Recent research has shed light on the plethora of mechanisms by which the gastrointestinal commensal microbiome can influence the local immune response in the gut (in particular, the impact of the immune system on epithelial barrier homeostasis and ensuring microbial diversity). However, an area that is much less well explored but of tremendous therapeutic interest is the impact the gut microbiome has on systemic cell-mediated immune responses. In this commentary, we highlight some key studies that are beginning to broadly examine the different mechanisms by which the gastrointestinal microbiome can impact the systemic immune compartment. Specifically, we discuss the effects of the gut microbiome on lymphocyte polarisation and trafficking, tailoring of resident immune cells in the liver, and output of circulating immune cells from the bone marrow. Finally, we explore contexts in which this new understanding of long-range effects of the gut microbiome can have implications, including cancer therapies and vaccination.
Eosinophils are key contributors to allergic pathology, however, increasingly eosinophils are described to have important roles in organ health and immunoregulation. Factors that impact these diverse functions of eosinophils are not understood. Here we show in allergic-type lung inflammation, metabolically distinct populations of eosinophils can be identified based on expression of Siglec-F (Siglec-Fhi and Siglec-Fint). Notably, the lung Siglec-Fhi population was responsive to the commensal microbiome, expressing the short-chain fatty acid receptor GPR109A. Animals deficient in GPR109A displayed augmented eosinophilia during allergy. Moreover, transferred GPR109A-deficient eosinophils released more eosinophil peroxidase than controls. Treatment with butyrate or vitamin B3, both GPR109A ligands, reduced Siglec-Fhi eosinophil frequency and activation, which was associated with apoptosis of Siglec-Fhi eosinophils. These findings identify GPR109A as an unappreciated regulator of glycolytic Siglec-Fhi eosinophils, raising the possibility of depleting pathological eosinophil populations in disease states while sparing those with homeostatic functions.
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