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1.
Mol Neurobiol ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34669146

RESUMO

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk human brain RNA sequencing studies have revealed sex differences in dysregulated molecular pathways related to energy production, neuronal function, and immune response; however, the sex differences in disease mechanisms are yet to be examined comprehensively on a single-cell level. We leveraged nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to perform a case versus control sex-stratified differential gene expression analysis and pathway network enrichment in a cell type-specific manner for each brain region. Our examination at the single-cell level revealed sex differences in AD prominently in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and networks to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology.

2.
Blood Cancer Discov ; 2(5): 434-449, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34514432

RESUMO

Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.

3.
EClinicalMedicine ; 40: 101099, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34490415

RESUMO

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding: Funded by Roche Sequencing Solutions, Inc.

6.
Cell ; 184(16): 4137-4153.e14, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34256014

RESUMO

Diet modulates the gut microbiome, which in turn can impact the immune system. Here, we determined how two microbiota-targeted dietary interventions, plant-based fiber and fermented foods, influence the human microbiome and immune system in healthy adults. Using a 17-week randomized, prospective study (n = 18/arm) combined with -omics measurements of microbiome and host, including extensive immune profiling, we found diet-specific effects. The high-fiber diet increased microbiome-encoded glycan-degrading carbohydrate active enzymes (CAZymes) despite stable microbial community diversity. Although cytokine response score (primary outcome) was unchanged, three distinct immunological trajectories in high-fiber consumers corresponded to baseline microbiota diversity. Alternatively, the high-fermented-food diet steadily increased microbiota diversity and decreased inflammatory markers. The data highlight how coupling dietary interventions to deep and longitudinal immune and microbiome profiling can provide individualized and population-wide insight. Fermented foods may be valuable in countering the decreased microbiome diversity and increased inflammation pervasive in industrialized society.

7.
Elife ; 102021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34009124

RESUMO

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA-sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.


Assuntos
Perfilação da Expressão Gênica , Heterogeneidade Genética , Ductos Pancreáticos/citologia , Análise de Célula Única , Transcriptoma , Animais , Linhagem Celular , Separação Celular , Dano ao DNA , Bases de Dados Genéticas , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Feminino , Geminina/genética , Geminina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Morfogênese , Osteopontina/genética , Osteopontina/metabolismo , Ductos Pancreáticos/metabolismo , Pancreatite Crônica/genética , Pancreatite Crônica/metabolismo , Pancreatite Crônica/patologia , Fenótipo , RNA-Seq
8.
bioRxiv ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33758859

RESUMO

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.

9.
Cell ; 184(3): 566-570, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33545032

RESUMO

Complex datasets provide opportunities for discoveries beyond their initial scope. Effective and rapid data sharing and management practices are crucial to realize this potential; however, they are harder to implement than post-publication access. Here, we introduce the concept of a "data sharing trust" to maximize the value of large datasets.


Assuntos
Comportamento Cooperativo , Disseminação de Informação , Modelos Teóricos , Confiança , Autoria , Humanos , Pesquisadores
10.
Nature ; 591(7848): 124-130, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33494096

RESUMO

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1-3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/fisiopatologia , Interferons/antagonistas & inibidores , Interferons/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Anticorpos Antivirais/sangue , Formação de Anticorpos , Sequência de Bases , COVID-19/sangue , COVID-19/virologia , Feminino , Humanos , Imunoglobulina G/imunologia , Interferons/metabolismo , Masculino , Neutrófilos/imunologia , Neutrófilos/patologia , Domínios Proteicos , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , Receptor de Interferon alfa e beta/metabolismo , Receptores de IgG/imunologia , Análise de Célula Única , Carga Viral/imunologia
11.
Bioinformatics ; 2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-33313640

RESUMO

SUMMARY: A visualization suite for major forms of bulk and single-cell RNAseq data in R. dittoSeq is color blindness-friendly by default, robustly documented to power ease-of-use, and allows highly customizable generation of both daily-use and publication-quality figures. AVAILABILITY AND IMPLEMENTATION: dittoSeq is an R package available through Bioconductor via an open source MIT license. SUPPLEMENTARY INFORMATION: Supplementary Code and figures are available at Bioinformatics online. Full vignettes are available through Bioconductor, https://bioconductor.org/packages/dittoSeq/, and github, github.com/dtm2451/dittoSeq/.

12.
Res Sq ; 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33140041

RESUMO

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

13.
bioRxiv ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33140050

RESUMO

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense. One Sentence Summary: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.

14.
J Clin Invest ; 130(11): 5800-5816, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33044226

RESUMO

Influenza is a significant cause of morbidity and mortality worldwide. Here we show changes in the abundance and activation states of more than 50 immune cell subsets in 35 individuals over 11 time points during human A/California/2009 (H1N1) virus challenge monitored using mass cytometry along with other clinical assessments. Peak change in monocyte, B cell, and T cell subset frequencies coincided with peak virus shedding, followed by marked activation of T and NK cells. Results led to the identification of CD38 as a critical regulator of plasmacytoid dendritic cell function in response to influenza virus. Machine learning using study-derived clinical parameters and single-cell data effectively classified and predicted susceptibility to infection. The coordinated immune cell dynamics defined in this study provide a framework for identifying novel correlates of protection in the evaluation of future influenza therapeutics.


Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Linfócitos T/imunologia , Feminino , Humanos , Masculino
15.
Am J Clin Nutr ; 111(6): 1127-1136, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186326

RESUMO

BACKGROUND: With the rising rates of obesity and associated metabolic disorders, there is a growing need for effective long-term weight-loss strategies, coupled with an understanding of how they interface with human physiology. Interest is growing in the potential role of gut microbes as they pertain to responses to different weight-loss diets; however, the ways that diet, the gut microbiota, and long-term weight loss influence one another is not well understood. OBJECTIVES: Our primary objective was to determine if baseline microbiota composition or diversity was associated with weight-loss success. A secondary objective was to track the longitudinal associations of changes to lower-carbohydrate or lower-fat diets and concomitant weight loss with the composition and diversity of the gut microbiota. METHODS: We used 16S ribosomal RNA gene amplicon sequencing to profile microbiota composition over a 12-mo period in 49 participants as part of a larger randomized dietary intervention study of participants consuming either a healthy low-carbohydrate or a healthy low-fat diet. RESULTS: While baseline microbiota composition was not predictive of weight loss, each diet resulted in substantial changes in the microbiota 3-mo after the start of the intervention; some of these changes were diet specific (14 taxonomic changes specific to the healthy low-carbohydrate diet, 12 taxonomic changes specific to the healthy low-fat diet) and others tracked with weight loss (7 taxonomic changes in both diets). After these initial shifts, the microbiota returned near its original baseline state for the remainder of the intervention, despite participants maintaining their diet and weight loss for the entire study. CONCLUSIONS: These results suggest a resilience to perturbation of the microbiota's starting profile. When considering the established contribution of obesity-associated microbiotas to weight gain in animal models, microbiota resilience may need to be overcome for long-term alterations to human physiology. This trial was registered at clinicaltrials.gov as NCT01826591.


Assuntos
Microbioma Gastrointestinal , Obesidade/dietoterapia , Adulto , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Dieta com Restrição de Carboidratos , Dieta com Restrição de Gorduras , Dieta Redutora , Fezes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/fisiopatologia , Perda de Peso , Adulto Jovem
16.
Nat Protoc ; 15(2): 398-420, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932774

RESUMO

High-dimensional single-cell technologies present new opportunities for biological discovery, but the complex nature of the resulting datasets makes it challenging to perform comprehensive analysis. One particular challenge is the analysis of single-cell time course datasets: how to identify unique cell populations and track how they change across time points. To facilitate this analysis, we developed FLOW-MAP, a graphical user interface (GUI)-based software tool that uses graph layout analysis with sequential time ordering to visualize cellular trajectories in high-dimensional single-cell datasets obtained from flow cytometry, mass cytometry or single-cell RNA sequencing (scRNAseq) experiments. Here we provide a detailed description of the FLOW-MAP algorithm and how to use the open-source R package FLOWMAPR via its GUI or with text-based commands. This approach can be applied to many dynamic processes, including in vitro stem cell differentiation, in vivo development, oncogenesis, the emergence of drug resistance and cell signaling dynamics. To demonstrate our approach, we perform a step-by-step analysis of a single-cell mass cytometry time course dataset from mouse embryonic stem cells differentiating into the three germ layers: endoderm, mesoderm and ectoderm. In addition, we demonstrate FLOW-MAP analysis of a previously published scRNAseq dataset. Using both synthetic and experimental datasets for comparison, we perform FLOW-MAP analysis side by side with other single-cell analysis methods, to illustrate when it is advantageous to use the FLOW-MAP approach. The protocol takes between 30 min and 1.5 h to complete.


Assuntos
Algoritmos , Gráficos por Computador , Análise de Célula Única/métodos , Interface Usuário-Computador , Software
17.
Cell Rep ; 29(7): 1961-1973.e4, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31722210

RESUMO

Sex differences in autoimmunity and infection suggest that a better understanding of molecular sex differences will improve the diagnosis and treatment of immune-related disease. We identified 144 differentially expressed genes, referred to as immune sex expression signature (iSEXS), between human males and females using an integrated multi-cohort analysis of blood transcriptome profiles from six discovery cohorts from five continents with 458 healthy individuals. We validated iSEXS in 11 additional cohorts of 524 peripheral blood samples. When we separated iSEXS into genes located on sex chromosomes (XY-iSEXS) or autosomes (autosomal-iSEXS), both modules distinguished males and females. iSEXS reflects sex differences in immune cell proportions, with female-associated genes showing higher expression by CD4+ T cells and male-associated genes showing higher expression by myeloid cells. Autosomal-iSEXS detected an increase in monocytes with age in females, reflected sex-differential immune cell dynamics during influenza infection, and predicted antibody response in males, but not females.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Influenza Humana/imunologia , Monócitos/imunologia , Caracteres Sexuais , Transcriptoma/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Influenza Humana/patologia , Masculino , Monócitos/patologia
18.
Immunity ; 51(2): 225-239, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31433970

RESUMO

The gut microbiota is a complex and plastic network of diverse organisms intricately connected with human physiology. Recent advances in profiling approaches of both the microbiota and the immune system now enable a deeper exploration of immunity-microbiota connections. An important next step is to elucidate a human-relevant "map" of microbial-immune wiring while focusing on animal studies to probe a prioritized subset of interactions. Here, we provide an overview of this field's current status and discuss two approaches for establishing priorities for detailed investigation: (1) longitudinal intervention studies in humans probing the dynamics of both the microbiota and the immune system and (2) the study of traditional populations to assess lost features of human microbial identity whose absence may be contributing to the rise of immunological disorders. These human-centered approaches offer a judicious path forward to understand the impact of the microbiota in immune development and function.


Assuntos
Microbioma Gastrointestinal/imunologia , Interações Hospedeiro-Patógeno , Sistema Imunitário , Animais , Homeostase , Humanos , Imunidade , Assistência Centrada no Paciente
19.
Gut Microbes ; 10(2): 216-227, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30118385

RESUMO

The study of traditional populations provides a view of human-associated microbes unperturbed by industrialization, as well as a window into the microbiota that co-evolved with humans. Here we discuss our recent work characterizing the microbiota from the Hadza hunter-gatherers of Tanzania. We found seasonal shifts in bacterial taxa, diversity, and carbohydrate utilization by the microbiota. When compared to the microbiota composition from other populations around the world, the Hadza microbiota shares bacterial families with other traditional societies that are rare or absent from microbiotas of industrialized nations. We present additional observations from the Hadza microbiota and their lifestyle and environment, including microbes detected on hands, water, and animal sources, how the microbiota varies with sex and age, and the short-term effects of introducing agricultural products into the diet. In the context of our previously published findings and of these additional observations, we discuss a path forward for future work.


Assuntos
Dieta/etnologia , Microbiologia Ambiental , Microbioma Gastrointestinal , Estilo de Vida/etnologia , Fatores Etários , Animais , Biodiversidade , Carboidratos da Dieta/metabolismo , Fezes/microbiologia , Feminino , Humanos , Masculino , Estações do Ano , Tanzânia/etnologia
20.
PLoS Biol ; 16(11): e2005396, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30439937

RESUMO

The composition of the gut microbiome in industrialized populations differs from those living traditional lifestyles. However, it has been difficult to separate the contributions of human genetic and geographic factors from lifestyle. Whether shifts away from the foraging lifestyle that characterize much of humanity's past influence the gut microbiome, and to what degree, remains unclear. Here, we characterize the stool bacterial composition of four Himalayan populations to investigate how the gut community changes in response to shifts in traditional human lifestyles. These groups led seminomadic hunting-gathering lifestyles until transitioning to varying levels of agricultural dependence upon farming. The Tharu began farming 250-300 years ago, the Raute and Raji transitioned 30-40 years ago, and the Chepang retain many aspects of a foraging lifestyle. We assess the contributions of dietary and environmental factors on their gut-associated microbes and find that differences in the lifestyles of Himalayan foragers and farmers are strongly correlated with microbial community variation. Furthermore, the gut microbiomes of all four traditional Himalayan populations are distinct from that of the Americans, indicating that industrialization may further exacerbate differences in the gut community. The Chepang foragers harbor an elevated abundance of taxa associated with foragers around the world. Conversely, the gut microbiomes of the populations that have transitioned to farming are more similar to those of Americans, with agricultural dependence and several associated lifestyle and environmental factors correlating with the extent of microbiome divergence from the foraging population. The gut microbiomes of Raute and Raji reveal an intermediate state between the Chepang and Tharu, indicating that divergence from a stereotypical foraging microbiome can occur within a single generation. Our results also show that environmental factors such as drinking water source and solid cooking fuel are significantly associated with the gut microbiome. Despite the pronounced differences in gut bacterial composition across populations, we found little differences in alpha diversity across lifestyles. These findings in genetically similar populations living in the same geographical region establish the key role of lifestyle in determining human gut microbiome composition and point to the next challenging steps of determining how large-scale gut microbiome reconfiguration impacts human biology.


Assuntos
Microbioma Gastrointestinal/genética , Estilo de Vida/etnologia , Microbiota/genética , Adulto , Bactérias/genética , Dieta , Dieta Paleolítica , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Genética Populacional/métodos , Geografia , Humanos , Masculino , Pessoa de Meia-Idade , Nepal/etnologia , RNA Ribossômico 16S/genética , População Rural
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