Trans-generational Transmission of Obesity and Obesity-induced Liver Disease -a Role for Maternal Microbiota and Toll-like receptors

现在人们普遍认识到，怀孕期间的饮食和营养是后代未来代谢健康的可改变的风险因素。“健康和疾病的发育规划假说”强调了生命早期的大量环境暴露，这些环境暴露会引起生命过程中代谢表型的改变(Armitage等人，2008年)。流行病学研究证明了孕期和产后早期母体饮食和荷尔蒙环境对疾病风险的影响，这些研究得到了动物模型的广泛支持，动物模型为发展规划现象及其在长期健康和疾病中的作用提供了宝贵的机械性见解和原则证明(Oben等人，2010年；Mouralidarane等人，2013年)。与这些现象有关并提供一种潜在的潜在机制的是肠道微生物组在连接免疫、新陈代谢和健康或代谢障碍表型的跨代传递方面的新作用(Hoffman等人，2017；Friedman 2018)。在英国，肥胖的人口流行率正在上升：目前成年人的肥胖率约为30%。在大约30年的时间里，它已经上涨了300%。同样，英国约30%的儿童和青少年超重或肥胖。此外，约26%的育龄妇女患有肥胖症，五分之一的孕妇患有肥胖症(HMGO，2007)。成人和青少年肥胖的后果包括2型糖尿病和肥胖性肝病(非酒精性脂肪性肝病)。像酒精性肝病一样，NAFLD可能会导致肝硬变，并可能需要肝移植、肝癌和死亡。在英国，NAFLD预计将在未来十年或更短的时间内成为肝移植最常见的原因(Asrani等人，2018年；Younossi，2018年)。我们之前在老鼠身上表明，肥胖女性的后代患肥胖症及其相关疾病的风险增加，包括NAFLD。具体地说，我们发现，出生后，当断奶后喂食肥胖饮食时，肥胖母亲的后代比喂养相同肥胖饮食的瘦母亲的后代食欲更强，摄入更多食物，从而拥有更高的体重、脂肪质量和NAFLD标志(Oben等人，2010年；Mouralidarane等人，2013年)。因此，肥胖及其相关的代谢紊乱可能会从母亲传给后代。通过交叉培养实验，肥胖母亲的后代由肥胖母亲抚养哺乳，肥胖母亲的后代由瘦弱母亲抚养哺乳，所有后代随后在断奶时接受对照饲料喂养，我们发现肥胖表型的传播主要发生在哺乳期，但母亲的表型和出生后饮食之间存在明显的交互作用(Oben等，2010；Mouralidarane等，2013)。这种肥胖的代际传播现象被称为发展规划。NAFLD的发育规划机制尚不确定，但似乎涉及免疫系统：特别是免疫系统的非专门化部分，即所谓的先天免疫系统。我们的观察发现，肥胖小鼠的后代会患上肥胖症和非酒精性脂肪肝，这一点在人类中得到了证实。研究目的：我们现在寻求通过肠道微生物区系进一步研究NAFLD的发育规划，利用新型药物来靶向肠道微生物区系的作用途径。目的：研究母体肠道微生物区系在肥胖和NAFLD跨代传播中的作用：1)无菌小鼠2)Toll样受体缺失小鼠3)Toll样受体拮抗剂4)大孔碳。

It is now widely recognised that diet and nutrition in pregnancy are modifiable risk factors for the future metabolic health of the offspring. The 'developmental programming of health and disease hypothesis' has highlighted numerous environmental exposuresin early life that give rise to modifications in metabolic phenotype across the life course (Armitage et al, 2008). Epidemiological studies which demonstrate influences of maternal diet and the hormonal environment in gestation and early post-natal life on disease risk profiles, are extensively supported by animal models which have been invaluable in providing mechanistic insight and proof of principle into the phenomenon of developmental programming and its role in long-term health and disease (Oben et al, 2010; Mouralidarane et al, 2013). Linked to these phenomena and providing a potential underlying mechanism is the emerging role of the gut microbiome in linking immunity, metabolism and the transgenerational transmission of a healthy or dysmetabolic phenotype (Hoffman et al, 2017; Friedman 2018). The population prevalence of obesity in the United Kingdom is rising: it stands currently in adults at about 30%. It has risen by 300% in about 30 years. Similarly, some 30% of children and adolescents in the UKare overweight or obese. Additionally, some 26% of women of reproductive age are obese and one in five pregnant women is obese (HMGO, 2007). The consequences of adult and adolescent obesity include type 2 diabetes and obesity-induced-liver disease liver(non-alcoholic fatty liver disease, NAFLD). NAFLD,like alcoholic liver disease,may result in liver cirrhosis and with a possible requirement for liver transplantation, liver cancer and death. In the UK, NAFLD is predicted to become the commonest cause for liver transplantation within the next decade or less (Asrani et al, 2018; Younossi , 2018). We previously showed in mice, that the offspring of obese females are at increased risk of obesity and its associated disorders, including NAFLD. Specifically,we showed that post-natally, when fed an obesogenic diet after weaning, the offspring of obese mothers had increasedappetite, consumed more chow and consequently had higher body weights, fat mass and markers of NAFLD than the offspring of lean mothers fed the same obesogenic diet (Oben et al, 2010; Mouralidarane et al, 2013). Therefore, obesity and its many associated metabolic disorders may be transmitted from mother to offspring. Through cross-fostering experiments, where offspring of lean mothers were fostered byobese mothers to suckle and offspring of obese mothers fostered by lean mothers to suckle, and all offspring were later fed a control diet on weaning, we showed that the transmission of the obese phenotype occurred mostly during the suckling period but there is clearly an interaction between the maternal phenotype and the postnatal diet (Oben et al, 2010; Mouralidarane et al, 2013). This phenomenon of trans-generational transmission of obesity is called Developmental Programming. The mechanism of Developmental Programming of NAFLD is uncertain but appears to involve the immune system: in particular,the non-specialised part of the immune system, the so-called innate immune system. Our observationsthat offspring of obese mice damsdevelop obesityand NAFLD have been confirmed in humans. Aim of the investigation: We now seek to further study the developmental programming of NAFLD by gut microbiota employing novel agents that target the pathways through which gut microbiota acts. Aims: To study the role of maternal gut microbiota in the trans-generational transmission of obesity and NAFLD using: 1) Germ free mice 2) Toll-like receptors null mice 3) A Toll-like receptor antagonising drug 4) Macro-porous carbon.