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Inflammatory Bowel Disease, Prediabetes, Preterm Birth Studies Reveal Microbiome-Host Interactions

NEW YORK (GenomeWeb) – Three research groups have characterized changes in the human microbiome and their effects on the host in the context of inflammatory bowel disease (IBD), prediabetes, and preterm birth and pregnancy.

The studies, which used multi-omic approaches, are part of the integrative Human Microbiome Project (iHMP) — the second phase of the Human Microbiome Project, which received $22 million in funding from the US National Institutes of Health in 2013. An overview of the project by the iHMP Research Network Consortium appeared in Nature this week and results from the individual studies were published in a series of papers.

In a study published in Nature, a group led by Curtis Huttenhower at the Harvard T.H. Chan School of Public Health followed 132 individuals with IBD, which includes Crohn's disease and ulcerative colitis, and healthy controls for one year. They characterized 651 colon biopsies at baseline, 529 blood samples, and 1,785 stool samples, looking at metagenomes, metatranscriptomes, proteomes, metabolomes, viromes, and other data types. They found an increase in facultative anaerobes, as well as disruptions in microbial transcription, metabolite pools, and antibody levels in the host serum that were associated with disease activity. According to the authors, the results and data are the most comprehensive description of host and microbial activities in IBD to date.

Researchers led by Michael Snyder at Stanford University School of Medicine, for a study also published in Nature this week, characterized 106 healthy and prediabetic individuals over four years, profiling their gut and nasal microbiomes, as well as their blood samples, looking at transcriptomes, metabolomes, cytokines, and proteomes. They found that many biochemical and microbial measurements remained stable during healthy periods but changed significantly when participants had respiratory viral infections or were vaccinated. In addition, the changes differed between insulin-sensitive and insulin-resistant individuals. "These deep multi-omics measurements enable us to investigate the early molecular signs of disease development at an individual level," the authors wrote. "Future efforts will help to provide additional mechanistic understanding of how the multi-omic factors affect health and are altered early in disease development, both at the cohort and individual levels."

A study led by Gregory Buck at Virginia Commonwealth University and published in Nature Medicine followed 1,572 pregnancies in women of diverse ancestries over time, generating omics data for samples of 597 pregnancies. They also studied 16S ribosomal RNA, metagenomic, metatranscriptomic, and cytokine profiles longitudinally in 45 women who experienced preterm birth and 90 controls, both predominantly of African ancestry. Women who gave birth prematurely, they found, had lower vaginal levels of Lactobacillus crispatus and higher levels of other taxa, which were also correlated with proinflammatory cytokines in vaginal fluid. "Taken together, our data suggest that, coupled with other clinical and possibly genetic factors, microbiome-associated taxonomic, metabolic, and immunologic biomarkers may be useful in defining the risk of [preterm birth], and that this risk might be assessed early in pregnancy," the authors concluded.

In a second study, also published in Nature Medicine, the VCU researchers investigated how the vaginal microbiome changes during pregnancy. Specifically, they profiled the vaginal microbiome of 613 pregnant and 1,969 non-pregnant women of African, Hispanic, or European ancestry, and they longitudinally sampled a cohort of 90 pregnant women. Vaginal microbiome composition and dynamics during pregnancy differed between ethnic background, they found, and Lactobacillus taxa appeared to be enriched in the microbiome of pregnant women. Overall, vaginal microbiome changes occurred early in pregnancy and were most significant in women of African or Hispanic ancestry, and some types of changes were associated with adverse pregnancy outcomes, including preterm birth. "Characterization of the composition of the vaginal microbiome is now readily achieved," the authors noted. "What remains is to verify the most favorable microbiome and the most effective strategy for intervention."

"[U]ndeniably, these studies provide the most comprehensive dynamic tracking of the health status of the human host and the characteristics of their microbiota that has been reported so far," Verónica Lloréns-Rico and Jeroen Raes of the Catholic University Leuven in Belgium wrote in a comment in Nature. "The generation of this rich resource is a landmark achievement."

They also noted that future studies will need to investigate how viral infections change the microbiome and whether they increase the risk of developing certain diseases or experiencing disease relapse.

Among the most interesting findings, they wrote, are the associations between certain microbes and pro- or anti-inflammatory cytokines, though no causal effect has been established yet.

They also pointed out weaknesses in the studies, for example their failure to account for factors such as diet or medication, the long intervals between measurements, the absence of absolute microbial abundance data, and the lack of replication in independent populations.

"Despite these limitations, one of the most valuable assets of the iHMP work is, undoubtedly, the fantastic trove of data that it provides, most of which is freely available, and which offers a useful resource for future research," they wrote