Composition of the gut microbiota transcends genetic determinants of malaria infection severity and influences pregnancy outcome
Composition of the gut microbiota transcends genetic determinants of malaria infection severity and influences pregnancy outcome
复制标题
DOI：
10.1016/j.ebiom.2019.05.052
复制
发表时间：
2019-05
期刊：
影响因子：
11.1
通讯作者：
Catherine D. Morffy Smith;Minghao Gong;Alicer K. Andrew;Brittany N. Russ;Yong Ge;M. Zadeh;C. Cooper;M. Mohamadzadeh;J. Moore
中科院分区：
文献类型：
--
作者：
Catherine D. Morffy Smith;Minghao Gong;Alicer K. Andrew;Brittany N. Russ;Yong Ge;M. Zadeh;C. Cooper;M. Mohamadzadeh;J. Moore
背景孕期疟疾感染是世界范围内母婴发病率和死亡率的主要原因。孕期疟疾的小鼠模型允许在易于处理的模型系统中探索母体疟疾感染与不良妊娠结局之间的联系机制。肠道微生物区系的组成已被证明影响近交系处女鼠对疟疾感染的易感性。在这项研究中，我们探索了肠道微生物区系对怀孕的近交系瑞士韦伯斯特鼠疟疾感染严重程度的调节能力。方法在瑞士韦伯斯特鼠中，通过广谱抗生素治疗扰乱本地肠道微生物，然后给予粪便微生物区系移植，改变了肠道微生物区系的组成，该微生物区系来自先前报道的具有肠道微生物的小鼠，以增强对疟疾的易感性或抵抗力。雌性小鼠感染P。Chabaudi Chabaudias在妊娠早期发生，并在整个妊娠期间跟踪感染和妊娠的进展。为了评估母体感染对胎儿结局的影响，在足月时处死母羊，以评估胎儿的大小和存活能力。或者，在没有母体发病率的情况下，通过剖腹产和培育幼崽来评估新生儿的存活率和断奶前的生长。一组受试者在妊娠中期也被安乐死，以评估感染和妊娠结局。结果发现，对感染的敏感性随着移植肠道微生物来源的不同而显著不同。寄生虫量与5种特定的OTUS的丰度呈负相关，其中包括粘液阿克曼氏菌和被归类为Allobaculum、Lactobacillas和S24-7种的OTUS。寄生虫负担的减少与产妇发病率的降低和妊娠结局的改善有关。与放在寄养水坝中的抗疟疾水坝的幼崽相比，寄生在高寄生虫负担的水坝中的幼崽在出生后的头几天存活率显著降低。在妊娠中期，所有组的血浆细胞因子水平相似，但感染母鼠胚胎中干扰素γ的表达升高，而IL-10仅在易感母鼠中表达升高。在后者中，在高密度感染下观察到单核细胞渗透的转录和显微镜证据；同样，在这一组中，疟疾血细胞的聚集增加。这些反应，加上胎盘血管的减少，可能会导致不良的妊娠结局。因此，高的母体寄生虫负担和相关的母体反应，潜在地由肠道微生物群落决定，对足月胎儿的健康和出生后早期的存活产生负面影响。说明在感染查鲍迪疟原虫的怀孕瑞士韦氏鼠中，肠道微生物群的组成超越了瑞士韦伯斯特鼠群体的杂交遗传，作为疟疾感染严重程度的决定因素，随后影响了暴露于疟疾的后代的妊娠结局。这篇手稿中报告的基础研究得到了佛罗里达大学兽医学院(JMM，MM和MG)、国家过敏和传染病研究所、国家糖尿病和消化系统疾病研究所以及肾脏疾病研究所的支持和国家卫生研究院尤尼斯·肯尼迪·施莱弗国家儿童健康和人类发展研究所，获奖号分别为T32AI060546(授予CDMS)、R01HD46860和R21AI111242(授予JMM)和R01 DK109560(授予MM)。MG得到了传染病和免疫学系和佛罗里达大学毕业生…的支持
BackgroundMalaria infection in pregnancy is a major cause of maternal and foetal morbidity and mortality worldwide. Mouse models for gestational malaria allow for the exploration of the mechanisms linking maternal malaria infection and poor pregnancy outcomes in a tractable model system. The composition of the gut microbiota has been shown to influence susceptibility to malaria infection in inbred virgin mice. In this study, we explore the ability of the gut microbiota to modulate malaria infection severity in pregnant outbred Swiss Webster mice.MethodsIn Swiss Webster mice, the composition of the gut microbiota was altered by disrupting the native gut microbes through broad-spectrum antibiotic treatment, followed by the administration of a faecal microbiota transplant derived from mice possessing gut microbes reported previously to confer susceptibility or resistance to malaria. Female mice were infected withP. chabaudi chabaudiAS in early gestation, and the progression of infection and pregnancy were tracked throughout gestation. To assess the impact of maternal infection on foetal outcomes, dams were sacrificed at term to assess foetal size and viability. Alternatively, pups were delivered by caesarean section and fostered to assess neonatal survival and pre-weaning growth in the absence of maternal morbidity. A group of dams was also euthanized at mid-gestation to assess infection and pregnancy outcomes.FindingsSusceptibility to infection varied significantly as a function of source of transplanted gut microbes. Parasite burden was negatively correlated with the abundance of five specific OTUs, includingAkkermansia muciniphilaand OTUs classified asAllobaculum,Lactobacillus, and S24-7 species. Reduced parasite burden was associated with reduced maternal morbidity and improved pregnancy outcomes. Pups produced by dams with high parasite burdens displayed a significant reduction in survival in the first days of life relative to those from malaria-resistant dams when placed with foster dams. At midgestation, plasma cytokine levels were similar across all groups, but expression of IFNγ in the conceptus was elevated in infected dams, and IL-10 only in susceptible dams. In the latter, transcriptional and microscopic evidence of monocytic infiltration was observed with high density infection; likewise, accumulation of malaria haemozoin was enhanced in this group. These responses, combined with reduced vascularization of the placenta in this group, may contribute to poor pregnancy outcomes. Thus, high maternal parasite burden and associated maternal responses, potentially dictated by the gut microbial community, negatively impacts term foetal health and survival in the early postnatal period.InterpretationThe composition of the gut microbiota inPlasmodium chabaudi chabaudiAS-infected pregnant Swiss Webster mice transcends the outbred genetics of the Swiss Webster mouse stock as a determinant of malaria infection severity, subsequently influencing pregnancy outcomes in malaria-exposed progeny.FundResearch reported in this manuscript was supported by the University of Florida College of Veterinary Medicine (JMM, MM, and MG), the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award numbers T32AI060546 (to CDMS), R01HD46860 and R21AI111242 (to JMM), and R01 DK109560 (to MM). MG was supported by Department of Infectious Diseases and Immunology and University of Florida graduate …