The concept of metabolic reprogramming has gained prominence in Immunology in the past 15 years. Historically, this concept can be traced back to the 1920s, when Otto Warburg discovered that tumor cells, in opposition to non-transformed cells, obtain their energy primarily from glycolysis, even in the presence of oxygen; this particular metabolic reprogramming was dubbed “aerobic glycolysis” and later referred to by others as “the Warburg effect".

A big leap in the sequence of events takes us to a seminal discovery undertaken in Craig B. Thompson´s lab in the early 2000s: Activated T lymphocytes switch their metabolism from oxidative phosphorylation to glycolysis. The Immunology community then realized that activated T lymphocytes and tumor cells share a preferential use of the glycolytic pathway. Moreover, when analyzing the role of co-stimulation in the metabolic reprogramming of T cells (through the CD28 receptor, in this case), the same group came up with the novel idea that immune co-stimulation is also a metabolic co-stimulation.

From here onwards, metabolic pathways in other immune cells were analyzed, and the result was that memory cells, effector cells, polarized macrophages, etc., could be metabolically distinguishable. In due course, the field of Immunometabolism flourished.

In parallel and due to the development of the Immunometabolism field, an emergent concept "metabolites as signaling molecules" is evolving. In this regard, lactate, the “by-product” of the Warburg effect, has been recognized as a cell-signaling molecule only recently, along with the identification of its receptor (GPR81). Succinate, fumarate, and itaconate, metabolites once considered exclusively as intermediates related with the Krebs cycle, have also been shown to act as signaling molecules.

The microbiota is another important source of metabolites and following the recognition that microbiota, intestinal bacteria in the first place, interact with the immune system and the search for possible mechanisms of communication, some bacterial-derived metabolites were also found to harbor cell signaling properties, as is the case for several short fatty acids.

In any given microenvironment, the amount of nutrients, diffusible metabolites, oxygen, and the microbiota composition is determinant for the immune cells' metabolic and activation status. In most studies on the metabolic reprogramming of immune cells, immunologists have used ligands for Pattern Recognition Receptors (LPS, -glycan, etc.), antigens (BCG, C. albicans, cell-free extracts, etc.), TCR-stimulating reagents (anti-CD3 mAbs, etc.) and the like, as stimuli. What about metabolites as inducers of metabolic reprogramming?

Thus, this Research Topic gladly receives the submission of Original Research, Methods, Brief Research Reports, and Review Articles focusing on the following sub-themes:

• Metabolites as inducers of metabolic reprogramming in immune cells.
• The role of microbiota and their metabolites in regulating immune cell metabolism.
• The microbiota in disease and the consequences for immunometabolism.
• The metabolome in the context of vaccination and the role of metabolites in shaping immunity.
• Tumor microbiome and metabolites in immune cells reprogramming.
• Genetic and epigenetic influences on the metabolome.
• How cellular metabolism can affect gene expression through epigenetic changes.

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Metabolite-induced metabolic reprogramming in the immune system