Probiotic effects on immunity and microbiome in HIV-1 discordant patients

Abstract

BackgroundSome HIV-1 infected patients are unable to completely recover normal CD4+ T-cell (CD4+) counts after achieving HIV-1 suppression with combined Antiretroviral Therapy (cART), hence being classified as immuno-discordant. The human microbiome plays a crucial role in maintaining immune homeostasis and is a potential target towards immune reconstitution.SettingRECOVER (NCT03542786) was a double-blind placebo-controlled clinical trial designed to evaluate if the novel probiotic i3.1 (AB-Biotics, Sant Cugat del Vallès, Spain) was able to improve immune reconstitution in HIV-1 infected immuno-discordant patients with stable cART and CD4+ counts <500 cells/mm3. The mixture consisted of two strains of L. plantarum and one of P. acidilactici, given with or without a fiber-based prebiotic.Methods71 patients were randomized 1:2:2 to Placebo, Probiotic or probiotic + prebiotic (Synbiotic), and were followed over 6 months + 3-month washout period, in which changes on systemic immune status and gut microbiome were evaluated. Primary endpoints were safety and tolerability of the investigational product. Secondary endpoints were changes on CD4+ and CD8+ T-cell (CD8+) counts, inflammation markers and faecal microbiome structure, defined by alpha diversity (Gene Richness), beta diversity (Bray-Curtis) and functional profile. Comparisons across/within groups were performed using standard/paired Wilcoxon test, respectively.ResultsAdverse event (AE) incidence was similar among groups (53%, 33%, and 55% in the Placebo, Probiotic and Synbiotic groups, respectively, the most common being grade 1 digestive AEs: flatulence, bloating and diarrhoea. Two grade 3 AEs were reported, all in the Synbiotic group: abdominal distension (possibly related) and malignant lung neoplasm (unrelated), and 1 grade 4 AE in the Placebo: hepatocarcinoma (unrelated). Synbiotic exposure was associated with a higher increase in CD4+/CD8+ T-cell (CD4/CD8) ratio at 6 months vs baseline (median=0.76(IQR=0.51) vs 0.72(0. 45), median change= 0.04(IQR=0.19), p = 0.03). At month 9, the Synbiotic group had a significant increase in CD4/CD8 ratio (0.827(0.55) vs 0.825(0.53), median change = 0.04(IQR=0.15), p= 0.02) relative to baseline, and higher CD4+ counts (447 (157) vs. 342(73) counts/ml, p = 0.03), and lower sCD14 values (2.16(0.67) vs 3.18(0.8), p = 0.008) than Placebo. No effect in immune parameters was observed in the Probiotic arm. None of the two interventions modified microbial gene richness (alpha diversity). However, intervention as categorical variable was associated with slight but significant effect on Bray-Curtis distance variance (Adonis R2 = 0.02, p = 0.005). Additionally, at month 6, Synbiotic intervention was associated with lower pathway abundances vs Placebo of Assimilatory Sulphate Reduction (8.79·10-6 (1.25·10-5) vs. 1.61·10-5 (2.77·10-5), p = 0.03) and biosynthesis of methionine (2.3·10-5 (3.17·10-5) vs. 4·10-5 (5.66·10-5), p = 0.03) and cysteine (1.83·10-5 (2.56·10-5) vs. 3.3·10-5 (4.62·10-5), p = 0.03). At month 6, probiotic detection in faeces was associated with significant decreases in C Reactive Protein (CRP) vs baseline (11.1(22) vs. 19.2(66), median change= -2.7 (13.2) ug/ml, p = 0.04) and lower IL-6 values (0.58(1.13) vs. 1.17(1.59) ug/ml, p = 0.02) when compared with samples with no detectable probiotic. No detection of the probiotic was associated with higher CD4/CD8 ratio at month 6 vs baseline (0.718(0.57) vs. 0.58(0.4), median change = 0.4(0.2), p = 0.02). After washout, probiotic non-detection was also associated with a significant increase in CD4+ counts (457(153) vs. 416(142), median change = 45(75), counts/ml, p = 0.005) and CD4/CD8 ratio (0.67(0.5) vs 0.59(0.49), median change = 0.04 (0.18), p = 0.02).ConclusionA synbiotic intervention with L. plantarum and P. acidilactici was safe and led to small increases in CD4/CD8 ratio and minor reductions in sCD14 of uncertain clinical significance. A probiotic with the same composition was also safe but did not achieve any impact on immune parameters or faecal microbiome composition.

Use of probiotic lactobacilli in the treatment of vaginal infections: In vitro and in vivo investigations

“…Clinical investigations have been conducted to validate the effects of lactobacilli for the treatment of people afflicted with viruses; nevertheless, the findings are not always positive. In a double-blind placebo-controlled clinical trial, intervention with L. plantarum and Pediococcus acidilactici was found to be safe and to lead to increases in the CD4/CD8 ratio and reductions in sCD14 in HIV-1 infected patients ( Blázquez-Bondia et al., 2022 ). However, using the probiotic Lactobacillus casei Shirota had no discernible impact on immunological activation indicators, NK cells, CD4+ and CD8+ subpopulations, or sCD14 levels in HIV-infected patients receiving suppressive antiretroviral treatment with poor CD4+ recovery over the course of a 12-week period ( Tenore et al., 2020 ).…”

Effect of intake of probiotics and probiotic fermented foods on clinical outcomes among people living with HIV: A systematic review and meta‐analysis

“…Two studies recruited females only [21, 42] and another recruited only males [41]. In terms of study design, there were 13 parallel‐arm randomised controlled trials (RCTs) [15, 16, 21, 33, 35–37, 40, 42, 43, 45–47], 1 crossover trial [39] and 7 before‐and‐after studies [17–19, 33, 34, 37, 40].…”

“…In one study from Spain [37], 100 PLHIV were randomly assigned to receive either a synbiotic, a probiotic or a placebo. Only 71 participants were included in the final analysis because of loss to follow‐up and major protocol deviations (especially antibiotic intake).…”

“…Studies of CD4 lymphocyte count were examined by whether participants included in the studies were HAARTexperienced (Table 1, [15, 19, 33-35, 37-41, 44-46]), HAART-naïve (Table 2, [16,21,36,42,43]) or both (Table 3, [17,18,47]). Studies among HAART-experienced individuals were further examined by whether follow-up lasted from 4 to 13 weeks [15,33,34,[37][38][39][40][41][44][45][46] or whether from 6 to 12-months [15,19,35,46].…”

“…Eleven studies reported on follow-up from 4 to 13 weeks among HAART-experienced PLHIV (Table 1, [15,33,34,[37][38][39][40][41][44][45][46]). Of these, three studies found statistically significant but modest effects of probiotic supplementation on CD4 lymphocyte counts [40,41,46].…”