Periodic Reporting for period 1 - NeuroVascOme (Gut microbiota-Neurovascular Interactions in Early Life)
Berichtszeitraum: 2020-07-01 bis 2022-06-30
The brain relies on a constant composition of its environment for proper development and function, maintained by the ‘brain-barriers’. These barriers also constitute an interface of communication between peripheral cues and the brain. One such source of peripheral signals is the gut-microbiota - an ecosystem of trillions of microorganisms that populate our guts. Though alterations in microbiota are associated with several neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and attention deficit hyperactivity disorder (ADHD), the exact mechanisms of communication are largely unknown.
The NeuroVascOme project asked whether this microbiota regulates the barriers in the developing brain through compounds that are produced by our gut microbes and reach the circulating blood, and consequently affect brain microenvironment and function.
Understanding this is particularly important given the multiple factors that are known to disrupt our microbiota, such as antibiotics, stress and birth by Caesarean section (C-section). C-section bypasses the birth canal, where the initial microbiota seeding happens, through vertical transmission of vaginal and faecal maternal microbiota to the new born. Moreover, this intervention is highly relevant in our society; according to recent research from World Health Organisation (WHO), C-section use continues to rise globally, now accounting for more than 1 in 5 (21%) of all childbirths. While C-section can be an essential and lifesaving surgery, it can put women and babies at unnecessary risk of short- and long-term health problems if performed when there is not medical need. One of the known risks of C-section, as mentioned above, is the disruption of the vertical transmission of maternal vaginal and faecal microbes to the new born. Moreover, a recent study showed that mice born by C-section display behavioural and cognitive deficits, that can be rescued by gut-microbiota based interventions, such as administration of pre- or probiotics.
Overall, we know little about the impact of gut microbiota disruption on our brains, especially in early life, when the brain is particularly vulnerable. Understanding how C-section can impact the developing brain through the disruption of the early-life microbiome, is essential for developing future microbiota-based strategies to enhance the microbiota composition in this vulnerable population.
The NeuroVascOme project asked whether this microbiota regulates the barriers in the developing brain through compounds that are produced by our gut microbes and reach the circulating blood, and consequently affect brain microenvironment and function.
Understanding this is particularly important given the multiple factors that are known to disrupt our microbiota, such as antibiotics, stress and birth by Caesarean section (C-section). C-section bypasses the birth canal, where the initial microbiota seeding happens, through vertical transmission of vaginal and faecal maternal microbiota to the new born. Moreover, this intervention is highly relevant in our society; according to recent research from World Health Organisation (WHO), C-section use continues to rise globally, now accounting for more than 1 in 5 (21%) of all childbirths. While C-section can be an essential and lifesaving surgery, it can put women and babies at unnecessary risk of short- and long-term health problems if performed when there is not medical need. One of the known risks of C-section, as mentioned above, is the disruption of the vertical transmission of maternal vaginal and faecal microbes to the new born. Moreover, a recent study showed that mice born by C-section display behavioural and cognitive deficits, that can be rescued by gut-microbiota based interventions, such as administration of pre- or probiotics.
Overall, we know little about the impact of gut microbiota disruption on our brains, especially in early life, when the brain is particularly vulnerable. Understanding how C-section can impact the developing brain through the disruption of the early-life microbiome, is essential for developing future microbiota-based strategies to enhance the microbiota composition in this vulnerable population.
We employed the C-section mouse model and focused on analysing the postnatal brain and in 7-10 old male and female mouse pups. This is a period when the gut microbiota composition has been shown to differ significantly when compared to vaginally-born pups.
We assessed the brain barriers’ function by injecting a fluorescent tracer into the circulation and observing how much of that tracer crossed the barriers into the brain. We observed that C-section mouse pups have an increased permeability of the brain barriers. To explore this further, we analysed the brain barriers’ cellular components with fluorescence microscopy. We identified a decrease in some important barrier components called ‘tight junctions’ in brain’s blood vessels. Moreover, we found that a type of immune cell associated to the brain barriers had an altered morphology in the brains of C-section-born pups. All these changes could underly the defective brain barrier function we observed with the fluorescent tracers.
Finally, we analysed the presence or absence of certain small molecules in the brains and found some differences between C-section and vaginally-delivered mouse pups. This could be a consequence of the altered brain barriers and microbiota composition.
Once our results have been through the scientific peer review process, we aim to share them with health care professionals and general public through our social media platforms and public events. This should contribute to taking more informed decisions about using C-section when there is no medical need. It is essential that this information reaches the health care providers and the parents.
Moreover, these results should also contribute to putting more focus in developing microbiota-based therapies for recovering the microbiota of C-section-delivered babies.
We assessed the brain barriers’ function by injecting a fluorescent tracer into the circulation and observing how much of that tracer crossed the barriers into the brain. We observed that C-section mouse pups have an increased permeability of the brain barriers. To explore this further, we analysed the brain barriers’ cellular components with fluorescence microscopy. We identified a decrease in some important barrier components called ‘tight junctions’ in brain’s blood vessels. Moreover, we found that a type of immune cell associated to the brain barriers had an altered morphology in the brains of C-section-born pups. All these changes could underly the defective brain barrier function we observed with the fluorescent tracers.
Finally, we analysed the presence or absence of certain small molecules in the brains and found some differences between C-section and vaginally-delivered mouse pups. This could be a consequence of the altered brain barriers and microbiota composition.
Once our results have been through the scientific peer review process, we aim to share them with health care professionals and general public through our social media platforms and public events. This should contribute to taking more informed decisions about using C-section when there is no medical need. It is essential that this information reaches the health care providers and the parents.
Moreover, these results should also contribute to putting more focus in developing microbiota-based therapies for recovering the microbiota of C-section-delivered babies.
We moved beyond previous research by examining the effects of C-section in both male and female animals in our mouse model. We were the first to compare brain barrier function upon C-section birth in early life, with the aim of better understanding the consequences if this intervention in the brain. This provides us with valuable information on the later consequences of these important, often life-saving, medical intervention, and the unique opportunity to develop strategies to overcome the C-section associated microbiota changes.