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影响后代未来代谢健康的可改变的危险因素。“健康和疾病的发展规划假说”强调了生命早期的许多环境暴露，这些环境暴露会导致整个生命过程中代谢表型的改变（Armitage等人，2008）。流行病学研究表明，母体饮食和妊娠期及产后早期生活中的激素环境对疾病风险状况的影响，得到了动物模型的广泛支持，这些动物模型在为发育规划现象及其在长期健康和疾病中的作用提供机制见解和原理证明方面具有宝贵价值（Oben等人，2010；Mouralidarane等人，2013）。与这些现象相关并提供潜在机制的是肠道微生物组在连接免疫、代谢和健康或代谢不良表型的跨代传播方面的新作用（Hoffman et al ., 2017; Friedman 2018）。英国的肥胖人口患病率正在上升：目前成年人的肥胖率约为30%。在大约30年的时间里，它增长了300%。同样，英国约30%的儿童和青少年超重或肥胖。此外，约26%的育龄妇女肥胖，五分之一的孕妇肥胖（HMGO， 2007年）。成人和青少年肥胖的后果包括2型糖尿病和肥胖引起的肝脏疾病（非酒精性脂肪性肝病，NAFLD）。NAFLD与酒精性肝病一样，可导致肝硬化，并可能需要肝移植、肝癌和死亡。在英国，预计NAFLD将在未来十年或更短时间内成为肝移植的最常见原因（Asrani et al ., 2018; Younossi, 2018）。我们之前在老鼠身上发现，肥胖雌性的后代患肥胖及其相关疾病（包括NAFLD）的风险增加。具体来说，我们发现，在出生后，当断奶后喂食致肥性饮食时，肥胖母亲的后代食欲增加，消耗更多的食物，因此体重、脂肪量和NAFLD标志物高于喂食相同致肥性饮食的瘦母亲的后代（Oben et al ., 2010; Mouralidarane et al ., 2013）。因此，肥胖及其相关的许多代谢紊乱可能会从母亲传给后代。我们通过交叉培养实验，将肥胖母鼠的后代由肥胖母鼠饲养哺乳，将肥胖母鼠的后代由肥胖母鼠饲养哺乳，并在断奶后饲喂对照饲料，发现肥胖表型的传播主要发生在哺乳期，但母体表型与产后饮食之间存在明显的相互作用（Oben et al, 2010; Mouralidarane et al, 2013）。这种肥胖的跨代传播现象被称为发育规划。NAFLD的发育机制尚不确定，但似乎与免疫系统有关：特别是免疫系统的非特化部分，即所谓的先天免疫系统。我们观察到肥胖小鼠的后代会发展为肥胖和NAFLD，这在人类中得到了证实。研究目的：我们现在寻求进一步研究肠道微生物群对NAFLD的发育规划，采用靶向肠道微生物群作用途径的新型药物。目的：研究母体肠道菌群在肥胖和NAFLD跨代遗传中的作用：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.