RESUMEN
Plasmids are extrachromosomal genetic elements that often encode fitness-enhancing features. However, many bacteria carry "cryptic" plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes and is 14 times as numerous as crAssphage, currently established as the most abundant extrachromosomal genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one's mother. pBI143 can transfer between Bacteroidales, and although it does not appear to impact bacterial host fitness in vivo, it can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an alternative approach to track human colonic inflammatory states.
Asunto(s)
Bacterias , Tracto Gastrointestinal , Metagenoma , Plásmidos , Humanos , Bacterias/genética , Bacteroidetes/genética , Heces/microbiología , Plásmidos/genéticaRESUMEN
Diet impacts human health, influencing body adiposity and the risk of developing cardiometabolic diseases. The gut microbiome is a key player in the diet-health axis, but while its bacterial fraction is widely studied, the role of micro-eukaryotes, including Blastocystis, is underexplored. We performed a global-scale analysis on 56,989 metagenomes and showed that human Blastocystis exhibits distinct prevalence patterns linked to geography, lifestyle, and dietary habits. Blastocystis presence defined a specific bacterial signature and was positively associated with more favorable cardiometabolic profiles and negatively with obesity (p < 1e-16) and disorders linked to altered gut ecology (p < 1e-8). In a diet intervention study involving 1,124 individuals, improvements in dietary quality were linked to weight loss and increases in Blastocystis prevalence (p = 0.003) and abundance (p < 1e-7). Our findings suggest a potentially beneficial role for Blastocystis, which may help explain personalized host responses to diet and downstream disease etiopathogenesis.
Asunto(s)
Blastocystis , Dieta , Microbioma Gastrointestinal , Obesidad , Humanos , Blastocystis/metabolismo , Masculino , Femenino , Infecciones por Blastocystis , Adulto , Persona de Mediana Edad , Intestinos/parasitología , Intestinos/microbiología , Enfermedades Cardiovasculares/prevención & control , MetagenomaRESUMEN
The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.
Asunto(s)
Hongos , Microbioma Gastrointestinal , Micobioma , Animales , Humanos , Masculino , Ratones , Heces/microbiología , Hongos/genética , Hongos/clasificación , Hongos/aislamiento & purificación , Genoma Fúngico/genética , Genómica , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/genética , Metagenoma , Filogenia , Femenino , Adulto , Persona de Mediana EdadRESUMEN
Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs) within the global microbiome and leverage a vast dataset of 63,410 metagenomes and 87,920 prokaryotic genomes from environmental and host-associated habitats to create the AMPSphere, a comprehensive catalog comprising 863,498 non-redundant peptides, few of which match existing databases. AMPSphere provides insights into the evolutionary origins of peptides, including by duplication or gene truncation of longer sequences, and we observed that AMP production varies by habitat. To validate our predictions, we synthesized and tested 100 AMPs against clinically relevant drug-resistant pathogens and human gut commensals both in vitro and in vivo. A total of 79 peptides were active, with 63 targeting pathogens. These active AMPs exhibited antibacterial activity by disrupting bacterial membranes. In conclusion, our approach identified nearly one million prokaryotic AMP sequences, an open-access resource for antibiotic discovery.
Asunto(s)
Péptidos Antimicrobianos , Aprendizaje Automático , Microbiota , Péptidos Antimicrobianos/farmacología , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/genética , Humanos , Animales , Antibacterianos/farmacología , Ratones , Metagenoma , Bacterias/efectos de los fármacos , Bacterias/genética , Microbioma Gastrointestinal/efectos de los fármacosRESUMEN
The gut microbiome modulates immune and metabolic health. Human microbiome data are biased toward industrialized populations, limiting our understanding of non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing on 351 fecal samples from the Hadza hunter-gatherers of Tanzania and comparative populations in Nepal and California. We recovered 91,662 genomes of bacteria, archaea, bacteriophages, and eukaryotes, 44% of which are absent from existing unified datasets. We identified 124 gut-resident species vanishing in industrialized populations and highlighted distinct aspects of the Hadza gut microbiome related to in situ replication rates, signatures of selection, and strain sharing. Industrialized gut microbes were found to be enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource, expands our understanding of microbes capable of colonizing the human gut, and clarifies the extensive perturbation induced by the industrialized lifestyle.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Humanos , Microbioma Gastrointestinal/genética , Metagenoma , Eucariontes , Secuenciación de Nucleótidos de Alto Rendimiento , MetagenómicaRESUMEN
Patescibacteria, also known as the candidate phyla radiation (CPR), are a diverse group of bacteria that constitute a disproportionately large fraction of microbial dark matter. Its few cultivated members, belonging mostly to Saccharibacteria, grow as epibionts on host Actinobacteria. Due to a lack of suitable tools, the genetic basis of this lifestyle and other unique features of Patescibacteira remain unexplored. Here, we show that Saccharibacteria exhibit natural competence, and we exploit this property for their genetic manipulation. Imaging of fluorescent protein-labeled Saccharibacteria provides high spatiotemporal resolution of phenomena accompanying epibiotic growth, and a transposon-insertion sequencing (Tn-seq) genome-wide screen reveals the contribution of enigmatic Saccharibacterial genes to growth on their hosts. Finally, we leverage metagenomic data to provide cutting-edge protein structure-based bioinformatic resources that support the strain Southlakia epibionticum and its corresponding host, Actinomyces israelii, as a model system for unlocking the molecular underpinnings of the epibiotic lifestyle.
Asunto(s)
Bacterias , Bacterias/clasificación , Bacterias/genética , Bacterias/crecimiento & desarrollo , Metagenoma , Metagenómica , Filogenia , Actinobacteria/fisiologíaRESUMEN
Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition. The application of a computational method called PARADIGM to a large dataset of cancer patients' longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.
Asunto(s)
Microbioma Gastrointestinal , Trasplante de Células Madre Hematopoyéticas , Microbiota , Neoplasias , Humanos , Microbioma Gastrointestinal/genética , Heces/microbiología , Metagenoma , Antibacterianos , Neoplasias/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Bacterias/genética , Proteínas Bacterianas/metabolismo , Microbioma Gastrointestinal , Metaboloma , Metagenoma , Microbiota , Adulto , Anciano , Anciano de 80 o más Años , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Proteínas Bacterianas/genética , Farmacorresistencia Microbiana , Heces/microbiología , Femenino , Inestabilidad Genómica , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Adulto JovenRESUMEN
A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.
Asunto(s)
Tejido Adiposo/microbiología , Traslocación Bacteriana , Microbioma Gastrointestinal , Mesenterio/microbiología , Tejido Adiposo/patología , Animales , Biodiversidad , Biomarcadores/metabolismo , Polaridad Celular , Células Cultivadas , Colitis Ulcerosa/patología , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/patología , Microbioma Gastrointestinal/genética , Regulación de la Expresión Génica , Vida Libre de Gérmenes , Humanos , Íleon/microbiología , Íleon/patología , Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , Metagenoma , Metagenómica , Ratones , Ratones Endogámicos C57BL , Fenotipo , ARN Ribosómico 16S/genética , Células Madre/metabolismoRESUMEN
The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Microbioma Gastrointestinal/fisiología , Microbiota/efectos de los fármacos , Adulto , Animales , Bacterias/clasificación , Biomarcadores Farmacológicos/metabolismo , Heces/microbiología , Femenino , Microbioma Gastrointestinal/genética , Voluntarios Sanos , Humanos , Masculino , Metagenoma/genética , Metagenómica/métodos , Ratones , Ratones Endogámicos C57BL , Microbiota/genética , Preparaciones Farmacéuticas/metabolismo , Medicina de Precisión/métodos , ARN Ribosómico 16S/genéticaRESUMEN
The lumen of the gastrointestinal (GI) tract is home to an enormous quantity of different bacterial species, our microbiota, that thrive in an often symbiotic relationship with the host. Given that the healthy host must regulate contact between the microbiota and its immune system to avoid overwhelming systemic immune activation, humans have evolved several mechanisms to attenuate systemic microbial translocation (MT) and its consequences. However, several diseases are associated with the failure of one or more of these mechanisms, with consequent immune activation and deleterious effects on health. Here, we discuss the mechanisms underlying MT, diseases associated with MT, and therapeutic interventions that aim to decrease it.
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Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Metagenoma/fisiología , Animales , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Enfermedades del Sistema Digestivo/inmunología , Enfermedades del Sistema Digestivo/microbiología , Enfermedades del Sistema Digestivo/terapia , Tracto Gastrointestinal/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Metagenoma/efectos de los fármacos , Probióticos/uso terapéuticoRESUMEN
The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host.
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Enfermedades Transmisibles/inmunología , Enfermedades Transmisibles/microbiología , Inflamación/inmunología , Inflamación/microbiología , Metagenoma/inmunología , Inmunidad Adaptativa , Animales , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Transducción de SeñalRESUMEN
The body-wide human microbiome plays a role in health, but its full diversity remains uncharacterized, particularly outside of the gut and in international populations. We leveraged 9,428 metagenomes to reconstruct 154,723 microbial genomes (45% of high quality) spanning body sites, ages, countries, and lifestyles. We recapitulated 4,930 species-level genome bins (SGBs), 77% without genomes in public repositories (unknown SGBs [uSGBs]). uSGBs are prevalent (in 93% of well-assembled samples), expand underrepresented phyla, and are enriched in non-Westernized populations (40% of the total SGBs). We annotated 2.85 M genes in SGBs, many associated with conditions including infant development (94,000) or Westernization (106,000). SGBs and uSGBs permit deeper microbiome analyses and increase the average mappability of metagenomic reads from 67.76% to 87.51% in the gut (median 94.26%) and 65.14% to 82.34% in the mouth. We thus identify thousands of microbial genomes from yet-to-be-named species, expand the pangenomes of human-associated microbes, and allow better exploitation of metagenomic technologies.
Asunto(s)
Metagenoma/genética , Metagenómica/métodos , Microbiota/genética , Macrodatos , Variación Genética/genética , Geografía , Humanos , Estilo de Vida , Filogenia , Análisis de Secuencia de ADN/métodosRESUMEN
Small proteins are traditionally overlooked due to computational and experimental difficulties in detecting them. To systematically identify small proteins, we carried out a comparative genomics study on 1,773 human-associated metagenomes from four different body sites. We describe >4,000 conserved protein families, the majority of which are novel; â¼30% of these protein families are predicted to be secreted or transmembrane. Over 90% of the small protein families have no known domain and almost half are not represented in reference genomes. We identify putative housekeeping, mammalian-specific, defense-related, and protein families that are likely to be horizontally transferred. We provide evidence of transcription and translation for a subset of these families. Our study suggests that small proteins are highly abundant and those of the human microbiome, in particular, may perform diverse functions that have not been previously reported.
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Microbiota , Proteínas/metabolismo , Secuencia de Aminoácidos , Comunicación Celular , Interacciones Huésped-Patógeno , Humanos , Metagenoma , Sistemas de Lectura Abierta/genética , Proteínas/química , Proteínas Ribosómicas/química , Proteínas Ribosómicas/metabolismo , Alineación de SecuenciaRESUMEN
Marine bacteria and archaea play key roles in global biogeochemistry. To improve our understanding of this complex microbiome, we employed single-cell genomics and a randomized, hypothesis-agnostic cell selection strategy to recover 12,715 partial genomes from the tropical and subtropical euphotic ocean. A substantial fraction of known prokaryoplankton coding potential was recovered from a single, 0.4 mL ocean sample, which indicates that genomic information disperses effectively across the globe. Yet, we found each genome to be unique, implying limited clonality within prokaryoplankton populations. Light harvesting and secondary metabolite biosynthetic pathways were numerous across lineages, highlighting the value of single-cell genomics to advance the identification of ecological roles and biotechnology potential of uncultured microbial groups. This genome collection enabled functional annotation and genus-level taxonomic assignments for >80% of individual metagenome reads from the tropical and subtropical surface ocean, thus offering a model to improve reference genome databases for complex microbiomes.
Asunto(s)
Metagenoma , Microbiota , Agua de Mar/microbiología , Archaea/clasificación , Archaea/genética , Bacterias/clasificación , Bacterias/genética , Metabolismo Energético , Metagenómica/métodos , Filogeografía , Plancton , Análisis de la Célula Individual/métodos , TranscriptomaRESUMEN
Ocean microbial communities strongly influence the biogeochemistry, food webs, and climate of our planet. Despite recent advances in understanding their taxonomic and genomic compositions, little is known about how their transcriptomes vary globally. Here, we present a dataset of 187 metatranscriptomes and 370 metagenomes from 126 globally distributed sampling stations and establish a resource of 47 million genes to study community-level transcriptomes across depth layers from pole-to-pole. We examine gene expression changes and community turnover as the underlying mechanisms shaping community transcriptomes along these axes of environmental variation and show how their individual contributions differ for multiple biogeochemically relevant processes. Furthermore, we find the relative contribution of gene expression changes to be significantly lower in polar than in non-polar waters and hypothesize that in polar regions, alterations in community activity in response to ocean warming will be driven more strongly by changes in organismal composition than by gene regulatory mechanisms. VIDEO ABSTRACT.
Asunto(s)
Regulación de la Expresión Génica , Metagenoma , Océanos y Mares , Transcriptoma/genética , Geografía , Microbiota/genética , Anotación de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Agua de Mar/microbiología , TemperaturaRESUMEN
Metagenomic sequencing is revolutionizing the detection and characterization of microbial species, and a wide variety of software tools are available to perform taxonomic classification of these data. The fast pace of development of these tools and the complexity of metagenomic data make it important that researchers are able to benchmark their performance. Here, we review current approaches for metagenomic analysis and evaluate the performance of 20 metagenomic classifiers using simulated and experimental datasets. We describe the key metrics used to assess performance, offer a framework for the comparison of additional classifiers, and discuss the future of metagenomic data analysis.
Asunto(s)
Bacterias/clasificación , Benchmarking/métodos , Hongos/clasificación , Metagenoma/genética , Metagenómica/métodos , Virus/clasificación , Bacterias/genética , Bases de Datos Genéticas , Hongos/genética , Filogenia , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Programas Informáticos , Virus/genéticaRESUMEN
Microbes drive most ecosystems and are modulated by viruses that impact their lifespan, gene flow, and metabolic outputs. However, ecosystem-level impacts of viral community diversity remain difficult to assess due to classification issues and few reference genomes. Here, we establish an â¼12-fold expanded global ocean DNA virome dataset of 195,728 viral populations, now including the Arctic Ocean, and validate that these populations form discrete genotypic clusters. Meta-community analyses revealed five ecological zones throughout the global ocean, including two distinct Arctic regions. Across the zones, local and global patterns and drivers in viral community diversity were established for both macrodiversity (inter-population diversity) and microdiversity (intra-population genetic variation). These patterns sometimes, but not always, paralleled those from macro-organisms and revealed temperate and tropical surface waters and the Arctic as biodiversity hotspots and mechanistic hypotheses to explain them. Such further understanding of ocean viruses is critical for broader inclusion in ecosystem models.
Asunto(s)
Organismos Acuáticos/genética , Biodiversidad , Virus ADN/genética , ADN Viral/genética , Metagenoma , Microbiología del AguaRESUMEN
The composite members of the microbiota face a range of selective pressures and must adapt to persist in the host. We highlight recent work characterizing the evolution and transfer of genetic information across nested scales of host-associated microbiota, which enable resilience to biotic and abiotic perturbations. At the strain level, we consider the preservation and diversification of adaptive information in progeny lineages. At the community level, we consider genetic exchange between distinct microbes in the ecosystem. Finally, we frame microbiomes as open systems subject to acquisition of novel information from foreign ecosystems through invasion by outsider microbes.
Asunto(s)
Evolución Molecular , Variación Genética , Metagenoma/genética , Microbiota/genética , Animales , Ecosistema , Transferencia de Gen Horizontal , Especificidad del Huésped , HumanosRESUMEN
Many US immigrant populations develop metabolic diseases post immigration, but the causes are not well understood. Although the microbiome plays a role in metabolic disease, there have been no studies measuring the effects of US immigration on the gut microbiome. We collected stool, dietary recalls, and anthropometrics from 514 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants and 19 Karen individuals sampled before and after immigration, as well as from 36 US-born European American individuals. Using 16S and deep shotgun metagenomic DNA sequencing, we found that migration from a non-Western country to the United States is associated with immediate loss of gut microbiome diversity and function in which US-associated strains and functions displace native strains and functions. These effects increase with duration of US residence and are compounded by obesity and across generations.