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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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Regulatory T cells and Toll-like receptor 2 and 4 mRNA expression in infants with colic treated with Lactobacillus reuteri DSM17938.
Savino, F, Galliano, I, Garro, M, Savino, A, Daprà, V, Montanari, P, Bergallo, M
Beneficial microbes. 2018;(6):917-925
Abstract
Regulatory T cells induce immune homeostasis and the expression of Toll like receptors (TLRs); subsequent inflammatory cytokine release may be involved. Recent studies have shown a microbial imbalance in the gut of colicky infants (with a prevalence of gram-negative bacteria, such as Escherichia coli), and accumulating evidence has shown the efficacy of a probiotic (Lactobacillus reuteri) in breastfed subjects, but the underlying mechanism remains undefined. The study enrolled 59 infants younger than 60 days, of whom 34 subjects had colic and 25 were healthy controls. With a double-blind, placebo-controlled randomised study performed in our unit from October 2016 to July 2017, infants with colic were randomly assigned to receive oral daily L. reuteri DSM17938 (1×108 cfu) or placebo for 28 days. Peripheral blood was collected to assess the expression of FoxP3, TLR2 and TLR4 mRNA using real-time TaqMan RT-PCR at baseline and after the study period. Our findings showed increased mRNA expression of the transcription factor forkhead box P3 (FoxP3) in infants treated with L. reuteri DSM 17938 for 28 days (P<0.009) and increased TLR2 and TLR4 mRNA expression in both treated and placebo subjects. After L. reuteri administration for 28 days in infants with colic, we observed a significant decrease in daily crying time (302.3±19.86 min/day on day 0 vs 76.75±22.15 min/day on day 28, P=0.001). This study provides evidence that the observed increase in FoxP3 expression and reduction in crying time might be responses to probiotic treatment, while the increase in TLR2 and TLR4 mRNA expression might be related to age. Exploiting these new findings may lead to an unprecedented level of therapeutic control over immune tolerance using probiotics.