Periodic Reporting for period 2 - EarlyCause (Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity)
Periodo di rendicontazione: 2021-07-01 al 2022-12-31
Early life stress (ELS) is the experience of stressful or adverse conditions during a child’s development, beginning anywhere from pregnancy to adolescence. When prenatal, ELS may be experienced because of maternal stress during pregnancy, while after birth, it can result from adverse events such as child abuse (sexual, physical, emotional) and neglect (emotional, physical), parental loss (death, separation), disease, accidents, exposure to war or terrorism-related events and/or natural disasters. ELS matters because it can have a long-lasting impact on a child’s development, health and wellbeing. For example, ELS can affect a child’s neurodevelopment increasing the risk of cognitive, emotional and behavioural problems. In addition, ELS can dysregulate important physiological functions affecting the way a child may respond to future stressors.
ELS is a key determinant of health, not just early in life, but across the lifespan. It is known to dramatically increase the risk to develop a mental or physical illness and has been repeatedly associated with depression, anxiety, personality disorder but also cardiovascular, metabolic and autoimmune diseases, and possibly cancer. However, the biological mechanisms through which ELS affects health remain unclear.
EarlyCause is investigating how ELS causes diseases in adulthood. Its approach is original and novel because it examines which aspects of ELS are linked to the concomitant development of psychological, cardiovascular and metabolic diseases together, a phenomenon called co-morbidity, which is responsible for the increased mortality linked to ELS. Further, EarlyCause assesses whether these co-morbid symptoms can be diminished or prevented by intervention to avoid disease.
ELS is a key determinant of health, not just early in life, but across the lifespan. It is known to dramatically increase the risk to develop a mental or physical illness and has been repeatedly associated with depression, anxiety, personality disorder but also cardiovascular, metabolic and autoimmune diseases, and possibly cancer. However, the biological mechanisms through which ELS affects health remain unclear.
EarlyCause is investigating how ELS causes diseases in adulthood. Its approach is original and novel because it examines which aspects of ELS are linked to the concomitant development of psychological, cardiovascular and metabolic diseases together, a phenomenon called co-morbidity, which is responsible for the increased mortality linked to ELS. Further, EarlyCause assesses whether these co-morbid symptoms can be diminished or prevented by intervention to avoid disease.
EarlyCause combines studies in large cohorts of humans across Europe, as well as in validated cellular and animal models, to identify the chain of molecular and biological events that are activated in the brain and body by ELS and result in clinical symptoms. We evaluated gene-environment correlations and causal effects of childhood maltreatment on physical and mental health using a genetically informed approach. We initiated intervention analyses to assess the moderating effect of exposure to environmental enrichment after postnatal stress on behaviour and cardiometabolic functions. We have produced extensive cell banks (approx. 50 vial) of hippocampal neuronal precursors, microglia and cardiomyocytes, which will be used subsequently to identify ELS-related insults in several tissues (brain, heart, pancreas, adipose tissue) (WP6).
With a novel gene set-based approach, we uncovered suggestive evidence that epigenetic regulation of developmental plasticity may be affected by early life adversity. We observed enrichment in immune and inflammatory pathways, elucidating putative biological mechanisms underlying multimorbidity of depression, diabetes and heart disease. In a postnatal stress model, we showed that female and male mice exposed to maternal stress have impaired glucose response and reduced weight when adult. We revealed that in adult animals exposed to postnatal trauma, cardiac functions are severely impaired, with a significant hypertrophy of heart tissues. Initial results of microbiome analyses indicated a trend for a change in the composition of the gut microbiota in exposed animals, with an imbalance in some genus compared to controls.
During the second reporting period, WP2 produced the first version of the EarlyCause Data Portal as the main component of the open-access research platform, which covers a whole range of data types spanning across different species such as mouse, rat, and human, as well as cell line data, and a rich search and browse environment for the scientific community and relevant ELS stakeholders. In WP3, we have further investigated and shown that prenatal and postnatal stress exposure associate with early manifestations of psycho-cardiometabolic risk, including greater emotional problems, higher adiposity and their co-occurrence in emerging adolescence. Additionally, we performed the first epigenome-wide study of gene-environment interactions on child DNA methylation levels, and found that common genetic variants interact with prenatal stress to influence DNA methylation patterns at birth. We also mapped gene-environment interplay on the developing brain to identify genetic variants that can impact brain structures when exposed to pre and post-natal stress.
WP5 showed that some minor changes occur in the blood metabolic profiling and cardiac biomarkers of the F1 stressed group, as well as heart abnormalities. Regarding gut microbia, we found that it could act as a vector of stress-related behavioral alterations through the gut-brain axis, and that it could be involved in the mechanisms that regulate systemic inflammation, and those associated with dopamine and corticosterone regulation. In WP6, we generated a robust protocol to obtain hypothalamic-like neurons starting from human induced pluripotent stem cells (iPSCs).
In WP7, we developed a proof-of-concept tool for creating digitalised cohorts from several longitudinal cohorts to generate and test life-course models of multimorbidity development. Our work allowed us to construct a series of useful tools via structural equation models, pipelines and cluster analyses to identify patterns of multi-morbidity trajectories, and mediators. We also initiated the construction of new conditional machine learning models for predicting comorbidities linking two conditions at a time, allowing specialists to access new tools and assess the risk of comorbidities in different medical domains.
WP8 continued to deliver key socio-economic impact assessments and expoitable results along five value streams: “new early-life-stress biomarkers”, “a clinical decision tool”, “microbiome models for usage in clinical practice”, “a research web portal”, and “clinical guideline recommendations following from EarlyCause project results”. Continous dissemination and communication of the project for both a general and a specialized audience have been accomplished.
With a novel gene set-based approach, we uncovered suggestive evidence that epigenetic regulation of developmental plasticity may be affected by early life adversity. We observed enrichment in immune and inflammatory pathways, elucidating putative biological mechanisms underlying multimorbidity of depression, diabetes and heart disease. In a postnatal stress model, we showed that female and male mice exposed to maternal stress have impaired glucose response and reduced weight when adult. We revealed that in adult animals exposed to postnatal trauma, cardiac functions are severely impaired, with a significant hypertrophy of heart tissues. Initial results of microbiome analyses indicated a trend for a change in the composition of the gut microbiota in exposed animals, with an imbalance in some genus compared to controls.
During the second reporting period, WP2 produced the first version of the EarlyCause Data Portal as the main component of the open-access research platform, which covers a whole range of data types spanning across different species such as mouse, rat, and human, as well as cell line data, and a rich search and browse environment for the scientific community and relevant ELS stakeholders. In WP3, we have further investigated and shown that prenatal and postnatal stress exposure associate with early manifestations of psycho-cardiometabolic risk, including greater emotional problems, higher adiposity and their co-occurrence in emerging adolescence. Additionally, we performed the first epigenome-wide study of gene-environment interactions on child DNA methylation levels, and found that common genetic variants interact with prenatal stress to influence DNA methylation patterns at birth. We also mapped gene-environment interplay on the developing brain to identify genetic variants that can impact brain structures when exposed to pre and post-natal stress.
WP5 showed that some minor changes occur in the blood metabolic profiling and cardiac biomarkers of the F1 stressed group, as well as heart abnormalities. Regarding gut microbia, we found that it could act as a vector of stress-related behavioral alterations through the gut-brain axis, and that it could be involved in the mechanisms that regulate systemic inflammation, and those associated with dopamine and corticosterone regulation. In WP6, we generated a robust protocol to obtain hypothalamic-like neurons starting from human induced pluripotent stem cells (iPSCs).
In WP7, we developed a proof-of-concept tool for creating digitalised cohorts from several longitudinal cohorts to generate and test life-course models of multimorbidity development. Our work allowed us to construct a series of useful tools via structural equation models, pipelines and cluster analyses to identify patterns of multi-morbidity trajectories, and mediators. We also initiated the construction of new conditional machine learning models for predicting comorbidities linking two conditions at a time, allowing specialists to access new tools and assess the risk of comorbidities in different medical domains.
WP8 continued to deliver key socio-economic impact assessments and expoitable results along five value streams: “new early-life-stress biomarkers”, “a clinical decision tool”, “microbiome models for usage in clinical practice”, “a research web portal”, and “clinical guideline recommendations following from EarlyCause project results”. Continous dissemination and communication of the project for both a general and a specialized audience have been accomplished.
The EarlyCause project will advance the state of the art by identifying causative mechanisms and molecular pathways that link ELS to depression, diabetes and heart disease, as well as their comorbid states. Furthermore, we will investigate new biomarkers from multiple biological scales and domains (epigenetics, inflammation, microbiome, neuroendocrine system) for improved early diagnosis and monitoring of multi-morbidity. By integrating the identified biological and environmental determinants, artificial intelligence powered clinical tools will be built for predictive modelling of multi-morbidity risk in future practice. By pinpointing the causative mechanisms and lifestyle moderators, we will open new routes for the prevention of ELS-induced multi-morbidity. EarlyCause will also lead to new research directions in social sciences, for raising awareness of the influence of early environment on health and disease, human well-being and community responsibility.R