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Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells’ profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.
Sara B. Fernandes; Neha D. Patil; Sophie Meriaux; Maud Theresine; Claude. P. Muller; Fleur A. D. Leenen; Martha M. C. Elwenspoek; Jacques Zimmer; Jonathan D. Turner. Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress. Frontiers in Immunology 2021, 12, 1 .
AMA StyleSara B. Fernandes, Neha D. Patil, Sophie Meriaux, Maud Theresine, Claude. P. Muller, Fleur A. D. Leenen, Martha M. C. Elwenspoek, Jacques Zimmer, Jonathan D. Turner. Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress. Frontiers in Immunology. 2021; 12 ():1.
Chicago/Turabian StyleSara B. Fernandes; Neha D. Patil; Sophie Meriaux; Maud Theresine; Claude. P. Muller; Fleur A. D. Leenen; Martha M. C. Elwenspoek; Jacques Zimmer; Jonathan D. Turner. 2021. "Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress." Frontiers in Immunology 12, no. : 1.
The consumption of prebiotic fibers to modulate the human gut microbiome is a promising strategy to positively impact health. Nevertheless, given the compositional complexity of the microbiome and its inter-individual variances, generalized recommendations on the source or amount of fiber supplements remain vague. This problem is further compounded by availability of tractable in vitro and in vivo models to validate certain fibers. We employed a gnotobiotic mouse model containing a 14-member synthetic human gut microbiome (SM) in vivo, characterized a priori for their ability to metabolize a collection of fibers in vitro. This SM contains 14 different strains belonging to five distinct phyla. Since soluble purified fibers have been a common subject of studies, we specifically investigated the effects of dietary concentrated raw fibers (CRFs)—containing fibers from pea, oat, psyllium, wheat and apple—on the compositional and functional alterations in the SM. We demonstrate that, compared to a fiber-free diet, CRF supplementation increased the abundance of fiber-degraders, namely Eubacterium rectale, Roseburia intestinalis and Bacteroides ovatus and decreased the abundance of the mucin-degrader Akkermansia muciniphila. These results were corroborated by a general increase of bacterial fiber-degrading α-glucosidase enzyme activity. Overall, our results highlight the ability of CRFs to enhance the microbial fiber-degrading capacity.
Alex Steimle; Mareike Neumann; Erica Grant; Jonathan Turner; Mahesh Desai. Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome. International Journal of Molecular Sciences 2021, 22, 6855 .
AMA StyleAlex Steimle, Mareike Neumann, Erica Grant, Jonathan Turner, Mahesh Desai. Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome. International Journal of Molecular Sciences. 2021; 22 (13):6855.
Chicago/Turabian StyleAlex Steimle; Mareike Neumann; Erica Grant; Jonathan Turner; Mahesh Desai. 2021. "Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome." International Journal of Molecular Sciences 22, no. 13: 6855.
Consumption of prebiotic fibers to modulate the human gut microbiome is a promising strategy to positively impact health. Nevertheless, given the compositional complexity of the microbiome and its inter-individual variances, generalized recommendations on the source or amount of fiber supplements remain vague. This problem is further compounded by availability of tractable in vitro and in vivo models to validate certain fibers. We employed a gnotobiotic mouse model containing an a priori characterized 14-member synthetic human gut microbiome (SM) for their ability to metabolize a suit of fibers in vitro; the SM contains 14 different strains belonging to five distinct phyla. Since soluble purified fibers have been a common subject of studies, we specifically investigated the effects of concentrated raw fibers (CRFs)—containing fibers from pea, oat, psyllium, wheat and apple—on the compositional and functional alterations in the SM. We demonstrate that, compared to a fiber-free diet, CRF supplementation increased the abundance of fiber-degraders namely Eubacterium rectale, Roseburia intestinalis and Bacteroides ovatus and decreased the abundance of the mucin-degrader Akkermansia muciniphila. These results were corroborated by a general increase of bacterial fiber-degrading α-glucosidase enzyme activity. Overall, our results highlight the ability of CRFs to enhance the microbial fiber-degrading capacity.
Alexander Steimle; Mareike Neumann; Erica Grant; Jonathan D Turner; Mahesh S Desai. Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome. 2021, 1 .
AMA StyleAlexander Steimle, Mareike Neumann, Erica Grant, Jonathan D Turner, Mahesh S Desai. Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome. . 2021; ():1.
Chicago/Turabian StyleAlexander Steimle; Mareike Neumann; Erica Grant; Jonathan D Turner; Mahesh S Desai. 2021. "Concentrated Raw Fibers Enhance the Fiber-Degrading Capacity of a Synthetic Human Gut Microbiome." , no. : 1.
DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such as regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine (5mC) but recently adenine methylation was also found to be present in eukaryotes. In mouse embryonic stem cells, 6-methyladenine (6mA) was associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination. Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and fetal development. In somatic cells there are clear tissue specificity in 6mA levels, with the highest 6mA levels being observed in the brain. In zebrafish, during the first 120 h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7–21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant during the same early life period may led to a decrease in the levels of this modification in female rats. The identification of the periods during which 6mA epigenetic marks are put in place increases our understanding of this mammalian epigenetic modification, and raises the possibility that it may be associated with developmental processes.
Sara B. Fernandes; Nathalie Grova; Sarah Roth; Radu Corneliu Duca; Lode Godderis; Pauline Guebels; Sophie B. Mériaux; Andrew I. Lumley; Pascaline Bouillaud-Kremarik; Isabelle Ernens; Yvan Devaux; Henri Schroeder; Jonathan D. Turner. N6-Methyladenine in Eukaryotic DNA: Tissue Distribution, Early Embryo Development, and Neuronal Toxicity. Frontiers in Genetics 2021, 12, 1 .
AMA StyleSara B. Fernandes, Nathalie Grova, Sarah Roth, Radu Corneliu Duca, Lode Godderis, Pauline Guebels, Sophie B. Mériaux, Andrew I. Lumley, Pascaline Bouillaud-Kremarik, Isabelle Ernens, Yvan Devaux, Henri Schroeder, Jonathan D. Turner. N6-Methyladenine in Eukaryotic DNA: Tissue Distribution, Early Embryo Development, and Neuronal Toxicity. Frontiers in Genetics. 2021; 12 ():1.
Chicago/Turabian StyleSara B. Fernandes; Nathalie Grova; Sarah Roth; Radu Corneliu Duca; Lode Godderis; Pauline Guebels; Sophie B. Mériaux; Andrew I. Lumley; Pascaline Bouillaud-Kremarik; Isabelle Ernens; Yvan Devaux; Henri Schroeder; Jonathan D. Turner. 2021. "N6-Methyladenine in Eukaryotic DNA: Tissue Distribution, Early Embryo Development, and Neuronal Toxicity." Frontiers in Genetics 12, no. : 1.
Asymptomatic individuals, called “silent spreaders” spread SARS-CoV-2 efficiently and have complicated control of the ongoing COVID-19 pandemic. As seen in previous influenza pandemics, socioeconomic and life-trajectory factors are important in disease progression and outcome. The demographics of the asymptomatic SARS-CoV-2 carriers are unknown. We used the CON-VINCE cohort of healthy, asymptomatic, and oligosymptomatic individuals that is statistically representative of the overall population of Luxembourg for age, gender, and residency to characterise this population. Gender (male), not smoking, and exposure to early-life or adult traumatic experiences increased the risk of IgA seropositivity, and the risk associated with early-life exposure was a dose-dependent metric, while some other known comorbidities of active COVID-19 do not impact it. As prior exposure to adversity is associated with negative psychobiological reactions to external stressors, we recorded psychological wellbeing during the study period. Exposure to traumatic events or concurrent autoimmune or rheumatic disease were associated with a worse evolution of anxiety and depressive symptoms throughout the lockdown period. The unique demographic profile of the “silent spreaders” highlights the role that the early-life period plays in determining our lifelong health trajectory and provides evidence that the developmental origins of health and disease is applicable to infectious diseases.
Cyrielle Holuka; Chantal Snoeck; Sophie Mériaux; Markus Ollert; Rejko Krüger; Jonathan Turner; the CON-VINCE Consortium. Adverse Life Trajectories Are a Risk Factor for SARS-CoV-2 IgA Seropositivity. Journal of Clinical Medicine 2021, 10, 2159 .
AMA StyleCyrielle Holuka, Chantal Snoeck, Sophie Mériaux, Markus Ollert, Rejko Krüger, Jonathan Turner, the CON-VINCE Consortium. Adverse Life Trajectories Are a Risk Factor for SARS-CoV-2 IgA Seropositivity. Journal of Clinical Medicine. 2021; 10 (10):2159.
Chicago/Turabian StyleCyrielle Holuka; Chantal Snoeck; Sophie Mériaux; Markus Ollert; Rejko Krüger; Jonathan Turner; the CON-VINCE Consortium. 2021. "Adverse Life Trajectories Are a Risk Factor for SARS-CoV-2 IgA Seropositivity." Journal of Clinical Medicine 10, no. 10: 2159.
There are many ‘faces’ of early life adversity (ELA), such as childhood trauma, institutionalisation, abuse or exposure to environmental toxins. These have been implicated in the onset and severity of a wide range of chronic non-communicable diseases later in life. The later-life disease risk has a well-established immunological component. This raises the question as to whether accelerated immune-ageing mechanistically links early-life adversity to the lifelong health trajectory resulting in either ‘poor’ or ‘healthy’ ageing. Here we examine observational and mechanistic studies of ELA and inflammageing, highlighting common and distinct features in these two life stages. Many biological processes appear in common including reduction in telomere length, increased immunosenescence, metabolic distortions and chronic (viral) infections. We propose that ELA shapes the developing immune, endocrine and nervous system in a non-reversible way, creating a distinct phenotype with accelerated immunosenescence and systemic inflammation. We conclude that ELA might act as an accelerator for inflammageing and age-related diseases. Furthermore, we now have the tools and cohorts to be able to dissect the interaction between ELA and later life phenotype. This should, in the near future, allow us to identify the ecological and mechanistic processes that are involved in ‘healthy’ or accelerated immune-ageing.
Myriam P. Merz; Jonathan D. Turner. Is early life adversity a trigger towards inflammageing? Experimental Gerontology 2021, 150, 111377 .
AMA StyleMyriam P. Merz, Jonathan D. Turner. Is early life adversity a trigger towards inflammageing? Experimental Gerontology. 2021; 150 ():111377.
Chicago/Turabian StyleMyriam P. Merz; Jonathan D. Turner. 2021. "Is early life adversity a trigger towards inflammageing?" Experimental Gerontology 150, no. : 111377.
Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD), the closest animal model available to the human situation, is known to similarly induce long lasting behavioural effects, to cause changes in the HPA axis and to have an impact in the immune system. Even though the immune responses to potential pathogens after early stress have been somehow documented, the mechanisms by which they occur are still not fully understood. Here, we have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells’ profile and response to target cell lines are significantly changed after childhood adversity. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. Altogether, these results lead us to conclude that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.
Sara B. Fernandes; Neha D. Patil; Sophie B. Meriaux; Maud Theresine; Fleur A.D. Leenen; Martha M.C. Elwenspoek; Jacques Zimmer; Jonathan D. Turner. Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psycho-Social Stress. 2021, 1 .
AMA StyleSara B. Fernandes, Neha D. Patil, Sophie B. Meriaux, Maud Theresine, Fleur A.D. Leenen, Martha M.C. Elwenspoek, Jacques Zimmer, Jonathan D. Turner. Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psycho-Social Stress. . 2021; ():1.
Chicago/Turabian StyleSara B. Fernandes; Neha D. Patil; Sophie B. Meriaux; Maud Theresine; Fleur A.D. Leenen; Martha M.C. Elwenspoek; Jacques Zimmer; Jonathan D. Turner. 2021. "Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psycho-Social Stress." , no. : 1.
The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal axis (HPA), and sympathetic nervous system activation. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis and have been linked to metabolic diseases including obesity, insulin resistance, and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of genes associated with glucose and lipid regulatory pathways and thereby control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, and the most prominent are early life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.
SnehaA Seal; Jonathan Turner. The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances. International Journal of Molecular Sciences 2021, 22, 3344 .
AMA StyleSnehaA Seal, Jonathan Turner. The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances. International Journal of Molecular Sciences. 2021; 22 (7):3344.
Chicago/Turabian StyleSnehaA Seal; Jonathan Turner. 2021. "The ‘Jekyll and Hyde’ of Gluconeogenesis: Early Life Adversity, Later Life Stress, and Metabolic Disturbances." International Journal of Molecular Sciences 22, no. 7: 3344.
There are many ‘faces’ of early life adversity (ELA), such as childhood trauma, institutionalization, abuse or exposure to environmental toxins. These have been implicated in the onset and severity of a wide range of chronic non-communicable diseases later in life. The later-life disease risk has a well-established immunological component. This raises the question as to whether accelerated immune-ageing mechanistically links early-life adversity to the lifelong health trajectory resulting in either ‘poor’ or ‘healthy’ ageing. Here we examine observational and mechanistic studies of ELA and inflammageing, highlighting common and distinct features in these two life stages. Many biological processes appear in common including reduction in telomere length, increased immuno-senescence, metabolic distortions and chronic (viral) infections. We propose that ELA shapes the developing immune, endocrine and nervous system in a non-reversible way, creating a distinct phenotype with accelerated immuno-senescence and systemic inflammation. We believe that ELA acts as an accelerator for inflammageing and age-related diseases. Furthermore, we now have the tools and cohorts to be able to dissect the interaction between early life adversity and later life phenotype. This should, in the near future, allow us to identify the ecological and mechanistic processes that are involved in ‘healthy’ or accelerated immune-ageing.
Myriam Merz; Jonathan D. Turner. Is Early Life Adversity a Trigger towards Inflammageing? 2021, 1 .
AMA StyleMyriam Merz, Jonathan D. Turner. Is Early Life Adversity a Trigger towards Inflammageing? . 2021; ():1.
Chicago/Turabian StyleMyriam Merz; Jonathan D. Turner. 2021. "Is Early Life Adversity a Trigger towards Inflammageing?" , no. : 1.
The potent neurotoxicity of benzo[a]pyrene (B[a]P) has been suggested to be a susceptibility factor accelerating the onset of brain tumours and the emergence of neurobehavioural disturbances. B[a]P has been shown to be neurotoxic, acting directly on both the central and peripheral nervous systems, as well as indirectly via peripheral organs like liver and gut. By using a realistic B[a]P exposure scenario (0.02–200 mg/kg/day, 10 days) in mice, we elucidated brain-specific B[a]P metabolism and at identified hydroxylated B[a]P metabolites in serum which could be used as markers of cognitive impairment. Repeated oral administration of B[a]P led to, at the doses of 20 and 200 mg/kg/day, significant overexpression of Cyp1a1/Cyp1b1 in 2 out of the 3 brain regions considered, thereby suggesting the ability of the brain to metabolize B[a]P itself. At the same doses, mice exhibited a reduction in anxiety in both the elevated plus maze and the hole board apparatus. Concomitantly, B[a]P triggered dose-dependent changes in Nmda subunit expression (Nr1 and Nr2a/Nr2b) in areas involved in cognition. We detected 9-OH-B[a]P and 7,8-diol-B[a]P in serum at the level for which cognitive impairment was observed. We suggest that these metabolites may, in the future be exploited as potent biomarkers of B[a]P-induced cognitive impairments.
Lynda Cherif; Lei Cao-Lei; Sophie Farinelle; Claude Muller; Jonathan Turner; Henri Schroeder; Nathalie Grova. Assessment of 9-OH- and 7,8-diol-benzo[a]pyrene in Blood as Potent Markers of Cognitive Impairment Related to benzo[a]pyrene Exposure: An Animal Model Study. Toxics 2021, 9, 50 .
AMA StyleLynda Cherif, Lei Cao-Lei, Sophie Farinelle, Claude Muller, Jonathan Turner, Henri Schroeder, Nathalie Grova. Assessment of 9-OH- and 7,8-diol-benzo[a]pyrene in Blood as Potent Markers of Cognitive Impairment Related to benzo[a]pyrene Exposure: An Animal Model Study. Toxics. 2021; 9 (3):50.
Chicago/Turabian StyleLynda Cherif; Lei Cao-Lei; Sophie Farinelle; Claude Muller; Jonathan Turner; Henri Schroeder; Nathalie Grova. 2021. "Assessment of 9-OH- and 7,8-diol-benzo[a]pyrene in Blood as Potent Markers of Cognitive Impairment Related to benzo[a]pyrene Exposure: An Animal Model Study." Toxics 9, no. 3: 50.
The physiological response to a psychological stressor broadly impacts energy metabolism. Inversely, changes in energy availability affect the physiological response to the stressor in terms of hypothalamus, pituitary adrenal gland axis and sympathetic nervous system activation upon exposure to a stressor. Glucocorticoids, the endpoint of the HPA axis, are critical checkpoints in endocrine control of energy homeostasis. Glucocorticoid actions have been linked to many severe metabolic diseases including obesity, insulin resistance and type 2 diabetes. Glucocorticoids, through the glucocorticoid receptor, activate transcription of many genes associated with glucose and lipid regulatory pathways and thereby intricately control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of glucocorticoid functions in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism. There are many elements in the external environment that induce lifelong changes in the HPA axis stress response and glucocorticoid levels, the most prominent are early-life adversity, or exposure to traumatic stress. We hypothesise that when the HPA axis is so disturbed after early-life adversity, it will fundamentally alter hepatic gluconeogenesis, inducing hyperglycaemia, and hence crystalise the significant lifelong risk of developing either the metabolic syndrome, or type 2 diabetes. This gives a “Jekyll and Hyde” role to gluconeogenesis, providing the necessary energy in situations of acute stress, but driving towards pathophysiological consequences when the HPA axis has been altered.
Snehaa V. Seal; Jonathan D. Turner. The ‘Jekyll and Hyde’ of Gluconeogenesis: Early-Life Adversity, Later Life Stress, and Metabolic Disturbances. 2021, 1 .
AMA StyleSnehaa V. Seal, Jonathan D. Turner. The ‘Jekyll and Hyde’ of Gluconeogenesis: Early-Life Adversity, Later Life Stress, and Metabolic Disturbances. . 2021; ():1.
Chicago/Turabian StyleSnehaa V. Seal; Jonathan D. Turner. 2021. "The ‘Jekyll and Hyde’ of Gluconeogenesis: Early-Life Adversity, Later Life Stress, and Metabolic Disturbances." , no. : 1.
A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19.
Cyrielle Holuka; Myriam P. Merz; Sara B. Fernandes; Eleftheria G. Charalambous; Snehaa V. Seal; Nathalie Grova; Jonathan D. Turner. The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity? International Journal of Molecular Sciences 2020, 21, 5094 .
AMA StyleCyrielle Holuka, Myriam P. Merz, Sara B. Fernandes, Eleftheria G. Charalambous, Snehaa V. Seal, Nathalie Grova, Jonathan D. Turner. The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity? International Journal of Molecular Sciences. 2020; 21 (14):5094.
Chicago/Turabian StyleCyrielle Holuka; Myriam P. Merz; Sara B. Fernandes; Eleftheria G. Charalambous; Snehaa V. Seal; Nathalie Grova; Jonathan D. Turner. 2020. "The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?" International Journal of Molecular Sciences 21, no. 14: 5094.
Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3’s negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.
Max Meyrath; Martyna Szpakowska; Julian Zeiner; Laurent Massotte; Myriam P. Merz; Tobias Benkel; Katharina Simon; Jochen Ohnmacht; Jonathan D. Turner; Rejko Krüger; Vincent Seutin; Markus Ollert; Evi Kostenis; Andy Chevigné. The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nature Communications 2020, 11, 1 -16.
AMA StyleMax Meyrath, Martyna Szpakowska, Julian Zeiner, Laurent Massotte, Myriam P. Merz, Tobias Benkel, Katharina Simon, Jochen Ohnmacht, Jonathan D. Turner, Rejko Krüger, Vincent Seutin, Markus Ollert, Evi Kostenis, Andy Chevigné. The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nature Communications. 2020; 11 (1):1-16.
Chicago/Turabian StyleMax Meyrath; Martyna Szpakowska; Julian Zeiner; Laurent Massotte; Myriam P. Merz; Tobias Benkel; Katharina Simon; Jochen Ohnmacht; Jonathan D. Turner; Rejko Krüger; Vincent Seutin; Markus Ollert; Evi Kostenis; Andy Chevigné. 2020. "The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides." Nature Communications 11, no. 1: 1-16.
The role of twins in research is evolving as we move further into the post-genomic era. With the re-definition of what a gene is, it is becoming clear that biological family members who share a specific genetic variant may well not have a similar risk for future disease. This has somewhat invalidated the prior rationale for twin studies. Case co-twin study designs, however, are slowly emerging as the ideal tool to identify both environmentally induced epigenetic marks and epigenetic disease-associated processes. Here, we propose that twin lives are not as identical as commonly assumed and that the case co-twin study design can be used to investigate the effects of the adult social environment. We present the elements in the (social) environment that are likely to affect the epigenome and measures in which twins may diverge. Using data from the German TwinLife registry, we confirm divergence in both the events that occur and the salience for the individual start as early as age 11. Case co-twin studies allow for the exploitation of these divergences, permitting the investigation of the role of not only the adult social environment, but also the salience of an event or environment for the individual, in determining lifelong health trajectories. In cases like social adversity where it is clearly not possible to perform a randomised-controlled trial, we propose that the case co-twin study design is the most rigorous manner with which to investigate epigenetic mechanisms encoding environmental exposure. The role of the case co-twin design will continue to evolve, as we argue that it will permit causal inference from observational data.
Jonathan D. Turner; Conchita D’Ambrosio; Claus Vögele; Martin Diewald. Twin Research in the Post-Genomic Era: Dissecting the Pathophysiological Effects of Adversity and the Social Environment. International Journal of Molecular Sciences 2020, 21, 3142 .
AMA StyleJonathan D. Turner, Conchita D’Ambrosio, Claus Vögele, Martin Diewald. Twin Research in the Post-Genomic Era: Dissecting the Pathophysiological Effects of Adversity and the Social Environment. International Journal of Molecular Sciences. 2020; 21 (9):3142.
Chicago/Turabian StyleJonathan D. Turner; Conchita D’Ambrosio; Claus Vögele; Martin Diewald. 2020. "Twin Research in the Post-Genomic Era: Dissecting the Pathophysiological Effects of Adversity and the Social Environment." International Journal of Molecular Sciences 21, no. 9: 3142.
Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine’s functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.
Henry Kurniawan; Davide G. Franchina; Luana Guerra; Lynn Bonetti; Leticia Soriano - Baguet; Melanie Grusdat; Lisa Schlicker; Oliver Hunewald; Catherine Dostert; Myriam P. Merz; Carole Binsfeld; Gordon S. Duncan; Sophie Farinelle; Yannic Nonnenmacher; Jillian Haight; Dennis Das Gupta; Anouk Ewen; Rabia Taskesen; Rashi Halder; Ying Chen; Christian Jäger; Markus Ollert; Paul Wilmes; Vasilis Vasiliou; Isaac Harris; Christiane B. Knobbe-Thomsen; Jonathan Turner; Tak W. Mak; Michael Lohoff; Johannes Meiser; Karsten Hiller; Dirk Brenner. Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function. Cell Metabolism 2020, 31, 920 -936.e7.
AMA StyleHenry Kurniawan, Davide G. Franchina, Luana Guerra, Lynn Bonetti, Leticia Soriano - Baguet, Melanie Grusdat, Lisa Schlicker, Oliver Hunewald, Catherine Dostert, Myriam P. Merz, Carole Binsfeld, Gordon S. Duncan, Sophie Farinelle, Yannic Nonnenmacher, Jillian Haight, Dennis Das Gupta, Anouk Ewen, Rabia Taskesen, Rashi Halder, Ying Chen, Christian Jäger, Markus Ollert, Paul Wilmes, Vasilis Vasiliou, Isaac Harris, Christiane B. Knobbe-Thomsen, Jonathan Turner, Tak W. Mak, Michael Lohoff, Johannes Meiser, Karsten Hiller, Dirk Brenner. Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function. Cell Metabolism. 2020; 31 (5):920-936.e7.
Chicago/Turabian StyleHenry Kurniawan; Davide G. Franchina; Luana Guerra; Lynn Bonetti; Leticia Soriano - Baguet; Melanie Grusdat; Lisa Schlicker; Oliver Hunewald; Catherine Dostert; Myriam P. Merz; Carole Binsfeld; Gordon S. Duncan; Sophie Farinelle; Yannic Nonnenmacher; Jillian Haight; Dennis Das Gupta; Anouk Ewen; Rabia Taskesen; Rashi Halder; Ying Chen; Christian Jäger; Markus Ollert; Paul Wilmes; Vasilis Vasiliou; Isaac Harris; Christiane B. Knobbe-Thomsen; Jonathan Turner; Tak W. Mak; Michael Lohoff; Johannes Meiser; Karsten Hiller; Dirk Brenner. 2020. "Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function." Cell Metabolism 31, no. 5: 920-936.e7.
When studying the factors which influence stress reactivity in within-subject designs, test-retest reproducibility data is needed to estimate power and sample size. We report such data regarding a new experimental stress protocol, based on simultaneous application of the socially evaluated, bilateral feet Cold Pressor Test (CPT) and the Paced Auditory Serial Addition Task (PASAT). Cardiovascular, neuroendocrine, and subjective (affective) stress responses of 32 healthy males were measured twice, at an interval of one week. The novel protocol induced substantial stress reactivity in all parameters at both test and retest. Cardiovascular reactivity remained unchanged, but cortisol and subjective responses were lower at second stress exposure, with high test-retest stability of neuroendocrine (r>.7) and cardiovascular measures (r = .5 to r = .9). PASAT performance improved. Response attenuation suggests habituation-like and/or learning effects. Data provided by our study demonstrate feasibility and power of this stress protocol for investigating changes in stress reactivity in repeated, within-subject designs.
Petra Bachmann; Johannes B. Finke; Dagmar Rebeck; Xinwei Zhang; Mauro F. Larra; Klaus P. Koch; Jonathan Turner; Hartmut Schächinger. Test-retest reproducibility of a combined physical and cognitive stressor. Biological Psychology 2019, 148, 107729 .
AMA StylePetra Bachmann, Johannes B. Finke, Dagmar Rebeck, Xinwei Zhang, Mauro F. Larra, Klaus P. Koch, Jonathan Turner, Hartmut Schächinger. Test-retest reproducibility of a combined physical and cognitive stressor. Biological Psychology. 2019; 148 ():107729.
Chicago/Turabian StylePetra Bachmann; Johannes B. Finke; Dagmar Rebeck; Xinwei Zhang; Mauro F. Larra; Klaus P. Koch; Jonathan Turner; Hartmut Schächinger. 2019. "Test-retest reproducibility of a combined physical and cognitive stressor." Biological Psychology 148, no. : 107729.
Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.
Martha M. C. Elwenspoek; Xenia Hengesch; Fleur A. D. Leenen; Krystel Sias; Sara Beatriz Fernandes; Violetta K. Schaan; Sophie B. Mériaux; Stephanie Schmitz; Fanny Bonnemberger; Hartmut Schächinger; Claus Vögele; Claude P. Muller; Jonathan D. Turner. Glucocorticoid receptor signaling in leukocytes after early life adversity. Development and Psychopathology 2019, 32, 853 -863.
AMA StyleMartha M. C. Elwenspoek, Xenia Hengesch, Fleur A. D. Leenen, Krystel Sias, Sara Beatriz Fernandes, Violetta K. Schaan, Sophie B. Mériaux, Stephanie Schmitz, Fanny Bonnemberger, Hartmut Schächinger, Claus Vögele, Claude P. Muller, Jonathan D. Turner. Glucocorticoid receptor signaling in leukocytes after early life adversity. Development and Psychopathology. 2019; 32 (3):853-863.
Chicago/Turabian StyleMartha M. C. Elwenspoek; Xenia Hengesch; Fleur A. D. Leenen; Krystel Sias; Sara Beatriz Fernandes; Violetta K. Schaan; Sophie B. Mériaux; Stephanie Schmitz; Fanny Bonnemberger; Hartmut Schächinger; Claus Vögele; Claude P. Muller; Jonathan D. Turner. 2019. "Glucocorticoid receptor signaling in leukocytes after early life adversity." Development and Psychopathology 32, no. 3: 853-863.
Secretion of the stress hormone cortisol follows a circadian rhythm and is stimulated following stress exposure. Cortisol regulates the transcription of several genes, primarily through activation of the glucocorticoid receptor (GR). Previously, we showed an upregulation of PERIOD genes PER1 and PER3 after pharmacological/glucocorticoid challenge in vivo and in vitro. The current study aims to investigate the temporal association between unstimulated, diurnal cortisol secretion and the expression of selected GR-target genes (PER1, PER2, PER3, FKBP5, GILZ and SDPR) in vivo to determine the timing of the most pronounced coupling between cortisol and mRNA expression. Unstimulated plasma and saliva cortisol concentrations and gene expression levels in whole blood were measured every 15 min from early morning until 16:00 h in 18 healthy men. Time-lagged correlations of cortisol concentrations with mRNA expression levels were assessed allowing lags between -240 and + 240 min. Strong positive correlations at non-zero lags between cortisol levels and the expression of FKBP5 (plasma: r = 0.74 (CI = 0.65-0.81), p < 0.001, lag + 90 min; saliva: r = 0.71 (CI = 0.61-0.78), p < 0.001, lag + 75 min), and GILZ (plasma: r = 0.59 (CI = 0.46-0.69), p < 0.001, lag + 30 min; saliva r = 0.53 (CI = 0.41-0.63), p < 0.001, lag +15 min) were observed. Expressions of PERIOD genes and SDPR correlated only weakly with cortisol (all |r| < 0.25). Our findings demonstrate strong correlations between cortisol secretion and gene expression in humans under unstimulated conditions. The observed time-lags can guide future research aiming to characterize glucocorticoid-dependent gene expression in clinical samples with stress-related disorders.
Türkan Yurtsever; Fabian Streit; Jerome C. Foo; Slavena Trifonova; Robert Kumsta; Claude P. Muller; Jonathan D. Turner; Jobst Meyer; Andrea B. Schote. Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans. Psychoneuroendocrinology 2019, 102, 63 -67.
AMA StyleTürkan Yurtsever, Fabian Streit, Jerome C. Foo, Slavena Trifonova, Robert Kumsta, Claude P. Muller, Jonathan D. Turner, Jobst Meyer, Andrea B. Schote. Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans. Psychoneuroendocrinology. 2019; 102 ():63-67.
Chicago/Turabian StyleTürkan Yurtsever; Fabian Streit; Jerome C. Foo; Slavena Trifonova; Robert Kumsta; Claude P. Muller; Jonathan D. Turner; Jobst Meyer; Andrea B. Schote. 2019. "Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans." Psychoneuroendocrinology 102, no. : 63-67.
The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical “Developmental Origins of Health and Disease” paradigm to include exposure to pollutants. This model has been refined over the years to give the current “three-hit” model that considers the individual’s genetic factors as a first “hit.” It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second “hit.” Together, these first two “hits” produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental “hit” in later life. It is only after the third “hit” that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.
Nathalie Grova; Henri Schroeder; Jean-Luc Olivier; Jonathan D. Turner. Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants. International Journal of Genomics 2019, 2019, 1 -19.
AMA StyleNathalie Grova, Henri Schroeder, Jean-Luc Olivier, Jonathan D. Turner. Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants. International Journal of Genomics. 2019; 2019 ():1-19.
Chicago/Turabian StyleNathalie Grova; Henri Schroeder; Jean-Luc Olivier; Jonathan D. Turner. 2019. "Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants." International Journal of Genomics 2019, no. : 1-19.
The negative health effects of early life adversity (ELA) continue long into adulthood. Changes in the physiological response to psychosocial stressors have been proposed to mediate this effect. However, many previous studies have come to contradicting conclusions as to whether ELA induces a long-term increase or decrease in stress reactivity. Therefore, we tested the association of ELA exposure and adult stress reactivity in a sample of early life adoptees and controls. Two previously validated stressful elements (bilateral feet CPT and the Paced Auditory Serial Addition Task (PASAT)) were combined in an extended Cold Pressor Test (CPT). This test was performed on 22 participants who had experienced severe ELA (separation from biological parents, institutionalization, and adoption in early childhood), and in 22 age-matched control participants. A prior history of ELA was associated with blunted reactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Cohen´s d = 0.680). Cardiovascular reactivity remained unchanged, and affective reactivity (self-report ratings) were increased in participants exposed to ELA compared to the control group (range Cohen´s d: 0.642-0.879). Our results suggest that the activity of the HPA axis reactivity was inhibited in ELA participants. Importantly, cardiovascular stress responsiveness was not affected by ELA. This separation of the HPA axis and cardiovascular stress responses may best be explained by ELA selectively enhancing central feedback-sensitivity to glucocorticoids, but preserving cardiovascular/ autonomic stress reactivity.
Xenia Hengesch; Martha M.C. Elwenspoek; Violetta K. Schaan; Mauro F. Larra; Johannes B. Finke; Xinwei Zhang; Petra Bachmann; Jonathan D. Turner; Claus Vögele; Claude P. Muller; Hartmut Schächinger. Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity. Child Abuse & Neglect 2018, 85, 137 -144.
AMA StyleXenia Hengesch, Martha M.C. Elwenspoek, Violetta K. Schaan, Mauro F. Larra, Johannes B. Finke, Xinwei Zhang, Petra Bachmann, Jonathan D. Turner, Claus Vögele, Claude P. Muller, Hartmut Schächinger. Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity. Child Abuse & Neglect. 2018; 85 ():137-144.
Chicago/Turabian StyleXenia Hengesch; Martha M.C. Elwenspoek; Violetta K. Schaan; Mauro F. Larra; Johannes B. Finke; Xinwei Zhang; Petra Bachmann; Jonathan D. Turner; Claus Vögele; Claude P. Muller; Hartmut Schächinger. 2018. "Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity." Child Abuse & Neglect 85, no. : 137-144.