Tracking humans and Their Microbiomes

As these GEITP pages have continued to emphasize: Multifactorial phenotypes — including complex diseases (e.g. type-2 diabetes, major depressive disorder), quantitative traits (e.g. body mass index, height), drug efficacy and adverse drug reactions, and responses to environmental toxicants (e.g. dioxin, cigarette smoke, arsenic) — refect contributions of genetics, epigenetic effects, environmental factors, endogenous influences, and each patient’s microbiome. The latest breakthroughs in microbiome research are the topics of this GEITP email and the next one [see three articles & one editorial attached; another article, plus editorial, on the vaginal microbiome will follow].

Studies from the US National Institutes of Health Integrative Human Microbiome Project (iHMP) provide a resource of microbial- and human-derived data — tracking the progression of two diseases (ulcerative colitis, type-2 diabetes) and pregnancy that should help us understand host-associated microorganisms and their interactions with their human host [see 2nd article & 3rd attachment editorial]. The Human Microbiome Project has now been carried out over a 10-year period (encompassing TWO phases) to provide resources, methods, and discoveries that link interactions between humans and their microbiomes to health-related outcomes. The recently completed second phase, the iHMP, comprised studies of dynamic changes in the microbiome and host under three conditions: pregnancy and preterm birth; inflammatory bowel diseases; and stressors that affect individuals with prediabetes. These results begin to: [a] elucidate mechanisms of host–microbiome interactions under these conditions, [b] provide unique data resources (at the HMP Data Coordination Center), and [c] represent a paradigm for future multi-omic studies of the human microbiome.

Inflammatory bowel diseases (IBDs) — which include Crohn disease and ulcerative colitis — are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. As part of the iHMP, authors [see attached 1st article] followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease flare-ups (as many as 24 time-points each; in total 2,965 stool, biopsy, and blood specimens). Authors provide a comprehensive view of functional dysbiosis (a microbial imbalance, or maladaptation — on, or inside, the body) in the gut microbiome during inflammatory bowel disease activity. Authors demonstrate a characteristic increase in facultative anaerobes [organisms that can live by aerobic respiration if O2 is present, but are also able to switch to fermentation (or anaerobic respiration) if O2 is lacking] at the expense of obligate anaerobes (organisms that die in presence of O2), as well as molecular disruptions in microbial transcription (DNA —> RNA, among e.g. clostridia bacteria), metabolite pools (e.g. 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 (different bacterial species), 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 (, provide the most comprehensive description, to date, of host and microbial activities in inflammatory bowel diseases.

To better understand the earliest stages of type-2 diabetes mellitus (T2D), authors [see 4th attachment] obtained samples from 106 healthy individuals, vs individuals with prediabetes over approximately four years and performed deep-profiling of transcriptomes, metabolomes, cytokines (substances secreted by certain cells of the immune system, which have an effect on other cells), and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: First, healthy profiles are distinct among individuals — while exhibiting diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization. However, immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association metabolomics analyses among the thousands of profiled molecules reveal specific host–microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Fourth, authors identified early personal molecular signatures in one individual that preceded the onset of T2D — including the inflammation markers interleukin-1-receptor agonist (IL1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signaling. This study reveals insights into pathways and responses that differ between healthy vs glucose-dysregulated individuals during health and disease. These data provide an open-access data resource to enable further research into healthy, prediabetic and T2D states. Everything attached is there — for your bedtime reading pleasure. 😊


Nature 30 May 2o19; 569: 641-648 & 655-662 & 653-671

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