The bacillus Calmette-Guérin (BCG) vaccine protects against tuberculosis and heterologous infections but elicits high inter-individual variation in specific and nonspecific, or trained, immune responses. While the gut microbiome is increasingly recognized as an important modulator of vaccine responses and immunity in general, its potential role in BCG-induced protection is largely unknown. Stool and blood were collected from 321 healthy adults before BCG vaccination, followed by blood sampling after 2 weeks and 3 months. Metagenomics based on de novo genome assembly reveals 43 immunomodulatory taxa. The nonspecific, trained immune response is detected by altered production of cytokines IL-6, IL-1β, and TNF-α upon ex vivo blood restimulation with Staphylococcus aureus and negatively correlates with abundance of Roseburia. The specific response, measured by IFN-γ production upon Mycobacterium tuberculosis stimulation, is associated positively with Ruminococcus and Eggerthella lenta. The identified immunomodulatory taxa also have the strongest effects on circulating metabolites, with Roseburia affecting phenylalanine metabolism. This is corroborated by abundances of relevant enzymes, suggesting alternate phenylalanine metabolism modules are activated in a Roseburia species-dependent manner. Variability in cytokine production after BCG vaccination is associated with the abundance of microbial genomes, which in turn affect or produce metabolites in circulation. Roseburia is found to alter both trained immune responses and phenylalanine metabolism, revealing microbes and microbial products that may alter BCG-induced immunity. Together, our findings contribute to the understanding of specific and trained immune responses after BCG vaccination.

中文翻译：

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肠道微生物组对卡介苗诱导的训练免疫的影响

卡介苗 (BCG) 疫苗可预防结核病和异源感染，但会在特异性和非特异性或经过训练的免疫反应中引起个体间的高度差异。虽然肠道微生物群越来越被认为是疫苗反应和免疫的重要调节剂，但其在 BCG 诱导的保护中的潜在作用在很大程度上是未知的。在接种卡介苗前从 321 名健康成人中采集粪便和血液，然后在 2 周和 3 个月后采集血液样本。基于从头基因组组装的宏基因组学揭示了 43 个免疫调节类群。在用金黄色葡萄球菌进行离体血液再刺激后，通过改变细胞因子 IL-6、IL-1β 和 TNF-α 的产生来检测非特异性、经过训练的免疫反应，并且与 Roseburia 的丰度呈负相关。具体回应，通过在结核分枝杆菌刺激下产生的 IFN-γ 测量，与瘤胃球菌和迟缓埃格氏菌呈正相关。已确定的免疫调节类群对循环代谢物也有最强的影响，其中 Roseburia 影响苯丙氨酸代谢。相关酶的丰度证实了这一点，表明交替的苯丙氨酸代谢模块以 Roseburia 物种依赖性方式被激活。BCG 疫苗接种后细胞因子产生的变化与微生物基因组的丰度有关，这反过来会影响或产生循环中的代谢物。Roseburia 被发现可以改变经过训练的免疫反应和苯丙氨酸代谢，揭示可能改变 BCG 诱导免疫的微生物和微生物产物。一起，