Robles-Vera, IñakiJarit-Cabanillas, AitorBrandi, PaolaMartínez-López, MaríaMartínez-Cano, SaraiRodrigo-Tapias, ManuelFemenía-Muiña, MarcosRedondo-Urzainqui, AnaNuñez, VanesaGonzález-Correa, CristinaMoleón, JavierDuarte, JuanConejero, LauraMata-Martínez, PabloDíez-Rivero, Carmen MaríaBergón-Gutiérrez, MartaFernández-López, IvánGómez, Manuel JQuintas, AnaDopazo, AnaSánchez-Cabo, FátimaPariente, EstherDel Fresno, CarlosSubiza, José LuisIborra, SalvadorSancho, David2025-07-092025-07-092025-02-11Immunity. 2025 Feb 11;58(2):381-396.e9.https://hdl.handle.net/20.500.12105/26810Impairment of the intestinal barrier allows the systemic translocation of commensal bacteria, inducing a proinflammatory state in the host. Here, we investigated innate immune responses following increased gut permeability upon administration of dextran sulfate sodium (DSS) in mice. We found that Enterococcus faecalis translocated to the bone marrow following DSS treatment and induced trained immunity (TI) hallmarks in bone-marrow-derived mouse macrophages and human monocytes. DSS treatment or heat-killed E. faecalis reprogrammed bone marrow progenitors (BMPs), resulting in enhanced inflammatory responses in vitro and in vivo and protection against subsequent pathogen infections. The C-type lectin receptor Mincle (Clec4e) was essential for E. faecalis-induced TI in BMPs. Clec4e mice showed impaired TI upon E. faecalis administration and reduced pathology following DSS treatment. Thus, Mincle sensing of E. faecalis induces TI that may have long-term effects on pathologies associated with increased gut permeability.We are grateful to members of the D.S. laboratory for discussions and critical reading of the manuscript, particularly to Gillian Dunphy. We thank Je´roˆ me Nigou for providing Mincle ligands and the CNIC facilities and personnel for assistance. I.R.-V. is funded by FJC2021-048099-I. M.M.-L. is supported by a Junior Leader postdoctoral fellowship from ‘‘la Caixa’’ Foundation (116923). A.R.-U. is supported by Community of Madrid (PIPF-2022/SALGL-2458). J.M. and C.G.-C. are predoctoral fellows of MINECO and Junta de Andalucı´a, respectively. C.d.F. is funded by Instituto de Salud Carlos III through the projects CP20/00106 and PI21-01178 (co-funded by European Union). J.D.’s laboratory is funded by Spanish Ministerio de Ciencia, Innovacio´ n y Universidades (MICIU) PID2020-116347RB-I00/AEI/10.13039/501100011033. Work in the D.S. laboratory is funded by the CNIC; by MICIU grants PID2022-137712OB-I00, CPP2021-008310, and CPP2022-009762 from the MICIU/AEI/10.13039/501100011033 Agencia Estatal de Investigacio´ n (AEI) and Unio´ n Europea NextGenerationEU/PRTR; by the Comunidad de Madrid (P2022/BMD-7333 INMUNOVAR-CM); by the Scientific Foundation of the Spanish Association Against Cancer (AECC-PRYGN246642SANC); by Worldwide Cancer Research (WWCR-25-0080); by the European Union (ERC-2023-PoC); by a research agreement with Inmunotek S.L.; and by ‘‘la Caixa’’ Foundation (LCF/PR/HR23/52430012 and LCF/PR/HR22/52420019). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICIU, and the Pro CNIC Foundation, and it is a Severo Ochoa Center of Excellence (CEX2020-001041-S, funded by MICIU/AEI/10.13039/501100011033). Work in the S.I. laboratory is funded by the MICIU, AEI, and FEDER through grants RTI2018-094484-B-I00, PID2021-125415OB-I00, and RYC-2016-19463.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Mincle receptorbone marrow progenitorsgut bacterial translocationinflammationmacrophagestrained immunityAttribution-NonCommercial-NoDerivatives 4.0 International39848243Immunityopen access