Background: Recent data suggest that biomarkers of gut epithelial barrier dysfunction, bacterial translocation and inflammation predict mortality and are possibly linked to altered gut immunity. A better understanding of the underlying mechanisms might help to design interventions targetting chronic inflammation.
Methods: We assessed biomarkers of inflammation (IL-6) and gut barrier (lipoteichoic acid [LTA], sCD14 and zonulin) in a clinical trial comparing three different ART initiation regimens on 33 ART naïve HIV+ subjects. Peripheral blood, rectal and duodenal biopsies were obtained at baseline and 9 months after randomization. Immunohistochemistry of biopsies was performed to determine CD4 T cells/mm2. Tissue was digested into single-cell suspensions for immunophenotyping. Spearman’s rank correlation coefficients were assessed at month 9 and associations between changes in continuous variables over time were analyzed using linear mixed models with random intercepts.
Results: In duodenum, T-cell density correlated with plasma markers of gut barrier integrity: for CD4 T-cells and zonulin, Rho 0.59, P=0.002; for CD8 T-cells and lipoteichoic acid , Rho 0.67, P<0.001.
From maturational subsets, we observed significant correlations between zonulin and naive (CCR7+CD45RA+) CD8-T cells in colon and duodenum (Rho -0.51, P<0.01 and Rho -0.58, P<0.01) as well as with EM (CCR7+CD45RA-) CD8-T cells in colon and duodenum (Rho -0.58, P<0.01 and Rho -0.44, P<0.01). The naive/memory CD8 T-cell ratio in colon and duodenum correlated with zonulin levels (Rho 0.52, P<0.01and Rho 0.54, P<0.01, respectively). Transitional memory (TM) (CCR7-CD45RA-CD27+CD28+) CD4 T cells correlated with IL-6 levels (Rho -0.51, P<0.01)
Linear mixed models identified variations of intestinal T cell phenotypes significantly associated with changes of systemic markers: in duodenum, CD4 and CD8-T cells/mm2, CD8+EM T cells and naive/memory CD8-T cell ratio predicted changes in zonulin levels, while in colon changes of CD4+TM predicted decreases of IL-6.
Conclusions: We observed a number of significant correlations between different intestinal T-cell phenotypes and systemic markers of inflammation and gut barrier integrity, suggesting that strategies aimed at modulating chronic inflammation may require targeting the gut immunity and/or gut microbial community composition.