Long-Term Suppressive cART Is Not Sufficient to Restore Intestinal Permeability and Gut Microbiota Compositional Changes

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.

Immunological age prediction in HIV-infected, ART-treated individuals

“…Additional markers in the index included soluble IL-2Rα (CD25), soluble CD163, neopterin, and D-dimer which have all been shown to be biomarkers for several inflammatory diseases indicating poor prognosis [ 36 , 37 ]. The intestinal Fatty Acid binding protein (iFABP) is a marker of microbial translocation and has been shown to remain elevated in HIV-infected individuals with ART [ 38 , 39 ]. A recent study has presented REG3α as a novel marker for gut damage in PWH that may be more informative than iFABP in assessing microbial translocation [ 40 ], however its relationship to Age is not yet known.…”

Cytomegalovirus as an Uninvited Guest in the Response to Vaccines in People Living with HIV

“…Depletion of mucosal CD4 T-cells upon HIV infection impairs the gut barrier integrity and leads to microbial translocation and microbiota changes [ 28 , 29 ]. However, despite effective ART and T-cell restoration, gut permeability and dysbiosis remain in PLWH and have been associated with systemic immune activation and non-AIDS comorbidities [ 30 , 31 ]. In addition, as the largest lymphoid organ, the gut constitutes a considerable reservoir for HIV, with low distribution of ART to this compartment [ 32 ].…”

“…Altogether, increased relative abundance of inflammation-inducing bacteria in their host is believed to constitute a driver of systemic immune activation in PLWH. However, the lack of adjustment for confounding factors of most studies prevents the identification of a direct causal link [ 30 ].…”

Effects of viremia and CD4 recovery on gut “microbiome-immunity” axis in treatment-naïve HIV-1-infected patients undergoing antiretroviral therapy

“…Currently, antiretroviral therapy (ART) has increased the life expectancy of HIV-infected patients, approximating it to that of the general population[ 26 ]. Interestingly, chronic inflammation and GM alterations persist in patients virologically suppressed by ART[ 27 ]. These data implicate that re-shaping the microbiota may be an adjuvant therapy in patients commencing successful ART[ 28 ].…”