RESUMO
The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identified Fusobacterium nucleatum and Anaerostipes hadrus with the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts.
Assuntos
Microbioma Gastrointestinal , Metagenoma , Metagenômica , Humanos , Microbioma Gastrointestinal/genética , Metagenômica/métodos , Aprendizado de Máquina , Fusobacterium nucleatum/genética , Bactérias/classificação , Bactérias/genéticaRESUMO
During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.
Assuntos
Aterosclerose , Microbioma Gastrointestinal , Microbiota , Clostridiales , Humanos , MetabolomaRESUMO
Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.
Assuntos
Disbiose/epidemiologia , Disbiose/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Bacteroides/isolamento & purificação , Estudos de Coortes , Estudos Transversais , Faecalibacterium/isolamento & purificação , Fezes/microbiologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Inflamatórias Intestinais/microbiologia , Masculino , Obesidade/microbiologia , PrevalênciaRESUMO
OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Obesidade Mórbida , Complexo Vitamínico B , Humanos , Camundongos , Animais , Prebióticos , Obesidade Mórbida/cirurgia , Biotina/farmacologia , Complexo Vitamínico B/farmacologia , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , InflamaçãoRESUMO
BACKGROUND & AIMS: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. METHODS: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days. PRIMARY OUTCOME: 50% reduction in neutrophil oxidative burst (OB) at 30 days. SECONDARY OUTCOMES: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis. RESULTS: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α- and interleukin-17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96). CONCLUSION: Rifaximin-α led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-α plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02019784. LAY SUMMARY: In this clinical trial, we examined the underlying mechanism of action of an antibiotic called rifaximin-α which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). We show that rifaximin-α suppresses gut bacteria that translocate from the mouth to the intestine and cause the intestinal wall to become leaky by breaking down the protective mucus barrier. This suppression resolves encephalopathy and reduces inflammation in the blood, preventing the development of infection.
Assuntos
Encefalopatia Hepática/tratamento farmacológico , Inflamação/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Mucinas/metabolismo , Rifaximina/farmacologia , Adulto , Idoso , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/metabolismo , Fármacos Gastrointestinais/farmacologia , Fármacos Gastrointestinais/uso terapêutico , Encefalopatia Hepática/fisiopatologia , Humanos , Inflamação/epidemiologia , Inflamação/prevenção & controle , Cirrose Hepática/epidemiologia , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mucinas/efeitos dos fármacos , Ontário/epidemiologia , Placebos , Rifaximina/metabolismo , Rifaximina/uso terapêuticoRESUMO
BACKGROUND AND AIMS: Cirrhosis is associated with changes in gut microbiome composition. Although acute-on-chronic liver failure (ACLF) is the most severe clinical stage of cirrhosis, there is lack of information about gut microbiome alterations in ACLF using quantitative metagenomics. We investigated the gut microbiome in patients with cirrhosis encompassing the whole spectrum of disease (compensated, acutely decompensated without ACLF, and ACLF). A group of healthy subjects was used as control subjects. METHODS: Stool samples were collected prospectively in 182 patients with cirrhosis. DNA library construction and sequencing were performed using the Ion Proton Sequencer (ThermoFisher Scientific, Waltham, MA). Microbial genes were grouped into clusters, denoted as metagenomic species. RESULTS: Cirrhosis was associated with a remarkable reduction in gene and metagenomic species richness compared with healthy subjects. This loss of richness correlated with disease stages and was particularly marked in patients with ACLF and persisted after adjustment for antibiotic therapy. ACLF was associated with a significant increase of Enterococcus and Peptostreptococcus sp and a reduction of some autochthonous bacteria. Gut microbiome alterations correlated with model for end-stage liver disease and Child-Pugh scores and organ failure and was associated with some complications, particularly hepatic encephalopathy and infections. Interestingly, gut microbiome predicted 3-month survival with good stable predictors. Functional analysis showed that patients with cirrhosis had enriched pathways related to ethanol production, γ-aminobutyric acid metabolism, and endotoxin biosynthesis, among others. CONCLUSIONS: Cirrhosis is characterized by marked alterations in gut microbiome that parallel disease stages with maximal changes in ACLF. Altered gut microbiome was associated with complications of cirrhosis and survival. Gut microbiome may contribute to disease progression and poor prognosis. These results should be confirmed in future studies.
Assuntos
Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/patologia , Microbioma Gastrointestinal/fisiologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Insuficiência Hepática Crônica Agudizada/mortalidade , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Cirrose Hepática/mortalidade , Masculino , Metagenômica , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Diosmectite, a natural colloidal clay, has been used worldwide for a number of approved indications, including the treatment of chronic functional diarrhea. Here, we used high-resolution whole metagenome shotgun sequencing to assess the impact of a 5 weeks administration of diosmectite (3 g/sachet, 3 sachets/day) on the fecal microbiota of 35 adults with functional chronic diarrhea. RESULTS: Gut microbiota was not impacted by diosmectite administration. In particular, richness remained stable and no microbial species displayed a significant evolution. Segregating patients either by diosmectite response (non responder, early responder, late responder) or by nationality (Great-Britain or Netherlands) yielded the same results. CONCLUSION: We concluded that no microbiota-related physiological alterations are expected upon long-term treatment with diosmectite. TRIAL REGISTRATION: Clinicaltrials.gov NCT03045926.
Assuntos
Diarreia/tratamento farmacológico , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Metagenoma , Silicatos/uso terapêutico , Adolescente , Adulto , Bactérias/classificação , Bactérias/genética , Doença Crônica/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.
Assuntos
Microbioma Gastrointestinal/fisiologia , Resistência à Insulina , Metaboloma , Soro/metabolismo , Aminoácidos de Cadeia Ramificada/biossíntese , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Bacteroides/fisiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/microbiologia , Jejum/sangue , Jejum/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/microbiologia , Humanos , Masculino , Metagenoma , Camundongos , Camundongos Endogâmicos C57BL , Países Baixos , Prevotella/fisiologiaRESUMO
OBJECTIVE: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health. DESIGN: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes. RESULTS: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion. CONCLUSION: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.
Assuntos
Biomarcadores/metabolismo , Microbioma Gastrointestinal , Hipuratos/metabolismo , Animais , Biodiversidade , Dinamarca , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metaboloma , Metagenômica , Camundongos , Pessoa de Meia-Idade , FenótipoRESUMO
In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.
Assuntos
Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Metformina/farmacologia , Biodiversidade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Microbioma Gastrointestinal/genética , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Metagenoma/efeitos dos fármacos , Metagenoma/fisiologia , Metformina/uso terapêutico , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND/OBJECTIVES: Based on the recent identification of E.coli heat shock protein ClpB as a mimetic of the anorexigenic α-melanocyte stimulating hormone (α-MSH), the objective of this study was to preclinically validate Hafnia alvei, a ClpB-producing commensal bacterium as a potential probiotic for appetite and body weight management in overweight and obesity. METHODS: The involvement of enterobacterial ClpB in the putative anti-obesity effects was studied using ClpB-deficient E.coli. A food-grade H. alvei HA4597 strain synthetizing the ClpB protein with an α-MSH-like motif was selected as a candidate probiotic to be tested in ob/ob and high-fat diet (HFD)-fed obese and overweight mice. The relevance of the enterobacterial ClpB gene to human obesity was studied by in silico analysis of fecal metagenomes of 569 healthy individuals from the "MetaHIT" database. RESULTS: Chronic per os administration of native but not ClpB-deficient E.coli strain reduced body weight gain (p < 0.05) and daily meal frequency (p < 0.001) in ob/ob mice. Oral gavage of H.alvei for 18 and 46 days in ob/ob and HFD-fed obese mice, respectively, was well tolerated, reduced body weight gain and fat mass in both obesity models (p < 0.05) and decreased food intake in hyperphagic ob/ob mice (p < 0.001). Elevated fat tissue levels of phosphorylated hormone-sensitive lipase were detected in H.alvei -treated ob/ob mice (p < 0.01). Enterobacterial ClpB gene richness was lower in obese vs. non-obese humans (p < 0.0001) and correlated negatively with BMI in genera of Enterobacter, Klebsiella and Hafnia. CONCLUSIONS: H.alvei HA4597 strain reduces food intake, body weight and fat mass gain in hyperphagic and obese mice. These data combined with low enterobacterial ClpB gene abundance in the microbiota of obese humans provide the rationale for using H.alvei as a probiotic for appetite and body weight management in overweight and obesity.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hafnia alvei , Probióticos/farmacologia , Animais , Apetite/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos ObesosRESUMO
MOTIVATION: Analysis toolkits for shotgun metagenomic data achieve strain-level characterization of complex microbial communities by capturing intra-species gene content variation. Yet, these tools are hampered by the extent of reference genomes that are far from covering all microbial variability, as many species are still not sequenced or have only few strains available. Binning co-abundant genes obtained from de novo assembly is a powerful reference-free technique to discover and reconstitute gene repertoire of microbial species. While current methods accurately identify species core parts, they miss many accessory genes or split them into small gene groups that remain unassociated to core clusters. RESULTS: We introduce MSPminer, a computationally efficient software tool that reconstitutes Metagenomic Species Pan-genomes (MSPs) by binning co-abundant genes across metagenomic samples. MSPminer relies on a new robust measure of proportionality coupled with an empirical classifier to group and distinguish not only species core genes but accessory genes also. Applied to a large scale metagenomic dataset, MSPminer successfully delineates in a few hours the gene repertoires of 1661 microbial species with similar specificity and higher sensitivity than existing tools. The taxonomic annotation of MSPs reveals microorganisms hitherto unknown and brings coherence in the nomenclature of the species of the human gut microbiota. The provided MSPs can be readily used for taxonomic profiling and biomarkers discovery in human gut metagenomic samples. In addition, MSPminer can be applied on gene count tables from other ecosystems to perform similar analyses. AVAILABILITY AND IMPLEMENTATION: The binary is freely available for non-commercial users at www.enterome.com/downloads. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Metagenômica , Microbiota , Genoma Bacteriano , Genoma Microbiano , Humanos , Metagenoma , SoftwareRESUMO
Liver cirrhosis occurs as a consequence of many chronic liver diseases that are prevalent worldwide. Here we characterize the gut microbiome in liver cirrhosis by comparing 98 patients and 83 healthy control individuals. We build a reference gene set for the cohort containing 2.69 million genes, 36.1% of which are novel. Quantitative metagenomics reveals 75,245 genes that differ in abundance between the patients and healthy individuals (false discovery rate < 0.0001) and can be grouped into 66 clusters representing cognate bacterial species; 28 are enriched in patients and 38 in control individuals. Most (54%) of the patient-enriched, taxonomically assigned species are of buccal origin, suggesting an invasion of the gut from the mouth in liver cirrhosis. Biomarkers specific to liver cirrhosis at gene and function levels are revealed by a comparison with those for type 2 diabetes and inflammatory bowel disease. On the basis of only 15 biomarkers, a highly accurate patient discrimination index is created and validated on an independent cohort. Thus microbiota-targeted biomarkers may be a powerful tool for diagnosis of different diseases.
Assuntos
Trato Gastrointestinal/microbiologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/microbiologia , Metagenômica , Microbiota/genética , Microbiota/fisiologia , Estudos de Casos e Controles , Doença Crônica , Diabetes Mellitus Tipo 2/microbiologia , Fezes/microbiologia , Marcadores Genéticos/genética , Saúde , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Boca/microbiologia , Filogenia , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: Decreased gut microbial gene richness (MGR) and compositional changes are associated with adverse metabolism in overweight or moderate obesity, but lack characterisation in severe obesity. Bariatric surgery (BS) improves metabolism and inflammation in severe obesity and is associated with gut microbiota modifications. Here, we characterised severe obesity-associated dysbiosis (ie, MGR, microbiota composition and functional characteristics) and assessed whether BS would rescue these changes. DESIGN: Sixty-one severely obese subjects, candidates for adjustable gastric banding (AGB, n=20) or Roux-en-Y-gastric bypass (RYGB, n=41), were enrolled. Twenty-four subjects were followed at 1, 3 and 12 months post-BS. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography mass spectrometry (LC-MS). Confirmation groups were included. RESULTS: Low gene richness (LGC) was present in 75% of patients and correlated with increased trunk-fat mass and comorbidities (type 2 diabetes, hypertension and severity). Seventy-eight metagenomic species were altered with LGC, among which 50% were associated with adverse body composition and metabolic phenotypes. Nine serum metabolites (including glutarate, 3-methoxyphenylacetic acid and L-histidine) and functional modules containing protein families involved in their metabolism were strongly associated with low MGR. BS increased MGR 1 year postsurgery, but most RYGB patients remained with low MGR 1 year post-BS, despite greater metabolic improvement than AGB patients. CONCLUSIONS: We identified major gut microbiota alterations in severe obesity, which include decreased MGR and related functional pathways linked with metabolic deteriorations. The lack of full rescue post-BS calls for additional strategies to improve the gut microbiota ecosystem and microbiome-host interactions in severe obesity. TRIAL REGISTRATION NUMBER: NCT01454232.
Assuntos
Cirurgia Bariátrica , Disbiose/etiologia , Microbioma Gastrointestinal , Obesidade Mórbida/microbiologia , Obesidade Mórbida/cirurgia , Adulto , Biomarcadores/sangue , Cromatografia Líquida , Comorbidade , Feminino , Humanos , Masculino , Espectrometria de Massas , Metagenômica , Fenótipo , Estudos Prospectivos , Fatores de RiscoRESUMO
The gut bacterial species Akkermansia muciniphila is associated with a healthier clinical profile. The purpose of this study was to determine the association between A. muciniphila and glucose homeostasis in patients undergoing bariatric surgery (BS): gastric banding (GB) or Roux-en-Y gastric bypass (RYGB). This nonrandomized prospective study included 65 women with severe obesity. Longitudinal analysis included subjects for whom A. muciniphila data were available at follow-up [1, 3, and 12 mo; GB (n = 10) or RYGB (n = 11)]. Glucose homeostasis markers were measured under fasting conditions (glucose, insulin, and HbA1c) or during an oral glucose tolerance test. Fecal microbiota was analyzed using shotgun metagenomics, and A. muciniphila relative abundance was assessed with 16S rRNA quantitative PCR. A. muciniphila relative abundance was significantly lower in severe obesity [mean body mass index, 45.7 kg/m2 (SD 5.4)] than in moderate obesity [33.2 kg/m2 (SD 3.8)] but not associated with glucose homeostasis markers. A significant increase in A. muciniphila relative abundance after RYGB was not correlated with metabolic improvement. Baseline A. muciniphila abundance was correlated with bacterial gene richness and was highest in the high-richness Ruminococcaceae enterotype. A. muciniphila increased in relative abundance after BS in patients with low baseline A. muciniphila abundance, especially those with a Bacteroides type 2 enterotype classification. Although decreased in severe obesity, relative abundance of A. muciniphila was not associated with glucose homeostasis before or after BS. A certain level of A. muciniphila abundance might be required to observe a beneficial link to health. The severity of obesity and gut dysbiosis may partly explain the discrepancy with previous findings in less obese populations.
Assuntos
Cirurgia Bariátrica , Microbioma Gastrointestinal , Obesidade Mórbida/microbiologia , Obesidade Mórbida/cirurgia , Verrucomicrobia , Adulto , Akkermansia , Disbiose , Fezes/microbiologia , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Nível de Saúde , Homeostase , Humanos , Resistência à Insulina , Estudos Longitudinais , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Complex gene-environment interactions are considered important in the development of obesity. The composition of the gut microbiota can determine the efficacy of energy harvest from food and changes in dietary composition have been associated with changes in the composition of gut microbial populations. The capacity to explore microbiota composition was markedly improved by the development of metagenomic approaches, which have already allowed production of the first human gut microbial gene catalogue and stratifying individuals by their gut genomic profile into different enterotypes, but the analyses were carried out mainly in non-intervention settings. To investigate the temporal relationships between food intake, gut microbiota and metabolic and inflammatory phenotypes, we conducted diet-induced weight-loss and weight-stabilization interventions in a study sample of 38 obese and 11 overweight individuals. Here we report that individuals with reduced microbial gene richness (40%) present more pronounced dys-metabolism and low-grade inflammation, as observed concomitantly in the accompanying paper. Dietary intervention improves low gene richness and clinical phenotypes, but seems to be less efficient for inflammation variables in individuals with lower gene richness. Low gene richness may therefore have predictive potential for the efficacy of intervention.
Assuntos
Dieta , Trato Gastrointestinal/microbiologia , Metagenoma/genética , Metabolismo Basal , Peso Corporal/efeitos dos fármacos , Dieta com Restrição de Carboidratos , Fibras na Dieta/farmacologia , Fibras na Dieta/uso terapêutico , Proteínas Alimentares/farmacologia , Ingestão de Alimentos , Ingestão de Energia , Feminino , Frutas , Trato Gastrointestinal/efeitos dos fármacos , Interação Gene-Ambiente , Genes Bacterianos/genética , Humanos , Inflamação/microbiologia , Masculino , Metagenoma/efeitos dos fármacos , Obesidade/dietoterapia , Obesidade/microbiologia , Sobrepeso/dietoterapia , Sobrepeso/microbiologia , Verduras , Redução de Peso/efeitos dos fármacosRESUMO
We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.
Assuntos
Bactérias/isolamento & purificação , Biomarcadores/metabolismo , Trato Gastrointestinal/microbiologia , Metagenoma , Adiposidade , Adulto , Bactérias/classificação , Bactérias/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Dieta , Dislipidemias/microbiologia , Metabolismo Energético , Europa (Continente)/etnologia , Feminino , Genes Bacterianos , Humanos , Inflamação/microbiologia , Resistência à Insulina , Masculino , Metagenoma/genética , Obesidade/metabolismo , Obesidade/microbiologia , Sobrepeso/metabolismo , Sobrepeso/microbiologia , Filogenia , Magreza/microbiologia , Aumento de Peso , Redução de Peso , População BrancaRESUMO
Background: Antibiotics are life-saving drugs but severely affect the gut microbiome with short-term consequences including diarrhea and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers. Methods: We performed a randomized controlled trial in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in 2 parallel groups, with or without DAV132 coadministration. Two control goups of 8 volunteers each receiving DAV132 alone, or a nonactive substitute, were added. Results: The coadministration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex vivo. Conclusions: DAV132 was highly effective to protect the gut microbiome of moxifloxacin-treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments. Clinical Trials Registration: NCT02176005.