Short chain fatty acids reduce inflamm-aging and ameliorate enhanced severity of acute lung injury in old mice

Abstract

A chronic pro-inflammatory milieu (inflamm-aging), associated with poorer prognosis in acute lung injury (ALI), is observed in the elderly. Gut microbiome-derived short chain fatty acids (SCFAs) are known to have immunomodulatory capabilities, but their impact on the gut-lung axis in aging is poorly understood. Here, we tested the hypothesis that SCFAs alleviate pulmonary inflamm-aging and ALI in old mice. Young (3 months) and old (18 months) male C57BL/6JRj mice received a mixture of 50 mM acetate, butyrate and propionate in drinking water or water only. Two weeks later, ALI was induced by intranasal application of 2.5 μg lipopolysaccharide/g BW (n=12/group) or saline (controls; n=8/group). After 24 h, lung mechanics were measured. The left lung was collected for stereology and the right lung for analysis of cytokine and gene expression, inflammatory cell activation and proteomics. Fecal pellets were collected for microbiome analysis. Proteome analysis revealed reduced inflammatory response (e.g. chemotaxis, migration, phagocytosis) with SCFA treatment in old mice, where the age-related difference in significantly expressed proteins was reduced by a factor of 6.2 in controls and 2.7 with ALI. No structural and functional differences were found in lungs with SCFA treatment in ALI, however, neutrophil and alveolar macrophage activation and pro-inflammatory cytokines were significantly reduced, particularly in old mice. Furthermore, microbiome composition changed in old mice with SCFA treatment. This provides new evidence that SCFAs play a beneficial role in the gut-lung axis of the aging organism by reducing pulmonary inflamm-aging and enhanced severity of ALI in old mice.