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

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.