Protective impacts of commensal protists on the human gut microbiome

PROJECT SUMMARY The human microbiome is a rich ecosystem that contains microbes from all domains of life, including bacteria, archaea, and eukaryotes such as fungi and protists. The gut microbiome exerts an important influence on the immune system, both in healthy and disease states. While the bacterial components of the microbiome have been well studied, little is known about the eukaryotic fraction. Eukaryotic protists, such as Blastocystis, are commonly found in the human gut. A growing body of evidence demonstrates that these commensal protists remodel the gut bacterial community and protect the host from gut inflammation, though the mechanisms of these actions remain completely unknown. These observations are at odds with traditional medical views that these protists are pathogenic; indeed, samples containing them are excluded from fecal microbiome transplant therapies due to a belief that they are harmful. Very little is known about the biology of commensal gut protists, including their genome sequences and how they interact with microbiome bacteria or the human host. In this proposal, high quality genomics of the most common human commensal protist Blastocysis will be established and two mechanisms of interaction with the microbiome and host will be investigated: bacterial predation and metabolite production. In Aim 1, high-quality, contiguous, and well-annotated genome assemblies of multiple Blastocystis subtypes will be generated. These high-quality assemblies will be used to determine the core and pan-genome content of the species and reveal functional pathways specific to individual subtypes that contribute to their microbiome functions. Using these genomes in combination with shotgun metagenomic sequencing will reveal whether this organism reproduces sexually. In Aim 2, the hypothesis that Blastocystis are bacterial predators will be tested through co-culturing experiments with bacteria identified to co-occur and co-exclude with these protists in the gut microbiome. In Aim 3, the small molecule repertoire of Blastocystis will be determined in vitro and in vivo, and how this organism influences the host-facing metabolome will be established. These experiments will further establish a rich source of metabolic data for future functional studies of host interactions. The work proposed here will establish gut commensal protist genomics and reveal fundamental mechanisms by which these organisms interact with the host and bacterial members of the microbiome. These findings have potential to indicate protists or their metabolites for use as probiotic interventions in inflammatory bowel diseases. The proposed work in this proposal will leverage the candidate’s expertise in the field of microbial eukaryotes with an expert interdisciplinary scientific advisory committee, enabling the candidate to establish a successful independent research program.