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Declaration of Interests
Authorship
Acknowledgments
Introduction The main clinical problems of people living with HIV (PLWH) in areas with adequate healthcare standards and continued antiretroviral therapy (ART) supply are increasingly related to premature aging (Paiardini and Müller-Trutwin, 2013). That is, a precocious development of type 2 diabetes, dislipidemia, cardiovascular diseases, osteoporosis and frailty syndrome. Such diseases have been related to structural or metabolic perturbations in the gut microbiota of non-HIV-infected subjects (Claesson et al., 2012; Koeth et al., 2013; Le Chatelier et al., 2013; Tang et al., 2013) whereas, in PLWH, have been linked to chronic inflammation, immune activation and endotoxemia (Brenchley et al., 2006; Douek, 2003; Sandler and Douek, 2012). Thus there is considerable interest in understanding the role of the human gut microbiome in HIV pathogenesis and, in particular, its ability to perpetuate chronic 5 aminolevulinic acid and foster immune senescence. This has immediate clinical implications because, in theory, it might be possible to gear the gut microbiota towards “healthier” equilibrium states with the host, which might allow, for example, to achieve faster immune reconstitution, improve vaccine responses or reduce HIV reservoirs. However, although expectations are high, the HIV microbiome science is still at its early stages, and much remains to be known. Simple questions such as whether there is a consistent HIV-specific dysbiosis pattern, or which factors are relevant in shaping the microbiome in PLWH remain unanswered. Initial cross-sectional studies in humans have provided contradictory associations between microbial richness and HIV serostatus, and suggested shifts from Bacteroides to Prevotella predominance following HIV-1 infection (Lozupone et al., 2013; Vázquez-Castellano et al., 2015). Such shifts, however, have neither been found in animal models (Handley et al., 2012) nor in studies matching for HIV-1 risk groups (Yu et al., 2013). Conversely, large international studies in healthy populations have shown that at least in resource-rich countries, the gut microbiome forms a composition landscape with density peaks that can stratify the human population into enterotypes dominated by Bacteroides, Prevotella and Ruminococcus, respectively (Arumugam et al., 2011; Koren et al., 2013). The origin and clinical significance of such enterotypes is uncertain, but they have been linked to genetic (Goodrich et al., 2014), as well as to lifestyle (Clarke et al., 2014; David et al., 2013; Wu et al., 2011) and environmental factors (Modi et al., 2014; Sommer and Bäckhed, 2013), including long-term dietary patterns and exercise. Thereby, associations between Prevotella or Bacteroides and HIV infection might be easily confounded by other factors. Obtaining reliable information at this level is critical to advance our understanding of HIV pathogenesis, as well as to define the specific targets of novel therapeutic interventions on the human gut microbiome.
Methods
Results
Discussion In two independent European cohorts with different ethnic and cultural background, the fecal microbiota of MSM was consistently richer and more diverse than that of non-MSM subjects, and was systematically enriched in genera from the Prevotella enterotype. The strength of such association was unusually high, reaching 95% accuracy in a microbial composition-based classifier. These findings have important implications for HIV microbiome science. To our knowledge, this is the first evidence that, in addition to genetic (Goodrich et al., 2014), lifestyle (Clarke et al., 2014; David et al., 2013; Wu et al., 2011) and environmental factors (Modi et al., 2014; Sommer and Bäckhed, 2013), factors related with sexual preference might also affect the gut microbiota composition. Based on our findings, previous associations between HIV infection and Prevotella might be explained by enrichment of HIV-infected groups by MSM relative to HIV-negative controls selected from hospital or research staff, gut biopsy donors, or college students (Lozupone et al., 2013; Mutlu et al., 2014; Vázquez-Castellano et al., 2015). Contradictory associations between HIV infection and microbial richness could also be affected by unbalances in the proportion of MSM between groups. Of note, a selection bias as such could also affect the interpretation of in silico inferences on bacterial metabolism, or even direct metabolomic or metatranscriptomic measurements, which also rely on bacterial composition.