The mechanisms underlying maternal obesity-induced microbial DNA accumulation in fetus and offspring metabolic abnormalities

母亲肥胖引起胎儿微生物 DNA 积累和后代代谢异常的机制

基本信息

批准号：
10650245
负责人：
Wei Ying
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650245
关键词：
Abnormal Cell Attenuated Bacterial DNA Blood Circulation Cells Childhood Circulation Complement 3a DNA Development Disease Distant Embryo Embryonic Development Embryonic Induction Extravasation Fetus Human Impairment Incidence Infiltration Inflammation Inflammatory Response Insulin Resistance Intestines Intravenous Knock-out Knockout Mice Leaky Gut Liver Macrophage Mediating Metabolic Metabolic Diseases Metabolic syndrome Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathogenesis Pathogenicity Pathway interactions Placenta Population Pregnancy Recovery Regulation Resolution Ribosomal RNA Risk Factors Role Stimulator of Interferon Genes Thinness Tissues Weaning Work complement C3 precursor experimental study extracellular vesicles insight insulin secretion insulin sensitivity intestinal barrier maternal microbiota maternal obesity metabolic phenotype microbial microbiota mouse model obesity development obesity in children obesity in pregnancy offspring offspring obesity pregnant prevent response

项目摘要

Project Summary/Abstract The increase in childhood obesity/Type 2 diabetes is paralleling a worldwide increase in obesity-associated metabolic syndrome. Maternal obesity is one of the key drivers tightly associated with the incidence of offspring obesity and metabolic disorders. However, the mechanisms underlying the impacts of maternal obesity on offspring metabolic disorders are not fully understood. Our recent work has led to the discovery that CRIg+ macrophages protect host cells from the gut microbial DNA-containing extracellular vesicle (mEV)-induced cellular abnormalities, whereas CRIg+ macrophages are absent in the context of obesity in both humans and mice, accompanied with enrichment of bacterial DNAs in host cells and worsen insulin sensitivity or insulin secretion. Intestinal mEVs can readily pass through the gut barrier of obese mice and further deliver microbial DNAs into key metabolic tissues. We further demonstrated the critical role of CRIg+ macrophages in clearing gut mEVs from bloodstream, as evidenced by a robust accumulation of microbial DNAs within key metabolic tissues in NCD CRIg-/- mice after intravenously injected with gut mEVs. By contrast, CRIg+ cells in NCD WT mice blocked the infiltration of gut mEVs through a C3-mediated mechanism, thus preventing the enrichment of bacterial DNAs in host cells. Recovery of CRIg+ cells efficiently attenuated tissue inflammation and metabolic disorders in obese mice. Depletion of microbial DNAs blunted the pathogenic effects of gut mEVs, while accumulation of microbial DNAs triggered the activation of cGAS/STING pathway for host cell abnormalities. By contrast, knockout of cGAS prevented microbial DNA- induced cellular disorders. These results lead to the conclusion that CRIg+ macrophages protect host cells from the pathogenesis of gut mEVs. We also found a significant reduction in CRIg+ macrophage population in maternal liver and placenta in obese pregnancy, concomitant with bacterial DNA enrichment in embryos. By contrast, lean pregnant mice harbored high abundance of CRIg+ macrophages in placenta, and no 16s rRNAs were detected in their embryos. Maternal gut mEVs can reach and deliver microbial DNAs into embryos in obese pregnant mice or lean CRIg-/- mice, but not in lean WT mice. Thus, this proposal seeks to reveal the important roles of CRIg+ macrophages in pregnancy and the impacts of maternal obesity-induced embryonic microbial DNA enrichment on offspring metabolic responses. We will further determine: 1) critical roles of maternal CRIg+ macrophages in blocking the infiltration of gut mEVs into embryos; 2) effects of maternal obesity on the development of embryonic CRIg+ macrophages; 3) effects of maternal obesity- induced embryonic microbial DNA accumulation on offspring tissue inflammation and metabolic phenotypes.

项目概要/摘要儿童肥胖/2 型糖尿病的增加与全球肥胖相关疾病的增加同时发生代谢综合征。孕产妇肥胖是与该病发病率密切相关的关键驱动因素之一后代肥胖和代谢紊乱。然而，孕产妇影响的潜在机制肥胖对后代代谢紊乱的影响尚不完全清楚。我们最近的工作发现 CRIg+ 巨噬细胞保护宿主细胞免受肠道微生物含有 DNA 的细胞外囊泡的侵害 (mEV) 诱导的细胞异常，而 CRIg+ 巨噬细胞在肥胖背景下不存在人类和小鼠，伴随着宿主细胞中细菌 DNA 的富集，导致胰岛素恶化敏感性或胰岛素分泌。肠道 mEV 可以轻松穿过肥胖小鼠的肠道屏障进一步将微生物 DNA 输送到关键的代谢组织中。我们进一步证明了 CRIg+ 的关键作用巨噬细胞从血液中清除肠道 mEV，微生物的大量积累证明了这一点静脉注射肠道 mEV 后，NCD CRIg-/- 小鼠关键代谢组织内的 DNA。相比之下， NCD WT 小鼠中的 CRIg+ 细胞通过 C3 介导的机制阻断肠道 mEV 的浸润，从而防止宿主细胞中细菌 DNA 的富集。 CRIg+细胞的恢复有效减弱肥胖小鼠的组织炎症和代谢紊乱。微生物 DNA 的耗尽削弱了肠道 mEV 的致病作用，而微生物 DNA 的积累则触发了宿主细胞异常的 cGAS/STING 通路。相比之下，cGAS 的敲除可以阻止微生物 DNA- 诱发细胞紊乱。这些结果得出 CRIg+ 巨噬细胞保护宿主细胞的结论从肠道 mEV 的发病机制来看。我们还发现 CRIg+ 巨噬细胞数量显着减少肥胖妊娠的母体肝脏和胎盘中存在细菌 DNA，同时在胚胎中富集细菌 DNA。相比之下，瘦怀孕小鼠的胎盘中含有大量 CRIg+ 巨噬细胞，并且没有 16s 在他们的胚胎中检测到了 rRNA。母体肠道 mEV 可以到达并将微生物 DNA 传递到肥胖怀孕小鼠或瘦 CRIg-/- 小鼠的胚胎，但不是瘦 WT 小鼠。因此，本提案旨在揭示 CRIg+ 巨噬细胞在妊娠中的重要作用以及母亲肥胖引起的影响胚胎微生物 DNA 富集对后代代谢反应的影响。我们将进一步确定：1）关键母体 CRIg+ 巨噬细胞在阻止肠道 mEV 渗入胚胎中的作用； 2）影响母亲肥胖对胚胎 CRIg+ 巨噬细胞发育的影响； 3）母亲肥胖的影响- 诱导胚胎微生物 DNA 积累对后代组织炎症和代谢表型的影响。