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Gut commensal microbiota drive tailored macrophage responses.

Josh Jones,K. García-Martínez,Yi-Yuan Lee,Matthew W Rhee,Rahul R. Nath,Sola Takahashi,Benjamin Grodner,Iwijn De Vlaminck,Cynthia A Leifer,Ilana L. Brito

Published 2025 in Cell Reports

ABSTRACT

Macrophages serve as sentinels at the intestinal surface, responding to organismal cues to drive proinflammatory or tolerogenic responses. To date, studies of combinations of these cues do not fully capture the heterogeneity of macrophage responses. To address this gap, we performed multiplexed single-cell RNA sequencing on 74,476 human monocyte-derived macrophages following exposure to 15 bacteria, mostly commensals. We observe clusters that appeared only after macrophage exposure to bacteria, and transcriptional responses within each cluster varied by species and Gram status. The proportion of each cluster also varied among exposure conditions. Macrophages exposed to defined combinations of organisms revealed that Fusobacterium nucleatum drives inflammatory responses, whereas Mediterraneibacter gnavus tempers them. Overall, our results show that macrophages distinguish between commensal organisms, relevant to intestinal diseases characterized by altered microbiome compositions. This sequencing dataset will be a useful resource to probe human macrophage response to a broad range of bacteria.

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