Il metabolismo del triptofano in HIV-1: ruolo dei probiotici nell’asse intestino-cervello

Background: Alteration of tryptophan metabolism, which is caused by the activity of the interferon-inducible enzyme IDO-1, has an important impact on HIV-1 infected patients quality of life, in particular it could be involved in the onset of neurocognitive disorder. In fact, a number of study showed a correlation between an alteration in tryptophan metabolism, with production of neurotoxic metabolites, immune activation and neopterin production in the central nervous system. The dysbiosis and its related immune activation observed in HIV-1 infection are some of the main causes of IDO expression in the gastrointestinal tract. By modulating the gut flora with probiotics we hypothesized to impact on three elements “dysbiosis - tryptophan metabolism - elevated markers of systemic immune activation” which doesn’t seem to be appropriately controlled by cART. Method: Thirty HIV-infected subjects, under suppressive cART and undetectable viremia, underwent endoscopic procedures for the isolation of lamina propria lymphocytes (LPL), blood and faeces collection and lumbar puncture for cerebrospinal fluid (CSF) collection prior to initiation of probiotics supplementation (T0) and after 6 months (T6). CSF neopterin levels were measured by ELISA assay. Immune activation, measured as CD4+CD38+HLA-DR+ T-cells, were assessed in both PBMC and LPL using flow citometry. IFNγ and IDO mRNA levels were measured by real-time PCR in both PBMC and LPL. Tryptophan level were quantified in the fecal samples through 1H-NMR analysis, and plasma serotonin levels were measured by ELISA assay. All measurements were performed at T0 and T6. Data were analyzed by Wilcoxon test. Results: We found that plasma neopterin were significantly lower at T6 compared with T0. Moreover, a significant reduction in IDO mRNA expression and CD4+CD38+HLA-DR+ T-cells frequency in both LPL and PBMC at T6 is observed, while a decrease of IFNγ mRNA occurs although it does not reach statistical significance. Finally, related to tryptophan metabolism, we observed a significant reduction of tryptophan in the feces and an increase in the levels of plasma serotonin, which is a direct product of tryptophan metabolism. Conclusions: We highlighted a relationship between probiotic supplementation, inflammation and serotonin levels. Overall our preliminary results indicate that probiotic supplementation could reduce neopterin levels in CSF, modulate tryptophan metabolism, through the reduction of IDO expression, and increase the levels of plasma serotonin, in order to reduce the side effects of the deregulation of tryptophan metabolism and its catabolites on the neurocognitive disorders of HIV-1 population.