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1.
Cell ; 187(8): 1834-1852.e19, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38569543

RESUMO

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.


Assuntos
Bactérias , Doenças Cardiovasculares , Colesterol , Microbioma Gastrointestinal , Humanos , Bactérias/metabolismo , Doenças Cardiovasculares/metabolismo , Colesterol/análise , Colesterol/sangue , Colesterol/metabolismo , Fezes/química , Estudos Longitudinais , Metaboloma , Metabolômica , RNA Ribossômico 16S/metabolismo
2.
Cell ; 185(26): 4921-4936.e15, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36563663

RESUMO

The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular-but not extensively hydrolyzed-formula were distinct from those of exclusively breastfed infants. Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life.


Assuntos
Microbioma Gastrointestinal , Microbiota , Feminino , Humanos , Lactente , Gravidez , Microbioma Gastrointestinal/genética , Microbiota/genética , Mães , Aleitamento Materno , Fezes , Sequências Repetitivas Dispersas
3.
Cell ; 185(23): 4280-4297.e12, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36323316

RESUMO

The gut microbiome has an important role in infant health and development. We characterized the fecal microbiome and metabolome of 222 young children in Dhaka, Bangladesh during the first two years of life. A distinct Bifidobacterium longum clade expanded with introduction of solid foods and harbored enzymes for utilizing both breast milk and solid food substrates. The clade was highly prevalent in Bangladesh, present globally (at lower prevalence), and correlated with many other gut taxa and metabolites, indicating an important role in gut ecology. We also found that the B. longum clades and associated metabolites were implicated in childhood diarrhea and early growth, including positive associations between growth measures and B. longum subsp. infantis, indolelactate and N-acetylglutamate. Our data demonstrate geographic, cultural, seasonal, and ecological heterogeneity that should be accounted for when identifying microbiome factors implicated in and potentially benefiting infant development.


Assuntos
Bifidobacterium longum , Lactente , Criança , Feminino , Humanos , Pré-Escolar , Bifidobacterium longum/metabolismo , Bifidobacterium/metabolismo , Desmame , Oligossacarídeos/metabolismo , Bangladesh , Leite Humano , Fezes/microbiologia
4.
Cell ; 184(16): 4168-4185.e21, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216539

RESUMO

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.


Assuntos
Autoimunidade/imunologia , Modelos Biológicos , Células Th17/imunologia , Acetiltransferases/metabolismo , Trifosfato de Adenosina/metabolismo , Aerobiose/efeitos dos fármacos , Algoritmos , Animais , Autoimunidade/efeitos dos fármacos , Cromatina/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Eflornitina/farmacologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Epigenoma , Ácidos Graxos/metabolismo , Glicólise/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Oxirredução/efeitos dos fármacos , Putrescina/metabolismo , Análise de Célula Única , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Transcriptoma/genética
5.
Cell ; 179(7): 1483-1498.e22, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31813625

RESUMO

Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Astrócitos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Fosfolipases A2 Secretórias/metabolismo , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Hexoquinase/metabolismo , Humanos , Ácido Láctico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosfolipases A2 Secretórias/genética
6.
Nature ; 626(7998): 419-426, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38052229

RESUMO

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.


Assuntos
Amidas , Ácidos e Sais Biliares , Ésteres , Ácidos Graxos , Metabolômica , Animais , Humanos , Bifidobacterium/metabolismo , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Clostridium/metabolismo , Estudos de Coortes , Doença de Crohn/metabolismo , Enterococcus/metabolismo , Ésteres/química , Ésteres/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Metabolômica/métodos , Fenótipo , Receptor de Pregnano X/metabolismo , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Amidas/química , Amidas/metabolismo
7.
Nature ; 603(7903): 907-912, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35296854

RESUMO

The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. Although it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory bile acids are associated with inflammatory pathologies in humans. Here we identify human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key TH17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase genes that are required for their biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of TH17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit TH17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.


Assuntos
Bactérias , Ácidos e Sais Biliares , Doenças Inflamatórias Intestinais , Bactérias/metabolismo , Diferenciação Celular , Trato Gastrointestinal/microbiologia , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Interleucina-17 , Ácido Litocólico/metabolismo , Ácido Litocólico/farmacologia , Células Th17
8.
Nature ; 579(7797): 123-129, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32103176

RESUMO

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.


Assuntos
Ácidos e Sais Biliares/biossíntese , Ácidos e Sais Biliares/química , Metabolômica , Microbiota/fisiologia , Animais , Ácidos e Sais Biliares/metabolismo , Ácido Cólico/biossíntese , Ácido Cólico/química , Ácido Cólico/metabolismo , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/microbiologia , Vida Livre de Germes , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Camundongos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo
9.
Mol Syst Biol ; 20(4): 338-361, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38467837

RESUMO

Microbial biochemistry is central to the pathophysiology of inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological properties of ~82k metabolic features in 546 Integrative Human Microbiome Project (iHMP/HMP2) metabolomes, using a newly developed methodology for bioactive compound prioritization from microbial communities. This suggested >1000 metabolic features as potentially bioactive in IBD and associated ~43% of prevalent, unannotated features with at least one well-characterized metabolite, thereby providing initial information for further characterization of a significant portion of the fecal metabolome. Prioritized features included known IBD-linked chemical families such as bile acids and short-chain fatty acids, and less-explored bilirubin, polyamine, and vitamin derivatives, and other microbial products. One of these, nicotinamide riboside, reduced colitis scores in DSS-treated mice. The method, MACARRoN, is generalizable with the potential to improve microbial community characterization and provide therapeutic candidates.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Metaboloma , Ácidos e Sais Biliares
10.
Nature ; 569(7758): 655-662, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31142855

RESUMO

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.


Assuntos
Microbioma Gastrointestinal/genética , Doenças Inflamatórias Intestinais/microbiologia , Animais , Fungos/patogenicidade , Microbioma Gastrointestinal/imunologia , Saúde , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/virologia , Filogenia , Especificidade da Espécie , Transcriptoma , Vírus/patogenicidade
11.
Proc Natl Acad Sci U S A ; 119(45): e2214900119, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36279426

RESUMO

Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17 cells. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against Citrobacter rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that ILC3-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as exacerbates autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.


Assuntos
Colite , Infecções por Enterobacteriaceae , Camundongos , Animais , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Interleucina-17 , Ornitina Descarboxilase/genética , Imunidade Inata , Putrescina , Colite/genética , Infecções por Enterobacteriaceae/genética , Células Th17/metabolismo , Ornitina , Antibacterianos , Interleucina 22
12.
Eur J Epidemiol ; 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38703248

RESUMO

There is growing interest in incorporating metabolomics into public health practice. However, Black women are under-represented in many metabolomics studies. If metabolomic profiles differ between Black and White women, this under-representation may exacerbate existing Black-White health disparities. We therefore aimed to estimate metabolomic differences between Black and White women in the U.S. We leveraged data from two prospective cohorts: the Nurses' Health Study (NHS; n = 2077) and Women's Health Initiative (WHI; n = 2128). The WHI served as the replication cohort. Plasma metabolites (n = 334) were measured via liquid chromatography-tandem mass spectrometry. Observed metabolomic differences were estimated using linear regression and metabolite set enrichment analyses. Residual metabolomic differences in a hypothetical population in which the distributions of 14 risk factors were equalized across racial groups were estimated using inverse odds ratio weighting. In the NHS, Black-White differences were observed for most metabolites (75 metabolites with observed differences ≥ |0.50| standard deviations). Black women had lower average levels than White women for most metabolites (e.g., for N6, N6-dimethlylysine, mean Black-White difference = - 0.98 standard deviations; 95% CI: - 1.11, - 0.84). In metabolite set enrichment analyses, Black women had lower levels of triglycerides, phosphatidylcholines, lysophosphatidylethanolamines, phosphatidylethanolamines, and organoheterocyclic compounds, but higher levels of phosphatidylethanolamine plasmalogens, phosphatidylcholine plasmalogens, cholesteryl esters, and carnitines. In a hypothetical population in which distributions of 14 risk factors were equalized, Black-White metabolomic differences persisted. Most results replicated in the WHI (88% of 272 metabolites available for replication). Substantial differences in metabolomic profiles exist between Black and White women. Future studies should prioritize racial representation.

13.
J Lipid Res ; 64(2): 100324, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36586437

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA-approved treatments, but FXR agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that high-fat diet-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Ácidos e Sais Biliares/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo
14.
Br J Cancer ; 127(6): 1076-1085, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35717425

RESUMO

BACKGROUND: Adiposity is consistently positively associated with postmenopausal breast cancer and inversely associated with premenopausal breast cancer risk, though the reasons for this difference remain unclear. METHODS: In this nested case-control study of 1649 breast cancer cases and 1649 matched controls from the Nurses' Health Study (NHS) and the NHSII, we selected lipid and polar metabolites correlated with BMI, waist circumference, weight change since age 18, or derived fat mass, and developed a metabolomic score for each measure using LASSO regression. Logistic regression was used to investigate the association between this score and breast cancer risk, adjusted for risk factors and stratified by menopausal status at blood draw and diagnosis. RESULTS: Metabolite scores developed among only premenopausal or postmenopausal women were highly correlated with scores developed in all women (r = 0.93-0.96). Higher metabolomic adiposity scores were generally inversely related to breast cancer risk among premenopausal women. Among postmenopausal women, significant positive trends with risk were observed (e.g., metabolomic waist circumference score OR Q4 vs. Q1 = 1.47, 95% CI = 1.03-2.08, P-trend = 0.01). CONCLUSIONS: Though the same metabolites represented adiposity in pre- and postmenopausal women, breast cancer risk associations differed suggesting that metabolic dysregulation may have a differential association with pre- vs. postmenopausal breast cancer.


Assuntos
Neoplasias da Mama , Enfermeiras e Enfermeiros , Adiposidade , Adolescente , Índice de Massa Corporal , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Obesidade/complicações , Pós-Menopausa , Pré-Menopausa , Fatores de Risco
15.
Nat Methods ; 13(9): 770-6, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27479327

RESUMO

Uncovering the molecular context of dysregulated metabolites is crucial to understand pathogenic pathways. However, their system-level analysis has been limited owing to challenges in global metabolite identification. Most metabolite features detected by untargeted metabolomics carried out by liquid-chromatography-mass spectrometry cannot be uniquely identified without additional, time-consuming experiments. We report a network-based approach, prize-collecting Steiner forest algorithm for integrative analysis of untargeted metabolomics (PIUMet), that infers molecular pathways and components via integrative analysis of metabolite features, without requiring their identification. We demonstrated PIUMet by analyzing changes in metabolism of sphingolipids, fatty acids and steroids in a Huntington's disease model. Additionally, PIUMet enabled us to elucidate putative identities of altered metabolite features in diseased cells, and infer experimentally undetected, disease-associated metabolites and dysregulated proteins. Finally, we established PIUMet's ability for integrative analysis of untargeted metabolomics data with proteomics data, demonstrating that this approach elicits disease-associated metabolites and proteins that cannot be inferred by individual analysis of these data.


Assuntos
Algoritmos , Doença de Huntington/metabolismo , Redes e Vias Metabólicas , Metabolômica/métodos , Redes Neurais de Computação , Bases de Dados de Proteínas , Ácidos Graxos/metabolismo , Humanos , Aprendizado de Máquina , Metabolômica/instrumentação , Esfingolipídeos/metabolismo , Esteroides/metabolismo
16.
Mol Psychiatry ; 23(12): 2287-2301, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29910467

RESUMO

Obesity and diabetes in humans are associated with increased rates of anxiety and depression. To understand the role of the gut microbiome and brain insulin resistance in these disorders, we evaluated behaviors and insulin action in brain of mice with diet-induced obesity (DIO) with and without antibiotic treatment. We find that DIO mice have behaviors reflective of increased anxiety and depression. This is associated with decreased insulin signaling and increased inflammation in in the nucleus accumbens and amygdala. Treatment with oral metronidazole or vancomycin decreases inflammation, improves insulin signaling in the brain and reduces signs of anxiety and depression. These effects are associated with changes in the levels of tryptophan, GABA, BDNF, amino acids, and multiple acylcarnitines, and are transferable to germ-free mice by fecal transplant. Thus, changes in gut microbiota can control brain insulin signaling and metabolite levels, and this leads to altered neurobehaviors.


Assuntos
Microbioma Gastrointestinal/fisiologia , Obesidade/metabolismo , Animais , Antibacterianos , Ansiedade , Encéfalo/metabolismo , Dieta Hiperlipídica , Microbioma Gastrointestinal/genética , Inflamação/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Metronidazol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microbiota , Obesidade/microbiologia , RNA Ribossômico 16S/efeitos dos fármacos , RNA Ribossômico 16S/genética , Vancomicina/farmacologia
17.
mBio ; 15(2): e0320823, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38236034

RESUMO

Mycobacterium tuberculosis (Mtb) can adopt a non-growing dormant state during infection that may be critical to both active and latent tuberculosis. During dormancy, Mtb is widely tolerant toward antibiotics, a significant obstacle in current anti-tubercular drug regimens, and retains the ability to persist in its environment. We aimed to identify novel mechanisms that permit Mtb to survive dormancy in an in vitro carbon starvation model using transposon insertion sequencing and gene expression analysis. We identified a previously uncharacterized component of the lipid transport machinery, omamC, which was upregulated and required for survival during carbon starvation. We show that OmamC plays a role both in increasing fatty acid stores during growth in rich media and enhancing fatty acid utilization during starvation. Besides its involvement in lipid metabolism, OmamC levels affected the expression of the anti-anti-sigma factor rv0516c and other genes to improve Mtb survival during carbon starvation and increase its tolerance toward rifampicin, a first-line drug effective against non-growing Mtb. Importantly, we show that Mtb can be eradicated during carbon starvation, in an OmamC-dependent manner, by inhibiting lipid metabolism with the lipase inhibitor tetrahydrolipstatin. This work casts new light into the survival processes of non-replicating, drug-tolerant Mtb by identifying new proteins involved in lipid metabolism required for the survival of dormant bacteria and exposing a potential vulnerability that could be exploited for antibiotic discovery.IMPORTANCETuberculosis is a global threat, with ~10 million yearly active cases. Many more people, however, live with "latent" infection, where Mycobacterium tuberculosis survives in a non-replicative form. When latent bacteria activate and regrow, they elicit immune responses and result in significant host damage. Replicating and non-growing bacilli can co-exist; however, non-growing bacteria are considerably less sensitive to antibiotics, thus complicating treatment by necessitating long treatment durations. Here, we sought to identify genes important for bacterial survival in this non-growing state using a carbon starvation model. We found that a previously uncharacterized gene, omamC, is involved in storing and utilizing fatty acids as bacteria transition between these two states. Importantly, inhibiting lipid metabolism using a lipase inhibitor eradicates non-growing bacteria. Thus, targeting lipid metabolism may be a viable strategy for treating the non-growing population in strategies to shorten treatment durations of tuberculosis.


Assuntos
Mycobacterium tuberculosis , Humanos , Mycobacterium tuberculosis/metabolismo , Ácidos Graxos/metabolismo , Antibacterianos/farmacologia , Carbono/metabolismo , Lipase/metabolismo
18.
bioRxiv ; 2024 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-38798570

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder and lacks disease-modifying therapies. We developed a Drosophila model for identifying novel glial-based therapeutic targets for PD. Human alpha-synuclein is expressed in neurons and individual genes are independently knocked down in glia. We performed a forward genetic screen, knocking down the entire Drosophila kinome in glia in alpha-synuclein expressing flies. Among the top hits were five genes (Ak1, Ak6, Adk1, Adk2, and awd) involved in adenosine metabolism. Knockdown of each gene improved locomotor dysfunction, rescued neurodegeneration, and increased brain adenosine levels. We determined that the mechanism of neuroprotection involves adenosine itself, as opposed to a downstream metabolite. We dove deeper into the mechanism for one gene, Ak1, finding rescue of dopaminergic neuron loss, alpha-synuclein aggregation, and bioenergetic dysfunction after glial Ak1 knockdown. We performed metabolomics in Drosophila and in human PD patients, allowing us to comprehensively characterize changes in purine metabolism and identify potential biomarkers of dysfunctional adenosine metabolism in people. These experiments support glial adenosine as a novel therapeutic target in PD.

19.
Cell Host Microbe ; 32(2): 209-226.e7, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38215740

RESUMO

Understanding the role of the microbiome in inflammatory diseases requires the identification of microbial effector molecules. We established an approach to link disease-associated microbes to microbial metabolites by integrating paired metagenomics, stool and plasma metabolomics, and culturomics. We identified host-microbial interactions correlated with disease activity, inflammation, and the clinical course of ulcerative colitis (UC) in the Predicting Response to Standardized Colitis Therapy (PROTECT) pediatric inception cohort. In severe disease, metabolite changes included increased dipeptides and tauro-conjugated bile acids (BAs) and decreased amino-acid-conjugated BAs in stool, whereas in plasma polyamines (N-acetylputrescine and N1-acetylspermidine) increased. Using patient samples and Veillonella parvula as a model, we uncovered nitrate- and lactate-dependent metabolic pathways, experimentally linking V. parvula expansion to immunomodulatory tryptophan metabolite production. Additionally, V. parvula metabolizes immunosuppressive thiopurine drugs through xdhA xanthine dehydrogenase, potentially impairing the therapeutic response. Our findings demonstrate that the microbiome contributes to disease-associated metabolite changes, underscoring the importance of these interactions in disease pathology and treatment.


Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , Humanos , Criança , Colite Ulcerativa/tratamento farmacológico , Interações entre Hospedeiro e Microrganismos , Microbioma Gastrointestinal/genética , Progressão da Doença , Genes Microbianos
20.
Cell Host Microbe ; 31(9): 1494-1506.e4, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37708852

RESUMO

Before initiation of antiretroviral therapy (ART), HIV-specific CD8+ T cells are dysfunctional and short lived. To better understand the relationship between the HIV reservoir in CD4+ T cells and the magnitude and differentiation status of HIV-specific CD8+ T cells, we investigated these cells from acute and chronic HIV-infected individuals after 2 years of ART. Although both the HIV reservoir and the CD8+ T cell responses declined significantly after 2 years of ART, sustained HIV-specific CD8+ T cell responses correlated with a greater reduction of integrated HIV provirus. However, the magnitude of CD8+ T cells specific for HIV Gag, Pol, Nef, and Vif proteins positively associated with the active reservoir size during ART, measured as cell-associated RNA. Importantly, high HIV DNA levels strongly associate with maintenance of short-lived HIV-specific CD8+ T cells, regardless of ART initiation time. Our data suggest that the active reservoir maintains HIV-specific CD8+ T cell magnitude but prevents their differentiation into functional cells.


Assuntos
Linfócitos T CD8-Positivos , Produtos do Gene vif , Humanos , Diferenciação Celular , Provírus , RNA
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