Strain population structure varies widely across bacterial species and predicts strain colonization in unrelated individuals

et al. 2021

Preprint

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SUMMARYThe 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.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Spindler

Siu

et al. 2021

Preprint

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“…S1A). As previously described [20][21][22] , these distances are the result of most isolates of a given species in an individual being replicates of the same strain that is reisolated many times, while the same strain is very rarely shared between unrelated individuals. Therefore, we count the number of unique strains for a species (i.e., strain richness; SR) within an individual i for a given species j (i.e., SR ij ) as the number of genomes with a k-mer distance of at least 0.04.…”

Section: Determining the Average Strain Richness Of Gut Bacterial Spe...mentioning

confidence: 91%

Gut microbiota bacterial strain richness is species specific and limits therapeutic engraftment

Chen-Liaw

Aggarwala

et al. 2022

Preprint

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Despite the fundamental role of strain variation in gut microbiota function, the number of unique strains of a species that can stably colonize the human gut is still unknown. In this work, we determine the strain richness of common gut species using thousands of sequenced bacterial isolates and metagenomes. We find that strain richness varies across species, is transferable by fecal microbiota transplantation, and is low in the gut compared to other environments. Therapeutic administration of supraphysiologic numbers of strains per species only temporarily increases recipient strain richness, which subsequently converges back to the population average. These results suggest that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and provide a theoretical framework for strain engraftment and replacement in fecal microbiota transplantation and defined live biotherapeutic products.

“…We calculated genomic distances at the resolution of bacterial strains ( Fig. 1 J ) by comparing the kmer-overlap between each pairwise combination of strains using a kmer size of 20 ( 38 ). For more distantly related taxa ( SI Appendix , Fig.…”

Section: Methodsmentioning

confidence: 99%

Species-specific CD4 ⁺ T cells enable prediction of mucosal immune phenotypes from microbiota composition

Spindler

Proc. Natl. Acad. Sci. U.S.A.

Suri

et al. 2023

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How bacterial strains within a complex human microbiota collectively shape intestinal T cell homeostasis is not well understood. Methods that quickly identify effector strains or species that drive specific mucosal T cell phenotypes are needed to define general principles for how the microbiota modulates host immunity. We colonize germ-free mice with defined communities of cultured strains and profile antigen-specific responses directed toward individual strains ex vivo. We find that lamina propria T cells are specific to bacterial strains at the species level and can discriminate between strains of the same species. Ex vivo restimulations consistently identify the strains within complex communities that induce Th17 responses in vivo, providing the potential to shape baseline immune tone via community composition. Using an adoptive transfer model of colitis, we find that lamina propria T cells respond to different bacterial strains in conditions of inflammation versus homeostasis. Collectively, our approach represents a unique method for efficiently predicting the relative impact of individual bacterial strains within a complex community and for parsing microbiota-dependent phenotypes into component fractions.