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Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial.
Goncalves-Mendes, N, Talvas, J, Dualé, C, Guttmann, A, Corbin, V, Marceau, G, Sapin, V, Brachet, P, Evrard, B, Laurichesse, H, et al
Frontiers in immunology. 2019;10:65
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This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in a sample of 38 deficient elderly persons, over 65-year olds, could improve influenza seroprotection and immune response. Vitamin D is known to both potentiate the innate immune response and inhibit the adaptive system, and so potentially modulate vaccination response. The participants were randomised into two arms: vitamin D supplementation group (D) and placebo group (P). The D group received 100,000 IU/15 days of cholecalciferol over a 3-month period after which both groups were given the influenza vaccine, and their blood was evaluated 28 days later. Several immune biomarkers were analysed including plasma cytokine profiles, phagocyte ROS production, and lymphocyte cells phenotyping to determine if Vitamin D enhanced immune response to the vaccination. No differences were found in serum ROS and antibody markers. However, Vitamin D supplementation did promote a higher TGFβ plasma level in response to influenza vaccination. Taken together, these results suggest that vitamin D supplementation is not an effective way to improve antibody response to influenza vaccine in deficient elderly people.
Abstract
Background: Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response. Objective: This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response. Design: Deficient volunteers (Vit-D serum <30 ng/mL) were assigned (V1) to receive either 100,000 IU/15 days of cholecalciferol (D, n = 19), or a placebo (P, n = 19), over a 3 month period. Influenza vaccination was performed at the end of this period (V2), and the vaccine response was evaluated 28 days later (V3). At each visit, serum cathelicidin, immune response to vaccination, plasma cytokines, lymphocyte phenotyping, and phagocyte ROS production were assessed. Results: Levels of serum 25-(OH)D increased after supplementation (D group, V1 vs. V2: 20.7 ± 5.7 vs. 44.3 ± 8.6 ng/mL, p < 0.001). No difference was observed for serum cathelicidin levels, antibody titers, and ROS production in D vs. P groups at V3. Lower plasma levels of TNFα (p = 0.040) and IL-6 (p = 0.046), and higher ones for TFGβ (p = 0.0028) were observed at V3. The Th1/Th2 ratio was lower in the D group at V2 (D: 0.12 ± 0.05 vs. P: 0.18 ± 0.05, p = 0.039). Conclusions: Vit-D supplementation promotes a higher TGFβ plasma level in response to influenza vaccination without improving antibody production. This supplementation seems to direct the lymphocyte polarization toward a tolerogenic immune response. A deeper characterization of metabolic and molecular pathways of these observations will aid in the understanding of Vit-D's effects on cell-mediated immunity in aging. This clinical trial was registered at clinicaltrials.gov as NCT01893385.
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Daily Nutritional Supplementation with Vitamin D₃ and Phenylbutyrate to Treatment-Naïve HIV Patients Tested in a Randomized Placebo-Controlled Trial.
Ashenafi, S, Amogne, W, Kassa, E, Gebreselassie, N, Bekele, A, Aseffa, G, Getachew, M, Aseffa, A, Worku, A, Hammar, U, et al
Nutrients. 2019;11(1)
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Poor nutritional status is common among human immunodeficiency virus (HIV)-infected patients including vitamin D (vitD3) deficiency. VitD3 together with phenylbutyrate (PBA) can induce an antimicrobial peptide called cathelicidin which has anti-viral properties. VitD3 and PBA can also enhance autophagy, a physiological process known to enhance destruction of intracellular viruses. The aim of this double-blind, placebo-controlled trial was to evaluate whether vitD3 + PBA could reduce viral replication and restore immune and nutritional status in HIV infection. 173 previously untreated HIV patients were randomised to receive either 5000 IU vitD3 and 500 mg PBA or placebos for 16 weeks with follow-up of a further 8 weeks. Most subjects had low plasma vitD3 levels at baseline which increased significantly in the vitD3 + PBA group compared with placebo at weeks 4, 8 and 16, indicating good compliance and response to the treatment. There were no statistical differences in any of the measured outcomes, including viral load, CD4 cells, CD8 cells and body mass index, between treatment and placebo group at any point during the study and follow-up.
Abstract
Poor nutritional status is common among human immunodeficiency virus (HIV)-infected patients including vitamin D (vitD₃) deficiency. We conducted a double-blinded, randomized, and placebo-controlled trial in Addis Ababa, Ethiopia, to investigate if daily nutritional supplementation with vitD₃ (5000 IU) and phenylbutyrate (PBA, 2 × 500 mg) could mediate beneficial effects in treatment-naïve HIV patients. Primary endpoint: the change in plasma HIV-1 comparing week 0 to 16 using modified intention-to-treat (mITT, n = 197) and per-protocol (n = 173) analyses. Secondary endpoints: longitudinal HIV viral load, T cell counts, body mass index (BMI), middle-upper-arm circumference (MUAC), and 25(OH)D₃ levels in plasma. Baseline characteristics were detectable viral loads (median 7897 copies/mL), low CD4⁺ (median 410 cells/µL), and elevated CD8⁺ (median 930 cells/µL) T cell counts. Most subjects were vitD₃ deficient at enrolment, but a gradual and significant improvement of vitD₃ status was demonstrated in the vitD₃ + PBA group compared with placebo (p < 0.0001) from week 0 to 16 (median 37.5 versus 115.5 nmol/L). No significant changes in HIV viral load, CD4⁺ or CD8⁺ T cell counts, BMI or MUAC could be detected. Clinical adverse events were similar in both groups. Daily vitD₃ + PBA for 16 weeks was well-tolerated and effectively improved vitD₃ status but did not reduce viral load, restore peripheral T cell counts or improve BMI or MUAC in HIV patients with slow progressive disease. Clinicaltrials.gov NCT01702974.
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A pilot, open labelled, randomised controlled trial of hypertonic saline nasal irrigation and gargling for the common cold.
Ramalingam, S, Graham, C, Dove, J, Morrice, L, Sheikh, A
Scientific reports. 2019;9(1):1015
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The common cold is a viral upper respiratory tract infection which affects adults and children worldwide, often multiple times a year. A large number of viruses cause these infections, making targeted antiviral treatment impractical. This small, randomised, controlled pilot trial (not blinded) of 68 adults aimed to assess the impact of salt-water nasal washing and throat gargling as many times as required (on average 3 times a day for 5 days) within 48 hours of symptom on-set on study recruitment and retention, as well as acceptability, symptom duration and viral shedding. The researchers found that nasal irrigation and gargling with a saline solution was acceptable to study participants. Illness duration was shortened by 1.9 days in the intervention arm, with significant reductions in the duration of runny nose, blocked nose, sneezing, cough and hoarseness of voice. The average quality of life score was also higher in the intervention arm, although this failed to reach significance. Viral shedding was higher in the intervention arm, with over the counter medication use 36% lower. There was also a lower rate of infection spread within households for the intervention arm. The authors call for a larger, placebo controlled trial to confirm these findings. Nutrition Practitioners supporting immunity in relation to the common cold virus may want to discuss the use of saline nasal irrigation with their clients as a simple measure to reduce symptoms and spread.
Abstract
There are no antivirals to treat viral upper respiratory tract infection (URTI). Since numerous viruses cause URTI, antiviral therapy is impractical. As we have evidence of chloride-ion dependent innate antiviral response in epithelial cells, we conducted a pilot, non-blinded, randomised controlled trial of hypertonic saline nasal irrigation and gargling (HSNIG) vs standard care on healthy adults within 48 hours of URTI onset to assess recruitment (primary outcome). Acceptability, symptom duration and viral shedding were secondary outcomes. Participants maintained a symptom diary until well for two days or a maximum of 14 days and collected 5 sequential mid-turbinate swabs to measure viral shedding. The intervention arm prepared hypertonic saline and performed HSNIG. We recruited 68 participants (2.6 participants/week; November 2014-March 2015). A participant declined after randomisation. Another was on antibiotics and hence removed (Intervention:32, Control:34). Follow up data was available from 61 (Intervention:30, Control:31). 87% found HSNIG acceptable, 93% thought HSNIG made a difference to their symptoms. In the intervention arm, duration of illness was lower by 1.9 days (p = 0.01), over-the-counter medications (OTCM) use by 36% (p = 0.004), transmission within household contacts by 35% (p = 0.006) and viral shedding by ≥0.5 log10/day (p = 0.04). We hence need a larger trial to confirm our findings.
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Crying Time and RORγ/FOXP3 Expression in Lactobacillus reuteri DSM17938-Treated Infants with Colic: A Randomized Trial.
Savino, F, Garro, M, Montanari, P, Galliano, I, Bergallo, M
The Journal of pediatrics. 2018;192:171-177.e1
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The causes of infant colic are unknown, but growing evidence shows a possible link with the gut microbiome. Increased inflammation has also been found in infants with colic, and this could be linked to dysbiosis. This double-blind, placebo-controlled clinical trial investigated whether supplementation with the probiotic Lactobacillus reuteri (L reuteri) DSM 17938 could reduce the crying time and modify inflammation in a group of infants with colic. Infants enrolled in the trial were less than 12 weeks old, with a healthy birth weight and predominantly breastfed. Infants with colic were given either 5 million colony-forming units (CFU) of L reuteri DSM 17938 or a placebo daily for 1 month. Crying times were significantly shortened among infants with colic given the probiotic, whilst the concentration of transcription factors for cells that help to regulate the immune system increased significantly. Infants treated with the probiotic showed an increase in the percentage of Lactobacillus and a decrease in the inflammatory marker faecal calprotectin. The authors concluded that their findings support the hypothesis that dysbiosis and inflammation may contribute to the onset of infant colic.
Abstract
OBJECTIVES To evaluate crying time, retinoid-related orphan receptor-γ (RORγ) and forkhead box P3 (FOXP3) messenger RNA levels (transcription factors that can modulate T cell responses to gut microbes), and to investigate gut microbiota and fecal calprotectin in infants treated with Lactobacillus reuteri for infantile colic. STUDY DESIGN A double-blind, placebo-controlled randomized trial was conducted in primary care in Torino from August 1, 2015 to September 30, 2016. Patients suffering from infantile colic were randomly assigned to receive daily oral L reuteri (1 × 108 colony forming unit) or placebo for 1 month. Daily crying times were recorded in a structured diary. FOXP3 and RORγ messenger RNA in the peripheral blood was assessed with real-time TaqMan reverse transcription polymerase chain reaction. Gut microbiota and fecal calprotectin were evaluated. RESULTS After infants with colic were supplemented with L reuteri DSM 17938 for 30 days, crying times were significantly shorter among infants with colic in the probiotic group compared with infants in the placebo group (74.67 ± 25.04 [IQR = 79] minutes /day vs 147.85 [IQR = 135] minutes /day [P = .001]). The FOXP3 concentration increased significantly (P = .009), resulting in decreased RORγ/FOXP3 ratios: 0.61 (IQR = 0.60) at day 0 and 0.48 (IQR = 0.28) at day 30 (P = .028). Furthermore, the probiotic increased the percentage of Lactobacillus (P = .049) and decreased fecal calprotectin (P = .0001). CONCLUSIONS Infants with colic treated with L reuteri for 30 days had a significantly decreased crying time and an increased FOXP3 concentration, resulting in a decreased RORγ/FOXP3 ratio. The treatment reduced fecal calprotectin. TRIAL REGISTRATION ClinicalTrials.gov: NCT00893711.
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Longitudinal Study of the Psoriasis-Associated Skin Microbiome during Therapy with Ustekinumab in a Randomized Phase 3b Clinical Trial.
Loesche, MA, Farahi, K, Capone, K, Fakharzadeh, S, Blauvelt, A, Duffin, KC, DePrimo, SE, Muñoz-Elías, EJ, Brodmerkel, C, Dasgupta, B, et al
The Journal of investigative dermatology. 2018;138(9):1973-1981
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Chronic plaque psoriasis is an immune-mediated disease of the skin and joints. A growing appreciation of the role of the innate immune system in psoriasis pathogenesis stems from the prominent role of inflammatory cytokines and cells associated with innate immunity in the disease and associations observed between psoriasis and genetic variations involved in innate immunity. The aim of this study was to assess changes of the skin microbiome in the setting of a longitudinal phase 3b study of patients receiving up to 2 years of ustekinumab therapy. Results show that prior to treatment, there were minor, body-site specific differences in microbial diversity and composition when comparing lesional with non-lesional skin. Microbial heterogeneity was greater in lesional skin than non-lesional skin. During ustekinumab treatment, the composition of microbiota diverged further between lesional and non-lesional skin across body sites. The divergence observed between lesional and non-lesional skin during ustekinumab treatment varied by body site. Authors conclude that their findings may help inform future study design and it may also have medically relevant implications for diagnostics and therapeutics involving the skin microbiome.
Abstract
Plaque psoriasis, a chronic inflammatory disease primarily affecting the skin, is thought to have a multifactorial etiology, including innate immune system dysregulation, environmental triggers, and genetic susceptibility. We sought to further understand the role of skin microbiota in psoriasis pathogenesis, as well as their response to therapy. We systematically analyzed dynamic microbiota colonizing psoriasis lesions and adjacent nonlesional skin in 114 patients prior to and during ustekinumab treatment in a phase 3b clinical trial. By sequencing the bacterial 16S ribosomal RNA gene from skin swab samples obtained at six anatomical sites, we identified minor, site-specific differences in microbial diversity and composition between pretreatment lesional and nonlesional skin. During therapy, microbial communities within lesional and nonlesional skin diverged, and body-site dispersion increased, reflecting microbial skin site-specificity. Microbiota demonstrated greater pretreatment heterogeneity in psoriatic lesions than in nonlesional skin, and variance increased as treatment progressed. Microbiota colonizing recurrent lesions did not overlap with pretreatment lesional microbiota, suggesting colonization patterns varied between initial and recurrent psoriatic lesions. While plaque psoriasis does not appear to be associated with specific microbes and/or microbial diversity, this large dataset provides insight into microbial variation associated with (i) disease in different body locations, (ii) initial versus recurrent lesions, and (iii) anti-IL12/23 therapy.
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Lack of immunogenicity of hydrolysed wheat flour in patients with coeliac disease after a short-term oral challenge.
Mandile, R, Picascia, S, Parrella, C, Camarca, A, Gobbetti, M, Greco, L, Troncone, R, Gianfrani, C, Auricchio, R
Alimentary pharmacology & therapeutics. 2017;46(4):440-446
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A gluten-free diet is currently the only reliable therapeutic approach for coeliac disease (CD), an immune-mediated condition where eating gluten causes intestinal inflammation. Hydrolysing wheat flour with a sourdough enriched with lactobacilli and fungal proteases has been shown to be effective in reducing the gluten in the bread baked with it to less that 10ppm (which should be safe for CD patients). This randomised prospective study was designed to confirm the lack of an immunological response to the hydrolysed gluten in CD patients, both in vitro and in vivo. 20 CD patients who were in clinical remission and had followed a gluten-free diet (GFD) for at least three years were enrolled into this study and randomised to receive either natural wheat (10g gluten per day) or hydrolysed wheat (10g hydrolysed gluten per day) for three days. In vitro studies using intestinal cells from three of the study participants showed that the hydrolysed gluten did not elicit an immune response, whilst the natural gluten did. In vivo, there were no statistically significant increases in immune reactivity in the hydrolysed gluten patients, and no-one in this group experienced any symptoms. In the natural wheat group significant increases in immune reactivity to gluten were seen although only one person experienced symptoms (abdominal pain). The authors conclude that wheat flour hydrolysed with an enriched sourdough may be an alternative for the CD patient’s diet.
Abstract
BACKGROUND A gluten-free diet is currently the only reliable therapeutic strategy that is approved for coeliac disease (CD). For many patients, however, compliance remains inadequate. AIM: To investigate the immunogenicity of wheat flour that was pre-treated with selected lactobacilli and fungal proteases (hydrolysed wheat gluten) in coeliac patients. METHODS The immunogenicity of hydrolysed wheat gluten was evaluated both in vitro in intestinal T cell lines (TCLs) and in vivo in treated CD patients after a short-term gluten challenge. Twenty treated CD patients were enrolled and equally randomised into two groups. The patients ate bread that was prepared with hydrolysed wheat flour or natural wheat flour (10 g of gluten/d for 3 days). The interferon (INF)-γ responses to natural gliadin and a 33-mer peptide were assessed by the enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) both before and 6 days after the start of the challenge. RESULTS Hydrolysed wheat was not able to activate the TCLs from the coeliac intestinal mucosa. Consistent with the in vitro results, no significant increase in INF-γ secretion was observed in patients who consumed hydrolysed wheat flour. Conversely, the consumption of natural wheat gluten mobilised INF-γ secreting cells in the blood (P<.05). CONCLUSIONS We confirm that fermentation of wheat flour with sourdough lactobacilli and fungal proteases is capable of abolishing the T cell immunogenicity of gluten in coeliac patients. Our data also validate the short-term oral challenge as a useful tool for testing the efficacy of novel therapeutic approaches.