Can plant-derived extracellular vesicles improve outcomes in pregnancies complicated by maternal obesity?
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
During pregnancy, the placenta forms the physical connection between a mother and her baby. One of its jobs is to transfer food and oxygen from maternal to fetal blood so that the fetus can grow properly. The placenta must transfer the right amount of nutrients because too little can cause the baby to grow less well and be born smaller than it should be. Poor growth is a major problem: many small babies die or, if they do survive, they are more likely to be ill or disabled during childhood. There's also a life-long impact on health as these infants have an increased chance of being overweight and developing heart disease or diabetes as adults.
One of the reasons the placenta might not work properly is when mum is overweight or is living with obesity. This is increasingly common in the UK with half of pregnant women having a body mass index in the overweight or obese range. This project is about helping these mums to have a better outcome for their babies by trying to find a treatment that will help the placenta do its job as it should.
It's already known that fetal growth is better if expectant mums eat a diet rich in fruit and vegetables. We don't know exactly how the fruit and vegetables have this effect but one idea is that there is some component within fruits and vegetables that makes the placenta work better. Our previous work has tried to find out what this component might be because a treatment based on a natural product is a particularly good idea for pregnancy disease, where unanticipated side effects could have devastating consequences for both mum and/or baby.
So far, our experiments have shown that very tiny particles from mashed-up watermelons can alter the way a laboratory model of the placenta works. We've also shown that when we give these watermelon particles to normal pregnant mice, the placenta grows better and produces more of the proteins needed to transfer nutrients from mum to fetus. We believe that the placenta is responding to messages from mum's gut as our preliminary investigations have shown that the watermelon particles alter the 'good' bacteria in mum's gut and reduce the number of harmful immune cells in the gut so that there is less inflammation.
In this project, we will give these watermelon particles to pregnant mice that are obese and see how they affect the placenta and the growth of the pups. We will also look at how communication between the gut and the placenta is altered. Finally, we will see how the pathways in obese mice that are 'rescued' by treatment with watermelon particles map onto those known to be affected in women living with obesity to gauge whether a trial in pregnant women would be the logical next step.
We expect that the data from all of these experiments will enable us to identify what links maternal diet to good placental growth and function. This will allow us to develop and eventually recommend, dietary changes based on fruit and vegetables that will help the placenta to work better in pregnancies at risk of poor fetal growth. In addition, we think that our data will be useful to other scientists working on plant-based therapies for other conditions such as cancer and cardiovascular disease.
New ways to prevent babies from being born too small are desperately needed. Not only do fetal growth problems cause distress for individual families, but they also leave hospitals with expensive obstetric/neonatal care bills and the prospect of looking after adults with long-term health problems. Society is left with an adult population that will have a poorer quality of life; life expectancy continues to increase but we are not aging healthily as in addition to obesity, the incidence of diabetes and cardiovascular disease is also increasing. So unless we find ways to prevent these conditions, many of our extra years will be plagued by illness.
One of the reasons the placenta might not work properly is when mum is overweight or is living with obesity. This is increasingly common in the UK with half of pregnant women having a body mass index in the overweight or obese range. This project is about helping these mums to have a better outcome for their babies by trying to find a treatment that will help the placenta do its job as it should.
It's already known that fetal growth is better if expectant mums eat a diet rich in fruit and vegetables. We don't know exactly how the fruit and vegetables have this effect but one idea is that there is some component within fruits and vegetables that makes the placenta work better. Our previous work has tried to find out what this component might be because a treatment based on a natural product is a particularly good idea for pregnancy disease, where unanticipated side effects could have devastating consequences for both mum and/or baby.
So far, our experiments have shown that very tiny particles from mashed-up watermelons can alter the way a laboratory model of the placenta works. We've also shown that when we give these watermelon particles to normal pregnant mice, the placenta grows better and produces more of the proteins needed to transfer nutrients from mum to fetus. We believe that the placenta is responding to messages from mum's gut as our preliminary investigations have shown that the watermelon particles alter the 'good' bacteria in mum's gut and reduce the number of harmful immune cells in the gut so that there is less inflammation.
In this project, we will give these watermelon particles to pregnant mice that are obese and see how they affect the placenta and the growth of the pups. We will also look at how communication between the gut and the placenta is altered. Finally, we will see how the pathways in obese mice that are 'rescued' by treatment with watermelon particles map onto those known to be affected in women living with obesity to gauge whether a trial in pregnant women would be the logical next step.
We expect that the data from all of these experiments will enable us to identify what links maternal diet to good placental growth and function. This will allow us to develop and eventually recommend, dietary changes based on fruit and vegetables that will help the placenta to work better in pregnancies at risk of poor fetal growth. In addition, we think that our data will be useful to other scientists working on plant-based therapies for other conditions such as cancer and cardiovascular disease.
New ways to prevent babies from being born too small are desperately needed. Not only do fetal growth problems cause distress for individual families, but they also leave hospitals with expensive obstetric/neonatal care bills and the prospect of looking after adults with long-term health problems. Society is left with an adult population that will have a poorer quality of life; life expectancy continues to increase but we are not aging healthily as in addition to obesity, the incidence of diabetes and cardiovascular disease is also increasing. So unless we find ways to prevent these conditions, many of our extra years will be plagued by illness.
Technical Summary
Events in pre-natal life influence future health yet half of babies born in the UK each year develop in the suboptimal environment posed by pregnancy in women who are overweight or living with obesity. As a result, 20% of these infants suffer fetal growth restriction (FGR) due to placental dysfunction caused by inflammation, mitochondrial dysfunction, oxidative and endoplasmic reticulum stress. The only FGR treatment option, iatrogenic premature delivery, exacerbates poor health outcomes. There is a desperate need for new interventions but any potential therapy must have minimal risk as placental anomalies are difficult to identify with precision, necessitating treatment of women at risk of FGR.
Our proposal explores the possibility of overcoming this problem by using a natural product - plant-derived extracellular vesicles - to optimise placental development/function. Using a mouse model of maternal obesity, we will build on our published work and new preliminary data showing that watermelon EVs (WMEVs) can, via interaction with the intestinal epithelium, immune system and microbiome, influence key aspects of trophoblast behaviour required for successful placentation by:
(i) determining how WMEVs, administered as a preventative or intervention strategy, affect molecular (metabolic, stress and inflammatory) mechanisms governing placental development and function;
(ii) investigating how WMEVs influence potential intestinal-placental communication channels (microbiome, immune system and epithelial integrity);
(iii) using informatics approaches together with published datasets to identify pathways (intestinal and/or placental) common to pregnant women living with obesity.
The incidence of pregnancy complicated by maternal obesity is set to increase. Identifying treatment strategies that protect the fetus from a suboptimal maternal environment could curb the perpetuation of metabolic disease into future generations, improving individual and population health.
Our proposal explores the possibility of overcoming this problem by using a natural product - plant-derived extracellular vesicles - to optimise placental development/function. Using a mouse model of maternal obesity, we will build on our published work and new preliminary data showing that watermelon EVs (WMEVs) can, via interaction with the intestinal epithelium, immune system and microbiome, influence key aspects of trophoblast behaviour required for successful placentation by:
(i) determining how WMEVs, administered as a preventative or intervention strategy, affect molecular (metabolic, stress and inflammatory) mechanisms governing placental development and function;
(ii) investigating how WMEVs influence potential intestinal-placental communication channels (microbiome, immune system and epithelial integrity);
(iii) using informatics approaches together with published datasets to identify pathways (intestinal and/or placental) common to pregnant women living with obesity.
The incidence of pregnancy complicated by maternal obesity is set to increase. Identifying treatment strategies that protect the fetus from a suboptimal maternal environment could curb the perpetuation of metabolic disease into future generations, improving individual and population health.
