Host genetic regulation of gut mycobiome offers insights into the gut–brain interaction

The gut microbiota is interdependent with the human host, with available evidence suggesting that gut bacteria are partially regulated by host genetic factors. Yet, whether host genetic control accounts for any inter-individual variations in the gut fungal community remains elusive. Here we delineate the host genetic architecture associated with both gut fungi and bacteria in Chinese populations. Our findings reveal 114 host-variant-fungal and 81 host-variant-bacterial associations, with four fungal taxa surpassing study-wide significance. Notably, variants influencing those two kingdoms colocalize with distinct expression quantitative trait loci (eQTLs) across 27 immune cell types, and the associated genes exhibit brain-enriched gene expression. Magnetic resonance imaging analysis reveals positive associations of the fungal genus Eremothecium with thalamus and frontal cortex volumes. In vitro experiments further confirm the strong riboflavin-producing capacity of Eremothecium and suggest its potential modulation of microglial responses. Overall, our study depicts a holistic picture of host genetic regulation of the human gut mycobiota, offering a fresh perspective on the role of intricate host–microbiome interplay in human health.