Increased mucosal neutrophil survival is associated with altered microbiota in HIV infection.

Gastrointestinal (GI) mucosal dysfunction predicts and likely contributes to non-infectious comorbidities and mortality in HIV infection and persists despite antiretroviral therapy. However, the mechanisms underlying this dysfunction remain incompletely understood. Neutrophils are important for containment of pathogens but can also contribute to tissue damage due to their release of reactive oxygen species and other potentially harmful effector molecules. Here we used a flow cytometry approach to investigate increased neutrophil lifespan as a mechanism for GI neutrophil accumulation in chronic, treated HIV infection and a potential role for gastrointestinal dysbiosis. We report that increased neutrophil survival contributes to neutrophil accumulation in colorectal biopsy tissue, thus implicating neutrophil lifespan as a new therapeutic target for mucosal inflammation in HIV infection. Additionally, we characterized the intestinal microbiome of colorectal biopsies using 16S rRNA sequencing. We found that a reduced Lactobacillus: Prevotella ratio associated with neutrophil survival, suggesting that intestinal bacteria may contribute to GI neutrophil accumulation in treated HIV infection. Finally, we provide evidence that Lactobacillus species uniquely decrease neutrophil survival and neutrophil frequency in vitro, which could have important therapeutic implications for reducing neutrophil-driven inflammation in HIV and other chronic inflammatory conditions. Author summary HIV infection results in chronic immune activation that leads to increased risk of other diseases and premature death, and this has been linked to gastrointestinal tract (GI) damage in infected individuals. In this study, we investigated neutrophils, a cell involved in the immune response to pathogens, in colorectal tissue of HIV-infected individuals receiving treatment. Because neutrophils use methods to contain pathogens that can also damage tissue and have been implicated in tissue damage in other GI diseases, it has been proposed that they contribute to GI damage in HIV infection. However, the role of neutrophils in GI damage in HIV has not been well studied. This study quantifies neutrophils in relation to other white blood cells in the GI tissues in HIV infection and demonstrates that they are increased in the GI in infected individuals. Additionally, we present evidence that neutrophils in the GI in HIV-infected individuals have a longer lifespan, which represents one potential reason for their increased frequency. Finally, we present data that different bacteria that naturally reside in the GI can alter neutrophil lifespan and that changes in the relative abundances of these bacteria in HIV infection may be contributing to increased neutrophil lifespan.