Bifidobacterium infantis supplementation in early life to improve immunity in infants exposed to HIV: a randomized, placebo-controlled, double-blind trial

早期生命微生物群在健康和疾病中发挥着重要作用，包括免疫发育和 母体微生物区系是婴儿微生物区系的主要决定因素。暴露在空气中的婴儿 艾滋病毒但未感染(IHEU)更容易感染疾病，生长发育迟缓，肠道微生物区系改变 免疫力较差，即使他们自己没有感染艾滋病毒。在IHEU和小鼠中，我们发现更高的 长双歧杆菌婴儿亚种在芽孢杆菌感染前后肠道内的相对丰度 卡介苗(卡介苗)接种可提高晚年的细胞免疫力。 肠道代谢物的变化，表明婴儿芽胞杆菌的丰度或代谢物与T细胞之间存在联系 豁免权。我们假设，婴儿早期补充双胞菌提供了一种改善病情的治疗途径。 免疫和随后的IHEU健康后果。因此，我们建议将200个母乳喂养的南方随机 非洲IHEU进入一项安慰剂对照的双盲婴儿杆菌ECV001试验(一种商品化的 已证实安全和健康结果的产品)与安慰剂相比。其目的是1)比较肠道微生物 IHEU的纵向结构和功能随机接受婴儿芽胞杆菌与早期安慰剂比较 评估与大便代谢组的相关性。婴儿粪便将使用鸟枪式元基因组学和 使用半靶向代谢组学的代谢组学。将比较微生物组的组成和功能 出生时、第4、7和36周的组间，并与4.2周的大便代谢组相关。 比较接受早期生命的IHEU患者的肠道粘膜完整性和调节性与炎症性T细胞比率 B.婴儿与安慰剂。在基线时，第4、7和36周微生物易位和全身性 炎症将通过ELISA进行评估，T细胞表型将使用多参数Flow进行 细胞学。我们将使用一种无监督的自组装匹配方法来比较T细胞亚群和 在接受婴儿杆菌感染和服用安慰剂的婴儿中，将研究结果与测量系统标记物相关联。3) 比较接受早期B型流感疫苗接种的IHEU患者T细胞对卡介苗接种的反应性和直线生长情况。 婴儿与安慰剂的对比。卡介苗疫苗应答将在第7周和第36周使用全血- 测定和流式细胞术，并使用长度为年龄Z评分36周龄的生长，并比较交叉 在组之间进行分段。卡介苗的免疫应答将一直与婴儿芽胞杆菌的丰度相关。 积分。最后，我们将开发一个关于婴儿杆菌补充剂对健康影响的综合模型。 使用从所有AIMS产生的数据对IHEU进行评估。确定婴儿巴氏杆菌ECV001是否为现成的 干预有效地改善了IHEU的肠道健康、炎症和免疫力，IHEU是一种日益增长和脆弱的 儿科人群，可以改善IHEU的临床管理和健康结果。这项建议 与撒哈拉以南非洲地区高度相关，那里高达30%的婴儿接触艾滋病毒。

The early life microbiome plays a significant role in health and disease, including immune development and maturation, and maternal microbiota is a major determinant of infant microbiota. Infants who are exposed to HIV but uninfected (iHEU) are more vulnerable to disease, have stunted growth, altered gut microbiota and poorer immunity, even when they are not infected with HIV themselves. In iHEU and mice we found that higher relative abundances of Bifidobacterium longum subspecies infantis in the gut around time of Bacillus Calmette–Guérin (BCG) vaccination results in improved cellular immunity later in life, which was accompanied changes in gut metabolome, suggesting a link between B. infantis abundance or metabolites and T cell immunity. We hypothesize that B. infantis supplementation in early life offers a therapeutic avenue to improve immunity and subsequent health outcomes in iHEU. We thus propose to randomize 200 breastfed South African iHEU into a placebo-controlled, double-blinded trial of B. infantis ECV001 (a commercially available product with proven safety and health outcomes) versus placebo. The aims are to 1) compare gut microbial structure and function longitudinally in iHEU randomized to receive B. infantis versus placebo in early life and evaluate associations with stool metabolome. Infant stool will be analysed using shotgun metagenomics and metabolome using semi-targeted metabolomics. The microbiome composition and function will be compared between groups at birth, week 4, 7 and 36 of life, and correlated with stool metabolome at week 4. 2) To compare gut mucosal integrity and regulatory versus inflammatory T cell ratios in iHEU who received early life B. infantis versus placebo. At baseline, weeks 4, 7 and 36 markers of microbial translocation and systemic inflammation will be assessed by ELISA and T cell phenotyping conducted using multi-parameter flow cytometry. We will use an unsupervised self-assembly matching approach to compare T cell subsets and correlate findings with measurements systemic markers in infants who received B. infantis versus placebo. 3) To compare T cell responsiveness to BCG vaccination and linear growth in iHEU who received early life B. infantis versus placebo. BCG vaccine responses will be measured at week 7 and 36 using a whole-blood- assay and flow cytometry, and growth at week 36 using length for age Z scores, and compared cross- sectionally between groups. BCG vaccine responses will be correlated with B. infantis abundance at all time points. Finally, we will develop an integrative model on the effects of B. infantis supplementation on the health of iHEU using data generated from all aims. Determining whether B. infantis ECV001, a readily available intervention, is effective in improving gut health, inflammation, and immunity in iHEU, a growing and vulnerable pediatric population, could result in improved clinical management and health outcomes of iHEU. This proposal is highly relevant for sub-Saharan Africa, where up to 30% of infants are exposed to HIV.