Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales DOI Creative Commons
James K. Carter, Dipankar Bhattacharya,

Joshua N. Borgerding

et al.

PLoS ONE, Journal Year: 2021, Volume and Issue: 16(1), P. e0244763 - e0244763

Published: Jan. 4, 2021

Background & aim Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that responsible for growing fraction cirrhosis and cancer cases worldwide. Changes in the gut microbiome have been implicated NASH pathogenesis, but lack suitable murine models has barrier to progress. We therefore characterized well-validated model establish its value modeling human disease. Methods The composition intestinal microbiota was monitored mice on 12- or 24-week protocol consisting high fat, sugar Western Diet (WD) plus once weekly i.p injection low-dose CCl 4 . Additional were subjected WD-only -only conditions assess independent effect these variables microbiome. Results There substantial remodeling mice, by declines both species diversity bacterial abundance. Based changes beta diversity, from clustered separately controls principal coordinate analyses. A comparison between with identified WD as primary driver early microbiome, resulting loss within 1 st week. signature emerged progressively at weeks 6 12, including, most notably, reproducible bloom Firmicute order Erysipelotrichales Conclusions established valuable study role microbes NASH, enabling us identify new signature.

Language: Английский

The association between the dietary index for gut microbiota and metabolic dysfunction-associated fatty liver disease: a cross-sectional study DOI Creative Commons
Yangyang Zheng,

Jinhui Hou,

Shiqi Guo

et al.

Diabetology & Metabolic Syndrome, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 17, 2025

The relationship between the gut microbiome and metabolic dysfunction-associated fatty liver disease (MAFLD) has garnered increasing attention. However, association dietary index for microbiota (DI-GM), a measure of diversity, MAFLD yet to be fully explored. Data from 2017-2020 National Health Nutrition Examination Survey (NHANES) were analyzed, including 7243 participants. DI-GM was investigated using weighted logistic regression, restricted cubic spline (RCS), subgroup analyses. A notable inverse identified prevalence MAFLD, with each 1-point increase in corresponding 6.1% reduction (OR = 0.939, 95% CI: 0.901-0.980). Individuals score 6 or higher had an adjusted OR 0.794 (95% 0.665-0.947) compared those 0-3. RCS analysis further revealed linear risk. Additionally, analyses suggested that race may modify (P interaction < 0.05). is inversely associated prevalence, appears significant modifier this relationship.

Language: Английский

Citations

5
The Molecular and Mechanistic Insights Based on Gut–Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement DOI Open Access
Yun Ji, Yue Yin, Lijun Sun

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(9), P. 3066 - 3066

Published: April 26, 2020

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most frequent classification of around globe. Along with sequencing technologies, gut microbiota has been regarded a vital factor for maintenance human and animal health mediation multiple diseases. The modulation mechanism affecting pathogenesis NAFLD becoming growing area concern. Recent advances in communication between hepatic tissue pave novel ways to better explain molecular mechanisms regarding pathological physiology NAFLD. In this review, we recapitulate current knowledge correlated development progression regulated by microbiome gut–liver axis, which may provide crucial therapeutic strategies These predominantly involve: (1) alteration profile; (2) effects components metabolites from bacteria (e.g., lipopolysaccharides (LPS), trimethylamine-N-oxide (TMAO), N,N,N-trimethyl-5-aminovaleric acid (TMAVA)); (3) impairment intestinal barrier function bile homeostasis. particular, prevention therapy assisted nutritional are highlighted, including probiotics, functional oligosaccharides, dietary fibers, ω-3 polyunsaturated acids, amino acids (L-tryptophan L-glutamine), carotenoids, polyphenols, based on targets excavated axis.

Language: Английский

Citations

90
Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma DOI Creative Commons

Jinkai Liu,

Wei Geng,

Hanyong Sun

et al.

Gut, Journal Year: 2021, Volume and Issue: 71(6), P. 1203 - 1213

Published: Aug. 3, 2021

Altered metabolites are important for the tumourigenicity of hepatocellular carcinoma (HCC). We performed integrative metabolomics analysis changes in portal venous blood and comparison with liver tissues stool samples HCC patients healthy donors.Serum (portal central vein), tissue (HCC tumour adjacent non-tumour, normal liver) were collected from 102 subjects (52 50 controls) discovery cohort; 100 (50 an independent validation cohort. Untargeted metabolomic profiling was using high-performance liquid chromatography-mass spectrometry. The function candidate validated hepatocyte cell lines.Detailed evaluation showed distinct clusters serum, control individuals (p<0.001). had significantly higher levels vein serum DL-3-phenyllactic acid, L-tryptophan, glycocholic acid 1-methylnicotinamide than controls, which associated impaired poor survival. On other hand, lower linoleic phenol controls. Linoleic inhibited proliferation, inferring their anti-HCC as protective metabolites.The metabolome revealed unreported metabolic alterations patients. In vein, we identified elevated depleted signifying that they might play a role development.

Language: Английский

Citations

84
Microbial Metabolites: Critical Regulators in NAFLD DOI Creative Commons
Xin Dai,

Huiqin Hou,

Wanru Zhang

et al.

Frontiers in Microbiology, Journal Year: 2020, Volume and Issue: 11

Published: Oct. 7, 2020

Nonalcoholic fatty liver disease (NAFLD) is the most common forms of chronic throughout world. The relationship between gut microbiota and NAFLD has been extensively investigated. involves in regulation by participating fermentation indigestible food, interacting with intestinal mucosal immune system, influencing barrier function leading to signaling alteration. Meanwhile, microbial metabolites not only affect signal transduction pathway gut, but also reach far away from gut. In this review, we focus on effects certain key such as short-chain acids, trimethylamine-N-oxide, bile endogenous ethanol indole NAFLD, summarize several potential therapies targeting gut-liver axis modulation including antibiotics, prebiotics, probiotics, acids fecal transplantation. Understanding complex interactions may provide crucial insight into pathogenesis treatment NAFLD.

Language: Английский

Citations

78
Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies DOI Open Access
Youngmin A. Lee, Scott L. Friedman

Journal of Internal Medicine, Journal Year: 2021, Volume and Issue: 291(1), P. 11 - 31

Published: Sept. 26, 2021

Abstract Non‐alcoholic fatty liver disease is comprised of either simple steatosis (non‐alcoholic liver) or a more advanced inflammatory and fibrogenic stage steatohepatitis [NASH]). NASH affects growing proportion the global adult pediatric population, leading to rising rates fibrosis hepatocellular carcinoma. multifactorial that part systemic metabolic disorder. Here, we provide an overview underpinnings pathogenesis established drivers inflammation fibrosis. Clarification underlying mechanisms will advance development novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches potential investigational derived from animal models including inflammasome, epigenetic reprogramming, Hippo signaling, Notch engineered T cells remove HSCs, HSC‐specific targeting therapies. Recently completed ongoing clinical trials antifibrotics discussed, illuminating expectation one yield benefit in coming years.

Language: Английский

Citations

73
Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy DOI Creative Commons

Mingming Zhao,

Haoran Wei,

Chenze Li

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: April 1, 2022

Abstract Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through production gut-derived metabolites. However, specific metabolites and their pathophysiological contribution cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine gut microbiota, was elevated with gradually increased risk mortality transplantation in a prospective cohort ( n = 1647). TMAVA treatment aggravated dysfunction high-fat diet-fed mice. Decreased fatty oxidation (FAO) is hallmark metabolic reprogramming diseased contributes impaired myocardial energetics contractile dysfunction. Proteomics uncovered that disturbed energy metabolism, leading inhibition FAO lipid accumulation. altered mitochondrial ultrastructure, respiration inhibited carnitine metabolism. Mice γ-butyrobetaine hydroxylase (BBOX) deficiency displayed similar phenotype, indicating functions BBOX. Finally, exogenous supplementation reversed induced hypertrophy. These data suggest microbiota-derived key determinant for synthesis subsequent FAO.

Language: Английский

Citations

68
Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response DOI Creative Commons
Yue Shen, Shengdi Wu, Yao Chen

et al.

Gut Microbes, Journal Year: 2022, Volume and Issue: 15(1)

Published: Dec. 15, 2022

Gut dysbiosis has been reported in chronic hepatitis B (CHB) infection, however its role CHB progression and antiviral treatment remains to be clarified. Herein, the present study aimed characterize gut microbiota (GM) patients with virus infection-associated liver diseases (HBV-CLD) by combining microbiome metabolome analyses evaluate their effects on peripheral immunity. Fecal samples from HBV-CLD (n = 64) healthy controls 17) were collected for 16s rRNA sequencing. metabolomics was measured untargeted liquid chromatography-mass spectrometry subgroups of 58 subjects. Lineage changes blood mononuclear cells (PBMCs) determined upon exposure bacterial extracts (BE) patients. Integrated revealed a remarkable shift metabolites patients, disease found two main contributing factors shift. Concordant decreases Turicibacter 4-hydroxyretinoic acid detected inversely correlated serum AST levels through host-microbiota-metabolite interaction analysis cirrhotic Moreover, depletion E.hallii group elevated choline restored 5-year treatment. PBMC BE non-cirrhotic enhanced expansion T helper 17 cells; however, cirrhotics attenuated 1 cell count. are compositional Peripheral immunity might an intermediate link microbe-host interplay underlying pathogenesis.

Language: Английский

Citations

50
Multiomics Analysis Reveals the Impact of Microbiota on Host Metabolism in Hepatic Steatosis DOI
Müjdat Zeybel, Muhammad Arif, Xiangyu Li

et al.

Advanced Science, Journal Year: 2022, Volume and Issue: 9(11)

Published: Feb. 7, 2022

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including microbiome. To decipher hepatic steatosis (HS) pathogenesis excluding critical confounding variants diabetes, 56 heterogenous MAFLD patients are characterized generating multiomics data oral gut metagenomics as well plasma metabolomics inflammatory proteomics data. The dysbiosis microbiome explored host-microbiome based on global metabolic revealed. These integrated using network HS's key features identified HS finally predicted these findings validated follow-up cohort, where 22 subjects with varying degree of characterized.

Language: Английский

Citations

43
Lactobacillus reuteri CCFM8631 Alleviates Hypercholesterolaemia Caused by the Paigen Atherogenic Diet by Regulating the Gut Microbiota DOI Open Access

Qianqian Wang,

Yufeng He, Li Xiu

et al.

Nutrients, Journal Year: 2022, Volume and Issue: 14(6), P. 1272 - 1272

Published: March 17, 2022

Cardiovascular disease has one of the highest global incidences and mortality rates. Atherosclerosis is main cause cardiovascular disease, hypercholesterolaemia hyperlipidaemia are risk factors for development atherosclerosis. Decreasing serum cholesterol triglyceride concentrations considered to be an effective strategy prevent atherosclerotic disease. Previous studies have shown that many diseases related gut microbiota dysbiosis. The positive regulation by probiotics may or treat certain diseases. In this study, Lactobacillus reuteri CCFM8631 treatment was decrease plasma total (TC), low-density lipoprotein-cholesterol, aspartate transaminase, alanine transaminase trimethylamine N-oxide concentrations, liver TC malondialdehyde recover superoxide dismutase in mice fed a Paigen atherogenic diet. addition, L. increased faecal short-chain fatty acid content (acetate, propionate butyrate), which accompanied increase relative abundance Deferribacteres, Lachnospiraceae NK4A136 group, Dubosiella; Erysipelatoclostridium Romboutsia activation butanoate vitamin B6 metabolism, leading alleviation hypercholesterolaemia.

Language: Английский

Citations

39
DT-109 ameliorates nonalcoholic steatohepatitis in nonhuman primates DOI Creative Commons
Pengxiang Qu, Oren Rom, Ke Li

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(5), P. 742 - 757.e10

Published: April 10, 2023

Nonalcoholic steatohepatitis (NASH) prevalence is rising with no pharmacotherapy approved. A major hurdle in NASH drug development the poor translatability of preclinical studies to safe/effective clinical outcomes, and recent failures highlight a need identify new targetable pathways. Dysregulated glycine metabolism has emerged as causative factor therapeutic target NASH. Here, we report that tripeptide DT-109 (Gly-Gly-Leu) dose-dependently attenuates fibrosis mice. To enhance probability successful translation, developed nonhuman primate model histologically transcriptionally mimics human Applying multiomics approach combining transcriptomics, proteomics, metabolomics, metagenomics, found reverses hepatic steatosis prevents progression primates, not only by stimulating fatty acid degradation glutathione formation, mice, but also modulating microbial bile metabolism. Our describe highly translatable for evaluation DT-109.

Language: Английский

Citations

39