The human gut microbiome has been associated with many health factors but variability between studies limits exploration of effects between them. Gut microbiota profiles are available for >2700 members of the deeply phenotyped TwinsUK cohort, providing a uniform platform for such comparisons. Here, we present gut microbiota association analyses for 38 common diseases and 51 medications within the cohort. We describe several novel associations, highlight associations common across multiple diseases, and determine which diseases and medications have the greatest association with the gut microbiota. These results provide a reference for future studies of the gut microbiome and its role in human health.

Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identify extensive cell-type specific expression changes: 6,711 genes and 10,724 transcripts, enriched in non-protein coding elements at early stages of differentiation. In addition, we discovered 7,881 novel splice junctions and 2,301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrate experimentally cell specific isoform usage, identifying NFIB as a regulator of megakaryocyte maturation -the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.

The human gut is inhabited by a complex and metabolically active microbial ecosystem. While many studies focused on the effect of individual microbial taxa on human health, their overall metabolic potential has been under-explored. Using whole-metagenome shotgun sequencing data in 1,004 twins, we first observed that unrelated subjects share, on average, almost double the number of metabolic pathways (82%) than species (43%). Then, using 673 blood and 713 faecal metabolites, we found metabolic pathways to be associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species showed less than 3,000 associations. Finally, we estimated that the microbiome was involved in a dialogue between 71% of faecal, and 15% of blood, metabolites. This study underlines the importance of studying the microbial metabolic potential rather than focusing purely on taxonomy to find therapeutic and diagnostic targets, and provides a unique resource describing the interplay between the microbiome and the systemic and faecal metabolic environments.

BackgroundCandida glabrata follows C. albicans as the second or third most prevalent cause of candidemia worldwide. These two pathogenic yeasts are distantly related, C. glabrata being part of the Nakaseomyces, a group more closely related to Saccharomyces cerevisiae. Although C. glabrata was thought to be the only pathogenic Nakaseomyces, two new pathogens have recently been described within this group: C. nivariensis and C. bracarensis. To gain insight into the genomic changes underlying the emergence of virulence, we sequenced the genomes of these two, and three other non-pathogenic Nakaseomyces, and compared them to other sequenced yeasts.ResultsOur results indicate that the two new pathogens are more closely related to the non-pathogenic N. delphensis than to C. glabrata. We uncover duplications and accelerated evolution that specifically affected genes in the lineage preceding the group containing N. delphensis and the three pathogens, which may provide clues to the higher propensity of this group to infect humans. Finally, the number of Epa-like adhesins is specifically enriched in the pathogens, particularly in C. glabrata.ConclusionsRemarkably, some features thought to be the result of adaptation of C. glabrata to a pathogenic lifestyle, are present throughout the Nakaseomyces, indicating these are rather ancient adaptations to other environments. Phylogeny suggests that human pathogenesis evolved several times, independently within the clade. The expansion of the EPA gene family in pathogens establishes an evolutionary link between adhesion and virulence phenotypes. Our analyses thus shed light onto the relationships between virulence and the recent genomic changes that occurred within the Nakaseomyces.Sequence Accession NumbersNakaseomyces delphensis: CAPT01000001 to CAPT01000179Candida bracarensis: CAPU01000001 to CAPU01000251Candida nivariensis: CAPV01000001 to CAPV01000123Candida castellii: CAPW01000001 to CAPW01000101Nakaseomyces bacillisporus: CAPX01000001 to CAPX01000186

The Génolevures Consortium 1 Our knowledge of yeast genomes remains largely dominated by the extensive studies on Saccharomyces cerevisiae and the consequences of its ancestral duplication, leaving the evolution of the entire class of hemiascomycetes only partly explored. We concentrate here on five species of Saccharomycetaceae, a large subdivision of hemiascomycetes, that we call ''protoploid'' because they diverged from the S. cerevisiae lineage prior to its genome duplication. We determined the complete genome sequences of three of these species: Kluyveromyces (Lachancea) thermotolerans and Saccharomyces (Lachancea) kluyveri (two members of the newly described Lachancea clade), and Zygosaccharomyces rouxii. We included in our comparisons the previously available sequences of Kluyveromyces lactis and Ashbya (Eremothecium) gossypii. Despite their broad evolutionary range and significant individual variations in each lineage, the five protoploid Saccharomycetaceae share a core repertoire of approximately 3300 protein families and a high degree of conserved synteny. Synteny blocks were used to define gene orthology and to infer ancestors. Far from representing minimal genomes without redundancy, the five protoploid yeasts contain numerous copies of paralogous genes, either dispersed or in tandem arrays, that, altogether, constitute a third of each genome. Ancient, conserved paralogs as well as novel, lineage-specific paralogs were identified.

Reduced gut microbiome diversity is associated with multiple disorders including metabolic syndrome (MetS) features, though metabolomic markers have not been investigated. Our objective was to identify blood metabolite markers of gut microbiome diversity, and explore their relationship with dietary intake and MetS. We examined associations between Shannon diversity and 292 metabolites profiled by the untargeted metabolomics provider Metabolon Inc. in 1529 females from TwinsUK using linear regressions adjusting for confounders and multiple testing (Bonferroni: P < 1.71 × 10−4). We replicated the top results in an independent sample of 420 individuals as well as discordant identical twin pairs and explored associations with self-reported intakes of 20 food groups. Longitudinal changes in circulating levels of the top metabolite, were examined for their association with food intake at baseline and with MetS at endpoint. Five metabolites were associated with microbiome diversity and replicated in the independent sample. Higher intakes of fruit and whole grains were associated with higher levels of hippurate cross-sectionally and longitudinally. An increasing hippurate trend was associated with reduced odds of having MetS (OR: 0.795[0.082]; P = 0.026). These data add further weight to the key role of the microbiome as a potential mediator of the impact of dietary intake on metabolic status and health.

The human gut is inhabited by a complex and metabolically active microbial ecosystem regulating host health. While many studies have focused on the effect of individual microbial taxa, the metabolic potential of the entire gut microbial ecosystem has been largely under-explored. We characterised the gut microbiome of 1,004 twins via whole shotgun metagenomic sequencing (average 39M reads per sample). We observed greater similarity, across unrelated individuals, for functional metabolic pathways (82%) than for taxonomic composition (43%). We conducted a microbiota-wide association study linking both taxonomic information and microbial metabolic pathways with 673 blood and 713 faecal metabolites (Metabolon, Inc.). Metabolic pathways associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species-level results identified less than 3,000 associations, suggesting that coordinated action of multiple taxa is required to affect the metabolome. Finally, we estimated that the microbiome mediated a crosstalk between 71% of faecal and 15% of blood metabolites, highlighting six key species (unclassified Subdoligranulum spp., Faecalibacterium prausnitzii, Roseburia inulinivorans, Methanobrevibacter smithii, Eubacterium rectale, and Akkermansia muciniphila). Because of the large inter-person variability in microbiome composition, our results underline the importance of studying gut microbial metabolic pathways rather than focusing purely on taxonomy to find therapeutic and diagnostic targets.

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