Obesity Phenotypes, Diabetes, and Cardiovascular Diseases

Circulation Research, Год журнала: 2020, Номер 126(11), С. 1477 - 1500

Опубликована: Май 21, 2020

This review addresses the interplay between obesity, type 2 diabetes mellitus, and cardiovascular diseases. It is proposed that generally defined by an excess of body fat causing prejudice to health, can no longer be evaluated solely mass index (expressed in kg/m ) because it represents a heterogeneous entity. For instance, several cardiometabolic imaging studies have shown some individuals who normal weight or are overweight at high risk if they visceral adipose tissue—a condition often accompanied accumulation normally lean tissues (ectopic deposition liver, heart, skeletal muscle, etc). On other hand, obese nevertheless much lower than expected when faced with energy intake ability expand their subcutaneous tissue mass, particularly gluteal-femoral area. Hence, excessive amounts ectopic largely define disease moderate obesity. There also rapidly expanding subgroup patients characterized (severe obesity). Severe obesity specific additional health issues should receive attention. Because difficulties normalizing content severe more aggressive treatments been studied this such as surgery, referred metabolic surgery. basis above, we propose refer obesities rather

Язык: Английский

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Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease

Cell Metabolism, Год журнала: 2017, Номер 25(5), С. 1054 - 1062.e5

Опубликована: Май 1, 2017

Язык: Английский

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The intestinal microbiota fuelling metabolic inflammation

Nature reviews. Immunology, Год журнала: 2019, Номер 20(1), С. 40 - 54

Опубликована: Авг. 6, 2019

Язык: Английский

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The role of the microbiome in NAFLD and NASH

EMBO Molecular Medicine, Год журнала: 2018, Номер 11(2)

Опубликована: Дек. 27, 2018

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of cardiometabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. It rapidly becoming most prevalent worldwide. A sizable minority NAFLD patients develop nonalcoholic steatohepatitis (NASH), characterized by inflammatory changes that can lead to progressive damage, cirrhosis, hepatocellular carcinoma. Recent studies have shown in addition genetic predisposition diet, gut microbiota affects carbohydrate lipid metabolism as well influences balance between pro-inflammatory anti-inflammatory effectors liver, thereby impacting its progression NASH In this review, we will explore impact microbiota-derived compounds on development NASH, unexplored factors related potential microbiome contributions common disease.

Язык: Английский

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Gut-liver axis: Pathophysiological concepts and clinical implications

Cell Metabolism, Год журнала: 2022, Номер 34(11), С. 1700 - 1718

Опубликована: Окт. 7, 2022

Язык: Английский

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

Hepatology, Год журнала: 2020, Номер 73(2), С. 833 - 842

Опубликована: Авг. 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.

Язык: Английский

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The Healthy Human Blood Microbiome: Fact or Fiction?

Frontiers in Cellular and Infection Microbiology, Год журнала: 2019, Номер 9

Опубликована: Май 8, 2019

The blood that flows perpetually through our veins and arteries performs numerous functions essential to survival. Besides distributing oxygen, this vast circulatory system facilitates nutrient transport, deters infection dispenses heat throughout bodies. Since human has traditionally been considered be an entirely sterile environment, comprising only blood-cells, platelets plasma, the detection of microbes in was consistently interpreted as indication infection. However, although a contentious concept, evidence for existence healthy blood-microbiome is steadily accumulating. While origins, identities these unanticipated micro-organisms remain elucidated, information on blood-borne microbial phylogeny gradually increasing. Given recent advances microbial-haematology, we review current literature concerning composition origin blood-microbiome, focusing bacteria their role configuration both diseased blood-microbiomes. Specifically, explore ways which dysbiosis supposedly innocuous bacterial microbiome may stimulate pathogenesis. In addition exploring relationship between development complex disorders, also address matter contamination, citing influence contaminants interpretation blood-derived datasets urging routine analysis laboratory controls ascertain taxonomic metabolic characteristics environmentally-derived contaminant-taxa.

Язык: Английский

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Gut Microbiome, Intestinal Permeability, and Tissue Bacteria in Metabolic Disease: Perpetrators or Bystanders?

Nutrients, Год журнала: 2020, Номер 12(4), С. 1082 - 1082

Опубликована: Апрель 14, 2020

The emerging evidence on the interconnectedness between gut microbiome and host metabolism has led to a paradigm shift in study of metabolic diseases such as obesity type 2 diabetes with implications both underlying pathophysiology potential treatment. Mounting preclinical clinical microbiota shifts, increased intestinal permeability disease, critical positioning barrier at interface environment internal milieu have rekindling “leaky gut” concept. Although circulation surrogate markers directly measurable been linked systemic inflammation mechanistic models behind this phenomenon are underdeveloped. Given repeated observations microorganisms several tissues congruent phylogenetic findings, we review current these unanticipated niches, focusing specifically interaction well extra-intestinal bacteria their joint contributions metabolism. We further address limitations studies suggest strategies drawing standard techniques for measurement, recent advancements microbial culture independent computational methodologies robustly develop concepts, which may be considerable value development prevention treatment strategies.

Язык: Английский

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Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity

Nature Metabolism, Год журнала: 2020, Номер 2(3), С. 233 - 242

Опубликована: Март 9, 2020

Язык: Английский

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Adipose tissue derived bacteria are associated with inflammation in obesity and type 2 diabetes

Gut, Год журнала: 2020, Номер 69(10), С. 1796 - 1806

Опубликована: Апрель 21, 2020

Objective Bacterial translocation to various organs including human adipose tissue (AT) due increased intestinal permeability remains poorly understood. We hypothesised that: (1) bacterial presence is highly specific and (2) related in composition quantity immune inflammatory metabolic burden. Design quantified sequenced the 16S rRNA gene blood AT samples (omental, mesenteric subcutaneous) of 75 subjects with obesity or without type 2 diabetes (T2D) used catalysed reporter deposition (CARD) – fluorescence situ hybridisation (FISH) detect bacteria AT. Results Under stringent experimental bioinformatic control for contaminants, DNA was detected omental, subcutaneous range 0.1 5 pg/µg isolate. Moreover, CARD-FISH allowed detection living, AT-borne bacteria. Proteobacteria Firmicutes were predominant phyla, associated cell infiltration, parameters a tissue-specific manner. differed between T2D clinical measures, systemic tissues-specific markers. Finally, treatment adipocytes vitro stimulated expression TNFA IL6 . Conclusions Our study provides contaminant aware evidence several ATs suggests an important role initiating sustaining local subclinical inflammation therefore impacting sequelae obesity.

Язык: Английский

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