Effect of gut microbiota-derived metabolites on T-helper 17 cells profile in patients on maintenance hemodialysis

Abstract

End-stage renal disease (ESRD) is closely associated with dysfunction of cellular immunity and chronic systemic inflammation. Intestinal dysbiosis plays an important role in these disorders. Meanwhile, the profile of T-helper type 17 (Th17) and influence of intestinal microbiota-derived metabolites on the Th17 subpopulation composition in ESRD patients have not been studied to date. The aim of the study was to investigate changes in the composition of the Th17 subpopulations in patients on maintenance hemodialysis, as well as to evaluate the relationship of the identified disorders with the content of microbial-derived uremic toxins (MDUT) and short-chain fatty acids (SCFA).

Methods. Flow cytometry data of peripheral blood samples, serum levels of p-cresyl sulfate (PCS), indoxyl sulfate (IS), trimethylamine-N-oxide (TMAO) and biomarkers of systemic inflammation, as well as fecal SCFA concentrations of acetate, propionate and butyrate were studied in 30 hemodialysis patients and 30 individuals with normal renal function in a comparative aspect. Spearman's rank correlation coefficient was used to evaluate the relationship between the factors.

Results. The intensity of systemic inflammation in ESRD patients was in direct dependence on serum MDUT concentration and in inverse dependence on the levels of fecal SCFAs. At the same time, dialysis patients showed a significant decrease in absolute concentrations of DP Th17 subpopulations and “classical” Th17 cells with no changes in the absolute and relative content of Th17 cells within the total pool of T-helper cells. In addition, a significant decrease in the proportion of Th17 cells within the pool of central memory T-helpers was detected in these patients, accompanied by a pronounced reduction in DN Th17 and Th17.1 subpopulations.

            The initially reduced absolute number of DN Th17 cells in dialysis patients was significantly directly correlated with the level of butyric acid and total content SCFA, but at the same time was inversely correlated with IL-1β and IL-6. In addition, absolute concentrations of DN Th17 and “classical” Th17 cells were significantly negatively correlated with serum levels of indoxyl sulfate and IL-6. Within the pool of central memory T-helper cells in hemodialysis subjects, the level of reduced DN Th17 was directly and significantly associated with propionic and butyric acid content, whereas the number of Th17.1 cells was closely related only to the concentration of butyric acid.

Conclusion. Reduced levels of SCFAs in dialysis patients may be associated with abnormalities in the subpopulation of Th17 within the total pool of T cells and the pool of central memory T cells. Immunoregulatory effect of MDUTs on Th17 profile requires further study.