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

Hepatitis C Virus and Hepatocellular Carcinoma: Pathogenetic Mechanisms and Impact of Direct-Acting Antivirals

INTRODUCTION: Globally, between 64 and 103 million people are chronically infected with Hepatitis C virus (HCV), with more than 4.6 million people in the United States and is associated with more than 15.000 deaths annually. Chronic infection can result in cirrhosis and hepatocellular carcinoma. EXPLANATION: Epidemiological studies have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC), mainly through chronic inflammation, cell deaths, and proliferation. Despite the new direct-acting antiviral drugs (DAA's) being able to clear the HCV, HCC recurrence rate in these patients is still observed. CONCLUSION: In this review we highlighted some aspects that could be involved in the onset of HCV-induced HCC such as immune system, viral factors and host genetics factors.Moreover, we focused on some of the last reports about the effects of DAA's on the HCV clearance and their potential implications in HCC recurrence

Type I/II interferon in HIV-1-infected patients: expression in gut mucosa and in peripheral blood mononuclear cells and its modification upon probiotic supplementation

Expression of type I and II interferon (IFN) was evaluated in gut-associated lymphoid tissue (GALT) and peripheral blood mononuclear cells (PBMCs) of HIV-1-positive patients on long-term, suppressive, antiretroviral therapy before and after probiotic supplementation. IFNα subtypes and IFNβ were expressed at higher levels in GALT compared to PBMC, whereas an opposite trend of expression was recorded for IFNγ. An increase of IFNα6, IFNα10, IFNα14, IFNα17, and IFNα21 and a decrease of IFNγ were observed in both anatomical sites after probiotic supplementation

Improvement of neuropsychological performances and reduction of immune-activation markers after probiotic supplementation and change of life-style in an HIV positive male: targeting the microbiota to act on gut-brain axis

The gut-brain axis is widely in uenced by the intestinal microbiota and dysbiosis is consequently associated with a large dysregulation of its functions. Probiotic supplementation, reducing the harmful effects of dysbiosis, has shown positive effects not only on gut and brain functions, but also on the control of the dangerous effects of immune activation. Mounting evidence has shown that neurocognitive impairment can be a secondary to the impairment of the microbiota-gut-brain axis in HIV positive patients. In this case report we analyzed the im- provement of neurocognitive performances associated with a reduction of levels of peripheral immune-activa- tion, after 6 months of probiotic supplementation. In this case, the achieved result may have been in uenced by a more comprehensive modi cation of the patient’s lifestyle with the introduction of a controlled diet and regular physical activity. Our observations suggest that integrate antiretroviral therapy and non-pharmacological tools into an overall approach, can be a useful strategy to control some non-AIDS related diseases

Systemic adipokines, hepatokines and interleukin-6 in HCV-monoinfected and HCV/HIV coinfected patients treated with direct antiviral agents (DAAs)

In this study, we demonstrated that that altered levels ofadipokines/hepatokines in HCV-infected patients, including HIV coinfected, can be restored by treatment with direct antiviral agents (DAAs), thus indicating the important metabolic changes occurring during the eradication of this viral infection

Modulation of tryptophan/serotonin pathway by probiotic supplementation in human immunodeficiency virus-positive patients: preliminary results of a new study approach

Background: To date, no data are available regarding the effects of probiotics on the pathway of tryptophan/serotonin metabolism among human immunodeficiency virus (HIV) 1–infected individuals. Because a condition of dysbiosis might be responsible for the altered use of tryptophan described in this population, the aim of this study was to investigate the link between probiotic supplementation and serotonin levels in combined antiretroviral therapy–treated patients and the subsistence of an interplay with inflammation. Methods: We conducted a pilot study that included 8 HIV-positive subjects. We collected blood and fecal samples before and after 6 months of probiotic supplementation, to measure the level of serotonin in serum and tryptophan in stool, the expression of CD38 and HLADR on peripheral CD4+ T lymphocytes (as immune activation markers), the expression of indoleamine 2,3-dioxygenase 1 messenger RNA (mRNA) and IFN-γ mRNA (as markers of tryptophan metabolism and systemic inflammation). Results: After probiotic supplementation, we observed a significant increase in concentration of serum serotonin (P=.008) and a decreased level of tryptophan in plasma. Moreover, a significant reduction in CD38 and HLA-DR expression on the surface of peripheral CD4+ T cells (P=.008) and a reduced expression of indoleamine 2,3-dioxygenase 1 mRNA on peripheral blood mononuclear cells (P=.04) were observed. Conclusions: Considering that this probiotic (Vivomixx® in EU; Visbiome® in USA) has an influence on tryptophan metabolism, larger studies on this topic are needed

Possible determinants of VSL#3 probiotic failure in preventing gastrointestinal adverse events associated with dacomitinib in patients with advanced non-small-cell lung cancer enrolled in ARCHER-1042 trial

Real clinical relevance of probiotics supplementation in preventing gastrointestinal adverse events associated with dacomitinib

IFN-stimulated gene expression is independent of the IFNL4 genotype in chronic HIV-1 infection

This study aimed to evaluate the association between the IFNL4 rs368234815 (ΔG/TT) dinucleotide polymorphism and the IFN response during chronic HIV-1 infection. We carried out genotyping analysis and measured the expression of IFN-stimulated genes (ISGs) (myxovirus resistance protein A [MxA], ISG15, ISG56, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like [APOBEC] 3F and APOBEC3G) on peripheral blood mononuclear cells collected from naïve and HAART-treated HIV-1-infected patients. There were no statistically significant differences in endogenous ISGs mRNA levels among HIV-1-positive patients bearing different IFNL4 genotypes, suggesting that ISG expression is independent of the IFNL4 genotype in HIV-1 infection

Sa1854 - Oral Bacteriotherapy Improves Gut Inflammation and Reduces Fecal Infectivity of HIV Subjects

INTRODUCTION The gastrointestinal tract is a major site of HIV localization and even though cART (combined AntiRetroviral Therapy) leads to suppression of HIV replication the gastrointestinal pathology is still persistent. In these patients increased levels of inflammation and decreased levels of mucosal repair and regeneration are observed. Consequently novel directions for dietary and therapeutic interventions that restore the immunological and epithelial integrity of the mucosal barrier are needed. Since HIV infected patients host in their gut a prevalence of several detrimental bacterial populations, attempts to modify their gut flora with probiotics is justified. PATIENTS and METHODS Ten subjects receiving combined antiretroviral therapy for HIV-1 were treated for 6 months with multistrain probiotic formulation containing Lactobacillus plantarum DSM24730, Streptococcus thermophilus DSM24731, Bifidobacterium breve DSM24732, L. paracasei DSM24733, L. delbrueckii subsp. bulgaricus DSM24734, L. acidophilus DSM 24735, B. longum DSM24736, B. infantis DSM24737 (Vivomixx in EU, Visbiome in USA). At baseline and 6 months, IELs density and enterocytes death via apoptosis as well as mitochondrial morphology were analyzed by immunoistichemical. Faecal water samples (FWS) were collected at T0 and after 6 month of probiotics treatment and checked for antiviral activity. RESULTS We observed the recovery of the integrity of the gut epithelial barrier by reducing IELs density and enterocytes death via apoptosis as well as mitochondrial morphology. This was associated to an improvement of quality of life. As compared to control, faecal water from patients treated with this specific formulation reduced viral replication in treated cells (C8166 cells, infected with T-cell tropic strain HIV-1 P1 at multiplicities of infection (MOIs) of 0.05 TCID50/ml for 1 hour at 37°C), both at 24h and 48h. The antiviral activity of faecal water from patients treated with probiotics for 6 months (T6 FWS) resulted higher than T0 (38% +/- 10) with a percentage of inhibition of 68% (+/- 24) at 24 hours, further confirmed by the results at 48h where percentage of inhibition of more than 90% was recorded. CONCLUSIONS Our results confirm the gut flora plays a role in the interactions host-HIV also in terms of resistance to the HIV infection and the benefits of this specific probiotic preparation for the amelioration of the intestinal inflammation of cART patients. However, not all the probiotic formulation are equally suited for HIV patients as previously reported therefore our data should not be extrapolated to other untested probiotic products