Gut microbial diversity in HIV infection post combined antiretroviral therapy: a key target for prevention of cardiovascular disease

Abstract

Purpose of review: Although the HIV-infected population is living longer and getting older under current treatment regimens, significant challenges arise for health management as the infection is associated with various premature aging phenotypes, particularly increased incidence of cardiovascular diseases (CVDs). Here we review the current understanding of HIV-related gut dysbiosis in association with CVD and advances in clinical trials aiming to restore gut microbial diversity.

Recent finding: Identification of a unique signature for gut dysbiosis in HIV infection between different cohorts remains challenging. However, low diversity of microbiota combined with the outgrowth of pathogenic bacterial species together with dysregulated metabolic pathways have been linked to compromised gut immunity, bacterial translocation and systemic inflammation, hence higher CVD risk among different cohorts. Data from recent clinical trials aiming to evaluate the tolerability and efficacy of probiotics in treated HIV+ patients are promising and support a significant increase in microbiota diversity and reduction of systemic inflammation. However, the impact of these microbial and immunological corrections on the prevalence of CVD in HIV+ patients remains unclear.

Summary: Positive immunological outcomes following enrichment of the gut microbial diversity have been documented, and further trials are in progress to evaluate the range of patients, with different immunological backgrounds, who might benefit from these treatments.

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FIGURE 1

Lower microbial diversity and dysregulated bacterial metabolic pathways accentuate systemic inflammation in HIV infection. Panel (a) under steady state conditions, gut lumen contains a significant diversity of bacterial communities that differ between individuals but remain relatively stable within single individual. Intact gut epithelium together with normal innate responses mediated by macrophages and dendritic cells, as well as with the Th17 normal T-cell functions (production of IL-17A and IL-17F, IL-22 and induction of antimicrobial proteins such as defensins), protects against microbial translocation and further inflammation. Panel (b) under HIV infection, gut epithelium integrity is compromised by epithelial cell death through apoptosis [45] and weakened tight junctions between cells [46] thus leading to enhanced translocation of microbes and microbial products. Together with the HIV-mediated depletion of Th17 cells [37] and enhanced expression of cytokines such as IL-32 [47] that amplifies the inflammatory process, this induces a persistent activation of immune cells and high levels of inflammatory cytokines in circulation. The compromised gut immune response is associated with a decrease in the diversity of microbiota composition and a dysregulated metabolism (lower production of certain amino acids such as proline, phenylalanine and lysine and accelerated catabolism of others such as tryptophan) [44^▪]. Accelerated tryptophan catabolism leads to increase in the kynurenine pathway, which is involved in the decrease of Th17 cell levels, thus further promoting a biased mucosal immunity. Dysregulated microbial metabolism also leads to increase in the trimethylamine [48^▪], a precursor for trimethylamine-N-oxide, a molecule involved in thrombosis risk [49^▪]. Ag, antigen; DC, dendritic cells; EC, epithelial cells.