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Key Points The gut microbiota is spatially stratified along the longitudinal and cross-sectional axes of the gut. Chemical and nutrient gradients, antimicrobial peptides and physical features of the gut contribute to differences in microbial community composition in different locations. The mucosal and lumenal microbiota of the gut represent distinct microbial communities. On a smaller scale, patchiness within these communities suggests that they are highly spatially organized. Diet imparts a large effect on microbial colonization and relative abundance, but some bacteria can thrive independently of dietary changes by living on host-derived nutrients such as mucin glycans. Therefore, the mucus layer can harbour a reservoir of bacteria that is maintained regardless of food intake. The appendix and colonic crypts may also be examples of such microbial reservoirs. Only a subset of gut symbionts are able to access the epithelial surface. Mucus, antimicrobial peptides and adaptive immune activity limit tissue accessibility. Direct interfacing between the host and microbial symbionts may be important for the maintenance of homeostasis. Immunomodulation by certain symbionts allows the host to tolerate intimate relationships with potentially beneficial microorganisms. This may be a way in which commensals distinguish themselves from pathogens and prevent their elimination by the immune system. Although many diseases have been associated with dysbiosis, an understanding of the function of the microbiota in health and disease requires the biogeography of the community to be considered. Recent studies in humans have found differences specific to the mucosal community in cases of inflammatory bowel disease and hepatic encephalopathy. The gut microbiota has a strong impact on host physiology. In this Review, Mazmanian and colleagues describe the mechanisms that control the biogeography of bacteria in the gut and discuss the importance of the spatial localization of the gut microbiota during health and disease. Animals assemble and maintain a diverse but host-specific gut microbial community. In addition to characteristic microbial compositions along the longitudinal axis of the intestines, discrete bacterial communities form in microhabitats, such as the gut lumen, colonic mucus layers and colonic crypts. In this Review, we examine how the spatial distribution of symbiotic bacteria among physical niches in the gut affects the development and maintenance of a resilient microbial ecosystem. We consider novel hypotheses for how nutrient selection, immune activation and other mechanisms control the biogeography of bacteria in the gut, and we discuss the relevance of this spatial heterogeneity to health and disease.

The genus Prevotella includes more than 50 characterized species that occur in varied natural habitats, although most Prevotella spp. are associated with humans. In the human microbiome, Prevotella spp. are highly abundant in various body sites, where they are key players in the balance between health and disease. Host factors related to diet, lifestyle and geography are fundamental in affecting the diversity and prevalence of Prevotella species and strains in the human microbiome. These factors, along with the ecological relationship of Prevotella with other members of the microbiome, likely determine the extent of the contribution of Prevotella to human metabolism and health. Here we review the diversity, prevalence and potential connection of Prevotella spp. in the human host, highlighting how genomic methods and analysis have improved and should further help in framing their ecological role. We also provide suggestions for future research to improve understanding of the possible functions of Prevotella spp. and the effects of the Western lifestyle and diet on the host–Prevotella symbiotic relationship in the context of maintaining human health.Prevotella is a genus of bacteria that commonly associate with humans, in various body sites. In this Review, Segata, Ercolini and colleagues discuss Prevotella diversity and the evidence for the involvement of these bacteria in human health and disease.

The composition of the human gut microbiota is linked to health and disease, but knowledge of individual microbial species is needed to decipher their biological roles. Despite extensive culturing and sequencing efforts, the complete bacterial repertoire of the human gut microbiota remains undefined. Here we identify 1,952 uncultured candidate bacterial species by reconstructing 92,143 metagenome-assembled genomes from 11,850 human gut microbiomes. These uncultured genomes substantially expand the known species repertoire of the collective human gut microbiota, with a 281% increase in phylogenetic diversity. Although the newly identified species are less prevalent in well-studied populations compared to reference isolate genomes, they improve classification of understudied African and South American samples by more than 200%. These candidate species encode hundreds of newly identified biosynthetic gene clusters and possess a distinctive functional capacity that might explain their elusive nature. Our work expands the known diversity of uncultured gut bacteria, which provides unprecedented resolution for taxonomic and functional characterization of the intestinal microbiota. The known species repertoire of the collective human gut microbiota is substantially expanded with the discovery of 1,952 uncultured bacterial species that greatly improve classification of understudied African and South American samples.

Key Points The gut microbiome is a neglected component of the first-pass metabolism of xenobiotics before reaching the general circulation. Direct microbial metabolism of xenobiotics and their metabolites often involves reduction or hydrolysis, but most of the enzymes responsible for these reactions remain unknown. Microbial metabolism influences both efficacy and toxicity, producing bioactive compounds, inactive metabolites and toxins. Relevant host–microbial interactions include the expression of host genes that are involved in drug transport and metabolism, the interference with host enzymatic activity and the modulation of immune responses. The translational implications of these studies include the development of novel co-therapies and the identification of new biomarkers and drugs. In this Review, Turnbaugh and colleagues discuss several mechanisms by which the human gut microbiome affects the metabolism of xenobiotics, including drugs and dietary compounds, and explore how this knowledge can be applied to improve the treatment of human disease. Although the importance of human genetic polymorphisms in therapeutic outcomes is well established, the role of our 'second genome' (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that have shed light on the mechanisms that link the human gut microbiome to the efficacy and toxicity of xenobiotics, including drugs, dietary compounds and environmental toxins. Continued progress in this area could enable more precise tools for predicting patient responses and for the development of a new generation of therapeutics based on, or targeted at, the gut microbiome. Indeed, the admirable goal of precision medicine may require us to first understand the microbial pharmacists within.

The gut is the richest ecosystem of microbes in the human body and has great influence on our health. Despite many efforts, the set of microbes inhabiting this environment is not fully known, limiting our ability to identify microbial content and to research it. In this work, we combine new microbial metagenomic assembled genomes from 51,052 samples, with previously published genomes to produce a curated set of 241,118 genomes. Based on this set, we procure a new and improved human gut microbiome reference set of 3594 high quality species genomes, which successfully matches 83.65% validation samples’ reads. This improved reference set contains 310 novel species, including one that exists in 19% of validation samples. Overall, this study provides a gut microbial genome reference set that can serve as a valuable resource for further research. Here, Leviatan et al. produce 241,118 genome assemblies to produce a new human gut microbiome reference set of 3,594 species genomes, of which 310 represent previously undescribed species, making the catalog a valuable resource for further research.

Gut microbiota plays an important role in pig health and production. Still, availability of sequenced genomes and functional information for most pig gut microbes remains limited. Here we perform a landscape survey of the swine gut microbiome, spanning extensive sample sources by deep metagenomic sequencing resulting in an expanded gene catalog named pig integrated gene catalog (PIGC), containing 17,237,052 complete genes clustered at 90% protein identity from 787 gut metagenomes, of which 28% are unknown proteins. Using binning analysis, 6339 metagenome-assembled genomes (MAGs) were obtained, which were clustered to 2673 species-level genome bins (SGBs), among which 86% (2309) SGBs are unknown based on current databases. Using the present gene catalog and MAGs, we identified several strain-level differences between the gut microbiome of wild boars and commercial Duroc pigs. PIGC and MAGs provide expanded resources for swine gut microbiome-related research. Here, the authors present a pig integrated gene catalog and metagenome-assembled genomes, which they construct from swine gut microbiomes spanning various ages, sexes, breeds, geographical locations, domestication, and gut locations by metagenomic sequencing, providing expanded resources for pig microbiome studies.

Differential abundance analysis is controversial throughout microbiome research. Gold standard approaches require laborious measurements of total microbial load, or absolute number of microorganisms, to accurately determine taxonomic shifts. Therefore, most studies rely on relative abundance data. Here, we demonstrate common pitfalls in comparing relative abundance across samples and identify two solutions that reveal microbial changes without the need to estimate total microbial load. We define the notion of “reference frames”, which provide deep intuition about the compositional nature of microbiome data. In an oral time series experiment, reference frames alleviate false positives and produce consistent results on both raw and cell-count normalized data. Furthermore, reference frames identify consistent, differentially abundant microbes previously undetected in two independent published datasets from subjects with atopic dermatitis. These methods allow reassessment of published relative abundance data to reveal reproducible microbial changes from standard sequencing output without the need for new assays. Most microbiome studies make conclusions based on changes in relative abundance of taxa, inferred from sequencing data. Here, the authors highlight common pitfalls in comparing relative abundance across samples, and identify solutions that reveal microbial changes without the need to estimate total microbial load.

The cow rumen is adapted for the breakdown of plant material into energy and nutrients, a task largely performed by enzymes encoded by the rumen microbiome. Here we present 913 draft bacterial and archaeal genomes assembled from over 800 Gb of rumen metagenomic sequence data derived from 43 Scottish cattle, using both metagenomic binning and Hi-C-based proximity-guided assembly. Most of these genomes represent previously unsequenced strains and species. The draft genomes contain over 69,000 proteins predicted to be involved in carbohydrate metabolism, over 90% of which do not have a good match in public databases. Inclusion of the 913 genomes presented here improves metagenomic read classification by sevenfold against our own data, and by fivefold against other publicly available rumen datasets. Thus, our dataset substantially improves the coverage of rumen microbial genomes in the public databases and represents a valuable resource for biomass-degrading enzyme discovery and studies of the rumen microbiome. Microbes in the cow rumen are crucial for the breakdown of plant material. Here, Stewart et al. assemble over 900 bacterial and archaeal genomes from the cow rumen microbiome, revealing new species and genes encoding enzymes with potential roles in carbohydrate metabolism.

Immediately after birth, newborn babies experience rapid colonization by microorganisms from their mothers and the surrounding environment 1 . Diseases in childhood and later in life are potentially mediated by the perturbation of the colonization of the infant gut microbiota 2 . However, the effects of delivery via caesarean section on the earliest stages of the acquisition and development of the gut microbiota, during the neonatal period (≤1 month), remain controversial 3 , 4 . Here we report the disrupted transmission of maternal Bacteroides strains, and high-level colonization by opportunistic pathogens associated with the hospital environment (including Enterococcus , Enterobacter and Klebsiella species), in babies delivered by caesarean section. These effects were also seen, to a lesser extent, in vaginally delivered babies whose mothers underwent antibiotic prophylaxis and in babies who were not breastfed during the neonatal period. We applied longitudinal sampling and whole-genome shotgun metagenomic analysis to 1,679 gut microbiota samples (taken at several time points during the neonatal period, and in infancy) from 596 full-term babies born in UK hospitals; for a subset of these babies, we collected additional matched samples from mothers (175 mothers paired with 178 babies). This analysis demonstrates that the mode of delivery is a significant factor that affects the composition of the gut microbiota throughout the neonatal period, and into infancy. Matched large-scale culturing and whole-genome sequencing of over 800 bacterial strains from these babies identified virulence factors and clinically relevant antimicrobial resistance in opportunistic pathogens that may predispose individuals to opportunistic infections. Our findings highlight the critical role of the local environment in establishing the gut microbiota in very early life, and identify colonization with antimicrobial-resistance-containing opportunistic pathogens as a previously underappreciated risk factor in hospital births. Delivery via caesarean section, maternal antibiotic prophylaxis and colonization by opportunistic pathogens associated with the hospital environment affect the composition of the gut microbiota of children from birth until infancy.

Reference genomes are essential for metagenomic analyses and functional characterization of the human gut microbiota. We present the Culturable Genome Reference (CGR), a collection of 1,520 nonredundant, high-quality draft genomes generated from >6,000 bacteria cultivated from fecal samples of healthy humans. Of the 1,520 genomes, which were chosen to cover all major bacterial phyla and genera in the human gut, 264 are not represented in existing reference genome catalogs. We show that this increase in the number of reference bacterial genomes improves the rate of mapping metagenomic sequencing reads from 50% to >70%, enabling higher-resolution descriptions of the human gut microbiome. We use the CGR genomes to annotate functions of 338 bacterial species, showing the utility of this resource for functional studies. We also carry out a pan-genome analysis of 38 important human gut species, which reveals the diversity and specificity of functional enrichment between their core and dispensable genomes. A resource of >1,500 bacterial reference genomes sheds light on the human gut microbiome.