Fatty Liver Disease and Gut Microbiota: A Comprehensive Update.

doi:10.14218/JCTH.2018.00008

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Fatty Liver Disease and Gut Microbiota: A Comprehensive Update.

Journal Article•DOI•

Fatty Liver Disease and Gut Microbiota: A Comprehensive Update.

Lyna Campo¹, Sara Eiseler¹, Tehilla Apfel¹, Nikolaos Pyrsopoulos¹•Institutions (1)

Rutgers University¹

28 Mar 2019-Journal of clinical and translational hepatology (J Clin Transl Hepatol)-Vol. 7, Iss: 1, pp 56-60

TL;DR: The current understanding of the roles of gut microbiota in mediating NAFLD development is summarized and possible gut microbiota-targeted therapies forNAFLD are discussed and conclusions on the therapeutic potential of manipulating gut microbiota to decrease the incidence and prevalence of fatty liver disease are drawn.

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Abstract: Nonalcoholic fatty liver disease (NAFLD) is the accumulation of fat in the liver in the absence of secondary causes. NAFLD is a multifactorial disease that results from the interaction of genetic predisposition and metabolic, inflammatory and environmental factors. Among these factors, dysregulation of gut microbiome has been linked to the development of fatty liver disease. The microbiome composition can be modified by dietary habits leading to gut microbiome dysbiosis, especially when a diet is rich in saturated fats, animal products and fructose sugars. Different species of bacteria in the gut metabolize nutrients differently, triggering different pathways that contribute to the accumulation of fat within the liver and triggering inflammatory cascades that promote liver damage. In this review, we summarize the current understanding of the roles of gut microbiota in mediating NAFLD development and discuss possible gut microbiota-targeted therapies for NAFLD. We summarize experimental and clinical evidence, and draw conclusions on the therapeutic potential of manipulating gut microbiota to decrease the incidence and prevalence of fatty liver disease.

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The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD).

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Daniela Maria Tanase¹, Evelina Maria Gosav¹, Claudia Florida Costea¹, Manuela Ciocoiu¹, Cristina Mihaela Lacatusu¹, Minela Aida Maranduca¹, Anca Ouatu¹, Mariana Floria¹ - Show less +4 more•Institutions (1)

Grigore T. Popa University of Medicine and Pharmacy¹

31 Jul 2020-Experimental Diabetes Research

TL;DR: The NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets are discussed.

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Abstract: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence and incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, and vice versa. This complex and intricate association is supported and mediated by insulin resistance (IR). In this review, we discuss the NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets.

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127 citations

Cites background from "Fatty Liver Disease and Gut Microbi..."

...Another theory suggest that gut microbiome alteration and dietary habits are another mechanism that induce and maintain T2DM and/or NAFLD [96, 97]....
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The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases

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Naga Chalasani¹, Zobair M. Younossi², Joel E. Lavine³, Michael Charlton⁴, Kenneth Cusi⁵, Mary E. Rinella⁶, Stephen A. Harrison⁷, Elizabeth M. Brunt⁸, Arun J. Sanyal⁹ - Show less +5 more•Institutions (9)

Indiana University¹, Inova Fairfax Hospital², Columbia University³, University of Chicago⁴, University of Florida⁵, Northwestern University⁶, Pinnacle Financial Partners⁷, Washington University in St. Louis⁸, Virginia Commonwealth University⁹

01 Jan 2017

TL;DR: The Grading of Recommendations, Assessment Development, and Evaluation (GRADE) system as discussed by the authors provides a data-supported approach to the diagnostic, therapeutic, and preventive aspects of NAFLD care.

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Abstract: This guidance provides a data-supported approach to the diagnostic, therapeutic, and preventive aspects of NAFLD care. A "Guidance" document is different from a "Guideline." Guidelines are developed by a multidisciplinary panel of experts and rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations, Assessment Development, and Evaluation (GRADE) system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This article is protected by copyright. All rights reserved.

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86 citations

Journal Article•DOI•

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

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Keisaku Sato¹, Fanyin Meng¹, Fanyin Meng², Heather Francis¹, Heather Francis², Nan Wu¹, Lixian Chen¹, Lindsey Kennedy¹, Tianhao Zhou³, Antonio Franchitto, Paolo Onori⁴, Eugenio Gaudio⁴, Shannon Glaser³, Gianfranco Alpini¹, Gianfranco Alpini² - Show less +11 more•Institutions (4)

Indiana University – Purdue University Indianapolis¹, Veterans Health Administration², Texas A&M University³, Sapienza University of Rome⁴

15 Feb 2020-Journal of Pineal Research

TL;DR: Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases.

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Abstract: Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress-induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.

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48 citations

Journal Article•DOI•

Biobanks for life sciences and personalized medicine: importance of standardization, biosafety, biosecurity, and data management

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Heimo Müller¹, Georges Dagher², Martina Loibner¹, Cornelia Stumptner¹, Penelope Kungl¹, Kurt Zatloukal¹ - Show less +2 more•Institutions (2)

Medical University of Graz¹, French Institute of Health and Medical Research²

01 Oct 2020-Current Opinion in Biotechnology

TL;DR: The review places special emphasis on pre-analytical procedures and international standards, which are essential to improving analytical data reliability and reproducibility, as well as on the increasing importance of data management.

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42 citations

Journal Article•DOI•

Beneficial Effects of Betaine: A Comprehensive Review.

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Madan Kumar Arumugam¹, Matthew C. Paal¹, Matthew C. Paal², Terrence M. Donohue², Terrence M. Donohue¹, Murali Ganesan¹, Murali Ganesan², Natalia A. Osna², Natalia A. Osna¹, Kusum K. Kharbanda¹, Kusum K. Kharbanda² - Show less +7 more•Institutions (2)

Veterans Health Administration¹, University of Nebraska Medical Center²

22 May 2021-Biology

TL;DR: Betaine's role in preventing/attenuating both alcohol-induced and metabolic-associated liver diseases has been well studied and is extensively reviewed in this paper, where the major physiological effects of betaine in whole-body health and its ability to protect against both liver- as well as non-liver-related diseases and conditions are described.

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Abstract: Medicinal herbs and many food ingredients possess favorable biological properties that contribute to their therapeutic activities. One such natural product is betaine, a stable, nontoxic natural substance that is present in animals, plants, and microorganisms. Betaine is also endogenously synthesized through the metabolism of choline or exogenously consumed through dietary intake. Betaine mainly functions as (i) an osmolyte and (ii) a methyl-group donor. This review describes the major physiological effects of betaine in whole-body health and its ability to protect against both liver- as well as non-liver-related diseases and conditions. Betaine's role in preventing/attenuating both alcohol-induced and metabolic-associated liver diseases has been well studied and is extensively reviewed here. Several studies show that betaine protects against the development of alcohol-induced hepatic steatosis, apoptosis, and accumulation of damaged proteins. Additionally, it can significantly prevent/attenuate progressive liver injury by preserving gut integrity and adipose function. The protective effects are primarily associated with the regulation of methionine metabolism through removing homocysteine and maintaining cellular SAM:SAH ratios. Similarly, betaine prevents metabolic-associated fatty liver disease and its progression. In addition, betaine has a neuroprotective role, preserves myocardial function, and prevents pancreatic steatosis. Betaine also attenuates oxidant stress, endoplasmic reticulum stress, inflammation, and cancer development. To conclude, betaine exerts significant therapeutic and biological effects that are potentially beneficial for alleviating a diverse number of human diseases and conditions.

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40 citations

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Journal Article•DOI•

An obesity-associated gut microbiome with increased capacity for energy harvest

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Peter J. Turnbaugh¹, Ruth E. Ley, Michael A. Mahowald, Vincent Magrini¹, Elaine R. Mardis¹, Jeffrey I. Gordon - Show less +2 more•Institutions (1)

Washington University in St. Louis¹

21 Dec 2006-Nature

TL;DR: It is demonstrated through metagenomic and biochemical analyses that changes in the relative abundance of the Bacteroidetes and Firmicutes affect the metabolic potential of the mouse gut microbiota and indicates that the obese microbiome has an increased capacity to harvest energy from the diet.

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Abstract: The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.

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10,126 citations

"Fatty Liver Disease and Gut Microbi..." refers background in this paper

...,(18) that showed that the transplantation of intestinal bacteria from genetically obese mice to lean mice significantly enhanced the effectiveness of intestinal energy absorption and increased the body weight of the leanmice.(18) Similarly, analysis of the gut microbiome in NAFLD patients revealed a lower percentage of Bacteroides and higher levels of Prevotella and Porphyromonas species compared to lean controls....
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Journal Article•DOI•

Microbial ecology: Human gut microbes associated with obesity

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Ruth E. Ley¹, Peter J. Turnbaugh¹, Samuel Klein¹, Jeffrey I. Gordon¹•Institutions (1)

Washington University in St. Louis¹

21 Dec 2006-Nature

TL;DR: It is shown that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet.

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Abstract: Two groups of beneficial bacteria are dominant in the human gut, the Bacteroidetes and the Firmicutes. Here we show that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet. Our findings indicate that obesity has a microbial component, which might have potential therapeutic implications.

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7,550 citations

Additional excerpts

...coli in the microbiomes of NAFLD patients.(17)...
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Journal Article•DOI•

Diet rapidly and reproducibly alters the human gut microbiome

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Lawrence A. David¹, Corinne F. Maurice¹, Rachel N. Carmody¹, David B. Gootenberg¹, Julie E. Button¹, Benjamin E. Wolfe¹, Alisha V. Ling², A. Sloan Devlin³, Yug Varma³, Michael A. Fischbach³, Sudha B. Biddinger², Rachel J. Dutton¹, Peter J. Turnbaugh¹ - Show less +9 more•Institutions (3)

Harvard University¹, Boston Children's Hospital², California Institute for Quantitative Biosciences³

23 Jan 2014-Nature

TL;DR: Increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease.

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Abstract: Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.

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7,032 citations

"Fatty Liver Disease and Gut Microbi..." refers background in this paper

...Also, the expression of genes for the degradation of polycyclic aromatic hydrocarbons (which are carcinogenic compounds), vitamin biosynthesis and b-lactamase are increased in individuals on an animal-based diet.(39) Fructose and saturated fat are more likely to stimulate hepatic lipid accumulation and progression to NASH....
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...Fructose and saturated fat are more likely to stimulate hepatic lipid accumulation and progression to NASH.(39) In mice, high-fructose diet stimulates gutderived portal endotoxemia, leading to liver steatosis through the activation of TLR4 and TNF-a....
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...This ultimately results in enhanced response to low-dose lipopolysaccharides, a bacterial endotoxin, leading to the liver inflammation and fibrosis as seen in NASH.20 It is therefore possible that a bacteria-mediated mechanism underlies the progression from simple fatty liver to NASH in humans as well....
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...The NASH patients were found to have significantly higher levels of blood ethanol levels when compared to obese and lean patients who did not have NASH.22 Interestingly, it is commonly noted that liver biopsies from patients with NASH have similar histology to liver biopsies from patients with alcoholic liver disease, perhaps pointing to a common promoter as the cause of the liver changes....
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...The current gold standard for the management of NAFLD is weight loss and minimizing metabolic risk factors.19 Data suggest that diet is the most important intervention to target NAFLD and NASH.19 A reduction in body weight of only 5% can improve steatosis and a reduction of 10% can improve steatohepatitis.36 However, many patients struggle to adhere to the recommended lifestyle modifications.1 Many interventions have been studied which could be beneficial for the management of NAFLD37Weight lossmedications, such as ursodeoxycholic acid, thiazolidinedione, polyunsaturated fatty acids, metformin, lipidlowering drugs and the antioxidant vitamins E and C treatments, have been assessed as treatment options for the management of NAFLD.1 However, the majority of the trials have been of short duration and did not include histological endpoints.1 The PIVENS trial was a large randomized controlled trial of vitamin E versus pioglitazone (a diabetic medication) for 96 weeks in nondiabetic NASH patients.38 A significant improvement in hepatic steatosis and lobular inflammation was demonstrated by both treatments, but neither had a significant effect on hepatic fibrosis scores.38 Guidelines suggest that in nondiabetic patients with biopsy proven NASH, the use of vitamin E is reasonable at a dose of 800 IU/day despite the reported inability to observe an effect on hepatic fibrosis scores.1,38 However, until further data supports its effectiveness, vitamin E should not be considered a standard treatment of NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.1,38 Larger randomized controlled trials focusing on histological endpoints are necessary to precisely assess the efficacy of current treatment options for NASH.1 The integrity of the gut microbiota depends in part on diet.39 “Plant-based diets” rich in vegetables, grains, fruits, and legumes, compared to “animal-based diets” composed of cheese, egg and meats, have demonstrated significant effects on gut bacteria composition.39 An animal-based diet promotes gut microbiota to increase the production of deoxycholic acid, a precursor to bile acids, and branched-chain fatty acids....
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Journal Article•DOI•

The gut microbiota as an environmental factor that regulates fat storage

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Fredrik Bäckhed¹, Hao Ding², Hao Ding³, Ting Wang¹, Lora V. Hooper, Gou Young Koh⁴, Andras Nagy², Clay F. Semenkovich¹, Jeffrey I. Gordon¹ - Show less +5 more•Institutions (4)

Washington University in St. Louis¹, University of Toronto², University of Manitoba³, KAIST⁴

02 Nov 2004-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: In this article, the authors found that conventionalization of adult germ-free C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake.

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Abstract: New therapeutic targets for noncognitive reductions in energy intake, absorption, or storage are crucial given the worldwide epidemic of obesity. The gut microbial community (microbiota) is essential for processing dietary polysaccharides. We found that conventionalization of adult germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake. Studies of GF and conventionalized mice revealed that the microbiota promotes absorption of monosaccharides from the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte factor (Fiaf), a member of the angiopoietin-like family of proteins, is selectively suppressed in the intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized, normal and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor and that its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. Studies of Rag1-/- animals indicate that these host responses do not require mature lymphocytes. Our findings suggest that the gut microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host. Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AY 667702--AY 668946).

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5,221 citations