Sarate Priya J, Srutkova Dagmar, Geissler Nora, Schwarzer Martin, Schabussova Irma, Inic-Kanada Aleksandra, Kozakova Hana, Wiedermann Ursula
Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, Novy Hradek, Czechia.
Front Immunol. 2021 Feb 17;11:612775. doi: 10.3389/fimmu.2020.612775. eCollection 2020.
A steady rise in the number of poly-sensitized patients has increased the demand for effective prophylactic strategies against multi-sensitivities. Probiotic bacteria have been successfully used in clinics and experimental models to prevent allergic mono-sensitization. In the present study, we have investigated whether probiotic bacteria could prevent poly-sensitization by imprinting on the immune system early in life. We used two recombinant variants of probiotic Nissle 1917 (EcN): i) EcN expressing birch and grass pollen, poly-allergen chimera construct (EcN-Chim), and ii) an "empty" EcN without allergen expression (EcN-Ctrl). Conventional mice (CV) were treated with either EcN-Chim or EcN-Ctrl in the last week of the gestation and lactation period. Gnotobiotic mice received one oral dose of either EcN-Chim or EcN-Ctrl before mating. The offspring from both models underwent systemic allergic poly-sensitization and intranasal challenge with recombinant birch and grass pollen allergens (rBet v 1, rPhl p 1, and rPhl p 5). In the CV setting, the colonization of offspring treatment of mothers reduced allergic airway inflammation (AAI) in offspring compared to poly-sensitized controls. Similarly, in a gnotobiotic model, AAI was reduced in EcN-Chim and EcN-Ctrl mono-colonized offspring. However, allergy prevention was more pronounced in the EcN-Ctrl mono-colonized offspring as compared to EcN-Chim. Mono-colonization with EcN-Ctrl was associated with a shift toward mixed Th1/Treg immune responses, increased expression of TLR2 and TLR4 in the lung, and maintained levels of zonulin-1 in lung epithelial cells as compared to GF poly-sensitized and EcN-Chim mono-colonized mice. This study is the first one to establish the model of allergic poly-sensitization in gnotobiotic mice. Using two different settings, gnotobiotic and conventional mice, we demonstrated that an early life intervention with the EcN without expressing an allergen is a powerful strategy to prevent poly-sensitization later in life.
多敏化患者数量的稳步上升，增加了对针对多种敏感性的有效预防策略的需求。益生菌已成功应用于临床和实验模型，以预防过敏性单敏化。在本研究中，我们调查了益生菌是否可以通过在生命早期对免疫系统进行印记来预防多敏化。我们使用了益生菌Nissle 1917（EcN）的两种重组变体：i）表达桦树和草花粉多过敏原嵌合体构建体的EcN（EcN-Chim），以及ii）不表达过敏原的“空”EcN（EcN-Ctrl）。在妊娠和哺乳期的最后一周，对常规小鼠（CV）用EcN-Chim或EcN-Ctrl进行处理。无菌小鼠在交配前口服一剂EcN-Chim或EcN-Ctrl。两个模型的后代均接受重组桦树和草花粉过敏原（rBet v 1、rPhl p 1和rPhl p 5）的全身过敏性多敏化和鼻内激发。在CV模型中，与多敏化对照组相比，母亲接受治疗的后代的定殖减少了后代的过敏性气道炎症（AAI）。同样，在无菌模型中，EcN-Chim和EcN-Ctrl单定殖的后代中AAI减少。然而，与EcN-Chim相比，EcN-Ctrl单定殖的后代中过敏预防更为明显。与GF多敏化和EcN-Chim单定殖的小鼠相比，EcN-Ctrl单定殖与向混合Th1/Treg免疫反应的转变、肺中TLR2和TLR4表达的增加以及肺上皮细胞中zonulin-1水平的维持有关。本研究首次在无菌小鼠中建立了过敏性多敏化模型。使用无菌和常规小鼠这两种不同的模型设置，我们证明了用不表达过敏原的EcN进行生命早期干预是预防生命后期多敏化的有效策略。
