Partner: Yaqrit Ltd
3rd Supervisor: Paul Long
The United Kingdom adult population prevalence of obesity is 30%. The children statistics are similarly alarming with 30% of children, overweight or obese. Additionally, 26% of women of reproductive age are obese and one in five pregnant women is obese. We have recently shown, in experimental models with highly rated publications, some of which are listed below, that the offspring of obese mothers have increased appetite, body weights, fat mass and markers of obesity-induced liver disease (non-alcoholic fatty liver disease, NAFLD), compared with offspring of lean mothers. Our murine model results have been confirmed in human such that the children of obese mothers show increased obesity and NAFLD. NAFLD is predicted to become the commonest cause of liver cirrhosis/failure and liver transplantation within the next decade or less. The precise mechanism through which this trans-generational transmission of obesity and NAFLD occurs remain unclear. Interesting, we showed that offspring of lean mice, fostered, and suckled by obese mothers from birth then weaned onto a normal diet developed had an increased appetite, ate more of the normal diet, became obese and developed NAFLD. Similarly, offspring of obese mothers, suckled by their own obese mothers and then weaned onto an obesogenic diet also became obese and developed NAFLD. The involved mechanism may involve the breast milk components consumed during suckling.
Obesity and NAFLD are also known to develop at least partially in response to gut microbiota. Our work in-progress is in confirmation of this. Commensal bacteria are transferred between co-housed animals and can cause the transmission of both obesity and NAFLD traits. It is likely, therefore that the transmission of obesity from mother to offspring during the peri-natal and post-natal periods is at least partially via the transmission of maternal commensal microbiota to the newborn. This has recently been strongly supported through the use of germ-free mice and their colonisation with stools from the offspring of obese human subjects. We now seek to continue our ongoing studies using agents that target the pathways through which the gut microbiota act. There are few groups who have published as much as we have and as advanced in this work as our Group.
A key process that normally occurs during birth and in the early post-natal feeding period during lactation may be the transmission of commensal microbiota from mother to offspring. Microbiota have previously been thought to be inert but are now being realised to be metabolically active and may in fact be regarded as an organ, the size of the liver, approximately 2kg. Importantly, the microbiota that colonise obese individuals is different in type and functionality to that colonising lean individuals. Therefore, it is possible that the observed trans-generational transmission of obesity and NAFLD and increasing rates of obesity and NAFLD is the result of the transmission of obese maternal microbiota to the newborn in combination, with the consumption of energy-dense foods acting synergistically with transmitted microbiota. A recent publication has strongly suggested that maternal microbiota may indeed be involved in the trans-generational of obesity and NAFLD. We now seek to further study the developmental programming of NAFLD by gut microbiota through 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 Germ free mice plus agents that specifically target the pathways through microbiota act. One such agent is a novel agent recently discovered by a young Pharmaceutical, Yaqrit Ltd (yaqrit.com). Yaqrit is a Pharmaceutical company spun-out from University College London, by a Group of Liver specialists, and developing exceedingly well. Our collaboration with Yaqrit is very strong. Besides the Medical research Council (UK), part of the PhD project funding is from Yaqrit. Part of the PhD time will therefore will be spent with Yaqrit with the possibility of growing with them and experiencing the Pharmaceutical environment. This of course not benefits the project in terms of the agents that Yaqrit will provide but also in providing Pharmaceutical work experience for the PhD student.
Essential Requirements: Given that the primary model is murine, it is essential that any potential PhD student has experience of working with animal models or at the very least feels comfortable working with murine models, specifically murine surgery, and murine body fluids eg murine blood and urine. The project is licensed by the Home Office and the Student has therefore to attend appropriate courses to acquire a Home Office License to allow such work to be performed.
Obesity as a driver of international differences in COVID?19 death rates: Gardiner J, Oben JA and Sutcliffe A (2021); Diabetes, Obesity and Metabolism 23, 1463-1470
Fat and Hidden Liver Cancer, Honap S and Oben JA (2021); Clinical Liver Disease, https://doi.org/10.1002/cld.1011 17 (2), 49-52
Maternal Perinatal Nutrition and Offspring Programming; Cordero P, …Oben JA (2020);
Principles of Nutrigenetics and Nutrigenomics, 121-127
Imbalance in gut microbes from babies born to obese mothers increases gut permeability and myeloid cell adaptations that provoke obesity and NAFLD, Soderborg K and Friedman JE (2018), Microb Cell 6:102-104.
Developmental programming of obesity and liver metabolism by maternal perinatal nutrition involves the melanocortin system; Cordero P… Taylor PD and Oben JA (2017).
Nutrients 9, 1041
Maternal Obesity Programs Offspring Non-Alcoholic Fatty Liver Disease via Innate Immune Dysfunction in Mice. Mouralidarane … Taylor PD & Oben JA. (2013); Hepatology 58, 128-138
Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice, Oben JA, Mouralidarane A…and Taylor PD. (2010). J Hepatology. 52: p. 913-20. (plus Editorial Comment).
Funding Source: This project is part of the MRC-DTP programme but is co-funded by King’s College London and the Industry partner Yaqrit Ltd.