Summary Studies in mice and humans have revealed intriguing associations between host genetics and the microbiome. Here we report a 16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs, a subset of which was previously reported. Tripling the sample narrowed the confidence intervals around heritability estimates and uncovered additional heritable taxa, some of which are validated in other studies. Repeat sampling of subjects showed heritable taxa to be temporally stable. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism and olfaction. We replicate an association between Bifidobacterium and the lactase (LCT) gene locus and identify an association between the host gene ALDH1L1 and SHA-98 bacteria, suggesting a link between formate production and blood pressure. Additional genes detected are involved in barrier defense and self/non-self recognition. Our results indicate that diet-sensing, metabolism, and immune defense are important drivers of human-microbiome co-evolution.

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ObjectiveProton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort.DesignWe investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study.ResultsWe identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut.ConclusionsOur findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences.

We show that a citizen science, self-selected cohort shipping samples through the mail at room temperature recaptures many known microbiome results from clinically collected cohorts and reveals new ones. Of particular interest is integrating n = 1 study data with the population data, showing that the extent of microbiome change after events such as surgery can exceed differences between distinct environmental biomes, and the effect of diverse plants in the diet, which we confirm with untargeted metabolomics on hundreds of samples.

The human gut microbiome plays a key role in human health1, but 16S characterization lacks quantitative functional annotation2. The fecal metabolome provides a functional readout of microbial activity and could be used as an intermediate phenotype mediating these interactions3. In the first comprehensive description of the fecal metabolome, examining 1116 metabolites of 786 individuals from a population-based twin study (TwinsUK), the fecal metabolome was found to be only modestly influenced by host genetics (h2=17.9%). One replicated locus at the NAT2 gene was associated with fecal metabolic traits. The fecal metabolome largely reflects gut microbial composition explaining on average 67.7% (±18.8%) of its variance. It is strongly associated with visceral fat mass, illustrating potential mechanisms underlying the well-established microbial influence on abdominal obesity. Fecal metabolic profiling appears as a novel tool to explore links between microbiome composition, host phenotypes, and heritable complex traits.