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1.
JAMA Netw Open ; 4(7): e2118811, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34323983

RESUMO

Importance: Previous studies have indicated that gut microbiome may be associated with development of type 2 diabetes. However, these studies are limited by small sample size and insufficient for confounding. Furthermore, which specific taxa play a role in the development of type 2 diabetes remains unclear. Objective: To examine associations of gut microbiome composition with insulin resistance and type 2 diabetes in a large population-based setting controlling for various sociodemographic and lifestyle factors. Design, Setting, and Participants: This cross-sectional analysis included 2166 participants from 2 Dutch population-based prospective cohorts: the Rotterdam Study and the LifeLines-DEEP study. Exposures: The 16S ribosomal RNA method was used to measure microbiome composition in stool samples collected between January 1, 2012, and December 31, 2013. The α diversity (Shannon, richness, and Inverse Simpson indexes), ß diversity (Bray-Curtis dissimilarity matrix), and taxa (from domain to genus level) were identified to reflect gut microbiome composition. Main Outcomes and Measures: Associations among α diversity, ß diversity, and taxa with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and with type 2 diabetes were examined. Glucose and insulin were measured to calculate the HOMA-IR. Type 2 diabetes cases were identified based on glucose levels and medical records from January 2012 to December 2013. Analyses were adjusted for technical covariates, lifestyle, sociodemographic, and medical factors. Data analysis was performed from January 1, 2018, to December 31, 2020. Results: There were 2166 participants in this study: 1418 from the Rotterdam Study (mean [SD] age, 62.4 [5.9] years; 815 [57.5%] male) and 748 from the LifeLines-DEEP study (mean [SD] age, 44.7 [13.4] years; 431 [57.6%] male); from this total, 193 type 2 diabetes cases were identified. Lower microbiome Shannon index and richness were associated with higher HOMA-IR (eg, Shannon index, -0.06; 95% CI, -0.10 to -0.02), and patients with type 2 diabetes had a lower richness than participants without diabetes (odds ratio [OR], 0.93; 95% CI, 0.88-0.99). The ß diversity (Bray-Curtis dissimilarity matrix) was associated with insulin resistance (R2 = 0.004, P = .001 in the Rotterdam Study and R2 = 0.005, P = .002 in the LifeLines-DEEP study). A total of 12 groups of bacteria were associated with HOMA-IR or type 2 diabetes. Specifically, a higher abundance of Christensenellaceae (ß = -0.08; 95% CI, -0.12 to -0.03: P < .001), Christensenellaceae R7 group (ß = -0.07; 95% CI, -0.12 to -0.03; P < .001), Marvinbryantia (ß = -0.07; 95% CI, -0.11 to -0.03; P < .001), Ruminococcaceae UCG005 (ß = -0.09; 95% CI, -0.13 to -0.05; P < .001), Ruminococcaceae UCG008 (ß = -0.07; 95% CI, -0.11 to -0.03; P < .001), Ruminococcaceae UCG010 (ß = -0.08; 95% CI, -0.12 to -0.04; P < .001), or Ruminococcaceae NK4A214 group (ß = -0.09; 95% CI, -0.13 to -0.05; P < .001) was associated with lower HOMA-IR. A higher abundance of Clostridiaceae 1 (OR, 0.51; 95% CI, 0.41-0.65; P < .001), Peptostreptococcaceae (OR, 0.56; 95% CI, 0.45-0.70; P < .001), C sensu stricto 1 (OR, 0.51; 95% CI, 0.40-0.65; P < .001), Intestinibacter (OR, 0.60; 95% CI, 0.48-0.76; P < .001), or Romboutsia (OR, 0.55; 95% CI, 0.44-0.70; P < .001) was associated with less type 2 diabetes. These bacteria are all known to produce butyrate. Conclusions and Relevance: In this cross-sectional study, higher microbiome α diversity, along with more butyrate-producing gut bacteria, was associated with less type 2 diabetes and with lower insulin resistance among individuals without diabetes. These findings could help provide insight into the etiology, pathogenesis, and treatment of type 2 diabetes.

2.
J Pediatr Gastroenterol Nutr ; 73(4): 485-490, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34269330

RESUMO

BACKGROUND AND AIMS: Biliary atresia (BA) is a cholestatic, fibro-obliterative cholangiopathy of unknown etiology. BA is primarily treated by a surgical approach, that is, the Kasai portoenterostomy (KPE), to obtain clearance of jaundice (COJ). The gut microbiota (GM) composition has been associated with the course of several cholestatic liver diseases. It is largely unknown, however, whether GM composition associates with the outcome of KPE. We compared the GM composition of BA patients and controls and assessed if GM composition before KPE was related to COJ after KPE. METHODS: We compared feces of term-born BA patients before KPE and controls (patients undergoing inguinal hernia repair) by 16S rRNA sequencing. Composition and alpha diversity of the GM were compared between BA and controls before KPE and after KPE, between patients with COJ versus without COJ (total serum bilirubin < or ≥20 µmol/L <6 months post-KPE). RESULTS: Alpha diversity was comparable between BA (n = 12, age 1.6 [1.3-1.8] months) and controls (n = 6, age 2.0 [1.4-2.1] months; P = 0.22). Compared with controls, BA patients had lower abundances of Bifidobacteriaceae (ß = -1.98, P < 0.001) and Lachnospiraceae (ß = -1.84, P = 0.007), and higher abundances of Streptococcus (ß = -1.13, P = 0.003). The alpha diversity before KPE correlated negatively with COJ (R = -0.63, P = 0.03). Lower alpha diversity pre-KPE was associated with COJ [+] (ßlogit = -0.64, P = 0.04). We observed greater abundances of genus Acinetobacter (ß = 1.27, P = 0.03) and family Clostridiaceae (ß = 1.45, P = 0.03) and lower abundances of the family Enterobacteriaceae (genera Klebsiella (ß = -1.21, P = 0.01), Salmonella (ß = -1.57, P = 0.02)) in COJ [+] versus COJ [-]. CONCLUSIONS: The GM of BA patients before Kasai portoenterostomy associates with outcome, clearance of jaundice, suggestive of predictive, and mechanistic roles of the gut microbiota composition in bile homeostasis.


Assuntos
Atresia Biliar , Microbioma Gastrointestinal , Icterícia , Atresia Biliar/cirurgia , Pré-Escolar , Humanos , Lactente , Portoenterostomia Hepática , RNA Ribossômico 16S/genética
4.
Cell Rep ; 35(7): 109132, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34010651

RESUMO

The human gut microbiome consists of bacteria, archaea, eukaryotes, and viruses. The gut viruses are relatively underexplored. Here, we longitudinally analyzed the gut virome composition in 11 healthy adults: its stability, variation, and the effect of a gluten-free diet. Using viral enrichment and a de novo assembly-based approach, we demonstrate the quantitative dynamics of the gut virome, including dsDNA, ssDNA, dsRNA, and ssRNA viruses. We observe highly divergent individual viral communities, carrying on an average 2,143 viral genomes, 13.1% of which were present at all 3 time points. In contrast to previous reports, the Siphoviridae family dominates over Microviridae in studied individual viromes. We also show individual viromes to be stable at the family level but to vary substantially at the genera and species levels. Finally, we demonstrate that lower initial diversity of the human gut virome leads to a more pronounced effect of the dietary intervention on its composition.

5.
Cell ; 184(9): 2302-2315.e12, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33838112

RESUMO

By following up the gut microbiome, 51 human phenotypes and plasma levels of 1,183 metabolites in 338 individuals after 4 years, we characterize microbial stability and variation in relation to host physiology. Using these individual-specific and temporally stable microbial profiles, including bacterial SNPs and structural variations, we develop a microbial fingerprinting method that shows up to 85% accuracy in classifying metagenomic samples taken 4 years apart. Application of our fingerprinting method to the independent HMP cohort results in 95% accuracy for samples taken 1 year apart. We further observe temporal changes in the abundance of multiple bacterial species, metabolic pathways, and structural variation, as well as strain replacement. We report 190 longitudinal microbial associations with host phenotypes and 519 associations with plasma metabolites. These associations are enriched for cardiometabolic traits, vitamin B, and uremic toxins. Finally, mediation analysis suggests that the gut microbiome may influence cardiometabolic health through its metabolites.


Assuntos
Bactérias/genética , Proteínas de Bactérias/metabolismo , Microbioma Gastrointestinal , Metaboloma , Metagenoma , Microbiota , Adulto , Idoso , Idoso de 80 Anos ou mais , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/metabolismo , Proteínas de Bactérias/genética , Resistência Microbiana a Medicamentos , Fezes/microbiologia , Feminino , Instabilidade Genômica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Virulência/genética , Fatores de Virulência/metabolismo , Adulto Jovem
6.
Gut ; 70(7): 1287-1298, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33811041

RESUMO

OBJECTIVE: The microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. We aim to unravel interactions between diet, gut microbiota and their functional ability to induce intestinal inflammation. DESIGN: We investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn's disease, ulcerative colitis, irritable bowel syndrome and the general population. Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Associations between diet and microbial features were explored per cohort, followed by a meta-analysis and heterogeneity estimation. RESULTS: We identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn's disease and UC (false discovery rate<0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, Ruminococcus species of the Blautia genus and endotoxin synthesis pathways. The opposite was found for plant foods and fish, which were positively associated with short-chain fatty acid-producing commensals and pathways of nutrient metabolism. CONCLUSION: We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.

7.
Nat Genet ; 53(2): 156-165, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462485

RESUMO

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.


Assuntos
Microbioma Gastrointestinal/fisiologia , Variação Genética , Locos de Características Quantitativas , Adolescente , Adulto , Bifidobacterium/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Microbioma Gastrointestinal/genética , Estudo de Associação Genômica Ampla , Humanos , Lactase/genética , Desequilíbrio de Ligação , Masculino , Análise da Randomização Mendeliana , Metabolismo/genética , RNA Ribossômico 16S
8.
Gut ; 70(2): 285-296, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32651235

RESUMO

OBJECTIVE: Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD. DESIGN: To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF <5% and exome copy number variations (CNVs) with site frequency <1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics. RESULTS: We identified 12 mbQTLs, including variants in the IBD-associated genes IL17REL, MYRF, SEC16A and WDR78. For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene MYRF (false discovery rate <0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in CYP2D6, GPR151 and CD160 genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in TNFSF15. CONCLUSION: This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.


Assuntos
Microbioma Gastrointestinal/genética , Predisposição Genética para Doença/genética , Doenças Inflamatórias Intestinais/etiologia , Sequenciamento Completo do Exoma , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Estudos de Casos e Controles , Variações do Número de Cópias de DNA/genética , Feminino , Frequência do Gene/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/microbiologia , Masculino , Proteínas de Membrana/genética , Metagenômica , Pessoa de Meia-Idade , Locos de Características Quantitativas/genética , Receptores de Interleucina-17/genética , Fatores de Transcrição/genética , Proteínas de Transporte Vesicular/genética
9.
Rheumatology (Oxford) ; 60(8): 3727-3737, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-33331911

RESUMO

OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a characteristic symptom of fibromyalgia, which has been shown to be associated with an altered gut microbiome. Microbiome studies to date have not examined the milder CWP phenotype specifically nor have they explored the role of raised BMI. The aim of this study was to investigate whether the microbiome is abnormal in CWP. METHODS: CWP was assessed using a standardized screening questionnaire in female volunteers from the TwinsUK cohort including 113 CWP cases and 1623 controls. The stool microbiome was characterized using 16S rRNA amplicon sequencing and amplicon sequence variants, and associations with CWP examined using linear mixed-effects models adjusting for BMI, age, diet, family relatedness and technical factors. RESULTS: Alpha diversity was significantly lower in CWP cases than controls (Mann-Whitney test, P-values 2.3e-04 and 1.2e-02, for Shannon and Simpson indices respectively). The species Coprococcus comes was significantly depleted in CWP cases (Padj = 3.04e-03). A genome-wide association study (GWAS) performed for C. comes in TwinsUK followed by meta-analysis with three Dutch cohorts (total n = 3521) resulted in nine suggestive regions, with the most convincing on chromosome 4 near the TRAM1L1 gene (rs76957229, P = 7.4e-8). A Mendelian randomization study based on the results of the GWAS did not support a causal role for C. comes on the development of CWP. CONCLUSIONS: We have demonstrated reduced diversity in the microbiome in CWP, indicating an involvement of the gut microbiota in CWP; prospectively the microbiome may offer therapeutic opportunities for this condition.


Assuntos
Dor Crônica/epidemiologia , Disbiose/epidemiologia , Microbioma Gastrointestinal/genética , Idoso , Índice de Massa Corporal , Dor Crônica/genética , Dor Crônica/microbiologia , Clostridiales , Disbiose/genética , Disbiose/microbiologia , Feminino , Humanos , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/microbiologia , RNA Ribossômico 16S
10.
Cell Rep ; 33(1): 108212, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33027657

RESUMO

Bile acids (BAs) are implicated in the etiology of obesity-related conditions such as non-alcoholic fatty liver disease. Differently structured BA species display variable signaling activities via farnesoid X receptor (FXR) and Takeda G protein-coupled BA receptor 1 (TGR5). This study profiles plasma and fecal BAs and plasma 7α-hydroxy-4-cholesten-3-one (C4) in 297 persons with obesity, identifies underlying genetic and microbial determinants, and establishes BA correlations with liver fat and plasma lipid parameters. We identify 27 genetic associations (p < 5 × 10-8) and 439 microbial correlations (FDR < 0.05) for 50 BA entities. Additionally, we report 111 correlations between BA and 88 lipid parameters (FDR < 0.05), mainly for C4 reflecting hepatic BA synthesis. Inter-individual variability in the plasma BA profile does not reflect hepatic BA synthetic pathways, but rather transport and metabolism within the enterohepatic circulation. Our study reveals genetic and microbial determinants of BAs in obesity and their relationship to disease-relevant lipid parameters that are important for the design of personalized therapies targeting BA-signaling pathways.


Assuntos
Ácidos e Sais Biliares/fisiologia , Metabolismo dos Lipídeos/genética , Fígado/patologia , Síndrome Metabólica/fisiopatologia , Obesidade/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade
11.
Nat Commun ; 11(1): 4018, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782301

RESUMO

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Consórcios Microbianos , Obesidade/microbiologia , Adulto , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Bactérias/metabolismo , Estudos de Coortes , Disbiose/metabolismo , Disbiose/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Especificidade de Hospedeiro , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Obesidade/metabolismo
12.
Nutrients ; 12(5)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32423041

RESUMO

Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by the ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculated that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a two-sample Mendelian randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous genome-wide association study (GWAS) of gut microbiota and outcome data from summary statistics of CeD GWAS and Immunochip studies. We identified a number of putative associations between gut microbiota single nucleotide polymorphisms (SNPs) associated with CeD. Regarding bacterial composition, most of the associated SNPs were related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we linked a number of SNPs to several bacterial metabolic pathways that seemed to be related to CeD. Overall, this study represented the first 2SMR approach to elucidate the relationship between microbiome and CeD.


Assuntos
Doença Celíaca/genética , Doença Celíaca/microbiologia , Microbioma Gastrointestinal/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética
13.
Nat Commun ; 11(1): 362, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953381

RESUMO

The human gut microbiota has now been associated with drug responses and efficacy, while chemical compounds present in these drugs can also impact the gut bacteria. However, drug-microbe interactions are still understudied in the clinical context, where polypharmacy and comorbidities co-occur. Here, we report relations between commonly used drugs and the gut microbiome. We performed metagenomics sequencing of faecal samples from a population cohort and two gastrointestinal disease cohorts. Differences between users and non-users were analysed per cohort, followed by a meta-analysis. While 19 of 41 drugs are found to be associated with microbial features, when controlling for the use of multiple medications, proton-pump inhibitors, metformin, antibiotics and laxatives show the strongest associations with the microbiome. We here provide evidence for extensive changes in taxonomy, metabolic potential and resistome in relation to commonly used drugs. This paves the way for future studies and has implications for current microbiome studies by demonstrating the need to correct for multiple drug use.


Assuntos
Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Metagenômica , Adulto , Antibacterianos/farmacologia , Antidepressivos/farmacologia , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos de Coortes , Biologia Computacional , Ecossistema , Fezes/microbiologia , Feminino , Humanos , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/microbiologia , Laxantes/farmacologia , Masculino , Metformina/farmacologia , Interações Microbianas/efeitos dos fármacos , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/farmacologia
14.
Eur J Hum Genet ; 28(3): 313-323, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31591516

RESUMO

Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.


Assuntos
Doença Celíaca/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Argentina , Doença Celíaca/patologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 22/genética , Europa (Continente) , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas rac de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/metabolismo
15.
Nat Commun ; 10(1): 5813, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862950

RESUMO

Gut microbiota has been implicated in major diseases affecting the human population and has also been linked to triglycerides and high-density lipoprotein levels in the circulation. Recent development in metabolomics allows classifying the lipoprotein particles into more details. Here, we examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance technology in 2309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort. We assess the relationship between gut microbiota and metabolites by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. We report an association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, ketone bodies, amino acids, and acute-phase reaction markers. These observations provide insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.


Assuntos
Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Metaboloma/fisiologia , Proteínas de Fase Aguda/isolamento & purificação , Proteínas de Fase Aguda/metabolismo , Adulto , Aminoácidos/sangue , Aminoácidos/isolamento & purificação , Aminoácidos/metabolismo , Bactérias/genética , Bactérias/isolamento & purificação , Estudos de Coortes , DNA Bacteriano/isolamento & purificação , Fezes/microbiologia , Feminino , Glicólise/fisiologia , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/isolamento & purificação , Lipoproteínas HDL/metabolismo , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Países Baixos , Espectroscopia de Prótons por Ressonância Magnética , RNA Ribossômico 16S/genética , Análise de Regressão , Triglicerídeos/sangue , Triglicerídeos/isolamento & purificação , Triglicerídeos/metabolismo
16.
BMC Biol ; 17(1): 84, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660953

RESUMO

The human gut harbors a complex ecosystem of microorganisms, including bacteria and viruses. With the rise of next-generation sequencing technologies, we have seen a quantum leap in the study of human-gut-inhabiting bacteria, yet the viruses that infect these bacteria, known as bacteriophages, remain underexplored. In this review, we focus on what is known about the role of bacteriophages in human health and the technical challenges involved in studying the gut virome, of which they are a major component. Lastly, we discuss what can be learned from studies of bacteriophages in other ecosystems.


Assuntos
Bacteriófagos/fisiologia , Microbioma Gastrointestinal/fisiologia , Metagenoma , Humanos , Metagenômica
17.
Nat Commun ; 10(1): 4881, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653850

RESUMO

Macrophage-mediated inflammation is thought to have a causal role in osteoarthritis-related pain and severity, and has been suggested to be triggered by endotoxins produced by the gastrointestinal microbiome. Here we investigate the relationship between joint pain and the gastrointestinal microbiome composition, and osteoarthritis-related knee pain in the Rotterdam Study; a large population based cohort study. We show that abundance of Streptococcus species is associated with increased knee pain, which we validate by absolute quantification of Streptococcus species. In addition, we replicate these results in 867 Caucasian adults of the Lifelines-DEEP study. Finally we show evidence that this association is driven by local inflammation in the knee joint. Our results indicate the microbiome is a possible therapeutic target for osteoarthritis-related knee pain.


Assuntos
Artralgia/microbiologia , Microbioma Gastrointestinal/genética , Osteoartrite do Joelho/microbiologia , Actinobacteria , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Artralgia/imunologia , Artrite/imunologia , Artrite/microbiologia , Bacteroidetes , Estudos de Coortes , Feminino , Firmicutes , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Masculino , Pessoa de Meia-Idade , Obesidade , Osteoartrite do Joelho/imunologia , Proteobactérias , Inibidores da Bomba de Prótons/uso terapêutico , RNA Ribossômico 16S/genética , Streptococcus
18.
Nat Microbiol ; 4(10): 1727-1736, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31285584

RESUMO

Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome.


Assuntos
Bacteriófagos/genética , Coevolução Biológica , Microbioma Gastrointestinal , Animais , Bacteriófagos/classificação , Bacteroidetes/classificação , Bacteroidetes/genética , Bacteroidetes/virologia , DNA Viral/genética , Fezes/virologia , Feminino , Variação Genética , Humanos , Masculino , Filogenia , Filogeografia , Primatas/virologia
19.
Circ Res ; 124(12): 1808-1820, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-30971183

RESUMO

RATIONALE: Altered gut microbial composition has been linked to cardiovascular diseases (CVDs), but its functional links to host metabolism and immunity in relation to CVD development remain unclear. OBJECTIVES: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes, and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts. METHODS AND RESULTS: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based LLD (Lifelines DEEP) cohort (n=978) and a clinical obesity cohort (n=297). After correcting for age, sex, and body mass index, the gut microbiome could explain ≤11.1% and 16.4% of the variation in plasma metabolites in the population-based and obesity cohorts, respectively. Obese-specific microbial associations were found for lipid compositions in the VLDL, IDL, and LDL lipoprotein subclasses. Bacterial L-methionine biosynthesis and a Ruminococcus species were associated to cardiovascular phenotypes in obese individuals, namely atherosclerosis and liver fat content, respectively. Integration of microbiome-diet-inflammation analysis in relation to metabolic risk score of CVD in the population cohort revealed 48 microbial pathways associated to CVD risk that were largely independent of diet and inflammation. Our data also showed that plasma levels rather than fecal levels of short-chain fatty acids were relevant to inflammation and CVD risk. CONCLUSIONS: This study presents the largest metagenome-based association study on plasma metabolism and microbiome relevance to diet, inflammation, CVD risk, and cardiometabolic phenotypes in both population-based and clinical obesity cohorts. Our findings identified novel bacterial species and pathways that associated to specific lipoprotein subclasses and revealed functional links between the gut microbiome and host health that provide a basis for developing microbiome-targeted therapy for disease prevention and treatment.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Microbioma Gastrointestinal/fisiologia , Metaboloma/fisiologia , Obesidade/epidemiologia , Obesidade/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Obesidade/genética , Fenótipo , Estudos Prospectivos , Fatores de Risco
20.
Nature ; 568(7750): 43-48, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30918406

RESUMO

Differences in the presence of even a few genes between otherwise identical bacterial strains may result in critical phenotypic differences. Here we systematically identify microbial genomic structural variants (SVs) and find them to be prevalent in the human gut microbiome across phyla and to replicate in different cohorts. SVs are enriched for CRISPR-associated and antibiotic-producing functions and depleted from housekeeping genes, suggesting that they have a role in microbial adaptation. We find multiple associations between SVs and host disease risk factors, many of which replicate in an independent cohort. Exploring genes that are clustered in the same SV, we uncover several possible mechanistic links between the microbiome and its host, including a region in Anaerostipes hadrus that encodes a composite inositol catabolism-butyrate biosynthesis pathway, the presence of which is associated with lower host metabolic disease risk. Overall, our results uncover a nascent layer of variability in the microbiome that is associated with microbial adaptation and host health.


Assuntos
Bactérias/genética , Suscetibilidade a Doenças/microbiologia , Microbioma Gastrointestinal/genética , Genes Bacterianos/genética , Variação Genética , Saúde , Interações entre Hospedeiro e Microrganismos/genética , Adaptação Fisiológica/genética , Bactérias/classificação , Bactérias/crescimento & desenvolvimento , Bactérias/metabolismo , Butiratos/metabolismo , Estudos de Coortes , Ecossistema , Eubacterium/genética , Eubacterium/metabolismo , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Inositol/metabolismo , Metagenômica , Viabilidade Microbiana/genética , Fatores de Risco
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