Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses

Juliette Lesbats, Aurélia Brillac, Julie A. Reisz, Parnika Mukherjee, Charlène Lhuissier, Mónica Fernández-Monreal, Jean-William Dupuy, Angèle Sequeira, Gaia Tioli, Celia De La Calle Arregui, Benoît Pinson, Daniel Wendisch, Benoît Rousseau, Alejo Efeyan, Leif Erik Sander, Angelo D’Alessandro and Johan Garaude ()
Additional contact information
Juliette Lesbats: U1211
Aurélia Brillac: U1211
Julie A. Reisz: Aurora
Parnika Mukherjee: Charité–Universitätsmedizin Berlin
Charlène Lhuissier: University of Bordeaux
Mónica Fernández-Monreal: Université de Bordeaux, CNRS, INSERM, Bordeaux Imaging Center (BIC)
Jean-William Dupuy: OncoProt
Angèle Sequeira: University of Bordeaux
Gaia Tioli: U1211
Celia De La Calle Arregui: Spanish National Cancer Research Center (CNIO)
Benoît Pinson: Université Bordeaux
Daniel Wendisch: Charité–Universitätsmedizin Berlin
Benoît Rousseau: Service Commun des Animaleries
Alejo Efeyan: Spanish National Cancer Research Center (CNIO)
Leif Erik Sander: Charité–Universitätsmedizin Berlin
Angelo D’Alessandro: Aurora
Johan Garaude: U1211

Nature, 2025, vol. 640, issue 8058, 524-533

Abstract: Abstract Macrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation1,2. Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1β secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies.

Date: 2025
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DOI: 10.1038/s41586-025-08629-4

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