Mining metagenomes reveals gut mycobiome alterations with metformin and type 2 diabetes mellitus

Multiple recent studies have implicated the gut mycobiome, the fungal component of the microbiome, in human diseases. Considering that the role of the bacterial microbiome (bacteriome) in metabolic disease is well established, it is plausible that the mycobiome could also play an important role. Yet, recent studies of the human mycobiome have been small with inconsistent findings regarding metabolic diseases, and they did not account for use of oral pharmaceuticals. Oral pharmaceuticals, including the antidiabetic drug metformin, interact with gut bacteria and alter microbial metabolism with subsequent consequences for host glucose regulation. However, the potential interactions of pharmaceuticals with gut fungi remain entirely unknown. In this article we reanalyze published shotgun metagenomics from 9 studies to quantify if and to what degree there is a conserved relationship between the gut mycobiome and metabolic disease. To ensure our inferences are reproducible and statistically rigorous, we use Bayesian multinomial logistic normal models to account for numerous sources of variation and potential confounding, including count variation, compositional constraints, and batch effects induced by differences in study design and sample processing. Using these methods, we analyze data from over 1,000 human metagenomic samples and identify consistent associations with fungal genera, type 2 diabetes mellitus, and metformin treatment. Beyond humans, we perform a novel murine study to show that these relationships are reproducible across species. Overall, we conclude that there is a consistent relationship between the gut mycobiome, T2D, and metformin treatment.