Macrophages are a highly diverse cell population, capable of displaying phenotypic plasticity and functional variability as a part of their different roles in homeostasis and disease. One of the key features of macrophages involves their differentiation into distinct activation phenotypes, ranging from antimicrobial/pro-inflammatory to resolving/anti-inflammatory, dependent also on their tissue localization. These characterizations are increasingly understood as a broad range of states that can coexist, dependent on macrophage ontogeny, tissue localization, and exposure to various perturbations 1, 2. To execute their diverse immunological programs, macrophages change their energy metabolism, a process termed ‘immunometabolism’. Immunometabolism involves the accumulation of tricarboxylic acid (TCA) intermediates that act as signaling molecules and mediate immune activation pathways of macrophages and therefore are considered as ‘immuno-metabolites’ [3]. Immunometabolism and its role in macrophage immune responses are also suggested to drive the outcome of infectious diseases [4].

As a major immune barrier, the gut is exposed to metabolites and immunomodulatory molecules from commensal microbiota during homeostasis, and to invasion of pathogens during disease. The gut epithelial barrier and the underlying immune compartment display a complex structured environment along its anatomical parts. The small intestine is characterized by long villi that facilitate nutrient absorption. The large intestine has a smooth epithelial layer and a thick mucus layer that provides a physical barrier from the gut flora. As an immunologically active organ, the different anatomical parts of the gut also display regional specialization of the immune system. In the upper tract, immunity includes mostly antimicrobial peptides and lymphoid cells, whereas colon immunity includes mostly Immunoglobulin A antibodies and Regulatory T-cells [5].

Here, we will review current concepts in macrophage immunometabolism with a specific focus on emerging methods that can now be applied to study macrophage immunometabolism in the gut during homeostasis and disease.