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Identifying a scalable, unbiased method for discovering which members of the human gut microbiota influence specific physiologic, metabolic, and immunologic phenotypes remains a challenge. We describe a method in which a clonally arrayed collection of cultured, sequenced bacteria was generated from one of several human fecal microbiota samples found to transmit a particular phenotype to recipient germ-free mice. Ninety-four bacterial consortia of diverse size, randomly drawn from the culture collection, were introduced into germ-free animals. We identified an unanticipated range of bacterial strains that promoted accumulation of colonic regulatory T cells (Tregs) and expansion of Nrp1lo/− peripheral Tregs, as well as strains that modulated mouse adiposity and cecal metabolite concentrations, using feature selection algorithms and follow-up monocolonizations. This combinatorial approach enables a systems-level understanding of microbial contributions to human biology.
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