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 tissue^2,3, 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 disease^4,5,6,7.

凋亡细胞的清除（称为胞吞作用）对于组织稳态和预防自身免疫至关重要¹ 。尽管过去的研究已经阐明了调节组织中稳态胞吞作用的局部分子信号^2,3 ，但远端产生的信号是否也调节稳态胞吞作用仍然难以捉摸。在这里，我们发现，大腹膜巨噬细胞（LPM）展示会损害广谱抗生素（ABX）处理、万古霉素处理和无菌体内小鼠的胞吞作用，所有这些小鼠的肠道微生物群都已耗尽。从机制上讲，微生物群衍生的短链脂肪酸丁酸酯可直接提高小鼠和人类巨噬细胞的胞吞作用效率和能力，并挽救 ABX 诱导的体内 LPM 胞吞作用缺陷。对体外丁酸盐处理的巨噬细胞进行批量信使 RNA 测序，并对从 ABX 处理和丁酸盐拯救的小鼠中分离出的 LPM 进行单细胞信使 RNA 测序，揭示了胞吞作用支持转录程序的调节。具体来说，我们发现，在 ABX 处理的小鼠的 LPM 中，胞吞作用受体 T 细胞免疫球蛋白和粘蛋白结构域 4（TIM-4、 Timd4 ）下调，但通过口服丁酸盐可以恢复。我们表明 TIM-4 是丁酸盐诱导的 LPM 胞吞作用能力增强所必需的，并且 LPM 胞吞作用在 ABX 撤除后会受到损害。在狼疮小鼠模型中，经过 ABX 治疗的小鼠表现出明显更严重的疾病。我们的结果表明，稳态胞吞作用依赖于远端代谢信号，并表明有缺陷的稳态胞吞作用可以解释 ABX 使用与炎症性疾病之间的联系^4,5,6,7 。