Defining Innate Immune Responses to the Human Gut Microbiota from Phylum to Strain

The functional potential of the gut microbiota remains largely uncharacterized. Efforts to understand how the immune system responds to commensal organisms have been hindered by the large number of strains that comprise the human gut microbiota. We develop a screening platform to measure innate immune responses towards 277 bacterial strains isolated from the human gut microbiota. We find that innate immune responses to gut derived bacteria are as strong as responses towards pathogenic bacteria, and vary from phylum to strain. Myeloid cells differentially rely upon TLR2 or TLR4 to sense particular taxa, an observation that predicts in vivo function. These innate immune responses can be modeled using combinations of up to 8 TLR agonists. Furthermore, the immunogenicity of strains is stable over time and following transplantation into new humans. Collectively, we demonstrate a powerful high-throughput approach to determine how commensal microorganisms shape innate immune phenotypes. ### Competing Interest Statement J.J.F. is on the scientific advisory board of Vedanta Biosciences, reports receiving research grants from Janssen Pharmaceuticals and reports receiving consulting fees from Innovation Pharmaceuticals, Janssen Pharmaceuticals, BiomX and Vedanta Biosciences.