Abstract
Background: We explored the long-term effects of cART on markers of gut damage, microbial translocation, and paired gut/blood microbiota composition, with a focus on the role exerted by different drug classes.Methods: We enrolled 41 cART naïve HIV-infected subjects, undergoing blood and fecal sampling prior to cART (T0) and after 12 (T12) and 24 (T24) months of therapy. Fifteen HIV-uninfected individuals were enrolled as controls. We analyzed: (i) T-cell homeostasis (flow cytometry); (ii) microbial translocation (sCD14, EndoCab, 16S rDNA); (iii) intestinal permeability and damage markers (LAC/MAN, I-FABP, fecal calprotectin); (iv) plasma and fecal microbiota composition (alpha- and beta-diversity, relative abundance); (v) functional metagenome predictions (PICRUSt).Results: Twelve and twenty four-month successful cART resulted in a rise in EndoCAb (p = 0.0001) and I-FABP (p = 0.039) vis-à-vis stable 16S rDNA, sCD14, calprotectin and LAC/MAN, along with reduced immune activation in the periphery. Furthermore, cART did not lead to substantial modifications of microbial composition in both plasma and feces and metabolic metagenome predictions. The stratification according to cART regimens revealed a feeble effect on microbiota composition in patients on NNRTI-based or INSTI-based regimens, but not PI-based regimens.Conclusions: We hereby show that 24 months of viro-immunological effective cART, while containing peripheral hyperactivation, exerts only minor effects on the gastrointestinal tract. Persistent alteration of plasma markers indicative of gut structural and functional impairment seemingly parallels enduring fecal dysbiosis, irrespective of drug classes, with no effect on metabolic metagenome predictions.
Highlights
We explored the long-term effects of combination antiretroviral therapy (cART) on markers of gut damage, microbial translocation, and paired gut/blood microbiota composition, with a focus on the role exerted by different drug classes
Because we initially demonstrated an influence of sexual behavior on fecal microbiome, in a sensitivity analysis we decided to investigate whether sexual orientation still accounts for fecal composition following 12 and 24- month cART
men who have sex with men (MSM) and MSW confirmed higher Prevotellaceae along with significant differences in the distribution of Bifidobacteriaceae, Bacteroideaceae, Succinivibrionaceae and Desulfovibrionaceae (Supplementary Figures 3A–H). We explored whether these cART-mediated microbiota shifts might be associated with markers of gut damage, microbial translocation, confirming possible associations between bacterial composition and their changes over time and gut damage/microbial translocation (Figure 3)
Summary
We explored the long-term effects of cART on markers of gut damage, microbial translocation, and paired gut/blood microbiota composition, with a focus on the role exerted by different drug classes. Gut microbial composition of cART-treated individuals is different from that of untreated subjects, the former display a microbial community structure distinct from that reported in the HIVuninfected population [3, 26, 28]. These findings allow for the speculation that enduring gut dysbiosis may contribute to the pathogenesis of residual clinical disease in the course of cART. Antiretroviral compounds per se could further promote dysbiosis [29] as well as impact on microbial translocation, inflammation/immune activation and the gut epithelial barrier damage [23, 24]
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