Laboratory of Immunoregulation, Sidra Medicine, Doha, Qatar.
Microbiome and Host-Microbes Interactions Laboratory, Sidra Medicine, Doha, Qatar.
J Transl Med. 2024 Nov 12;22(1):1021. doi: 10.1186/s12967-024-05850-z.
Pediatric cow milk allergies (CMA) can occur in immunoglobulin (Ig) E and non-IgE-mediated forms. Unlike IgE-mediated allergies, the mechanisms of disease pathogenesis in non-IgE-mediated food allergy and an association with microbiome has not been well established. Previous studies have identified the presence of altered humoral responses to gut bacteria in IgE mediated allergies. Here, we analyzed IgA, IgE and IgG responses to gut bacteria in subjects with either IgE or non-IgE mediated CMA to identify relative proportions of Ig-coated bacteria and characterize unique disease specific microbial signatures.
Multi-parametric flow cytometry analysis was used to identify IgA, IgE and IgG responses to gut bacteria in CMA patients. Cell sorting of Ig coated gut bacteria was subsequently performed followed by high throughput 16S rRNA gene sequencing and specific patterns of humoral responses to gut bacteria assessed in each study group.
We identified significant alterations in IgA and IgG gut bacterial coating patterns in CMA subjects. Proportions of IgA-coated bacteria were decreased in IgE mediated CMA subjects without atopic dermatitis (ALL) and non-IgE mediated CMA subjects (ENP), compared to healthy controls (CON). In comparison, IgG-coated bacteria was significantly elevated in CMA subjects with atopic dermatitis (AD). Alpha and beta diversities displayed significant differences in IgA-, IgE-, and IgG-coated bacteria in AD and ENP groups. Significant differences in bacteria coated by IgA, IgE and IgG were detected at Phyla, Genus and Species levels and associated bacterial dysbiosis in IgE and non-IgE mediated allergies were identified. Linear discriminant analysis (LDA) effect size (LEFse) revealed unique disease associated bacterial signatures, including several pathogenic bacteria namely Bacteroides fragilis, Ruminococcus gnavus, Eubacterium dolichum, Fusobacterium, Clostridium neonatale and Robinsoniella peoriensis. Receiver operating characteristic curve analysis confirmed the efficiency of using the bacterial signatures identified as biomarkers for disease.
Altered IgA and IgG responses to gut bacteria were identified in CMA subjects. The disease-specific responses were associated with alterations in bacterial diversity and concomitant dysbiosis of Ig-coated bacteria in IgE-mediated and non-IgE-mediated CMA pediatric subjects. The identification of pathogenic bacteria uniquely associated with different classes of allergic disease indicates a role of these bacteria in driving disease-specific pathological phenotypes.
小儿牛奶过敏（CMA）可发生在免疫球蛋白（Ig）E 和非 IgE 介导的形式。与 IgE 介导的过敏反应不同，非 IgE 介导的食物过敏发病机制以及与微生物组的关联尚未得到很好的证实。先前的研究已经确定了 IgE 介导的过敏反应中对肠道细菌存在改变的体液反应。在这里，我们分析了 IgE 或非 IgE 介导的 CMA 患者对肠道细菌的 IgA、IgE 和 IgG 反应，以确定 Ig 包被细菌的相对比例，并描述独特的疾病特异性微生物特征。
使用多参数流式细胞术分析来鉴定 CMA 患者对肠道细菌的 IgA、IgE 和 IgG 反应。随后对 Ig 包被的肠道细菌进行细胞分选，然后进行高通量 16S rRNA 基因测序，并在每个研究组中评估对肠道细菌的体液反应的特定模式。
我们发现 CMA 患者的 IgA 和 IgG 肠道细菌包被模式存在显著改变。与健康对照组（CON）相比，无特应性皮炎（ALL）和非 IgE 介导的 CMA 患者（ENP）的 IgE 介导的 CMA 患者的 IgA 包被细菌比例降低。相比之下，特应性皮炎（AD）的 CMA 患者的 IgG 包被细菌显著升高。AD 和 ENP 组的 IgA-、IgE-和 IgG-包被细菌的α和β多样性显示出显著差异。在门、属和种水平检测到 IgA、IgE 和 IgG 包被的细菌存在显著差异，并鉴定出 IgE 和非 IgE 介导的过敏反应中细菌的失调。线性判别分析（LDA）效应大小（LEFse）揭示了与疾病相关的独特细菌特征，包括几种致病性细菌，如梭状芽孢杆菌、瘤胃球菌、真杆菌、梭菌、新生儿梭菌和罗比氏罗宾逊菌。接收者操作特征曲线分析证实了使用鉴定出的细菌特征作为疾病生物标志物的效率。
在 CMA 患者中鉴定出对肠道细菌的 IgA 和 IgG 反应改变。疾病特异性反应与 IgE 介导和非 IgE 介导的 CMA 儿科患者中细菌多样性的改变以及伴随的 Ig 包被细菌的失调有关。与不同类别的过敏性疾病相关的独特致病性细菌的鉴定表明这些细菌在驱动疾病特异性病理表型中起作用。
