.7521] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 09/19/2012] [Accepted: 09/25/2012] [Indexed: 02/07/2023]
Abstract
CONTEXT A symbiotic relationship between the liver and intestinal tract enables the healthy status of both organs. Microflora resident in intestinal lumen plays a significant role in hepatocytes function. Alterations to the type and amount of microorganisms that live in the intestinal tract can result in serious and harmful liver dysfunctions such as cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, and hepatic encephalopathy. An increased number of pathogens, especially enterobacteriaceae, enterococci, and streptococci species causes the elevation of intestinal permeability and bacterial translocation. The presence of high levels of lipopolysaccharide (LPS) and bacterial substances in the blood result in a portal hypertension and ensuing hepatocytes damage. Several methods including the usage of antibiotics, prebiotics, and probiotics can be used to prevent the overgrowth of pathogens. Compared to prebiotic and antibiotic therapy, probiotics strains are a safer and less expensive therapy. Probiotics are "live microorganisms (according to the FAO/WHO) which when administered in adequate amounts confer a health benefit on the host". EVIDENCE ACQUISITIONS Data from numerous preclinical and clinical trials allows for control of the flora bacteria quantity, decreases in compounds derived from bacteria, and lowers proinflammatory production such as TNF-α, IL-6 and IFN-γ via down-regulation of the nuclear factor kappa B (NF-κ B). RESULTS On the other hand, probiotic can reduce the urease activity of bacterial microflora. Furthermore, probiotic decreases fecal pH value and reduces ammonia adsorption. In addition, the serum level of liver enzymes and other substances synthesized by the liver are modulated subsequent to probiotic consumption. CONCLUSIONS According to our knowledge, Probiotic therapy as a safe, inexpensive and a noninvasive strategy can reduce pathophysiological symptoms and improve different types of liver diseases without side effects.
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Affiliation(s)
- Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Abbas Ali Imani Fooladi, Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran. Tel.: +98-2188068924, Fax: +98-2188068924, E-mail:
| | | | - Mohammad Reza Nourani
- Tissue Engineering Division, Chemical Injury Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Soghra Khani
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
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Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; 55:885-904. [PMID: 22278337 DOI: 10.1007/s00125-011-2446-4] [Citation(s) in RCA: 481] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Accepted: 12/02/2011] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liver-related complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardio-metabolic risk in NAFLD. METHODS Publications through November 2011 were systematically reviewed by two authors. Outcomes evaluated though standard methods were: histological/radiological/biochemical features of NAFLD, variables of glucose metabolism and cardiovascular risk factors. Seventy-eight randomised trials were included (38 in NASH, 40 in NAFLD): 41% assessed post-treatment histology, 71% assessed glucose metabolism and 88% assessed cardiovascular risk factors. Lifestyle intervention, thiazolidinediones, metformin and antioxidants were most extensively evaluated. RESULTS Lifestyle-induced weight loss was safe and improved cardio-metabolic risk profile; a weight loss ≥7% improved histological disease activity, but was achieved by <50% patients. Statins and polyunsaturated fatty acids improved steatosis, but their effects on liver histology are unknown. Thiazolidinediones improved histological disease activity, glucose, lipid and inflammatory variables and delayed fibrosis progression. Pioglitazone also improved blood pressure. Weight gain (up to 4.8%) was common. Antioxidants yielded mixed histological results: vitamin E improved histological disease activity when administered for 2 years, but increased insulin resistance and plasma triacylglycerols. CONCLUSIONS/INTERPRETATION Weight loss is safe, and improves liver histology and cardio-metabolic profile. For patients not responding to lifestyle intervention, pioglitazone improves histological disease activity, slows fibrosis progression and extensively ameliorates cardio-metabolic endpoints. Further randomised controlled trials (RCTs) of adequate size and duration will assess long-term safety and efficacy of proposed treatments on clinical outcomes.
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Affiliation(s)
- G Musso
- Gradenigo Hospital, C.so Regina Margherita 8, Turin, Italy.
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Abstract
OBJECTIVE Various lines of evidence suggest that malfunctioning of the gut-liver axis contributes to hepatic damage of rodents and humans with nonalcoholic fatty liver disease. We evaluated the effects of short-term probiotic treatment in children with obesity-related liver disease who were noncompliant with lifestyle interventions. PATIENTS AND METHODS Twenty obese children (age 10.7 ± 2.1 years) with persisting hypertransaminasemia and ultrasonographic (US) bright liver were enrolled in this double-blind, placebo-controlled pilot study. At baseline, patients underwent clinical and laboratory anthropometric evaluation, measurement of the US hepatorenal ratio, standard liver function tests, oral glucose tolerance test, serum tumor necrosis factor-alpha, the glucose hydrogen breath test, and evaluation of serum antibodies to antipeptidoglycan-polysaccharide polymers. After exclusion of causes of liver disease other than obesity, patients received either probiotic Lactobacillus rhamnosus strain GG (12 billion CFU/day) or placebo for 8 weeks. RESULTS Multivariate analysis after probiotic treatment revealed a significant decrease in alanine aminotransferase (average variation vs placebo P = 0.03) and in antipeptidoglycan-polysaccharide antibodies (average variation vs placebo P = 0.03) irrespective of changes in BMI z score and visceral fat. Tumor necrosis factor-alpha, and US bright liver parameters remained fairly stable. CONCLUSIONS Probiotic L rhamnosus strain GG warrants consideration as a therapeutic tool to treat hypertransaminasemia in hepatopathic obese children noncompliant with lifestyle interventions.
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Scarpellini E, Campanale M, Leone D, Purchiaroni F, Vitale G, Lauritano EC, Gasbarrini A. Gut microbiota and obesity. Intern Emerg Med 2010; 5 Suppl 1:S53-6. [PMID: 20865475 DOI: 10.1007/s11739-010-0450-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Intestinal epithelium, mucosal immune system, and bacterial flora represent a morpho-functional system on dynamic balance responsible for the intestinal metabolic and trophic functions, and the regulation of mucosal and systemic host's immunity. Obesity is a pathological condition affecting a growing number of people especially in the Western countries resulting from the failure of the organism's energetic balance based on the perfect equality of income, waste, and storage. Recent evidences explain the mechanisms for the microbial regulation of the host's metabolism both in health and disease. In particular, animal studies have explained how quali-/quantitative changes in microflora composition are able to affect the absorption of the nutrients and the energy distribution. Antibiotics, prebiotics, probiotics, and symbiotics are the instruments utilized in the current clinical practice to modulate the intestinal bacterial flora in man both in health and pathologic conditions with promising preliminary results on prevention and therapy of obesity and related metabolic diseases.
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Affiliation(s)
- Emidio Scarpellini
- Internal Medicine Department, Gemelli Hospital, Catholic University of Sacred Heart, Largo A. Gemelli 8, 00168, Rome, Italy
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Abstract
The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle--including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake--may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders.
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Yin YN, Yu QF, Fu N, Liu XW, Lu FG. Effects of four Bifidobacteria on obesity in high-fat diet induced rats. World J Gastroenterol 2010; 16:3394-401. [PMID: 20632441 PMCID: PMC2904885 DOI: 10.3748/wjg.v16.i27.3394] [Citation(s) in RCA: 184] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the effects of four Bifidobacteria strains (Bifidobacteria L66-5, L75-4, M13-4 and FS31-12, originated from normal human intestines) on weight gain, lipid metabolism, glucose metabolism in an obese murine model induced by high-fat diet.
METHODS: Forty-eight Sprague-Dawley rats were randomly divided into six groups. Control group received standard chow, model group received high-fat diet, and intervention groups received high-fat diet added with different Bifidobacteria strains isolated from healthy volunteers’ fresh feces. All rats were executed at the 6th weekend. Body weight (BW), obese indexes, oral glucose tolerance test, serum and liver lipid and serum insulin (INS) were tested. Liver lipid deposition was classified pathologically.
RESULTS: Compared with the model group, B. M13-4 improved BW gains (264.27 ± 26.91 vs 212.55 ± 18.54, P = 0.001) while B. L66-5 induced a decrease in BW (188.47 ± 11.96 vs 212.55 ± 18.54, P = 0.043). The rest two strains had no significant change in BW. All the four strains can reduce serum and liver triglyceride and significantly alleviate the lipid deposition in liver. All strains showed a trend of lowing serum and liver total cholesterol while B. L66-5 and B. FS31-12 did so more significantly. In addition, all the four strains showed no significant differences in serum INS and glucose level.
CONCLUSION: The response of energy metabolism to administration of Bifidobacteria is strain dependent. Different strains of Bifidobacteria might drive different directions of fat distribution.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) has become increasingly recognized as the most common cause of abnormal liver enzymes in the last few decades and is among the most common forms of chronic liver disease in the Western world and across the globe. With the growing epidemic of obesity and diabetes, NAFLD is estimated to affect about one-quarter of the US population. Although most patients with NAFLD have nonprogressive bland steatosis, a minority of patients develop the histological subtype of nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, hepatocellular carcinoma, and liver-related death. This is especially true when NASH patients have type 2 diabetes. Treatment of NAFLD should therefore be directed towards patients with established NASH. Sustained weight loss seems to improve insulin resistance and associated NASH. In fact, weight loss with bariatric surgery leads to biochemical and histological improvement in morbidly obese patients with NASH. Several pharmacologic agents have been studied in an effort to improve insulin resistance and pro-inflammatory mediators potentially responsible for the development and progression of NASH. While some studies have shown initial promise, none has established long-term efficacy using randomized clinical trials. This paper briefly reviews the epidemiology, natural history, and pathophysiology of NAFLD and NASH and then focuses on the clinical trials of various therapeutic modalities for NAFLD. These include weight loss agents, bariatric surgery, insulin-sensitizing agents, lipid-lowering agents, antioxidants, probiotics, anti-tumor necrosis factor agents, cytoprotective and other novel agents.
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Affiliation(s)
- Brian Lam
- Center for Liver Diseases at Inova Fairfax Hospital, Falls Church, VA, USA
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Musso G, Gambino R, Cassader M. Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr Opin Lipidol 2010; 21:76-83. [PMID: 19915460 DOI: 10.1097/mol.0b013e3283347ebb] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW To examine the role of gut microbiota in the regulation of host energy homeostasis and its role in the pathogenesis of obesity, diabetes and nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS Experimental models highlight several mechanisms connecting gut microbiota to host energy metabolism: increased energy harvesting from the diet, regulation of appetite through gut peptide, secretion, regulation of tissue-free fatty acid composition and uptake, storage and oxidation, modulation of intestinal barrier by glucagon-like peptide-2 secretion, activation of innate immunity and hepatic fibrogenesis through the lipopolysaccharide (LPS)-toll-like receptor-4 axis.Gut microbiota manipulation through antibiotics, prebiotics and probiotics yields encouraging results for the treatment of obesity, diabetes and NAFLD in animal models, but data in humans are currently scarce. SUMMARY Gut microbiota manipulation yielded encouraging results for the treatment of different metabolic disorders in experimental models. However, changing intestinal microbiota may be more difficult in free-living individuals compared to standardized laboratory models, and its long-term consequences are unknown. To safely and effectively change human gut microflora, future research should highlight the complex hormonal, immunomodulatory and metabolic mechanisms underlying microbiota-host interactions in different tissues and candidate treatments should be evaluated in well designed trials with patient-oriented end-points.
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Petta S, Muratore C, Craxì A. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Dig Liver Dis 2009; 41:615-25. [PMID: 19223251 DOI: 10.1016/j.dld.2009.01.004] [Citation(s) in RCA: 192] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2008] [Revised: 12/31/2008] [Accepted: 01/08/2009] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease is the clinical hepatic expression of metabolic syndrome. The prevalence of non-alcoholic fatty liver disease is around 20-30%, and with a rapid increase in the metabolic risk factors in the general population, non-alcoholic fatty liver disease has become the most common cause of liver disease worldwide. A fraction (20-30%) of non-alcoholic fatty liver disease patients develop a potentially progressive hepatic disorder, namely non-alcoholic steatohepatitis, leading to end-stage liver disease. The pathogenesis of non-alcoholic fatty liver disease is not entirely understood, and even if insulin resistance is a major pathogenetic key, many other factors are implicated in both liver fat accumulation and disease progression to non-alcoholic steatohepatitis. In this review we aim to examine the literature, principally concerning human non-alcoholic fatty liver disease pathogenesis, and to identify the newest, most promising clinical and basic research data.
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Affiliation(s)
- S Petta
- Cattedra & Unità Operativa di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.
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Affiliation(s)
| | | | - Sourabh Aggarwal
- Internist at the Western Michigan University School of Medicine in Kalamazoo.
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