Short-chain fatty acids, as key metabolites of gut microbiota, improve inflamm-aging and lung injury in old mice

With advancing age, a low-grad proinflammatory milieu (inflamm-aging) is observed. It is associated with the development of chronic lung diseases and a poorer prognosis in acute lung injury (ALI). Gut microbiome-derived short-chain fatty acids (SCFAs) are known to have immunomodulatory abilities, but their function in the gut-lung axis in aging is poorly understood. Here, we analyzed the gut microbiome and its impact on inflammatory signaling in the aging lung and tested the effects of SCFAs in young (3 month) and old (18 month) mice. The mice received regular drinking water or water with a mixture of 50 mM acetate, butyrate, and propionate for 2 weeks. Afterwards, ALI was induced by intranasal lipopolysaccharide (LPS; n=12/group) administration, while controls (n=8/group) received saline. Fecal pellets were sampled for gut microbiome analysis before and after LPS or saline treatment. The left lung lobe was collected for histology and right lung lobes for cytokine and gene expression analysis, inflammatory cell activation, and proteomics. Different gut microbial taxa correlated positively with pulmonary inflammation in aging, suggesting their impact on inflamm-aging in the gut-lung axis. The supplementation of SCFAs reduced inflamm-aging, oxidative stress, metabolic alteration, and enhanced activation of myeloid cells in the lungs of old mice. The enhanced inflammatory signaling in ALI of old mice was also reduced by SCFA treatment. In summary, the study provides evidence that SCFAs play a beneficial role in the gut-lung axis of the aging organism by reducing pulmonary inflamm-aging and ameliorating enhanced severity of ALI in old mice.