Abstract
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.
Highlights
Gastrointestinal (GI) mucosal damage and immune dysfunction drive chronic inflammation and microbial translocation in HIV infection, which predict and likely contribute to noninfectious comorbidities and mortality[1,2,3,4,5]
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 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
Summary
Gastrointestinal (GI) mucosal damage and immune dysfunction drive chronic inflammation and microbial translocation in HIV infection, which predict and likely contribute to noninfectious comorbidities and mortality[1,2,3,4,5]. Long-term antiretroviral therapy (ART) partially restores mucosal damage, a degree of mucosal immune dysfunction and inflammation persists and is associated with morbidities and mortality[6,7,8]. Improving the understanding of this persistent mucosal dysfunction and inflammation during ART is a major hurdle for the development of targeted therapies that may promote health and decrease morbidities and mortality in HIV-infected individuals. The role of neutrophils in HIV infection is not well understood. A better understanding of the mechanisms involved in neutrophil accumulation in the GI in HIV infection is necessary to develop new strategies to alleviate GI inflammation in HIV infection
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