1.
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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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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Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.
Zmora, N, Zilberman-Schapira, G, Suez, J, Mor, U, Dori-Bachash, M, Bashiardes, S, Kotler, E, Zur, M, Regev-Lehavi, D, Brik, RB, et al
Cell. 2018;174(6):1388-1405.e21
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Evidence regarding the efficacy of probiotics in colonising the gut mucosa are sparse. The authors investigated whether probiotics colonise the gut mucosa in mice and humans, using both gut mucosa and stool samples. They found that, in both mice and humans, results from stool samples only partially correlate with colonisation of the gut mucosa as determined through gut mucosa samples. Whilst results were fairly uniform in mice, in humans a person-specific resistance to colonisation of the gut mucosa by probiotics was observed. Inter-person variation could be predicted by the composition of the pre-probiotic microbiome and host immune features.
Abstract
Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.