Periodic Reporting for period 1 - MaterHypoBiota (MaterHypoBiota: Exploring the role of maternal gut microbiota on hypothalamic neurodevelopment and metabolic programming in offspring.)
Okres sprawozdawczy: 2023-09-01 do 2025-08-31
The escalating high prevalence of metabolic disease, as obesity and type 2 diabetes, represents one of the most significant burden of modern society, given its impact on health and economy. Particularly troublesome is the high level of overweight and obesity in children. According to the latest WHO estimations (2022-2024), 1 in 4 children aged of 7-9 years is living with overweight or obesity.
These estimations highlight the urgent need to better understand the mechanisms involved in the onset of these early pathological conditions, in order to develop more effective therapeutic intervention strategies aimed at halting the onset of juvenile obesity and prevent development of lifelong metabolic disorders.
Although the causes of these metabolic disorders are complex and multifactorial and are not yet fully understood, an increasing amount of evidence suggest that alteration of the maternal environment during gestation and early post-natal life may disrupt the development of brain circuits, leading to enduring metabolic consequences in the offspring. Recent evidence linked maternal gut microbiota (mGM) with enduring consequences on social behaviour and cognition. However, whether mGM affects the development of hypothalamic circuits regulating energy homeostasis remains unknown. In addition, despite evidence suggesting that mGM is required for the development of blood-brain barriers, its role in the development of blood-hypothalamic barrier (BHB) has not been investigated. The overarching goal of MaterHypoBiota project is to characterize the role of maternal gut microbiota in the development of hypothalamic metabolic circuits and blood-hypothalamic barrier properties and whether it has long-term consequences on energy balance regulation in offspring (Fig1).
These estimations highlight the urgent need to better understand the mechanisms involved in the onset of these early pathological conditions, in order to develop more effective therapeutic intervention strategies aimed at halting the onset of juvenile obesity and prevent development of lifelong metabolic disorders.
Although the causes of these metabolic disorders are complex and multifactorial and are not yet fully understood, an increasing amount of evidence suggest that alteration of the maternal environment during gestation and early post-natal life may disrupt the development of brain circuits, leading to enduring metabolic consequences in the offspring. Recent evidence linked maternal gut microbiota (mGM) with enduring consequences on social behaviour and cognition. However, whether mGM affects the development of hypothalamic circuits regulating energy homeostasis remains unknown. In addition, despite evidence suggesting that mGM is required for the development of blood-brain barriers, its role in the development of blood-hypothalamic barrier (BHB) has not been investigated. The overarching goal of MaterHypoBiota project is to characterize the role of maternal gut microbiota in the development of hypothalamic metabolic circuits and blood-hypothalamic barrier properties and whether it has long-term consequences on energy balance regulation in offspring (Fig1).
To elucidate the function of mGM on the programming of energy balance in offspring, a complementary set of developmental neurobiology, microbiology, physiological and neuroendocrine approaches were used. Below, we report the key findings of MaterHypoBiota project.
1) Development and validation of a new model of maternal gut microbiota alteration. (Fig2)
We developed a new research model to study how changes in the maternal gut microbiota —known as dysbiosis—during pregnancy and lactation can impact offspring. We did this by giving to dams a controlled cocktail of broad-spectrum antibiotics (ABX), starting from the day of conception, throughout the gestation until the end of lactation (2A). During treatment, the offspring were never directly in contact with the antibiotics.
We confirmed that the antibiotics significantly reduced the number of gut bacteria in the treated mothers (mABX), compared to those who did not receive antibiotics (mCT) (2B), without affecting the course of pregnancy.
We found no traces of antibiotics in the blood of either the mothers or their offspring. This means the antibiotics stayed in the mother’s gut and rules out a direct contribution of the drugs to the physiological changes observed in offspring.
2) Exploration of the short- and long-term consequences of maternal gut microbiota alteration on offspring energy balance. (Fig3 and Fig4)
To understand how changes in maternal gut microbiota during pregnancy and lactation affect the descendants’ metabolism later in life, we ran a series of metabolic tests on the offspring of mothers who had been treated with antibiotics (offABX) and compared them to offspring of untreated mothers (offCT).
At birth, all pups weighed the same; nevertheless, during lactation, those born to antibiotic-treated mothers weighed less (3A). After weaning, however, these same offspring grew faster than their peers (3B) —catching up due to increase in size (3C). Similar findings were found between male and female offspring.
At adulthood, male offspring from antibiotic-treated mothers showed several metabolic changes as better insulin sensitivity (a key factor in preventing diabetes) (3D), faster clearance of fats from the blood after a meal (3E) and a greater ability to use fat for energy (3F). These metabolic changes were only seen in males, not females.
3) Explanation of physiological results, by identification of potential target organ.
Next, we looked at whether the metabolic changes seen in male offspring from antibiotic-treated mothers were connected to differences in specific brain cells (called POMC and AgRP neurons) that control metabolism by regulating appetite and energy expenditure. We found no major differences in the density of these key brain circuits between the two groups (4B).
However, we did notice something else: there were subtle changes in a specific brain region called the median eminence, which acts as a bridge between the brain and the rest of the body. This area plays a vital role in controlling metabolism, so even small changes here could have important effects on how the body uses energy.
Altogether, our findings summarized above suggest that maternal gut health during pregnancy and lactation shapes the health of the offspring and can have lasting effects on the progeny’s metabolism by modulating the development of specific brain region.
4) Identification of the mechanisms(s) by which microbiota exerts its effects
To understand the mechanism(s) by which the maternal gut microbiota influences the progeny’s energy metabolism throughout life, we conducted a special experiment – defined as conventionalization. We transferred healthy gut bacteria from untreated mothers to those whose gut bacteria had been altered by antibiotics. This transfer helped correct some of the metabolic changes in the offspring, proving that maternal gut health directly affects offspring energy balance and metabolism.
By analysing blood samples from both mothers and offspring, we identified few specific substances produced by gut bacteria (i.e. metabolites) that are likely passed from mother to offspring during pregnancy and lactation. These substances may explain the brain and metabolic changes we observed in offspring.
We plan to give these specific bacterial metabolites to offspring with altered metabolism to see if they can reverse the effects of maternal dysbiosis. This will help us confirm whether changes in gut bacteria are truly responsible for the metabolic and brain differences we’ve found.
1) Development and validation of a new model of maternal gut microbiota alteration. (Fig2)
We developed a new research model to study how changes in the maternal gut microbiota —known as dysbiosis—during pregnancy and lactation can impact offspring. We did this by giving to dams a controlled cocktail of broad-spectrum antibiotics (ABX), starting from the day of conception, throughout the gestation until the end of lactation (2A). During treatment, the offspring were never directly in contact with the antibiotics.
We confirmed that the antibiotics significantly reduced the number of gut bacteria in the treated mothers (mABX), compared to those who did not receive antibiotics (mCT) (2B), without affecting the course of pregnancy.
We found no traces of antibiotics in the blood of either the mothers or their offspring. This means the antibiotics stayed in the mother’s gut and rules out a direct contribution of the drugs to the physiological changes observed in offspring.
2) Exploration of the short- and long-term consequences of maternal gut microbiota alteration on offspring energy balance. (Fig3 and Fig4)
To understand how changes in maternal gut microbiota during pregnancy and lactation affect the descendants’ metabolism later in life, we ran a series of metabolic tests on the offspring of mothers who had been treated with antibiotics (offABX) and compared them to offspring of untreated mothers (offCT).
At birth, all pups weighed the same; nevertheless, during lactation, those born to antibiotic-treated mothers weighed less (3A). After weaning, however, these same offspring grew faster than their peers (3B) —catching up due to increase in size (3C). Similar findings were found between male and female offspring.
At adulthood, male offspring from antibiotic-treated mothers showed several metabolic changes as better insulin sensitivity (a key factor in preventing diabetes) (3D), faster clearance of fats from the blood after a meal (3E) and a greater ability to use fat for energy (3F). These metabolic changes were only seen in males, not females.
3) Explanation of physiological results, by identification of potential target organ.
Next, we looked at whether the metabolic changes seen in male offspring from antibiotic-treated mothers were connected to differences in specific brain cells (called POMC and AgRP neurons) that control metabolism by regulating appetite and energy expenditure. We found no major differences in the density of these key brain circuits between the two groups (4B).
However, we did notice something else: there were subtle changes in a specific brain region called the median eminence, which acts as a bridge between the brain and the rest of the body. This area plays a vital role in controlling metabolism, so even small changes here could have important effects on how the body uses energy.
Altogether, our findings summarized above suggest that maternal gut health during pregnancy and lactation shapes the health of the offspring and can have lasting effects on the progeny’s metabolism by modulating the development of specific brain region.
4) Identification of the mechanisms(s) by which microbiota exerts its effects
To understand the mechanism(s) by which the maternal gut microbiota influences the progeny’s energy metabolism throughout life, we conducted a special experiment – defined as conventionalization. We transferred healthy gut bacteria from untreated mothers to those whose gut bacteria had been altered by antibiotics. This transfer helped correct some of the metabolic changes in the offspring, proving that maternal gut health directly affects offspring energy balance and metabolism.
By analysing blood samples from both mothers and offspring, we identified few specific substances produced by gut bacteria (i.e. metabolites) that are likely passed from mother to offspring during pregnancy and lactation. These substances may explain the brain and metabolic changes we observed in offspring.
We plan to give these specific bacterial metabolites to offspring with altered metabolism to see if they can reverse the effects of maternal dysbiosis. This will help us confirm whether changes in gut bacteria are truly responsible for the metabolic and brain differences we’ve found.
Overall, the MaterHypoBiota project has revealed an important new connection: maternal gut bacteria during pregnancy and lactation play a crucial role in shaping how he offspring’s body manages energy for life. Our findings suggests that maternal gut bacteria help guide the development of key brain structures that link the body and brain, and orchestrate whole-body energy homeostasis.
What’s Next? While our MSCA funding has ended, this ground-breaking work will continue. We will explore how other organs might contribute to the metabolic changes we’ve seen in offspring, and we’re building new partnerships with researchers around the world to deepen our understanding.
Interestingly, female offspring don’t show the same metabolic changes as males—but they do experience delayed puberty, which can affect their reproductive health. Like metabolism, reproduction is also controlled by the brain, suggesting that maternal gut health may influence both energy balance and reproductive development in the descendent.
This research opens the door to new ways of supporting healthier futures for all children, starting even before birth. By understanding the powerful role of maternal gut microbiota, we hope to develop better advice and interventions for families everywhere.
What’s Next? While our MSCA funding has ended, this ground-breaking work will continue. We will explore how other organs might contribute to the metabolic changes we’ve seen in offspring, and we’re building new partnerships with researchers around the world to deepen our understanding.
Interestingly, female offspring don’t show the same metabolic changes as males—but they do experience delayed puberty, which can affect their reproductive health. Like metabolism, reproduction is also controlled by the brain, suggesting that maternal gut health may influence both energy balance and reproductive development in the descendent.
This research opens the door to new ways of supporting healthier futures for all children, starting even before birth. By understanding the powerful role of maternal gut microbiota, we hope to develop better advice and interventions for families everywhere.