Broad-spectrum antibiotics disrupt homeostatic efferocytosis Journal Article
| Authors: | Saavedra, P. H. V.; Trzeciak, A. J.; Lipshutz, A.; Daman, A. W.; O’Neal, A. J.; Liu, Z. L.; Wang, Z.; Romero-Pichardo, J. E.; Rojas, W. S.; Zago, G.; van den Brink, M. R. M.; Josefowicz, S. Z.; Lucas, C. D.; Anderson, C. J.; Rudensky, A. Y.; Perry, J. S. A. |
| Article Title: | Broad-spectrum antibiotics disrupt homeostatic efferocytosis |
| Abstract: | The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4–7. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | controlled study; antibiotic agent; unclassified drug; human cell; genetics; drug withdrawal; nonhuman; letter; polymerase chain reaction; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; apoptosis; confocal microscopy; animal experiment; animal model; membrane proteins; dexamethasone; genetic transcription; cell differentiation; drug effect; enzyme linked immunosorbent assay; mice, inbred c57bl; c57bl mouse; antiinfective agent; anti-bacterial agents; immunoglobulin g; messenger rna; cd11b antigen; escherichia coli; membrane protein; ras protein; down regulation; systemic lupus erythematosus; upregulation; oxidative stress; vancomycin; intestine flora; macrophage; phagocytosis; macrophages; homeostasis; rna 16s; metronidazole; dna extraction; fluorescence activated cell sorting; g protein coupled receptor; rac protein; butyric acid; histone deacetylase 3; rho factor; kanamycin; histone methylation; ampicillin; homeostasis and regulation; peritoneum macrophage; histone acetylation; butyrates; immunoglobulin deposition; fluorescence intensity; time lapse imaging; autoinflammatory disease; humans; human; male; female; fecal microbiota transplantation; rna sequencing; dysbiosis; macrophages, peritoneal; gastrointestinal microbiome; macrophage culture; efferocytosis; single cell rna seq; illumina sequencing; apoptosis assay; g protein coupled receptor 109a; g protein coupled receptor 41; g protein coupled receptor 43; tim-4 protein, mouse; blk rna sequencing |
| Journal Title: | Nature Metabolism |
| Volume: | 6 |
| Issue: | 9 |
| ISSN: | 2522-5812 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-09-01 |
| Start Page: | 1682 |
| End Page: | 1694 |
| Language: | English |
| DOI: | 10.1038/s42255-024-01107-7 |
| PUBMED: | 39122784 |
| PROVIDER: | scopus |
| PMCID: | PMC7616532 |
| DOI/URL: | |
| Notes: | Letter -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Justin Perry -- Source: Scopus |
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