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Cell Jul 2023The gut microbiome modulates immune and metabolic health. Human microbiome data are biased toward industrialized populations, limiting our understanding of...
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.
Topics: Humans; Gastrointestinal Microbiome; Microbiota; Metagenome; Eukaryota; High-Throughput Nucleotide Sequencing; Metagenomics
PubMed: 37348505
DOI: 10.1016/j.cell.2023.05.046 -
Nature Oct 2023Metagenomes encode an enormous diversity of proteins, reflecting a multiplicity of functions and activities. Exploration of this vast sequence space has been limited to...
Metagenomes encode an enormous diversity of proteins, reflecting a multiplicity of functions and activities. Exploration of this vast sequence space has been limited to a comparative analysis against reference microbial genomes and protein families derived from those genomes. Here, to examine the scale of yet untapped functional diversity beyond what is currently possible through the lens of reference genomes, we develop a computational approach to generate reference-free protein families from the sequence space in metagenomes. We analyse 26,931 metagenomes and identify 1.17 billion protein sequences longer than 35 amino acids with no similarity to any sequences from 102,491 reference genomes or the Pfam database. Using massively parallel graph-based clustering, we group these proteins into 106,198 novel sequence clusters with more than 100 members, doubling the number of protein families obtained from the reference genomes clustered using the same approach. We annotate these families on the basis of their taxonomic, habitat, geographical and gene neighbourhood distributions and, where sufficient sequence diversity is available, predict protein three-dimensional models, revealing novel structures. Overall, our results uncover an enormously diverse functional space, highlighting the importance of further exploring the microbial functional dark matter.
Topics: Cluster Analysis; Metagenome; Metagenomics; Proteins; Databases, Protein; Protein Conformation; Microbiology
PubMed: 37821698
DOI: 10.1038/s41586-023-06583-7 -
Trends in Ecology & Evolution Oct 2023The environmental niche concept describes the distribution of a taxon in the environment and can be used to understand community dynamics, biological invasions, and the... (Review)
Review
The environmental niche concept describes the distribution of a taxon in the environment and can be used to understand community dynamics, biological invasions, and the impact of environmental changes. The uses and applications are still restricted in microbial ecology, largely due to the complexity of microbial systems and associated methodological limitations. The development of shotgun metagenomics and metatranscriptomics opens new ways to investigate the microbial niche by focusing on the metabolic niche within the environmental space. Here, we propose the metabolic niche framework, which, by defining the fundamental and realised metabolic niche of microorganisms, has the potential to not only provide novel insights into habitat preferences and the metabolism associated, but also to inform on metabolic plasticity, niche shifts, and microbial invasions.
Topics: Ecosystem; Metagenomics
PubMed: 37236880
DOI: 10.1016/j.tree.2023.04.015 -
Nature Methods Nov 2023Host-microbe interactions have been linked to health and disease states through the use of microbial taxonomic profiling, mostly via 16S ribosomal RNA gene sequencing....
Host-microbe interactions have been linked to health and disease states through the use of microbial taxonomic profiling, mostly via 16S ribosomal RNA gene sequencing. However, many mechanistic insights remain elusive, in part because studying the genomes of microbes associated with mammalian tissue is difficult due to the high ratio of host to microbial DNA in such samples. Here we describe a microbial-enrichment method (MEM), which we demonstrate on a wide range of sample types, including saliva, stool, intestinal scrapings, and intestinal mucosal biopsies. MEM enabled high-throughput characterization of microbial metagenomes from human intestinal biopsies by reducing host DNA more than 1,000-fold with minimal microbial community changes (roughly 90% of taxa had no significant differences between MEM-treated and untreated control groups). Shotgun sequencing of MEM-treated human intestinal biopsies enabled characterization of both high- and low-abundance microbial taxa, pathways and genes longitudinally along the gastrointestinal tract. We report the construction of metagenome-assembled genomes directly from human intestinal biopsies for bacteria and archaea at relative abundances as low as 1%. Analysis of metagenome-assembled genomes reveals distinct subpopulation structures between the small and large intestine for some taxa. MEM opens a path for the microbiome field to acquire deeper insights into host-microbe interactions by enabling in-depth characterization of host-tissue-associated microbial communities.
Topics: Animals; Humans; Metagenome; Microbiota; Bacteria; DNA; Gastrointestinal Tract; RNA, Ribosomal, 16S; Metagenomics; High-Throughput Nucleotide Sequencing; Mammals
PubMed: 37828152
DOI: 10.1038/s41592-023-02025-4 -
Cell Host & Microbe Jul 2023The human gut microbiome composition is generally in a stable dynamic equilibrium, but it can deteriorate into dysbiotic states detrimental to host health. To...
The human gut microbiome composition is generally in a stable dynamic equilibrium, but it can deteriorate into dysbiotic states detrimental to host health. To disentangle the inherent complexity and capture the ecological spectrum of microbiome variability, we used 5,230 gut metagenomes to characterize signatures of bacteria commonly co-occurring, termed enterosignatures (ESs). We find five generalizable ESs dominated by either Bacteroides, Firmicutes, Prevotella, Bifidobacterium, or Escherichia. This model confirms key ecological characteristics known from previous enterotype concepts, while enabling the detection of gradual shifts in community structures. Temporal analysis implies that the Bacteroides-associated ES is "core" in the resilience of westernized gut microbiomes, while combinations with other ESs often complement the functional spectrum. The model reliably detects atypical gut microbiomes correlated with adverse host health conditions and/or the presence of pathobionts. ESs provide an interpretable and generic model that enables an intuitive characterization of gut microbiome composition in health and disease.
Topics: Humans; Gastrointestinal Microbiome; Microbiota; Bacteria; Metagenome; Firmicutes; Bacteroides; Feces
PubMed: 37339626
DOI: 10.1016/j.chom.2023.05.024 -
Cell Oct 2023Patescibacteria, also known as the candidate phyla radiation (CPR), are a diverse group of bacteria that constitute a disproportionately large fraction of microbial dark...
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.
Topics: Bacteria; Metagenome; Metagenomics; Phylogeny; Actinobacteria
PubMed: 37683634
DOI: 10.1016/j.cell.2023.08.017 -
DNA Research : An International Journal... Dec 2023Various microorganisms exist in environments, and each of them has its optimal growth temperature (OGT). The relationship between genomic information and OGT of each...
Various microorganisms exist in environments, and each of them has its optimal growth temperature (OGT). The relationship between genomic information and OGT of each species has long been studied, and one such study revealed that OGT of prokaryotes can be accurately predicted based on the fraction of seven amino acids (IVYWREL) among all encoded amino-acid sequences in its genome. Extending this discovery, we developed a 'Metagenomic Thermometer' as a means of predicting environmental temperature based on metagenomic sequences. Temperature prediction of diverse environments using publicly available metagenomic data revealed that the Metagenomic Thermometer can predict environmental temperatures with small temperature changes and little influx of microorganisms from other environments. The accuracy of the Metagenomic Thermometer was also confirmed by a demonstration experiment using an artificial hot water canal. The Metagenomic Thermometer was also applied to human gut metagenomic samples, yielding a reasonably accurate value for human body temperature. The result further suggests that deep body temperature determines the dominant lineage of the gut community. Metagenomic Thermometer provides a new insight into temperature-driven community assembly based on amino-acid composition rather than microbial taxa.
Topics: Humans; Thermometers; Metagenome; Metagenomics; Genomics
PubMed: 37940329
DOI: 10.1093/dnares/dsad024 -
Cell Reports. Medicine Oct 2023The complex interplay between microbiota and immunity is important to human health. To explore how altered adaptive immunity influences the microbiome, we characterize...
The complex interplay between microbiota and immunity is important to human health. To explore how altered adaptive immunity influences the microbiome, we characterize skin, nares, and gut microbiota of patients with recombination-activating gene (RAG) deficiency-a rare genetically defined inborn error of immunity (IEI) that results in a broad spectrum of clinical phenotypes. Integrating de novo assembly of metagenomes from RAG-deficient patients with reference genome catalogs provides an expansive multi-kingdom view of microbial diversity. RAG-deficient patient microbiomes exhibit inter-individual variation, including expansion of opportunistic pathogens (e.g., Corynebacterium bovis, Haemophilus influenzae), and a relative loss of body site specificity. We identify 35 and 27 bacterial species derived from skin/nares and gut microbiomes, respectively, which are distinct to RAG-deficient patients compared to healthy individuals. Underscoring IEI patients as potential reservoirs for viral persistence and evolution, we further characterize the colonization of eukaryotic RNA viruses (e.g., Coronavirus 229E, Norovirus GII) in this patient population.
Topics: Humans; Microbiota; Gastrointestinal Microbiome; Skin; Metagenome
PubMed: 37757827
DOI: 10.1016/j.xcrm.2023.101205 -
Cell Host & Microbe Nov 2023The effect of gut bacteria on the response to immune checkpoint inhibitors (ICIs) has been studied, but the relationship between fungi and ICI responses is not fully...
The effect of gut bacteria on the response to immune checkpoint inhibitors (ICIs) has been studied, but the relationship between fungi and ICI responses is not fully understood. Herein, 862 fecal metagenomes from 9 different cohorts were integrated for the identification of differentially abundant fungi and subsequent construction of random forest (RF) models to predict ICI responses. Fungal markers demonstrate excellent performance, with an average area under the curve (AUC) of 0.87. Their performance improves even further, reaching an average AUC of 0.89 when combined with bacterial markers. Higher enrichment of exhausted T cells is detected in responders, as predicted by fungal markers. Multi-kingdom network and functional analysis reveal that the fungus Schizosaccharomyces octosporus may ferment starch into short-chain fatty acids in responders. This study provides a fungal profile of the ICI response and the identification of multi-kingdom microbial markers with good performance that may improve the overall applicability of ICI therapy.
Topics: Humans; Gastrointestinal Microbiome; Metagenome; Immunotherapy; Bacteria; Neoplasms
PubMed: 37944495
DOI: 10.1016/j.chom.2023.10.005 -
Microbiology Spectrum Aug 2023Vaginal dysbiosis in women reduces the abundance of species and increases that of anaerobic fastidious bacteria. This dysbiotic condition in the vagina, called...
Vaginal dysbiosis in women reduces the abundance of species and increases that of anaerobic fastidious bacteria. This dysbiotic condition in the vagina, called bacterial vaginosis (BV), can be symptomatic with odorous vaginal discharges or asymptomatic and affects a third of women of reproductive age. Three unclassified bacterial species designated BV-associated bacteria 1, 2, and 3 (BVAB-1, -2, and -3) in 2005 were found to be highly preponderant in the vagina of females with BV. Here, we used sequence homology and phylogenetics analyses to identify the actual species of BVAB-1, -2, and -3 and found BVAB-1 to be genomosp. BVAB-1, BVAB-2 to be bacterium strain CHIC02, and BVAB-3 to be Mageeibacillus indolicus, respectively. These are anaerobic and uncultured species that can be identified only through metagenomics. Long-read sequencing of BV specimens can also enable a genomic reassembly of these species' genomes from metagenomes. Species-specific identification of these pathogens and the availability of their genomes from assembled metagenomes will advance our understanding of their biology, facilitate the design of sensitive diagnostics and drugs, and enhance the treatment of BV. For many years since 2005, BVAB, an important pathogen of the female vaginal tract that is associated with BV, has been identified using PCR without knowing its actual species. Without a full genome of these pathogens, a better understanding of their pathogenicity, treatment, resistance, and diagnostics cannot be reached. In this analysis, we use the DNA of BVAB-1, -2, and -3 to determine their actual species to enhance further research into their pathogenicity, resistance, diagnosis, and treatment.
Topics: Female; Humans; Vaginosis, Bacterial; Bacteria; Vagina; Metagenome; Polymerase Chain Reaction
PubMed: 37347202
DOI: 10.1128/spectrum.04676-22