Type-2 diabetes mellitus enhancesKlebsiella pneumoniaepathogenesis

Abstract

AbstractKlebsiella pneumoniaeis an opportunistic pathogen and an important cause of pneumonia, bacteremia, and urinary tract infection.K. pneumoniaeinfections are historically associated with diabetes mellitus. There is a fundamental gap in our understanding of how diabetes mellitus, specifically type 2 diabetes, influencesK. pneumoniaepathogenesis.K. pneumoniaepathogenesis is a multifactorial process that often begins with gut colonization, followed by an escape from the gut to peripheral sites, leading to host damage and infection. We hypothesized that type 2 diabetes enhancesK. pneumoniaepathogenesis. To test this, we used well-established mouse models ofK. pneumoniaecolonization and lung infection in conjunction with a mouse model of spontaneous type 2 diabetes mellitus (T2DM). We show that T2DM enhances susceptibility to bothK. pneumoniaecolonization and infection. The enhancement of gut colonization is dependent on T2DM-induced modulation of the gut microbiota community structure. In contrast, lung infection is exacerbated by the increased availability of amino acids in the lung, which is associated with higher levels of vascular endothelial growth factor. These data lay the foundation for mechanistic interrogation of the relationship betweenK. pneumoniaepathogenesis and type 2 diabetes mellitus, and explicitly establish T2DM as a risk factor forK. pneumoniaedisease.