AbstractThe 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.

摘要凋亡细胞的清除，称为细胞增多症，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细胞增多症的局部分子信号2,3，但远端产生的信号是否也调节稳态细胞增多症仍然难以捉摸。

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.

在这里，我们显示大腹膜巨噬细胞（LPM）显示在体内广谱抗生素（ABX）处理的，万古霉素处理的和无菌的小鼠中损害细胞增多，所有这些小鼠都具有耗尽的肠道微生物群。从机制上讲，微生物群衍生的短链脂肪酸丁酸盐直接提高了小鼠和人巨噬细胞的胞吞作用效率和能力，并在体内挽救了ABX诱导的LPM胞吞作用缺陷。

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.

丁酸盐处理的巨噬细胞的体外大量信使RNA测序和从ABX处理和丁酸盐拯救的小鼠分离的LPM的单细胞信使RNA测序揭示了细胞胞吞作用支持性转录程序的调节。具体而言，我们发现含有4（TIM-4，Timd4）的细胞增多症受体T细胞免疫球蛋白和粘蛋白结构域在ABX处理的小鼠的LPM中下调，但通过口服丁酸盐拯救。

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 disease4,5,6,7..

我们显示TIM-4是丁酸盐诱导的LPM细胞增多能力增强所必需的，并且LPM细胞增多症在停用ABX后受损。ABX治疗的小鼠在狼疮小鼠模型中表现出明显更严重的疾病。我们的研究结果表明，稳态细胞增多症依赖于远端代谢信号，并表明有缺陷的稳态细胞增多症可能解释了ABX使用与炎症性疾病之间的联系4,5,6,7。。

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Fig. 1: The intestinal microbiome supports peripheral efferocytosis.Fig. 2: Butyrate boosts efferocytosis via induction of efferocytotic transcriptional programmes.Fig. 3: Exogenous butyrate rescues ABX-induced defects in LPM efferocytosis.Fig. 4: Treatment with antibiotics induces prolonged peripheral efferocytosis defects..

图1：肠道微生物组支持外周细胞增多症。图2：丁酸盐通过诱导细胞生成转录程序促进细胞增多。图3：外源性丁酸盐可以挽救ABX诱导的LPM细胞增多症缺陷。图4：抗生素治疗会导致外周血细胞增多症缺陷延长。。

Data availability

数据可用性

All data supporting the present study are available within the paper and Supplementary Information. Source data are provided with this paper or can be found in GEO (GSE270512, GSE270514 and GSE270751) and SRA (PRJNA1128534).

支持本研究的所有数据均可在论文和补充信息中找到。本文提供了源数据，或者可以在GEO（GSE270512，GSE270514和GSE270751）和SRA（PRJNA1128534）中找到。

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This work was supported by grants to J.S.A.P. from the NIH (grant nos. NCI 5R00CA237728; NIGMS 1DP2GM146337), to S.Z.J. from the NIH (grant nos. NIAID R01AI148416; NIGMS RM1GM139738), BWF-Path Award and the Hirschl Weill-Caulier Award, a Wellcome Trust Career Development Award to C.J.A. (grant no. 225923/Z/22/Z), a Medical Research Council (MRC) Clinician Scientist award (grant no.

这项工作得到了美国国立卫生研究院对J.S.A.P.的资助（资助号NCI 5R00CA237728；NIGMS 1DP2GM146337），美国国立卫生研究院对S.Z.J.的资助（资助号NIAID R01AI148416；NIGMS RM1GM139738），BWF Path奖和Hirschl Weill Caulier奖，C.J.A的Wellcome Trust职业发展奖（资助号225923/Z/22/Z），医学研究委员会（MRC）临床医生-科学家奖（资助号：。

MR/X019314/1) and an MRC Programme grant (no. MR/W019264/1) to C.D.L., and a MSKCC Cancer Center Support grant no. P30CA008748. Figures 1a,c,g,h, 2a, 3a,b,g and 4d were created using the commercial version of BioRender.Author informationAuthor notesPedro H. V. SaavedraPresent address: Department of Biology, Northeastern University, Boston, MA, USAAuthors and AffiliationsImmunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USAPedro H.

MR/X019314/1）和MRC计划拨款（编号MR/W019264/1）给C.D.L.，以及MSKCC癌症中心支持拨款编号P30CA008748。图1a，c，g，h，2a，3a，b，g和4d是使用BioRender的商业版本创建的。作者信息作者notesPedro H.V.SaavedraPresent地址：美国马萨诸塞州波士顿东北大学生物学系作者和附属机构美国纽约州纪念斯隆·凯特琳癌症中心斯隆·凯特琳研究所免疫学计划。

V. Saavedra, Alissa J. Trzeciak, Allie Lipshutz, Anya J. O’Neal, Zong-Lin Liu, Zhaoquan Wang, Jesús E. Romero-Pichardo, Waleska Saitz Rojas, Giulia Zago, Marcel R. M. van den Brink, Alexander Y. Rudensky & Justin S. A. PerryImmunology and Microbial Pathogenesis Program, Weill Cornell Medical College, Cornell University, New York, NY, USAAndrew W.

五、 Saavedra，Alissa J.Trzeciak，Allie Lipshutz，Anya J.O'Neal，Zong Lin Liu，Zhaoquan Wang，Jesús E.Romero Pichardo，Waleska Saitz Rojas，Giulia Zago，Marcel R.M.van den Brink，Alexander Y.Rudensky＆Justin s.A.PerryImmunology and Microbacial Pathogence Program，康奈尔大学威尔康奈尔医学院，纽约，美国安德鲁·W。

Daman, Zhaoquan Wang, Steven Z. Josefowicz, Alexander Y. Rudensky & Justin S. A. PerryDepartment of Pathology and Laboratory Medicine, Weill Cornell Medical College,.

达曼（Daman），王兆权（Zhaoquan Wang），史蒂文（Steven Z.Josefowicz），亚历山大（Alexander Y.Rudensky）和贾斯汀（Justin S.A.PerryDepartment of Pathology and Laboratory Medicine），威尔·康奈尔医学院（Weill Cornell Medical College），。

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PubMed Google ScholarContributionsP.H.V.S. and J.S.A.P. conceived and directed the study, with P.H.V.S. performing most experiments. A.J.T., A.L., A.J.O., Z-L.L., Z.W., W.S.R., G.Z. and J.E.R-P. assisted with some experiments. A.W.D. and S.Z.J. performed ChIP–seq experiments.

PubMed谷歌学术贡献SP。H、 V.S.和J.S.A.P.构思并指导了这项研究，P.H.V.S.进行了大多数实验。A、 J.T.，A.L.，A.J.O.，Z-L.L.，Z.W.，W.S.R.，G.Z.和J.E.R-P.协助了一些实验。A、 W.D.和S.Z.J.进行了ChIP-seq实验。

M.R.M.v.d.B., C.D.L., C.J.A. and A.Y.R. provided essential insights and reagents. P.H.V.S. and J.S.A.P. wrote the paper with input from all authors.Corresponding authorsCorrespondence to.

M、 R.M.v.d.B.，C.d.L.，C.J.A.和A.Y.R.提供了重要的见解和试剂。P、 H.V.S.和J.S.A.P.在所有作者的意见下撰写了这篇论文。。

Pedro H. V. Saavedra or Justin S. A. Perry.Ethics declarations

佩德罗·H·V·萨维德拉或贾斯汀·S·A·佩里。道德宣言

Competing interests

相互竞争的利益

J.S.A.P. is a cofounder of Atish Technologies. A.Y.R. is a Scientific Advisory Board member and has equity in Sonoma Biotherapeutics, Santa Ana Bio, RAPT Therapeutics and Vedanta Biosciences. He is a Scientific Executive Board member of Amgen and BioInvent and is a co-inventor or has intellectual property (IP) licensed to Takeda that is unrelated to the content of the present study.

J、 S.A.P.是Atish Technologies的联合创始人。A、 Y.R.是科学顾问委员会成员，拥有Sonoma Biotherapeutics、Santa Ana Bio、RAPT Therapeutics和Vedanta Biosciences的股权。他是安进和生物发明公司的科学执行委员会成员，是共同发明人或拥有与本研究内容无关的武田知识产权（IP）。

M.R.M.v.d.B. has received research support and stock options from Seres Therapeutics, and stock options from Notch Therapeutics and Pluto Therapeutics; he has received royalties from Wolters Kluwer; he has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Vor Biopharma, Rheos Medicines, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Ceramedix, Lygenesis, Pluto Therapeutics, GlaksoSmithKline, Da Volterra, Thymofox, Garuda, Novartis (Spouse), Synthekine (Spouse), Beigene (Spouse) and Kite (Spouse); he has IP Licensing with Seres Therapeutics and Juno Therapeutics; and he holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization).

M、 R.M.v.d.B.获得了Seres Therapeutics的研究支持和股票期权，以及Notch Therapeutics和Pluto Therapeutics的股票期权；他收到了Wolters Kluwer的版税；他曾咨询过Seres Therapeutics，Vor Biopharma，Rheos Medicines，Frazier Healthcare Partners，Nektar Therapeutics，Notch Therapeutics，Ceramedix，Lygenesis，Pluto Therapeutics，GlaksoSmithKline，Da Volterra，Thymofox，Garuda，Novartis（配偶），Synthekine（配偶），Beigene（配偶）和Kite（配偶）的顾问委员会，并从中获得酬金；他拥有Seres Therapeutics和Juno Therapeutics的IP许可证；他在DKMS（非营利组织）的基金会董事会中担任受托人角色。

Memorial Sloan Kettering has institutional financial interests relative to Seres Therapeutics. The other authors declare no competing interests..

Memorial Sloan Kettering拥有与Seres Therapeutics相关的机构财务利益。其他作者声明没有利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature Metabolism thanks Zaida Ramirez-Ortiz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Yanina-Yasmin Pesch, in collaboration with the Nature Metabolism team.

《自然代谢》感谢Zaida Ramirez Ortiz和另一位匿名审稿人对这项工作的同行评审做出的贡献。主要处理编辑：Yanina Yasmin Pesch，与《自然代谢》团队合作。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 The intestinal microbiome supports peripheral efferocytosis.(a) Representative flow cytometry gating to identify large peritoneal macrophages (LPMs; CD11b + F4/80+ cells), the primary tissue-resident macrophage and phagocyte in the peritoneum.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据扩展数据图1肠道微生物组支持外周细胞增多症。（a） 代表性的流式细胞术门控以鉴定大的腹膜巨噬细胞（LPM；CD11b+ F4/80+细胞），腹膜中的主要组织驻留巨噬细胞和吞噬细胞。

(b) Representative flow cytometry plots of LPMs from peritoneal lavage of mice following antibiotics treatment for indicated days (Day 0 = blue, Day 3 = light green, Day 7 = dark green). (c) Percentage of LPMs isolated from peritoneal lavage in (a) (D0 n = 5, D3 = 6, D7 n = 6). (d) Percentage of LPMs from SPF (n = 6) (blue) and GF (n = 6) (purple) mice.

（b） 抗生素治疗指定天数（第0天=蓝色，第3天=浅绿色，第7天=深绿色）后，来自小鼠腹膜灌洗液的LPM的代表性流式细胞术图。（c） （a）中从腹膜灌洗中分离的LPM的百分比（D0 n=5，D3 n=6，D7 n=6）。（d） 来自SPF（n=6）（蓝色）和GF（n=6）（紫色）小鼠的LPM百分比。

(e) In vitro efferocytosis analysis of primary macrophages from SPF (n = 2) or GF (n = 2) mice. (f) Representative flow cytometry plots of PI and AnnexinV staining of thymocytes 6 h after dexamethasone injection. (g) Percentage of LPMs from C57BL6/J (n = 8) (blue) and J:DO (n = 9) (brown) mice. All bar graphs represent means + s.e.m.

（e） 来自SPF（n=2）或GF（n=2）小鼠的原代巨噬细胞的体外细胞胞吞作用分析。（f） 地塞米松注射后6小时胸腺细胞PI和AnnexinV染色的代表性流式细胞术图。（g） 来自C57BL6/J（n=8）（蓝色）和J:DO（n=9）（棕色）小鼠的LPM百分比。所有条形图代表平均值+标准误。

Statistics were performed by one-way ANOVA in c and d, two-tailed t-test in e and f. *p < .05; ****p < .0001. ns - not significant.Source dataExtended Data Fig. 2 Butyrate boosts efferocytosis via induction of efferocytotic transcriptional programs.(a) Mature macrophages were conditioned with butyrate (1 mM) for 3d prior to efferocytosis assay.

统计数据通过c和d的单因素方差分析，e和f的双尾t检验进行。*p<0.05****p<0.0001。ns-不重要。来源数据扩展数据图2丁酸盐通过诱导细胞增殖转录程序促进细胞增多。（a） 。

Conditioned macrophages were subsequently incubated with apoptotic mouse thymocytes co-labeled with CypHer5E and CTY at a 1:10 ratio for 1 h. Shown is summary data from flow cytometry analysis of efferocytosis efficiency (left, CypHer5E+ macrophages) and capacity (right, CTY MFI in macrophages). Data are from three independe.

。数据来自三个独立的。

Nat Metab (2024). https://doi.org/10.1038/s42255-024-01107-7Download citationReceived: 08 May 2024Accepted: 11 July 2024Published: 09 August 2024DOI: https://doi.org/10.1038/s42255-024-01107-7Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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主题

AntibioticsAutoimmunityMetabolismMicrobiomePhagocytes

抗生素自身免疫代谢微生物脑细胞