The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota

Background & AimsPeriodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology.MethodsC57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction.ResultsCDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different.ConclusionsSwallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.

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Lycium barbarum polysaccharide combined with aerobic exercise ameliorated nonalcoholic fatty liver disease through restoring gut microbiota, intestinal barrier and inhibiting hepatic inflammation

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2021.05.066 ◽

2021 ◽

Author(s):

Lu-Lu Gao ◽

Jia-Min Ma ◽

Yan-Na Fan ◽

Yan-Nan Zhang ◽

Rui Ge ◽

...

Keyword(s):

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Intestinal Barrier ◽

Hepatic Inflammation ◽

Lycium Barbarum ◽

Nonalcoholic Fatty Liver ◽

Lycium Barbarum Polysaccharide

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Impact of Hypocaloric Hyperproteic Diet on Gut Microbiota in Overweight or Obese Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study

Digestive Diseases and Sciences ◽

10.1007/s10620-016-4179-1 ◽

2016 ◽

Vol 61 (9) ◽

pp. 2721-2731 ◽

Cited By ~ 28

Author(s):

Zoltan Pataky ◽

Laurence Genton ◽

Laurent Spahr ◽

Vladimir Lazarevic ◽

Sylvain Terraz ◽

...

Keyword(s):

Liver Disease ◽

Pilot Study ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Obese Patients ◽

Nonalcoholic Fatty Liver

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Implication of Gut Microbiota in Nonalcoholic Fatty Liver Disease

PLoS Pathogens ◽

10.1371/journal.ppat.1004559 ◽

2015 ◽

Vol 11 (1) ◽

pp. e1004559 ◽

Cited By ~ 63

Author(s):

Jerome Boursier ◽

Anna Mae Diehl

Keyword(s):

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver

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Gut Microbiota Changes in Nonalcoholic Fatty Liver Disease and Concomitant Cardiovascular Diseases

10.1101/2020.07.27.224329 ◽

2020 ◽

Author(s):

Olena H. Kurinna

Keyword(s):

Liver Disease ◽

Cardiovascular Diseases ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Statistical Significance ◽

Microbiota Composition ◽

Nonalcoholic Fatty Liver ◽

Gut Microbiota Composition

AbstractNonalcoholic fatty liver disease (NAFLD) bears serious economic consequences for the health care system worldwide and Ukraine, in particular. Cardiovascular diseases (CVD) are the main cause of mortality in NAFLD patients. Changes in the gut microbiota composition can be regarded as a potential mechanism of CVD in NAFLD patients.The purpose of this work was to investigate changes in major gut microbiota phylotypes, Bacteroidetes, Firmicutes and Actinobacteria with quantification of Firmicutes/Bacteroidetes in NAFLD patients with concomitant CVD.The author enrolled 120 NAFLD subjects (25 with concomitant arterial hypertension (AH) and 24 with coronary artery disease (CAD)). The gut microbiota composition was assessed by qPCR.Resultsthe author found a marked tendency towards an increase in the concentration of Bacteroidetes (by 37.11% and 21.30%, respectively) with a decrease in Firmicutes (by 7.38% and 7.77%, respectively) in both groups with comorbid CAD and AH with the identified changes not reaching a statistical significance. The author quantified a statistically significant decrease in the concentration of Actinobacteria in patients with NAFLD with concomitant CAD at 41.37% (p<0.05) as compared with those with an isolated NAFLD. In patients with concomitant AH, the content of Actinobacteria dropped by 12.35%, which was statistically insignificant.Conclusionsthe author established changes in the intestinal microbiota, namely decrease in Actinobacteria in patients with CAD, which requires further research.

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Disease-Associated Gut Microbiota Reduces the Profile of Secondary Bile Acids in Pediatric Nonalcoholic Fatty Liver Disease

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.698852 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiake Yu ◽

Hu Zhang ◽

Liya Chen ◽

Yufei Ruan ◽

Yiping Chen ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Bile Acids ◽

Fatty Liver Disease ◽

Healthy Children ◽

Nonalcoholic Fatty Liver ◽

Secondary Bile Acids

Children with nonalcoholic fatty liver disease (NAFLD) display an altered gut microbiota compared with healthy children. However, little is known about the fecal bile acid profiles and their association with gut microbiota dysbiosis in pediatric NAFLD. A total of 68 children were enrolled in this study, including 32 NAFLD patients and 36 healthy children. Fecal samples were collected and analyzed by metagenomic sequencing to determine the changes in the gut microbiota of children with NAFLD, and an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system was used to quantify the concentrations of primary and secondary bile acids. The associations between the gut microbiota and concentrations of primary and secondary bile acids in the fecal samples were then analyzed. We found that children with NAFLD exhibited reduced levels of secondary bile acids and alterations in bile acid biotransforming-related bacteria in the feces. Notably, the decrease in Eubacterium and Ruminococcaceae bacteria, which express bile salt hydrolase and 7α-dehydroxylase, was significantly positively correlated with the level of fecal lithocholic acid (LCA). However, the level of fecal LCA was negatively associated with the abundance of the potential pathogen Escherichia coli that was enriched in children with NAFLD. Pediatric NAFLD is characterized by an altered profile of gut microbiota and fecal bile acids. This study demonstrates that the disease-associated gut microbiota is linked with decreased concentrations of secondary bile acids in the feces. The disease-associated gut microbiota likely inhibits the conversion of primary to secondary bile acids.

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The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background

Gastroenterology Research and Practice ◽

10.1155/2016/2862173 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 46

Author(s):

Jinsheng Yu ◽

Sharon Marsh ◽

Junbo Hu ◽

Wenke Feng ◽

Chaodong Wu

Keyword(s):

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Genetic Variants ◽

Genetic Background ◽

Fatty Liver Disease ◽

Genome Wide Association Studies ◽

Nonalcoholic Fatty Liver ◽

Pathogenic Mechanisms

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) inPNPLA3and rs58542926 (Glu167Lys) inTM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression.

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Role of Bile Acids in Dysbiosis and Treatment of Nonalcoholic Fatty Liver Disease

Mediators of Inflammation ◽

10.1155/2019/7659509 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Caihua Wang ◽

Chunpeng Zhu ◽

Liming Shao ◽

Jun Ye ◽

Yimin Shen ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Bile Acids ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Bile Acid Receptors

Nonalcoholic fatty liver disease (NAFLD) is a major health threat around the world and is characterized by dysbiosis. Primary bile acids are synthesized in the liver and converted into secondary bile acids by gut microbiota. Recent studies support the role of bile acids in modulating dysbiosis and NAFLD, while the mechanisms are not well elucidated. Dysbiosis may alter the size and the composition of the bile acid pool, resulting in reduced signaling of bile acid receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). These receptors are essential in lipid and glucose metabolism, and impaired bile acid signaling may cause NAFLD. Bile acids also reciprocally regulate the gut microbiota directly via antibacterial activity and indirectly via FXR. Therefore, bile acid signaling is closely linked to dysbiosis and NAFLD. During the past decade, stimulation of bile acid receptors with their agonists has been extensively explored for the treatment of NAFLD in both animal models and clinical trials. Early evidence has suggested the potential of bile acid receptor agonists in NAFLD management, but their long-term safety and effectiveness need further clarification.

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The Role of Probiotics in Nonalcoholic Fatty Liver Disease: A New Insight into Therapeutic Strategies

Nutrients ◽

10.3390/nu11112642 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2642 ◽

Cited By ~ 10

Author(s):

Marica Meroni ◽

Miriam Longo ◽

Paola Dongiovanni

Keyword(s):

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Bacterial Overgrowth ◽

Therapeutic Interventions ◽

Mucosal Inflammation ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of pathological hepatic conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which may predispose to liver cirrhosis and hepatocellular carcinoma (HCC). Due to the epidemic obesity, NAFLD is representing a global health issue and the leading cause of liver damage worldwide. The pathogenesis of NAFLD is closely related to insulin resistance (IR), adiposity and physical inactivity as well as genetic and epigenetic factors corroborate to the development and progression of hepatic steatosis and liver injury. Emerging evidence has outlined the implication of gut microbiota and gut-derived endotoxins as actively contributors to NAFLD pathophysiology probably due to the tight anatomo-functional crosstalk between the gut and the liver. Obesity, nutrition and environmental factors might alter intestinal permeability producing a favorable micro-environment for bacterial overgrowth, mucosal inflammation and translocation of both invasive pathogens and harmful byproducts, which, in turn, influence hepatic fat composition and exacerbated pro-inflammatory and fibrotic processes. To date, no therapeutic interventions are available for NAFLD prevention and management, except for modifications in lifestyle, diet and physical exercise even though they show discouraging results due to the poor compliance of patients. The premise of this review is to discuss the role of gut–liver axis in NAFLD and emphasize the beneficial effects of probiotics on gut microbiota composition as a novel attractive therapeutic strategy to introduce in clinical practice.

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