State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Zhejiang Provincal People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
Front Immunol. 2021 Jun 15;12:694344. doi: 10.3389/fimmu.2021.694344. eCollection 2021.
Immunodeficiency is a very common condition in suboptimal health status and during the development or treatment of many diseases. Recently, probiotics have become an important means for immune regulation. The present study aimed to investigate the mechanism of the immunomodulatory effect of a combination of live , , , and (CBLEB), which is a drug used by approximately 10 million patients every year, on cyclophosphamide-immunosuppressed rats. Cyclophosphamide (40 mg/kg) was intraperitoneally injected to induce immunosuppression in a rat model on days 1, 2, 3, and 10. Starting from day 4, the rats were continuously gavaged with CBLEB solution for 15 days. The samples were collected to determine routine blood test parameters, liver and kidney functions, serum cytokine levels, gut microbiota, fecal and serum metabolomes, transcriptomes, and histopathological features. The results indicated that CBLEB treatment reduced cyclophosphamide-induced death, weight loss, and damage to the gut, liver, spleen, and lungs and eliminated a cyclophosphamide-induced increase in the mean hemoglobin content and GGT, M-CSF, and MIP-3α levels and a decrease in the red blood cell distribution width and total protein and creatinine levels in the blood. Additionally, CBLEB corrected cyclophosphamide-induced dysbiosis of the gut microbiota and eliminated all cyclophosphamide-induced alterations at the phylum level in rat feces, including the enrichment in Proteobacteria, Fusobacteriota, and Actinobacteriota and depletion of Spirochaetota and Cyanobacteria. Furthermore, CBLEB treatment alleviated cyclophosphamide-induced alterations in the whole fecal metabolome profile, including enrichment in 1-heptadecanol, succinic acid, hexadecane-1,2-diol, nonadecanoic acid, and pentadecanoic acid and depletion of benzenepropanoic acid and hexane. CBLEB treatment also alleviated cyclophosphamide-induced enrichment in serum D-lyxose and depletion of serum succinic acid, D-galactose, L-5-oxoproline, L-alanine, and malic acid. The results of transcriptome analysis indicated that the mechanism of the effect of CBLEB was related to the induction of recovery of cyclophosphamide-altered carbohydrate metabolism and signal transduction. In conclusion, the present study provides an experimental basis and comprehensive analysis of application of CBLEB for the treatment of immunodeficiency.
免疫缺陷是一种在身体状况不佳和许多疾病的发展或治疗过程中非常常见的情况。最近，益生菌已成为免疫调节的重要手段。本研究旨在探讨一种由活菌、死菌、孢子和芽胞（CBLEB）组成的药物组合调节免疫的机制，该药物每年约有 1000 万患者使用。采用腹腔注射环磷酰胺（40mg/kg）在大鼠模型上诱导免疫抑制，于第 1、2、3 和 10 天给药。从第 4 天开始，大鼠连续 15 天灌胃 CBLEB 溶液。采集样本以测定常规血液检查参数、肝肾功能、血清细胞因子水平、肠道微生物群、粪便和血清代谢组学、转录组学和组织病理学特征。结果表明，CBLEB 治疗可降低环磷酰胺诱导的死亡、体重减轻和肠道、肝脏、脾脏和肺部损伤，并消除环磷酰胺诱导的血红蛋白含量和 GGT、M-CSF 和 MIP-3α 水平升高以及红细胞分布宽度和总蛋白和肌酐水平降低。此外，CBLEB 纠正了肠道微生物群的环磷酰胺诱导的失调，并消除了大鼠粪便中环磷酰胺诱导的所有门水平的改变，包括厚壁菌门、梭杆菌门和放线菌门的富集以及螺旋体门和蓝细菌门的减少。此外，CBLEB 治疗缓解了环磷酰胺诱导的整个粪便代谢组学谱的改变，包括 1-十七烷醇、琥珀酸、十六烷-1,2-二醇、正十九烷酸和十五烷酸的富集以及苯丙酸和己烷的减少。CBLEB 治疗还缓解了环磷酰胺诱导的血清 D-木糖的富集和血清琥珀酸、D-半乳糖、L-5-氧脯氨酸、L-丙氨酸和苹果酸的减少。转录组分析的结果表明，CBLEB 作用的机制与诱导环磷酰胺改变的碳水化合物代谢和信号转导的恢复有关。总之，本研究为 CBLEB 治疗免疫缺陷提供了实验依据和综合分析。
