Influence of Early Life Gut Microbiota of HIV-Exposed Uninfected Infants on Inflammation, Growth and Immunity to Enteric Pathogens

由于获得抗逆转录病毒治疗的机会增加，围产期艾滋病毒传播率大幅下降 在怀孕和哺乳期间。然而，这导致了越来越多的婴儿感染艾滋病毒- 暴露但未感染(IHEU)。IHEU表现为炎症、免疫激活和免疫增强 精疲力竭可能是由它们肠道微生物区系变化引起的。接触艾滋病毒也与身体受损有关 婴儿的生长(发育迟缓)。多项研究表明，与艾滋病毒相比，IHEU患者发育迟缓的证据 未暴露的婴儿(IHU)。此外，营养不良研究还与慢性肠道炎症有关，这也是 与肠道微生物区系改变有关，在婴儿中发育受损。受损背后的机制(S) IHEU的增长还不清楚。IHEU中肠道炎症的加剧可能与 发育迟缓。然而，IHEU中的肠道微生物区系是否会导致生长受损还没有得到正式测试。 除了生长，肠道微生物区系还会影响免疫发育。具体地说，早期的微生物区系组成 生命会留下持久的免疫后果。IHEU显示包括肠道在内的高传染性发病率 病原体。例如，研究表明，IHEU表现出较高的肠源性埃希氏菌流行率。 大肠埃希菌(EPEC)和隐孢子虫与未暴露的同行进行比较。肠道微生物区系已被证明 通过不同的机制来预防肠道病原体，包括定植、抵抗和改变 粘膜免疫。目前尚不清楚IHEU中的肠道微生物区系是否增强了对肠道病原体的敏感性。 人类研究是建立在相关性的基础上的，这种相关性限制了推断因果关系的能力。我们将利用一个无菌新生儿 用小鼠模型研究IHEU早期粪便微生物区系在推动这些临床症状中的作用 表型。此外，我们将使用EPEC的新生小鼠模型来测试粪便微生物区系之间的因果关系 以及对肠道病原体的免疫力。我们假设IHEU早期的肠道微生物区系导致 发炎，生长不良，对肠道病原体的免疫力减弱。我们建议检验这一假设 具体目标如下。 目的1：研究IHEU早期肠道微生物区系是否会引起肠道和全身炎症 并在婴儿期损害线性生长。 目的2：研究IHEU早期肠道微生物区系是否损害对肠道病原体的免疫

Rates of perinatal HIV transmission have fallen substantially due to increased access to antiretroviral therapy during pregnancy and breastfeeding. However, this has led to a growing population of infants who are HIV- exposed but uninfected (iHEU). iHEU display heightened inflammation, immune activation and immune exhaustion potentially driven by their altered gut microbiota. HIV exposure has also been linked to impaired growth (stunting) in infants. Multiple studies have shown evidence of stunting in iHEU compared to HIV unexposed infants (iHU). In addition, malnutrition studies have linked chronic intestinal inflammation, which also associated with gut microbiota alteration, in infants to impaired growth. The mechanism(s) behind impaired growth in iHEU are not understood. It is plausible that heightened intestinal inflammation in iHEU may associate with stunting. However, whether the gut microbiota in iHEU causes impaired growth has not been formally tested. Beyond growth, the gut microbiota impacts immune development. Specifically, microbiota composition early in life imprint lasting immunological consequences. iHEU display high infectious morbidity including to enteric pathogens. For example, studies have shown that iHEU exhibit high prevalence of enteropathogenic Escherichia coli (EPEC) and Cryptosporidium spp compared to unexposed counterparts. The gut microbiota has been shown to protect against enteric pathogens via various mechanisms including colonization resistance and alteration of mucosal immunity. Whether gut microbiota in iHEU enhance susceptibility to enteric pathogens is unknown. Human studies are based on correlations which limit ability to infer causation. We will utilize a germ-free neonatal mouse model to investigate the causal role of the early stool microbiota in iHEU in driving these clinical phenotypes. In addition, we will use a neonatal mouse model of EPEC to test causality between stool microbiota and immunity to enteric pathogens. We hypothesize that the gut microbiota of iHEU early in life causes inflammation, poor growth and impairs immunity to enteric pathogens. We propose to test this hypothesis with the following specific aims. Aim 1: To investigate whether the early life gut microbiota of iHEU causes intestinal and systemic inflammation and impaired linear growth during infancy. Aim 2: To investigate whether the early life gut microbiota of iHEU impairs immunity to enteric pathogens