Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases

Genomic variation and strain-specific functional adaptation in the human gut microbiome during early life

The human gut microbiome matures towards the adult composition during the first years of life and is implicated in early immune development. Here, we investigate the effects of microbial genomic diversity on gut microbiome development using integrated early childhood data sets collected in the DIABIMMUNE study in Finland, Estonia and Russian Karelia. We show that gut microbial diversity is associated with household location and linear growth of children. Single nucleotide polymorphism- and metagenomic assembly-based strain tracking revealed large and highly dynamic microbial pangenomes, especially in the genus Bacteroides, in which we identified evidence of variability deriving from Bacteroides-targeting bacteriophages. Our analyses revealed functional consequences of strain diversity; only 10% of Finnish infants harboured Bifidobacterium longum subsp. infantis, a subspecies specialized in human milk metabolism, whereas Russian infants commonly maintained a probiotic Bifidobacterium bifidum strain in infancy. Groups of bacteria contributing to diverse, characterized metabolic pathways converged to highly subject-specific configurations over the first two years of life. This longitudinal study extends the current view of early gut microbial community assembly based on strain-level genomic variation.Peer reviewe

Predictive ability of host genetics and rumen microbiome for subclinical ketosis

Subclinical metabolic disorders such as ketosis cause substantial economic losses for dairy farmers in addition to the serious welfare issues they pose for dairy cows. Major hurdles in genetic improvement against metabolic disorders such as ketosis include difficulties in large-scale phenotype recording and low heritability of traits. Milk concentrations of ketone bodies, such as acetone and β-hydroxybutyric acid (BHB), might be useful indicators to select cows for low susceptibility to ketosis. However, heritability estimates reported for milk BHB and acetone in several dairy cattle breeds were low. The rumen microbial community has been reported to play a significant role in host energy homeostasis and metabolic and physiologic adaptations. The current study aims at investigating the effects of cows' genome and rumen microbial composition on concentrations of acetone and BHB in milk, and identifying specific rumen microbial taxa associated with variation in milk acetone and BHB concentrations. We determined the concentrations of acetone and BHB in milk using nuclear magnetic resonance spectroscopy on morning milk samples collected from 277 Danish Holstein cows. Imputed high-density genotype data were available for these cows. Using genomic and microbial prediction models with a 10-fold resampling strategy, we found that rumen microbial composition explains a larger proportion of the variation in milk concentrations of acetone and BHB than do host genetics. Moreover, we identified associations between milk acetone and BHB with some specific bacterial and archaeal operational taxonomic units previously reported to have low to moderate heritability, presenting an opportunity for genetic improvement. However, higher covariation between specific microbial taxa and milk acetone and BHB concentrations might not necessarily indicate a causal relationship; therefore further validation is needed before considering implementation in selection programs.publishedVersio

Cytokine-specific autoantibodies shape the gut microbiome in autoimmune polyendocrine syndrome type 1

Background: Gastrointestinal dysfunction is a frequent and disabling manifestation of autoimmune polyendocrine syndrome type 1 (APS-1), a rare monogenic multiorgan autoimmune disease caused by the loss of central AIRE-controlled immune tolerance. Objectives: This study aimed to understand the role of the gut microbiome in APS-1 symptoms and potentially alleviate common gastrointestinal symptoms by probiotic intervention. Methods: This study characterized the fecal microbiomes of 28 patients with APS-1 and searched for associations with gastrointestinal symptoms, circulating anti-cytokine autoantibodies, and tryptophan-related metabolites. Additionally, daily doses of the probiotic Lactobacillus rhamnosus GG were administered for 3 months. Results: Of 581 metagenomic operational taxonomic units (mOTUs) characterized in total, 14 were significantly associated with patients with APS-1 compared with healthy controls, with 6 mOTUs depleted and 8 enriched in patients with APS-1. Four overabundant mOTUs were significantly associated with severity of constipation. Phylogenetically conserved microbial associations with autoantibodies against cytokines were observed. After the 3-month intervention with the probiotic L rhamnosus GG, a subset of gastrointestinal symptoms were alleviated. L rhamnosus GG abundance was increased postintervention and corresponded with decreased abundances of Alistipes onderdonkii and Collinsella aerofaciens, 2 species positively associated with severity of diarrhea in patients with APS-1. Conclusions: The APS-1 microbiome correlates with several APS-1 symptoms, some of which are alleviated after a 3-month L rhamnosus GG intervention. Autoantibodies against cytokines appear to shape the gut microbiome by positively correlating with a taxonomically consistent group of bacteria

Genome binning of viral entities from bulk metagenomics data

Despite the accelerating number of uncultivated virus sequences discovered in metagenomics and their apparent importance for health and disease, the human gut virome and its interactions with bacteria in the gastrointestinal tract are not well understood. This is partly due to a paucity of whole-virome datasets and limitations in current approaches for identifying viral sequences in metagenomics data. Here, combining a deep-learning based metagenomics binning algorithm with paired metagenome and metavirome datasets, we develop Phages from Metagenomics Binning (PHAMB), an approach that allows the binning of thousands of viral genomes directly from bulk metagenomics data, while simultaneously enabling clustering of viral genomes into accurate taxonomic viral populations. When applied on the Human Microbiome Project 2 (HMP2) dataset, PHAMB recovered 6,077 high-quality genomes from 1,024 viral populations, and identified viral-microbial host interactions. PHAMB can be advantageously applied to existing and future metagenomes to illuminate viral ecological dynamics with other microbiome constituents

Predictive ability of host genetics and rumen microbiome for subclinical ketosis

Subclinical metabolic disorders such as ketosis cause substantial economic losses for dairy farmers in addition to the serious welfare issues they pose for dairy cows. Major hurdles in genetic improvement against metabolic disorders such as ketosis include difficulties in large-scale phenotype recording and low heritability of traits. Milk concentrations of ketone bodies, such as acetone and β-hydroxybutyric acid (BHB), might be useful indicators to select cows for low susceptibility to ketosis. However, heritability estimates reported for milk BHB and acetone in several dairy cattle breeds were low. The rumen microbial community has been reported to play a significant role in host energy homeostasis and metabolic and physiologic adaptations. The current study aims at investigating the effects of cows' genome and rumen microbial composition on concentrations of acetone and BHB in milk, and identifying specific rumen microbial taxa associated with variation in milk acetone and BHB concentrations. We determined the concentrations of acetone and BHB in milk using nuclear magnetic resonance spectroscopy on morning milk samples collected from 277 Danish Holstein cows. Imputed high-density genotype data were available for these cows. Using genomic and microbial prediction models with a 10-fold resampling strategy, we found that rumen microbial composition explains a larger proportion of the variation in milk concentrations of acetone and BHB than do host genetics. Moreover, we identified associations between milk acetone and BHB with some specific bacterial and archaeal operational taxonomic units previously reported to have low to moderate heritability, presenting an opportunity for genetic improvement. However, higher covariation between specific microbial taxa and milk acetone and BHB concentrations might not necessarily indicate a causal relationship; therefore further validation is needed before considering implementation in selection programs

Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level

The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a Glade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health

Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis

Intestinal adaptive immune responses influence host health, yet only a few intestinal bacteria species that induce cognate adaptive immune responses during homeostasis have been identified. Here, we show that Akkermansia muciniphila, an intestinal bacterium associated with systemic effects on host metabolism and PD-1 checkpoint immunotherapy, induces immunoglobulin G1 (IgG1) antibodies and antigen-specific T cell responses in mice. Unlike previously characterized mucosal responses, T cell responses to A. muciniphila are limited to T follicular helper cells in a gnotobiotic setting, without appreciable induction of other T helper fates or migration to the lamina propria. However, A. muciniphila-specific responses are context dependent and adopt other fates in conventional mice. These findings suggest that, during homeostasis, contextual signals influence T cell responses to the microbiota and modulate host immune function