Low protein diet protects liver function upon Salmonella infection by metabolic reprogramming of macrophages

Background & Aims: Western diets are the underlying cause of metabolic and liver diseases. Recent trend to limit the consumption of protein-rich animal products has become more prominent. This dietary change entails decreased protein consumption; however, it is still unknown how this affects innate immunity. Here, we studied the influence of a low protein diet (LPD) on the liver response to bacterial infection. Methods: Mice were fed a LPD and exposed to Salmonella enterica serotype Typhimurium infection. Mechanistic studies were done in vitro where bone marrow derived macrophages were cultured in a low-aa media to mimic in vivo reduction of protein availability and challenged with bacterial endotoxin. Results: We found that a LPD protects from S Typhimurium-induced liver damage. Bulk- and 10xsingle cell-RNA sequencing of liver tissues and isolated immune cells showed reduced activation of myeloid cells in mice fed with LPD after S Typhimurium infection. Mechanistically, we found reduced activation of the mammalian target of rapamycin (mTOR) pathway whilst increased phagocytosis and activation of autophagy in LPD-programmed macrophages. Dietary restoration of leucine reverted the protective effects of a LPD and restored the damaging effects of Salmonella on liver parenchyma in mice. Conclusions: Low protein diet protects the liver form S Typhimurium-induced tissue damage via modulating macrophage autophagy and phagocytosis. Our result support the causal role of dietary components on the fitness of the immune system. ### Competing Interest Statement The authors have declared no competing interest.