Roles of gut-microbiota and probiotics in chronic urticaria: A systematic review and meta-analysis.

Abstract

Chronic urticaria (CU) is an immune-mediated disease that manifests with recurrent wheals. Gut microbiota is important in regulation of the immune system. Implication of gut microbiota in immune-mediated skin diseases, such as atopic dermatitis, had been well-documented.1 A systematic review and a meta-analysis were conducted to examine roles of the gut microbiota and probiotics in CU. The databases were searched up until 31 May 2021. These studies compared the gut microbiota among patients with CU and the control groups; randomised controlled trials (RCT) that compared the efficacy of probiotics and placebo among patients with CU were also included. Analyses based on risk ratio (RR) and standardised mean difference (SMD) were conducted; heterogeneity between the studies was also assessed using I2 statistic. A random effects model was adopted. All analyses were performed using Comprehensive Meta-Analysis Version 3 (Biostat, Inc., Englewood, NJ, USA). Seven studies (five case–control studies and two RCTs.) met the inclusion criteria (Fig. 1). Characteristics and detailed data of these studies were summarised in Table 1 and Supplemental Table 1. All five case–control studies showed that the gut microbiota among patients with CU had a significantly different composition when compared to the control groups. Two out of the three studies regarding the gut-microbiome showed that patients with CU had a lower alpha diversity. However, due to a high within-study heterogeneity, quantitative analysis was not performed. Alpha diversity was significantly lower among patients with CU. Beta diversity was significantly different between patients with CU and the controls. Escherichia coli was significantly higher among patients with CU. Faecalibacterium prausnitzii, Prevotella copri and Bacteroides were significantly lower among patients with CU. 16S rRNA gene sequencing (stool) Metabolomic analyses (serum) Alpha diversity was significantly lower among patients with CSU. Abundance of Bacteroides, Faecalibacterium, Bifidobacterium and unidentified Ruminococcaceae were significantly reduced among patients with CSU. The serum metabolome analysis revealed reduced levels of docosahexaenoic acid, arachidonic acid, glutamate and succinic acid among patients with CSU. Alpha diversity was not significantly different among patients with CSU versus the healthy controls, but beta diversity was significantly different between the two groups. Relative abundance of the Proteobacteria, Bacilli, Enterobacteriales and Enterobacteriaceae was significantly increased among patients with CSU. Relative abundance of Megamonas, Megasphaera and Dialister was significantly decreased among patients with CSU. 52 CU patients (42 finished) 21 probiotics vs 21 placebo No difference in UAS7. Improved quality of life in probiotic group. 213 CU children (206 finished) 104 probiotics vs 102 placebo Unclear risk The two RCTs involved prescription of probiotics including Bifidobacterium and strains of Lactobacillus. Pooled analysis of the two RCTs showed that the probiotic group had a significantly higher prevalence of good clinical response when compared to the placebo group (i.e. significant response and complete response: RR = 1.297; 95% confidence interval [CI] = 1.111–1.513; I2 = 0%; complete response: RR = 1.597; 95% CI = 1.228–2.077; I2 = 0%) (Fig. 2). The probiotic group also had a significantly better improvement in urticaria score (SMD = 0.398; 95% CI = 0.147–0.650; I2 = 0%) (Fig. 2). Altered bacterial diversity in the gut could disrupt the mucosal immune tolerance by promoting regulatory T (Treg) cells to react to dietary antigens.2 Aberrant cytokine expression and dysfunction of Treg cells are common among patients with CU.3 The use of probiotics could skew the T1/T2 balance towards T1 by inhibiting T2 cytokines or indirectly induce the production of IL-10 and Treg cells.4 Dysbiosis of the gut microbiota among patients with CU could result in dysregulation of the immune system, which supports the rationale to modify gut microbiota with probiotics. One major limitation of this study is the differences in the kinds, amounts and durations of adjuvant probiotics being prescribed, which resulted in smaller number of studies conducted and a smaller heterogeneity within the study. Another important limitation is confounding bias, such as different dietary habits and the use of oral antihistamine; these could modify the gut microbiota and thus change efficacy of probiotics. In conclusion, this study demonstrated that composition of the gut microbiota among patients with CU is generally different from healthy people; additionally, the use of probiotics is an efficacious adjuvant therapy. Future investigations are needed to determine the appropriate regimen and dosage of probiotic supplementation. This project was supported by cooperative research from Cathay General Hospital (CGH-MR-A10821). Its contents were solely the responsibility of the authors and did not necessarily represent the official views of the donor. Table S1. Detailed data and clinical response of treatment in randomised controlled trials. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.