Intestinal resident macrophages (MΦs) regulate gastrointestinal homeostasis via production of an anti-inflammatory cytokine interleukin (IL)-10. Although a constant replenishment by circulating monocytes is required to maintain the pool of resident MΦs in the colonic mucosa, the homeostatic regulation of MΦ in the small intestine (SI) remains unclear. Here, we demonstrate that direct stimulation by dietary amino acids regulates the homeostasis of intestinal MΦs in the SI. Mice that received total parenteral nutrition (TPN), which deprives the animals of enteral nutrients, displayed a significant decrease of IL-10-producing MΦs in the SI, whereas the IL-10-producing CD4+T cells remained intact. Likewise, enteral nutrient deprivation selectively affected the monocyte-derived F4/80+MΦ population, but not non-monocytic precursor-derived CD103+ dendritic cells. Notably, in contrast to colonic MΦs, the replenishment of SI MΦs and their IL-10 production were not regulated by the gut microbiota. Rather, SI MΦs were directly regulated by dietary amino acids. Collectively, our study highlights the diet-dependent, microbiota-independent regulation of IL-10-producing resident MΦs in the SI.
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