Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites

Gut, Journal Year: 2020, Volume and Issue: 70(4), P. 761 - 774

Published: July 21, 2020

Objective Non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an increasing healthcare burden worldwide. We examined the role of dietary cholesterol in driving NAFLD–HCC through modulating gut microbiota and its metabolites. Design High-fat/high-cholesterol (HFHC), high-fat/low-cholesterol or normal chow diet was fed to C57BL/6 male littermates for 14 months. Cholesterol-lowering drug atorvastatin administered HFHC-fed mice. Germ-free mice were transplanted with stools from different diets determine direct modulated-microbiota NAFLD–HCC. Gut analysed by 16S rRNA sequencing serum metabolites liquid chromatography–mass spectrometry (LC–MS) metabolomic analysis. Faecal microbial compositions 59 hypercholesterolemia patients 39 healthy controls. Results High led sequential progression steatosis, steatohepatitis, fibrosis eventually HCC mice, concomitant insulin resistance. Cholesterol-induced formation associated dysbiosis. The composition clustered distinctly along stages steatohepatitis HCC. Mucispirillum, Desulfovibrio, Anaerotruncus Desulfovibrionaceae increased sequentially; while Bifidobacterium Bacteroides depleted which corroborated human hypercholesteremia patients. Dietary induced bacterial alteration including taurocholic acid decreased 3-indolepropionic acid. gavaged HFHC manifested hepatic lipid accumulation, inflammation cell proliferation. Moreover, restored cholesterol-induced dysbiosis completely prevented development. Conclusions drives inducing Cholesterol inhibitory therapy manipulation may be effective strategies prevention.

Language: Английский

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Gut-liver axis: Pathophysiological concepts and clinical implications

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(11), P. 1700 - 1718

Published: Oct. 7, 2022

Language: Английский

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Gut microbiome, liver immunology, and liver diseases

Cellular and Molecular Immunology, Journal Year: 2020, Volume and Issue: 18(1), P. 4 - 17

Published: Dec. 14, 2020

Language: Английский

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Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity

Nature Metabolism, Journal Year: 2021, Volume and Issue: 3(12), P. 1596 - 1607

Published: Dec. 20, 2021

Language: Английский

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Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

Hepatology, Journal Year: 2020, Volume and Issue: 73(2), P. 833 - 842

Published: Aug. 12, 2020

Nonalcoholic fatty liver disease (NAFLD) is an epidemic disease, affecting approximately one quarter of the entire population in world.(1) This encompasses a broad spectrum clinical phenotypes ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrotic NASH, advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Although inflammation NAFLD appears less prognostically relevant when compared fibrosis,(2) latter may be cumulative result former.(3) Noninvasive assessment fibrosis (e.g., by transient elastography) has reduced need for invasive procedures such as biopsy,(4) although late-stage trials still require histologic endpoints. The plays crucial role glucose lipid metabolism. frequently present obesity reflects risk factor many metabolic diseases type 2 diabetes (T2D).(5) In turn, T2D associated with up 90% patients. been linked various extrahepatic disorders cardiovascular complications(6) chronic kidney disease.(7) Furthermore, not only major HCC but also increased rate malignancies gastrointestinal gynecological malignancies.(4) cancer seems even higher than itself.(8) As such, prototypic systemic disorder targeting organs throughout body. pathophysiology underlying this complex incompletely understood. A decade ago, we proposed multiple parallel hits hypothesis which lipotoxicity adipose tissue (AT) alterations gut microbial functions contribute evolution NAFLD.(9) Progress over last was substantial that AT inflammation(10) microbiome (and related metabolites) evolved players pathogenesis NAFLD.(11, 12) dietary components other proinflammatory potential have identified. Finally, genetic pathways play manifestation; several hits, patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, membrane-bound O-acyltransferase 7, hydroxysteroid 17-beta dehydrogenase 13, are involved especially metabolism.(13) review, will discuss pathophysiological factors focusing on intricate triangular interplay between tract, AT, liver. Normal composed adipocytes, fibroblasts, endothelial cells, resident macrophages cells immune system collectively regulate host metabolism energy storage.(14) White depots comprise visceral (VAT) subcutaneous (SAT), which, together liver, participate acid health, communicates control homeostasis.(15) obesity, characterized cytokine chemokine expression infiltration example, leukocytes, serve fuel local inflammation. inflammatory state contributes inflammation, deteriorate insulin resistance, exemplifying aspects AT–liver axis.(9, 10) hallmarks influx macrophages, cluster differentiation 4–positive (CD4+) CD8+ T dendritic natural killer (NK) cytokines/chemokines.(16) Primary cues remain poorly explored arguably involve diet-induced stress subsequently induces response cell infiltration. initial fueled self-maintained tissue-infiltrating cells. For recruitment (ATMs) dependent chemokines C-C motif ligand (CCL2), expressed obese animals patients.(17) Adaptive immunity cells) recruited antigen-presenting precedes ATM accumulation.(18) Expression (besides CCL2) CCL5 (also known regulated upon activation, normal expressed, secreted) or CCL13 patients.(19) Importantly, most these cytokines tumor necrosis alpha (TNFα), interleukin 1-beta (IL-1β), IL-6. TNFα first described adipokine obesity-related resistance murine models, its human obesity.(20) Similarly, preclinical evidence indicated key IL-1β IL-1α-deficient, IL-1β-deficient, 1 IL-1 receptor–deficient mice protected against high-fat diet–induced resistance(21); expression.(22) IL-37, anti-inflammatory family member, highly subjects able improve experimental models.(23, 24) IL-6 produced mostly ATMs adipocytes.(25) importance SAT source circulating convincingly demonstrated, 15%-35% being derived tissue.(26) Both VAT produce large amounts disorders, both sources biologically affect sensitivity.(27) We investigated morbidly patients undergoing bariatric surgery. TNFα, IL-1β, IL-6, strongly after successful weight loss.(23, 28) adiponectin leptin (prototypic immunomodulatory adipokines) critically disorders.(29) Collectively, studies highlight cellular, cytokine, adipokine. networks (see Fig. 1). Clinical provide cellular molecular correlate degree disease. Du Plessis colleagues studied transcriptomic profiles VAT, functional characteristics ATMs, severity 113 surgery.(30) They found genes comparing NASH. NASH exhibited number CD11c+CD206+ (C-C motif) receptor–positive accompanied release chemokines. Most importantly, directly correlated inflammation.(30) study investigating 3,197 participants observed independently obesity.(31) no proof concept NAFLD, they clearly link light (mechanistic) report axis disorders. Insulin hallmark NAFLD,(32) occurs tissues muscle, AT.(33) While it commonly conceived emerges consequent recent demonstrated through monocyte chemoattractant protein 1–regulated leukocyte recruitment.(34) These findings interesting accelerates lipolysis mitogen-activated kinase (MAPK) signaling, results activation ß3-adrenergic receptor.(35) Lipolysis enhanced free export promoting potentially NAFLD. line this, correlates (especially fibrosis); improvement pioglitazone, peroxisome proliferator–activated receptor-gamma agonist, resulted decrease hepatocyte ballooning patients.(36) Indeed, NAFLD.(37) study, authors established macrophage measuring soluble CD183, proposing acids might involved. support crosstalk aforementioned notable, descriptive can indirect mammals. Bijnen transplanted lean, obese, ATM-depleted lean Ldr−/− mice.(38) transplantation injury pronounced AT. Liver paralleled numbers neutrophils, effect mainly attributed synthesis neutrophil chemotaxis proteins (C-X-C ligands 14 16 ATM.(38) previously hypothesized tissue-specific knockout (KO) models AT-specific KO mice) would reveal numerous reported took advantage adipocyte-specific mouse models; few discussed here. deletion receptor and/or insulin-like growth severe lipodystrophy progressive resembling dysplastic nodules at week 52.(39) Lipid peroxidation critical mechanism model.(39) deficiency hormone-sensitive lipase causes increase lipodystrophy, impaired synthesis, resistance.(40) contrast, lipoprotein angiopoietin-like 4 (which controls metabolism) attenuates steatosis, atherosclerosis.(41) shown I interferon worsens perturbation, gain, intolerance.(42) However, did impact our model. indicate specific hubs deserve dissected more detail. Various impinge gut–liver axis. shaped metabolites hormones system.(43) section made deciphering intestinal microbiota identification NASH-associated signature,(44) preceded smaller NAFLD.(45) abundance Proteobacteria, Enterobacteriaceae, Escherichia coli differed microbiomes(45); association Bacteroidetes simple healthy controls.(46) Boursier histology-proven 57 patients.(47) Bacteroides depending while Prevotella decreased. convincing example signature comes Loomba colleagues.(44) 86 histologically defined identified 37 bacterial species, allowed them distinguish mild versus fibrosis. Advanced Proteobacteria Firmicutes Faecalibacterium prausnitzii. Such prevalent case cirrhosis.(48) An important bacteria-derived endotoxin disease-contributing had claimed already 20 years ago.(49) confirmed presence livers. Patients concentrations similar accumulation hepatocytes, toll-like macrophages.(50) Further intrahepatic another reporting portal tract.(51) Experimental endotoxin-producing strains Enterobacter cloacae B29, PY102, Klebsiella pneumoniae A7 promoted germ-free diet.(52) Moreover, ethanol-producing isolated caused oral gavaging.(53) Due space constraints, do barrier NAFLD.(54) Vice versa, modulate susceptibility excellently reviewed recently(55) conclusion, overwhelming underpins very exciting rapidly evolving topic (i.e., AT) blood) expands beyond dysbiosis Bacterial 16S ribosomal DNA indeed detected blood, diabetes,(56) blood NAFLD.(57) tissue, material taxa two cohorts NAFLD.(51) Sookoian colleagues(51) severely (similar microbiome). different including solid cancers,(58) T2D, obesity.(59) reminiscent omental, SAT, subjects.(60) Schierwagen central, hepatic, venous peripheral cirrhosis receiving transjugular portosystemic shunt(61); some bacteria could cultivated sites. and, cases, live circulation diseased liver/AT. implications health describe compelling window opportunity research were considered sterile. Metagenomic sequencing metabolite screens (metabolomics) allow insight into repertoire communities. metabolomics recently.(12) Hoyles plasma urine metabolome, fecal metagenome bacteria), transcriptome transcriptional profile) women.(62) phenylacetate) steatosis. Fecal transfer women high-grade feeding phenylacetate mice.(62) search vein dysfunction, Koh discovered imidazole propionate, microbially histidine-derived metabolite.(63) metabolite, propionate affected signaling p38 MAPK phosphorylation p62, finally mechanistic target rapamycin.(63) Levels N,N,N-trimethyl-5-aminovaleric acid, bacteria, serum NAFLD; deteriorated steatosis.(64) Other 3-(4-hydroxphenyl)lactate discriminated without unknown.(65) combination 10 showed powerful discriminatory effects detecting greater diagnostic accuracy Fibrosis-4 index.(66) increasingly recognized intestine, Future fascinating insights bears therapeutic) use. Besides pathways, interactions. Colonic sensitivity under diet.(67) By generating macrophage-specific epithelium–specific mice, decreased colonic permeability, improved tolerance, highlighting gut–AT axis.(67) Interestingly, products commensal L-lactate acetate enterocyte altered storage oxidation.(68) distal effects, influencing lipid-driven atherosclerosis Many exert development NAFLD.(69) Dietary metabolism(70) act microbiome, referred "dysbiosis."(71) so far damage Western diet high fat consumption intake alcohol, salt, refrained grains, fructose, red processed meat developing progressing NAFLD.(69, 72) volunteers endotoxemia low-grade inflammation.(73) Trans-fatty unsaturated vegetables enriched snack foods, fried margarines. Intake trans-fat negatively all-cause mortality coronary heart mortality.(74) well studied. Trans-fat single function tests index.(75) Preclinical data propose trans-fats promote cholesterogenesis,(76) trans-fat-induced if trans-fatty deleted pool, exact mechanisms elusive.(77) Fructose fibrosis.(78) triggers de novo lipogenesis process involves microbiota-derived acetate.(79) subjects, however, excess isocaloric fructose 8 weeks detrimental liver.(80) raises doubts whether damages Wheat amylase trypsin inhibitors, common wheat component, activates macrophages(81) aggravates inflammation.(82) converts nutrients choline carnitine trimethylamine, metabolized flavin monooxygenases trimethylamine N-oxide (TMAO),(83) discontinuation TMAO levels within weeks.(84) Numerous diseases.(85) relationship trial 60 biopsy-proven lower betaine betaine/choline ratio.(86) Administration diet, involving bile farnesoid X antagonism.(87) Therefore, food thereby initiate processes outside tract. oppose above-described pool metabolites. indole, tryptophan derivate microbiota, improves mice; low NAFLD.(88) interventional using either low-sugar diet,(89) carbohydrate-restricted diet,(90) Mediterranean diet(91) beneficial defined. intervention promising strategy treat future.(69) decade, tract emerged drivers Despite fact pathogenesis, randomized controlled specifically lacking. Altered involving, NAFLD.(92) Interactions bidirectional, experiments transgenic exemplified plethora define loss behind metabolism.(33, 54, 93) corroborated 2010 hypothesis,(9) forming based gained animal trials. better understanding translation novel therapeutics endemic gratefully acknowledge Austrian Federal Ministry Science, Research, Economy National Foundation Technology, Development. All contributions discussion content wrote, edited article.

Language: Английский

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The gut–liver axis and gut microbiota in health and liver disease

Nature Reviews Microbiology, Journal Year: 2023, Volume and Issue: 21(11), P. 719 - 733

Published: June 14, 2023

Language: Английский

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Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 13, 2022

Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form NAFL, can be progressive and more susceptible to developing cirrhosis hepatocellular carcinoma. Currently, lifestyle interventions are most essential effective strategies for preventing controlling NAFL without development fibrosis. While there still limited appropriate drugs specifically treat NAFL/NASH, growing progress is being seen in elucidating pathogenesis identifying therapeutic targets. In this review, we discussed recent developments etiology prospective targets, as well pharmacological candidates pre/clinical trials patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, Importantly, evidence elucidates that disruption gut-liver axis microbe-derived metabolites drive NAFL/NASH. Extracellular vesicles (EVs) act signaling mediator, resulting accumulation, macrophage stellate cell activation, further promoting inflammation fibrosis progression during Targeting gut microbiota or EVs may serve new treatment Finally, other mechanisms, such therapy genetic approaches, also have enormous potential. Incorporating different mechanisms personalized medicine improve efficacy better benefit patients

Language: Английский

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Protection against Metabolic Associated Fatty Liver Disease by Protocatechuic Acid

Gut Microbes, Journal Year: 2023, Volume and Issue: 15(1)

Published: July 28, 2023

Gut microbiota-diet interaction has been identified as a key factor of metabolic associated fatty liver disease (MAFLD). Recent studies suggested that dietary polyphenols may protect against MAFLD by regulating gut microbiota; however, the underlying mechanisms remain elusive. We first investigated effects cyanidin 3-glucoside and its phenolic metabolites on high-fat diet induced in C57BL/6J mice, protocatechuic acid (PCA) showed significant positive effect. Next, regulation PCA lipid metabolism microbiota were explored mouse model fecal transplantation (FMT) experiment. Dietary reduced intraperitoneal hepatic fat deposition with lower levels transaminases (AST & ALT) inflammatory cytokines (IL-1β, IL-2, IL-6, TNF-α MCP-1), but higher HDL-c/LDL-c ratio. Characterization indicated decreased Firmicutes/Bacteroidetes ratio mainly reducing relative abundance genus Enterococcus, which was positively correlated LDL-c, AST, ALT most up-regulated lipids lipidomics analysis. FMT experiments Enterococcus faecalis caused inflammation, insulin resistance expression carnitine palmitoyltransferase-1 alpha (CPT1α), can be reversed through inhibiting faecalis. Transcriptomics analysis decrease fibroblast growth 1 (Fgf1), recovered Fgf1 insulin-like binding protein 2 (Igfbp2), receptor substrate (Irs1) (Irs2). These results demonstrated high proportion accelerates CPT1α Fgf1, prevented supplementation PCA.

Language: Английский

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Gut microbiota and metabolic biomarkers in metabolic dysfunction–associated steatotic liver disease

Hepatology Communications, Journal Year: 2024, Volume and Issue: 8(3)

Published: Feb. 26, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD), a replacement of the nomenclature employed for NAFLD, is most prevalent chronic worldwide. Despite its high global prevalence, NAFLD often under-recognized due to absence reliable noninvasive biomarkers diagnosis and staging. Growing evidence suggests that gut microbiome plays significant role in occurrence progression by causing immune dysregulation metabolic alterations dysbiosis. The rapid advancement sequencing tools metabolomics has enabled identification signatures microbiota-derived metabolite profiles numerous clinical studies related NAFLD. Overall, these have shown decrease α-diversity changes microbiota abundance, characterized increased levels Escherichia Prevotella, decreased Akkermansia muciniphila Faecalibacterium patients with Furthermore, bile acids, short-chain fatty trimethylamine N-oxide, tryptophan metabolites are believed be closely associated onset In this review, we provide novel insights into vital pathogenesis Specifically, summarize major classes thereby highlighting links between specific bacterial species certain

Language: Английский

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Therapeutic potential of traditional Chinese medicine in the prevention and treatment of digestive inflammatory cancer transformation: Portulaca oleracea L. as a promising drug

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 327, P. 117999 - 117999

Published: March 4, 2024

Traditional Chinese medicine (TCM) has been used for centuries to treat various types of inflammation and tumors the digestive system. Portulaca oleracea L. (POL), in TCM thousands years. The chemical composition POL is variable includes flavonoids, alkaloids, terpenoids organic acids other classes natural compounds. Many these compounds exhibit powerful anti-inflammatory anti-cancer-transforming effects In this review, we focus on potential therapeutic role NASH, gastritis colitis their associated cancers, with a pharmacological properties mechanisms action main active POL. information data its ingredients were collated from resources like ethnobotanical textbooks literature databases such as CNKI, VIP (Chinese literature), PubMed, Science Direct, Elsevier Google Scholar (English literatures), Wiley, Springer, Tailor Francis, Scopus, Inflibnet. Kaempferol, luteolin, myricetin, quercetin, genistein, EPA, DHA, melatonin found improve NASH NASH-HCC, while kaempferol, apigenin, quercetin played gastric cancer. Apigenin, lupeol, vitamin C have treatment cancers. discovery beneficial supports idea that could be promising novel candidate prevention inflammation-related cancers However, clinical describing mode naturally are still lacking. addition, pharmacokinetic compounds, changes drug dose absorption rates, cannot extrapolated animal models need measured patients trials. On one hand, systematic meta-analysis existing publications containing needs carried out. studies hepatic renal toxicity also needed. Additionally, well-designed preclinical validate performed, thus hopefully providing basis validation benefits

Language: Английский

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