{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Saavedra PHV"],"funding":["U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)","U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences","U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)","NIAID NIH HHS","U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)","U.S. Department of Health &amp; Human Services | NIH | NIH Office of the Director","Burroughs Wellcome Fund (BWF)","U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)","Burroughs Wellcome Fund","Medical Research Council","U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute","NCI NIH HHS","Wellcome Trust","NIGMS NIH HHS"],"pagination":["1682-1694"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7616532"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(9)"],"pubmed_abstract":["The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity<sup>1</sup>. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue<sup>2,3</sup>, 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 disease<sup>4-7</sup>."],"journal":["Nature metabolism"],"pubmed_title":["Broad-spectrum antibiotics disrupt homeostatic efferocytosis."],"pmcid":["PMC7616532"],"funding_grant_id":["PATH","5R00CA237728","P30 CA008748","1DP2GM146337","R00 CA237728","RM1GM139738","MR/X019314/1","DP2 GM146337","RM1 GM139738","MR/W019264/1","R01 AI148416","225923/Z/22/Z","P30CA008748","R01AI148416"],"pubmed_authors":["Trzeciak AJ","van den Brink MRM","Rudensky AY","Zago G","Daman AW","Liu ZL","Lucas CD","Lipshutz A","Saavedra PHV","O'Neal AJ","Romero-Pichardo JE","Rojas WS","Wang Z","Anderson CJ","Perry JSA","Josefowicz SZ"],"additional_accession":[]},"is_claimable":false,"name":"Broad-spectrum antibiotics disrupt homeostatic efferocytosis.","description":"The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity<sup>1</sup>. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue<sup>2,3</sup>, 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 disease<sup>4-7</sup>.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Sep","modification":"2026-05-13T14:46:12.517Z","creation":"2025-04-04T08:21:39.813Z"},"accession":"S-EPMC7616532","cross_references":{"pubmed":["39122784"],"doi":["10.1038/s42255-024-01107-7"]}}