Macrophage Phagocytic Impairment is Associated with Dysbiosis of the Respiratory Microbiome in Frail Older Adults

Summary Advanced age and frailty are risk factors for pulmonary infections, which are the leading cause of death in older adults. The mechanism behind increased susceptibility to infection is poorly understood, but interactions between innate immunity and the respiratory microbiome may be implicated. We investigated changes to monocyte-derived macrophage function, and the respiratory microbiome in healthy young adults, healthy older adults, and frail older adults. We found that macrophage phagocytosis and efferocytosis is impaired in frail older adults, associated with elevated pro-inflammatory cytokine secretion and a failure to regulate expression of phagocytic receptors CD14 and CD36. Pre-treatment of macrophages with a PPARγ agonist restored phagocytosis, implicating this pathway in cellular dysfunction. Accompanying respiratory microbiome showed reduced bacterial diversity and richness in older adults, which was more advanced in frail older adults. These results are consistent with a macrophage predation defect in the lungs during frailty which may impact bacterial diversity, and may be improved via manipulation of the PPARγ pathway. Graphical abstract