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首页> 外文期刊>EBioMedicine >Composition of the gut microbiota transcends genetic determinants of malaria infection severity and influences pregnancy outcome
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Composition of the gut microbiota transcends genetic determinants of malaria infection severity and influences pregnancy outcome

机译：肠道菌群的组成超越了疟疾感染严重程度的遗传决定因素，并影响了妊娠结局

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Background Malaria 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. Methods In 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 with P. chabaudi chabaudi AS 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. Findings Susceptibility 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, including Akkermansia muciniphila and OTUs classified as Allobaculum , 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. Interpretation The composition of the gut microbiota in Plasmodium chabaudi chabaudi AS-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. Fund Research 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 assistantships. AA was supported by the 2017–2019 Peach State LSAMP Bridge to the Doctorate Program at the University of Georgia (National Science Foundation, Award # 1702361). The content is solely the responsibility of the authors and does not necessarily represent official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, or the National Institutes of Health.
机译：背景技术怀孕期间的疟疾感染是全世界母婴发病率和死亡率的主要原因。妊娠疟疾的小鼠模型允许在可处理的模型系统中探索将孕产妇疟疾感染和不良妊娠结局联系起来的机制。肠道菌群的组成已显示会影响近交纯种小鼠对疟疾感染的敏感性。在这项研究中，我们探索了肠道微生物群调节怀孕的近交瑞士韦伯斯特小鼠的疟疾感染严重程度的能力。方法在Swiss Webster小鼠中，通过广谱抗生素治疗破坏天然肠道微生物，然后施用源自先前报道的具有肠道微生物的小鼠的粪便微生物菌群，改变肠道微生物群的组成，这些小鼠据报道具有肠道易感性或耐药性疟疾。雌性小鼠在妊娠早期就感染了沙巴氏杆菌Chabaudi AS，并在整个妊娠期间追踪了感染和妊娠的进程。为了评估母体感染对胎儿结局的影响，足月时将水坝处死以评估胎儿的大小和生存能力。或者，通过剖腹产术将幼崽分娩，并在没有产妇发病率的情况下培育幼崽以评估新生儿存活率和断奶前生长。还在妊娠中期对一组水坝实施了安乐死，以评估感染和妊娠结局。调查结果感染的易感性随肠道肠道微生物来源的变化而显着不同。寄生虫负担与5种特定OTU的含量呈负相关，其中包括5种特定的OTU（包括阿克曼曼丝菌和分类为Allobaculum，Lactobacillus和S24-7种的OTU）。降低的寄生虫负担与降低孕产妇发病率和改善妊娠结局有关。与寄生虫水坝相比，寄生虫负担高的水坝产生的幼仔在生命的最初几天中存活率显着降低。妊娠中期，所有组的血浆细胞因子水平均相似，但受感染的大坝中概念中的IFNγ表达升高，仅对易感大坝中的IL-10表达升高。在后者中，在高密度感染下观察到单核细胞浸润的转录和微观证据。同样，该组中疟疾血红蛋白的蓄积增加。这些反应，再加上胎盘血管生成减少，可能导致不良的妊娠结局。因此，可能由肠道微生物群落决定的高产妇寄生虫负担和相关的产妇反应会对出生后早期的足月胎儿健康和生存产生负面影响。解释疟原虫chabaudi chabaudi AS感染的怀孕的Swiss Webster小鼠肠道菌群的组成超越了Swiss Webster小鼠原种的近交遗传学，可以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怀孕结果。本手稿中报道的基金研究得到了佛罗里达大学兽医学院（JMM，MM和MG），美国国立过敏和传染病研究所，美国糖尿病与消化与肾脏病研究所以及Eunice Kennedy的支持。美国国立卫生研究院的斯莱弗国家儿童健康与人类发展研究所，奖项编号T32AI060546（授予CDMS），R01HD46860和R21AI111242（授予JMM）以及R01 DK109560（授予MM）。 MG得到传染病和免疫学系和佛罗里达大学研究生助学金的支持。机管局得到了乔治亚大学2017-2019年桃州立大学LSAMP博士学位计划的资助（国家科学基金会，编号1702361）。内容仅是作者的责任，并不一定代表Eunice Kennedy Shriver国家儿童健康与人类发展研究所，美国过敏与传染病研究所，美国糖尿病与消化与肾脏病研究所的官方观点，或国立卫生研究院。

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