A global metagenomic map of urban microbiomes and antimicrobial resistance.

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome.

The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.

Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens.

Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. A total of 9.3% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 804 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting expression quantitative trait locus (eQTL). Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are key to controlling infection.

Human genetics shape the gut microbiome.

Host genetics and the gut microbiome can both influence metabolic phenotypes. However, whether host genetic variation shapes the gut microbiome and interacts with it to affect host phenotype is unclear. Here, we compared microbiotas across >1,000 fecal samples obtained from the TwinsUK population, including 416 twin pairs. We identified many microbial taxa whose abundances were influenced by host genetics. The most heritable taxon, the family Christensenellaceae, formed a co-occurrence network with other heritable Bacteria and with methanogenic Archaea. Furthermore, Christensenellaceae and its partners were enriched in individuals with low body mass index (BMI). An obese-associated microbiome was amended with Christensenella minuta, a cultured member of the Christensenellaceae, and transplanted to germ-free mice. C. minuta amendment reduced weight gain and altered the microbiome of recipient mice. Our findings indicate that host genetics influence the composition of the human gut microbiome and can do so in ways that impact host metabolism.

Public human microbiome data are dominated by highly developed countries.

The importance of sampling from globally representative populations has been well established in human genomics. In human microbiome research, however, we lack a full understanding of the global distribution of sampling in research studies. This information is crucial to better understand global patterns of microbiome-associated diseases and to extend the health benefits of this research to all populations. Here, we analyze the country of origin of all 444,829 human microbiome samples that are available from the world's 3 largest genomic data repositories, including the Sequence Read Archive (SRA). The samples are from 2,592 studies of 19 body sites, including 220,017 samples of the gut microbiome. We show that more than 71% of samples with a known origin come from Europe, the United States, and Canada, including 46.8% from the US alone, despite the country representing only 4.3% of the global population. We also find that central and southern Asia is the most underrepresented region: Countries such as India, Pakistan, and Bangladesh account for more than a quarter of the world population but make up only 1.8% of human microbiome samples. These results demonstrate a critical need to ensure more global representation of participants in microbiome studies.

Temporal patterns of gut microbiota in lemurs (Eulemur rubriventer) living in intact and disturbed habitats in a novel sample type.

The gut microbiome is a plastic phenotype; gut microbial composition is highly variable across an individual host's lifetime and between host social groups, and this variation has consequences for host health. However, we do not yet fully understand how longitudinal microbial dynamics and their social drivers may be influenced by ecological stressors, such as habitat degradation. Answering these questions is difficult in most wild animal systems, as it requires long-term collections of matched host, microbiome, and environmental trait data. To test if temporal and social influences on microbiome composition differ by the history of human disturbance, we leveraged banked, desiccated fecal samples collected over 5 months in 2004 from two ecologically distinct populations of wild, red-bellied lemurs (Eulemur rubriventer) that are part of a long-term study system. We found that social group explained more variation in microbiome composition than host population membership did, and that temporal variation in common microbial taxa was similar between populations, despite differences in history of human disturbance. Furthermore, we found that social group membership and collection month were both more important than individual lemur identity. Taken together, our results suggest that synchronized environments use can lead to synchronized microbial dynamics over time, even between habitats of varying quality, and that desiccated samples could become a viable approach for studying primate gut microbiota. Our work opens the door for other projects to utilize historic biological sample data sets to answer novel temporal microbiome questions in an ecological context.

Multi-Omics Analyses Show Disease, Diet, and Transcriptome Interactions With the Virome.

BACKGROUND & AIMS: The gut virome includes eukaryotic viruses and bacteriophages that can shape the gut bacterial community and elicit host responses. The virome can be implicated in diseases, such as irritable bowel syndrome (IBS), where gut bacteria play an important role in pathogenesis. We provide a comprehensive and longitudinal characterization of the virome, including DNA and RNA viruses and paired multi-omics data in a cohort of healthy subjects and patients with IBS. METHODS: We selected 2 consecutive stool samples per subject from a longitudinal study cohort and performed metagenomic sequencing on DNA and RNA viruses after enriching for viral-like particles. Viral sequence abundance was evaluated over time, as well as in the context of diet, bacterial composition and function, metabolite levels, colonic gene expression, host genetics, and IBS subsets. RESULTS: We found that the gut virome was temporally stable and correlated with the colonic transcriptome. We identified IBS-subset-specific changes in phage populations; Microviridae, Myoviridae, and Podoviridae species were elevated in diarrhea-predominant IBS, and other Microviridae and Myoviridae species were elevated in constipation-predominant IBS compared to healthy controls. We identified correlations between subsets of the virome and bacterial composition (unclassifiable "dark matter" and phages) and diet (eukaryotic viruses). CONCLUSIONS: We found that the gut virome is stable over time but varies among subsets of patients with IBS. It can be affected by diet and potentially influences host function via interactions with gut bacteria and/or altering host gene expression.

Rxivist.org: Sorting biology preprints using social media and readership metrics.

Preprints have arrived. In increasing numbers, researchers across the life sciences are embracing the once-niche practice, shaking off decades of reluctance and posting hundreds of papers per week to preprint servers, sharing their findings with the community before embarking on the weary march through peer review. However, there are limited methods for individuals sifting through this avalanche of research to identify the preprints that are most relevant to their interests. Here, we describe Rxivist.org, a website that indexes all preprints posted to bioRxiv.org, the largest preprint server in the life sciences, and allows users to filter and sort papers based on download metrics and Twitter activity over a variety of categories and time periods. In this work, we hope to make it easier for readers to find relevant research on bioRxiv and to improve the visibility of preprints currently being read and discussed online.

Challenges and recommendations to improve the installability and archival stability of omics computational tools.

Developing new software tools for analysis of large-scale biological data is a key component of advancing modern biomedical research. Scientific reproduction of published findings requires running computational tools on data generated by such studies, yet little attention is presently allocated to the installability and archival stability of computational software tools. Scientific journals require data and code sharing, but none currently require authors to guarantee the continuing functionality of newly published tools. We have estimated the archival stability of computational biology software tools by performing an empirical analysis of the internet presence for 36,702 omics software resources published from 2005 to 2017. We found that almost 28% of all resources are currently not accessible through uniform resource locators (URLs) published in the paper they first appeared in. Among the 98 software tools selected for our installability test, 51% were deemed "easy to install," and 28% of the tools failed to be installed at all because of problems in the implementation. Moreover, for papers introducing new software, we found that the number of citations significantly increased when authors provided an easy installation process. We propose for incorporation into journal policy several practical solutions for increasing the widespread installability and archival stability of published bioinformatics software.

Functional Genomics of Host-Microbiome Interactions in Humans.

The human microbiome has been linked to various host phenotypes and has been implicated in many complex human diseases. Recent genome-wide association studies (GWASs) have used microbiome variation as a complex trait and have uncovered human genetic variants that are associated with the microbiome. Here we summarize results from these studies and illustrate potential regulatory mechanisms by which host genetic variation can interact with microbiome composition. We argue that, similar to human GWASs, it is important to use functional genomics techniques to gain a mechanistic understanding of causal host-microbiome interactions and their role in human disease. We highlight experimental, functional, and computational genomics methodologies for the study of the genomic basis of host-microbiome interactions and describe how these approaches can be utilized to explain how human genetic variation can modulate the effects of the microbiome on the host.

Gut microbiota diversity across ethnicities in the United States.

Composed of hundreds of microbial species, the composition of the human gut microbiota can vary with chronic diseases underlying health disparities that disproportionally affect ethnic minorities. However, the influence of ethnicity on the gut microbiota remains largely unexplored and lacks reproducible generalizations across studies. By distilling associations between ethnicity and differences in two US-based 16S gut microbiota data sets including 1,673 individuals, we report 12 microbial genera and families that reproducibly vary by ethnicity. Interestingly, a majority of these microbial taxa, including the most heritable bacterial family, Christensenellaceae, overlap with genetically associated taxa and form co-occurring clusters linked by similar fermentative and methanogenic metabolic processes. These results demonstrate recurrent associations between specific taxa in the gut microbiota and ethnicity, providing hypotheses for examining specific members of the gut microbiota as mediators of health disparities.

Colorectal cancer mutational profiles correlate with defined microbial communities in the tumor microenvironment.

Variation in the gut microbiome has been linked to colorectal cancer (CRC), as well as to host genetic variation. However, we do not know whether, in addition to baseline host genetics, somatic mutational profiles in CRC tumors interact with the surrounding tumor microbiome, and if so, whether these changes can be used to understand microbe-host interactions with potential functional biological relevance. Here, we characterized the association between CRC microbial communities and tumor mutations using microbiome profiling and whole-exome sequencing in 44 pairs of tumors and matched normal tissues. We found statistically significant associations between loss-of-function mutations in tumor genes and shifts in the abundances of specific sets of bacterial taxa, suggestive of potential functional interaction. This correlation allows us to statistically predict interactions between loss-of-function tumor mutations in cancer-related genes and pathways, including MAPK and Wnt signaling, solely based on the composition of the microbiome. In conclusion, our study shows that CRC microbiomes are correlated with tumor mutational profiles, pointing towards possible mechanisms of molecular interaction.

Mapping gastrointestinal gene expression patterns in wild primates and humans via fecal RNA-seq.

BACKGROUND: Limited accessibility to intestinal epithelial tissue in wild animals and humans makes it challenging to study patterns of intestinal gene regulation, and hence to monitor physiological status and health in field conditions. To explore solutions to this limitation, we have used a noninvasive approach via fecal RNA-seq, for the quantification of gene expression markers in gastrointestinal cells of free-range primates and a forager human population. Thus, a combination of poly(A) mRNA enrichment and rRNA depletion methods was used in tandem with RNA-seq to quantify and compare gastrointestinal gene expression patterns in fecal samples of wild Gorilla gorilla gorilla (n = 9) and BaAka hunter-gatherers (n = 10) from The Dzanga Sangha Protected Areas, Central African Republic. RESULTS: Although only a small fraction (< 4.9%) of intestinal mRNA signals was recovered, the data was sufficient to detect significant functional differences between gorillas and humans, at the gene and pathway levels. These intestinal gene expression differences were specifically associated with metabolic and immune functions. Additionally, non-host RNA-seq reads were used to gain preliminary insights on the subjects' dietary habits, intestinal microbiomes, and infection prevalence, via identification of fungi, nematode, arthropod and plant RNA. CONCLUSIONS: Overall, the results suggest that fecal RNA-seq, targeting gastrointestinal epithelial cells can be used to evaluate primate intestinal physiology and gut gene regulation, in samples obtained in challenging conditions in situ. The approach used herein may be useful to obtain information on primate intestinal health, while revealing preliminary insights into foraging ecology, microbiome, and diet.

Genes, geology and germs: gut microbiota across a primate hybrid zone are explained by site soil properties, not host species.

Gut microbiota in geographically isolated host populations are often distinct. These differences have been attributed to between-population differences in host behaviours, environments, genetics and geographical distance. However, which factors are most important remains unknown. Here, we fill this gap for baboons by leveraging information on 13 environmental variables from 14 baboon populations spanning a natural hybrid zone. Sampling across a hybrid zone allowed us to additionally test whether phylosymbiosis (codiversification between hosts and their microbiota) is detectable in admixed, closely related primates. We found little evidence of genetic effects: none of host genetic ancestry, host genetic relatedness nor genetic distance between host populations were strong predictors of baboon gut microbiota. Instead, gut microbiota were best explained by the baboons' environments, especially the soil's geologic history and exchangeable sodium. Indeed, soil effects were 15 times stronger than those of host-population FST, perhaps because soil predicts which foods are present, or because baboons are terrestrial and consume soil microbes incidentally with their food. Our results support an emerging picture in which environmental variation is the dominant predictor of host-associated microbiomes. We are the first to show that such effects overshadow host species identity among members of the same primate genus.

Archaic Hominin Introgression in Africa Contributes to Functional Salivary MUC7 Genetic Variation.

One of the most abundant proteins in human saliva, mucin-7, is encoded by the MUC7 gene, which harbors copy number variable subexonic repeats (PTS-repeats) that affect the size and glycosylation potential of this protein. We recently documented the adaptive evolution of MUC7 subexonic copy number variation among primates. Yet, the evolution of MUC7 genetic variation in humans remained unexplored. Here, we found that PTS-repeat copy number variation has evolved recurrently in the human lineage, thereby generating multiple haplotypic backgrounds carrying five or six PTS-repeat copy number alleles. Contrary to previous studies, we found no associations between the copy number of PTS-repeats and protection against asthma. Instead, we revealed a significant association of MUC7 haplotypic variation with the composition of the oral microbiome. Furthermore, based on in-depth simulations, we conclude that a divergent MUC7 haplotype likely originated in an unknown African hominin population and introgressed into ancestors of modern Africans.

The gut microbiome of nonhuman primates: Lessons in ecology and evolution.

The mammalian gastrointestinal (GI) tract is home to trillions of bacteria that play a substantial role in host metabolism and immunity. While progress has been made in understanding the role that microbial communities play in human health and disease, much less attention has been given to host-associated microbiomes in nonhuman primates (NHPs). Here we review past and current research exploring the gut microbiome of NHPs. First, we summarize methods for characterization of the NHP gut microbiome. Then we discuss variation in gut microbiome composition and function across different NHP taxa. Finally, we highlight how studying the gut microbiome offers new insights into primate nutrition, physiology, and immune system function, as well as enhances our understanding of primate ecology and evolution. Microbiome approaches are useful tools for studying relevant issues in primate ecology. Further study of the gut microbiome of NHPs will offer new insight into primate ecology and evolution as well as human health.

Variation in Rural African Gut Microbiota Is Strongly Correlated with Colonization by Entamoeba and Subsistence.

The human gut microbiota is impacted by host nutrition and health status and therefore represents a potentially adaptive phenotype influenced by metabolic and immune constraints. Previous studies contrasting rural populations in developing countries to urban industrialized ones have shown that industrialization is strongly correlated with patterns in human gut microbiota; however, we know little about the relative contribution of factors such as climate, diet, medicine, hygiene practices, host genetics, and parasitism. Here, we focus on fine-scale comparisons of African rural populations in order to (i) contrast the gut microbiota of populations inhabiting similar environments but having different traditional subsistence modes and either shared or distinct genetic ancestry, and (ii) examine the relationship between gut parasites and bacterial communities. Characterizing the fecal microbiota of Pygmy hunter-gatherers as well as Bantu individuals from both farming and fishing populations in Southwest Cameroon, we found that the gut parasite Entamoeba is significantly correlated with microbiome composition and diversity. We show that across populations, colonization by this protozoa can be predicted with 79% accuracy based on the composition of an individual's gut microbiota, and that several of the taxa most important for distinguishing Entamoeba absence or presence are signature taxa for autoimmune disorders. We also found gut communities to vary significantly with subsistence mode, notably with some taxa previously shown to be enriched in other hunter-gatherers groups (in Tanzania and Peru) also discriminating hunter-gatherers from neighboring farming or fishing populations in Cameroon.

Multi-omic approaches for host-microbiome data integration.

The gut microbiome interacts with the host through complex networks that affect physiology and health outcomes. It is becoming clear that these interactions can be measured across many different omics layers, including the genome, transcriptome, epigenome, metabolome, and proteome, among others. Multi-omic studies of the microbiome can provide insight into the mechanisms underlying host-microbe interactions. As more omics layers are considered, increasingly sophisticated statistical methods are required to integrate them. In this review, we provide an overview of approaches currently used to characterize multi-omic interactions between host and microbiome data. While a large number of studies have generated a deeper understanding of host-microbiome interactions, there is still a need for standardization across approaches. Furthermore, microbiome studies would also benefit from the collection and curation of large, publicly available multi-omics datasets.

Assembly, stability, and dynamics of the infant gut microbiome are linked to bacterial strains and functions in mother's milk.

The establishment of the gut microbiome in early life is critical for healthy infant development. Although human milk is recommended as the sole source of nutrition for the human infant, little is known about how variation in milk composition, and especially the milk microbiome, shapes the microbial communities in the infant gut. Here, we quantified the similarity between the maternal milk and the infant gut microbiome using 507 metagenomic samples collected from 195 mother-infant pairs at one, three, and six months postpartum. We found that the microbial taxonomic overlap between milk and the infant gut was driven by bifidobacteria, in particular by B. longum. Infant stool samples dominated by B. longum also showed higher temporal stability compared to samples dominated by other species. We identified two instances of strain sharing between maternal milk and the infant gut, one involving a commensal (B. longum) and one a pathobiont (K. pneumoniae). In addition, strain sharing between unrelated infants was higher among infants born at the same hospital compared to infants born in different hospitals, suggesting a potential role of the hospital environment in shaping the infant gut microbiome composition. The infant gut microbiome at one month compared to six months of age was enriched in metabolic pathways associated with de-novo molecule biosynthesis, suggesting that early colonisers might be more versatile and metabolically independent compared to later colonizers. Lastly, we found a significant overlap in antimicrobial resistance genes carriage between the mother's milk and their infant's gut microbiome. Taken together, our results suggest that the human milk microbiome has an important role in the assembly, composition, and stability of the infant gut microbiome.