Mouse macrophages visualized in confocal microscopy image. Nuclei are shown in blue and the actin network in orange. © Mónica Fernández Monreal, Bordeaux Imaging Centre
The authors consider this new capacity of macrophages –the defensive cells that cleanse the body by ingesting pathogens such as bacteria and viruses– as “surprising”.
In an infection, macrophages 'eat' about a hundred bacteria. It is not yet technically possible, though, to determine how important are for the body the nutrients we now know it obtains this way.
The study also shows the different use that macrophages make of bacteria depending on whether they are alive or dead when ingested.
This result opens up the possibility of using metabolites to modulate the immune response to vaccines or in cancer immunotherapy.
Macrophages are defensive cells that cleanse the body by destroying pathogens, such as bacteria and viruses, while ingesting them. A study published today in the scientific journal Nature reveals a new function for macrophages: to extract nutrients directly from pathogens. This is “surprising”, say the authors of the study, French research groups that have collaborated with Alejo Efeyan, from the Spanish National Cancer Research Center (CNIO).
“This is the first time” that this ability of macrophages has been proved, says Johan Garaude, Inserm researcher and lead author. Macrophages are cells of the immune system with the ability to ingest debris – such as damaged cells – and large pathogens, a phenomenon known as phagocytosis. Their role is key in the maintenance and proper functioning of the body’s tissues.
It is not yet technically possible to elucidate how important this energy is for the organism that macrophages obtain by digesting infectious agents: “Our work suggests that it is important for macrophages that have this phagocytosis capacity. For the immune system in general, we can’t say yet,” Garaude argues.
Under normal conditions, macrophages eat only a few bacteria, “as a ‘sample’ of the composition of the microbiome [the microorganisms that normally live in the body, such as the intestinal flora],” he adds. But when there is infection, “macrophages can easily ‘eat’ up to 100 bacteria. At least that’s what we see in vitro, in the laboratory.”
Death bacteria provide more energy
The work published in Nature also shows that macrophages extract nutrients more efficiently from dead bacteria than from live bacteria. The authors compared macrophage metabolism in different environments: with live bacteria, with dead bacteria and also in the presence of a bacterial membrane component that is known to activate macrophages.
To begin with, the results show that macrophages that have phagocytosed whole bacteria, dead or alive, have a very different metabolism from those that have been activated only by the bacterial membrane. This suggests “that macrophages use bacteria as a source of nutrients to maintain their own metabolism and also to ensure the specificity of their function in the immune system,” analyzes Garaude.
But they also observed that macrophages that have digested dead bacteria are much more likely to survive in a nutrient-poor environment. “This difference may favor macrophage survival when there is an infection, because in infected tissues there is a shortage of nutrients; the bacteria, which reproduce at high speed, have already eaten them,” Garaude explains.
Infectious agents recycled into nutrients
The CNIO group has contributed to unveiling the molecular factors involved in the macrophage digestion machinery.
As Alejo Efeyan, head of CNIO’s Metabolism and Cell Signaling Group, explains, this work discovers that when macrophages scrap a pathogen they also “recycle its components, in the form of nutrients and energy that are then used by the immune cell”. Their role has been “to help understand how the cellular digestion machinery and the detection of the recycled nutrients are important for this recycling process to work, and for tuning the immune response”.
Understanding that recycling varies depending on whether the ingested bacteria are alive or dead is also “critically important, because an active infection is much more alarming to the immune system than one that is already under control,” says Efeyan. “By digesting a live bacterium, macrophages produce messages that attract more defensive cells.”
Relevance for future vaccines
Although the importance of this mechanism in bacterial infections remains to be explored, the authors point out that these results open new avenues for fighting antibiotic resistance, or for innovative approaches in the field of vaccines.
For example, the different response of macrophages to digest live and dead bacteria provides clues on how to use certain nutrients in order to modulate the defensive response.
“The idea would be to add certain metabolites to direct the action of the immune system,” explains Garaude. “By adding metabolites, you could modify – support or slow down – the immune response that is required in a vaccine, either in the face of infections or in the case of immunotherapy against cancer or inflammatory diseases.”
Reference article
Juliette Lesbats, Aurélia Brillac, Julie A. Reisz, Parnika Mukherjee, Charlène Lhuissier, Mónica Fernández-Monreal, Jean-William Dupuy, Angèle Sequeira4, Gaia Tioli, Celia De La Calle Arregui, Benoît Pinson, Daniel Wendisch, Benoît Rousseau, Alejo Efeyan, Leif. E Sander, Angelo D’Alessandro, y Johan Garaude, Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses, Nature, 2025
DOI: https://doi.org/10.1038/s41586-025-08629-4