Gestational stress and perinatal SSRIs differentially impact the maternal and neonatal microbiome-gut-brain axis.

Selective serotonin reuptake inhibitors (SSRIs) are the most popular antidepressant medications used to manage perinatal mood disturbances, yet our understanding of how they affect the microbiome-gut-brain axis of the mother and offspring is limited. The purpose of this study was to determine how peripartum SSRI treatment may prevent the effects of gestational stress on plasticity in the maternal hippocampus, plasticity in the neonatal brain and related changes in gut microbiota. To do this Sprague-Dawley female rats were left untreated or subjected to unpredictable stress during pregnancy. Half of the females were supplemented daily with fluoxetine. On postpartum day 2 brains were collected for measurement of plasticity (neurogenesis and microglia content) in the maternal hippocampus and in the neonatal brain. Glucocorticoid receptor density was also investigated in the maternal hippocampus. Microbiota composition was analyzed in fecal samples of dams during and after pregnancy, and colon tissue samples from offspring on postnatal day 2. Main findings show there are significant changes to the maternal microbiome-gut-brain axis that may be fundamental to mediating plasticity in the maternal hippocampus. In addition, there is significant impact of gestational stress on neonatal gut microbiota and brain microglia density, while the effects of SSRIs are limited. This is the first study to explore the impact of gestational stress and SSRIs on the microbiome-gut-brain axis in the mother and neonate. Findings from this study will help inform pathways to intervention strategies including stress reduction techniques and/or microbiota targeted nutritional approaches directed towards improving maternal gut health and outcomes for mother and neonate.

[1]  P. Albert,et al.  Rewiring of the Serotonin System in Major Depression , 2021, Frontiers in Psychiatry.

[2]  J. Pawluski,et al.  Less can be more: Fine tuning the maternal brain , 2021, Neuroscience & Biobehavioral Reviews.

[3]  L. Hayes,et al.  Developmental Stressors Induce Innate Immune Memory in Microglia and Contribute to Disease Risk , 2021, International journal of molecular sciences.

[4]  G. Garrity,et al.  Valid publication of the names of forty-two phyla of prokaryotes. , 2021, International journal of systematic and evolutionary microbiology.

[5]  T. Gur,et al.  Prenatal stress-induced disruptions in microbial and host tryptophan metabolism and transport , 2021, Behavioural Brain Research.

[6]  E. Hsiao,et al.  Interactions between maternal fluoxetine exposure, the maternal gut microbiome and fetal neurodevelopment in mice , 2021, Behavioural Brain Research.

[7]  Steven P. Miller,et al.  Prenatal antidepressant exposure and sex differences in neonatal corpus callosum microstructure. , 2021, Developmental psychobiology.

[8]  Tao Sun,et al.  Prenatal stress leads to deficits in brain development, mood related behaviors and gut microbiota in offspring , 2021, Neurobiology of Stress.

[9]  V. Bergink,et al.  Long-term prenatal effects of antidepressant use on the risk of affective disorders in the offspring: a register-based cohort study , 2021, Neuropsychopharmacology.

[10]  Francesco Valeri,et al.  How biological sex of the host shapes its gut microbiota , 2021, Frontiers in Neuroendocrinology.

[11]  T. Oberlander,et al.  Prenatal exposure to maternal depression is related to the functional connectivity organization underlying emotion perception in 8-10-month-old infants - Preliminary findings. , 2021, Infant behavior & development.

[12]  He Yan,et al.  Antidepressants fluoxetine and amitriptyline induce alterations in intestinal microbiota and gut microbiome function in rats exposed to chronic unpredictable mild stress , 2021, Translational Psychiatry.

[13]  J. Cryan,et al.  Priming for Life: Early Life Nutrition and the Microbiota-Gut-Brain Axis , 2021, Nutrients.

[14]  R. Baldassano,et al.  Remodeling of the maternal gut microbiome during pregnancy is shaped by parity , 2020, bioRxiv.

[15]  L. Mâsse,et al.  Perinatal selective serotonin reuptake inhibitor (SSRI) and other antidepressant exposure effects on anxiety and depressive behaviors in offspring: A review of findings in humans and rodent models. , 2020, Reproductive toxicology.

[16]  D. Erny,et al.  The microbiota–microglia axis in central nervous system disorders , 2020, Brain pathology.

[17]  E. Hsiao,et al.  The maternal microbiome modulates fetal neurodevelopment in mice , 2020, Nature.

[18]  S. Lian,et al.  Characterization of Gut Microbiota in Prenatal Cold Stress Offspring Rats by 16S rRNA Sequencing , 2020, Animals : an open access journal from MDPI.

[19]  M. Bailey,et al.  Prenatal stress causes intrauterine inflammation and serotonergic dysfunction, and long-term behavioral deficits through microbe- and CCL2-dependent mechanisms , 2020, Translational Psychiatry.

[20]  M. Evans,et al.  Unique maternal immune and functional microbial profiles during prenatal stress , 2020, Scientific Reports.

[21]  V. Bergink,et al.  Long-Term Effects of Intrauterine Exposure to Antidepressants on Physical, Neurodevelopmental, and Psychiatric Outcomes: A Systematic Review. , 2020, The Journal of clinical psychiatry.

[22]  P. Lledo,et al.  Changes in Gut Microbiota by Chronic Stress Impair the Efficacy of Fluoxetine. , 2020, Cell reports.

[23]  J. Zwicker,et al.  Differences in White Matter Microstructure Among Children With Developmental Coordination Disorder , 2020, JAMA network open.

[24]  T. Bale,et al.  Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression , 2020, Gut microbes.

[25]  V. Bergink,et al.  The international prevalence of antidepressant use before, during, and after pregnancy: A systematic review and meta-analysis of timing, type of prescriptions and geographical variability. , 2019, Journal of affective disorders.

[26]  J. Homberg,et al.  Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: A systematic review and meta-analyses of animal studies , 2019, Neuroscience & Biobehavioral Reviews.

[27]  T. Bale,et al.  Prenatal and postnatal contributions of the maternal microbiome on offspring programming , 2019, Frontiers in Neuroendocrinology.

[28]  N. Bray The microbiota–gut–brain axis , 2019 .

[29]  Eli Reuveni,et al.  Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior , 2019, Translational Psychiatry.

[30]  H. Smidt,et al.  Association between Psychosocial Stress and Fecal Microbiota in Pregnant Women , 2019, Scientific Reports.

[31]  Jacob M. Allen,et al.  Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring , 2019, Behavioural Brain Research.

[32]  S. de Lacalle,et al.  Perinatal fluoxetine has enduring sexually differentiated effects on neurobehavioral outcomes related to social behaviors , 2019, Neuropharmacology.

[33]  L. Mâsse,et al.  A 6-year longitudinal study: Are maternal depressive symptoms and Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant treatment during pregnancy associated with everyday measures of executive function in young children? , 2019, Early human development.

[34]  T. Oberlander,et al.  Selective serotonin reuptake inhibitor effects on neural biomarkers of perinatal depression , 2018, Archives of Women's Mental Health.

[35]  T. Bale,et al.  The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus , 2018, Nature Neuroscience.

[36]  A. Pariente,et al.  Patterns of antidepressant use during pregnancy: a nationwide population‐based cohort study , 2018, British journal of clinical pharmacology.

[37]  M. Kimmel,et al.  Emerging literature in the Microbiota-Brain Axis and Perinatal Mood and Anxiety Disorders , 2018, Psychoneuroendocrinology.

[38]  J. Pawluski,et al.  Perinatal SSRI medications and offspring hippocampal plasticity: interaction with maternal stress and sex , 2018, Hormones.

[39]  G. Hammond,et al.  Perinatal fluoxetine increases hippocampal neurogenesis and reverses the lasting effects of pre-gestational stress on serum corticosterone, but not on maternal behavior, in the rat dam , 2018, Behavioural Brain Research.

[40]  H. Stevens,et al.  The role of glucocorticoid, interleukin-1β, and antioxidants in prenatal stress effects on embryonic microglia , 2018, Journal of Neuroinflammation.

[41]  L. Mâsse,et al.  Perinatal selective serotonin reuptake inhibitor (SSRI) effects on body weight at birth and beyond: A review of animal and human studies. , 2018, Reproductive toxicology.

[42]  T. Oberlander,et al.  Perinatal selective serotonin reuptake inhibitor medication (SSRI) effects on social behaviors, neurodevelopment and the epigenome , 2018, Neuroscience & Biobehavioral Reviews.

[43]  S. Lacalle,et al.  Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre-gestational maternal stress , 2017, Psychoneuroendocrinology.

[44]  T. Oberlander,et al.  Variations in Neurodevelopmental Outcomes in Children with Prenatal SSRI Antidepressant Exposure , 2017, Birth defects research.

[45]  C. Angelotta,et al.  Treating Depression during Pregnancy: Are We Asking the Right Questions? , 2017, Birth defects research.

[46]  L. Zwaigenbaum,et al.  Disentangling Maternal Depression and Antidepressant Use During Pregnancy as Risks for Autism in Children. , 2017, JAMA.

[47]  Tara Gomes,et al.  Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children , 2017, JAMA.

[48]  T. Bale,et al.  Stress during pregnancy alters temporal and spatial dynamics of the maternal and offspring microbiome in a sex-specific manner , 2017, Scientific Reports.

[49]  Steven P. Miller,et al.  Antenatal exposure to antidepressants is associated with altered brain development in very preterm-born neonates , 2017, Neuroscience.

[50]  T. Dinan,et al.  Early-life adversity and brain development: Is the microbiome a missing piece of the puzzle? , 2017, Neuroscience.

[51]  A. Fleming,et al.  The Neurobiology of Postpartum Anxiety and Depression , 2017, Trends in Neurosciences.

[52]  B. Leuner,et al.  A survey of neuroimmune changes in pregnant and postpartum female rats , 2017, Brain, Behavior, and Immunity.

[53]  E. Dempsey,et al.  The Composition of Human Milk and Infant Faecal Microbiota Over the First Three Months of Life: A Pilot Study , 2017, Scientific Reports.

[54]  C. Limatola,et al.  Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment , 2016, Brain, Behavior, and Immunity.

[55]  H. Steinbusch,et al.  Gestational stress and fluoxetine treatment differentially affect plasticity, methylation and serotonin levels in the PFC and hippocampus of rat dams , 2016, Neuroscience.

[56]  S. Clinton,et al.  Of rodents and humans: A comparative review of the neurobehavioral effects of early life SSRI exposure in preclinical and clinical research , 2016, International Journal of Developmental Neuroscience.

[57]  T. Oberlander,et al.  Developmental Effects of Prenatal Selective Serotonin Reuptake Inhibitor Exposure in Perspective: Are We Comparing Apples to Apples? , 2016, Journal of the American Academy of Child and Adolescent Psychiatry.

[58]  C. Zeanah,et al.  The Neurobiological Impact of Postpartum Maternal Depression: Prevention and Intervention Approaches. , 2016, Child and adolescent psychiatric clinics of North America.

[59]  T. Dinan,et al.  A gut (microbiome) feeling about the brain , 2016, Current opinion in gastroenterology.

[60]  Sudhakar Selvaraj,et al.  Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness , 2016, Psychopharmacology.

[61]  O. Howes,et al.  Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness , 2016, Psychopharmacology.

[62]  Craig H. Kinsley,et al.  Neuroplasticity in the maternal hippocampus: Relation to cognition and effects of repeated stress , 2016, Hormones and Behavior.

[63]  C. Bielajew,et al.  Environmental manipulation affects depressive-like behaviours in female Wistar-Kyoto rats , 2015, Behavioural Brain Research.

[64]  A. Nadjar,et al.  Microglia in neuronal plasticity: Influence of stress , 2015, Neuropharmacology.

[65]  Z. Hua,et al.  Use of 16S rRNA Gene-Targeted Group-Specific Primers for Real-Time PCR Analysis of Predominant Bacteria in Mouse Feces , 2015, Applied and Environmental Microbiology.

[66]  H. Steinbusch,et al.  Developmental exposure to SSRIs, in addition to maternal stress, has long-term sex-dependent effects on hippocampal plasticity , 2015, Psychopharmacology.

[67]  K. Korpela,et al.  Maternal prenatal stress is associated with the infant intestinal microbiota , 2015, Psychoneuroendocrinology.

[68]  D. Slattery,et al.  Hippocampal Plasticity during the Peripartum Period: Influence of Sex Steroids, Stress and Ageing , 2014, Journal of neuroendocrinology.

[69]  M L Phillips,et al.  In Search of Neural Endophenotypes of Postpartum Psychopathology and Disrupted Maternal Caregiving , 2014, Journal of neuroendocrinology.

[70]  D. Tibboel,et al.  Perinatal maternal stress and serotonin signaling: effects on pain sensitivity in offspring. , 2014, Developmental psychobiology.

[71]  H. Steinbusch,et al.  Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats , 2014, Neural plasticity.

[72]  U. Högberg,et al.  The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring , 2013, Front. Cell. Neurosci..

[73]  Pelin Yilmaz,et al.  The SILVA ribosomal RNA gene database project: improved data processing and web-based tools , 2012, Nucleic Acids Res..

[74]  H. Steinbusch,et al.  Developmental fluoxetine exposure differentially alters central and peripheral measures of the HPA system in adolescent male and female offspring , 2012, Neuroscience.

[75]  H. Steinbusch,et al.  Fluoxetine during Development Reverses the Effects of Prenatal Stress on Depressive-Like Behavior and Hippocampal Neurogenesis in Adolescence , 2011, PloS one.

[76]  J. Pawluski Perinatal Selective Serotonin Reuptake Inhibitor Exposure: Impact on Brain Development and Neural Plasticity , 2011, Neuroendocrinology.

[77]  H. Steinbusch,et al.  Stress and the pregnant female: Impact on hippocampal cell proliferation, but not affective-like behaviors , 2011, Hormones and Behavior.

[78]  William A. Walters,et al.  QIIME allows analysis of high-throughput community sequencing data , 2010, Nature Methods.

[79]  T. Field Prenatal Depression and Selective Serotonin Reuptake Inhibitors , 2010, The International journal of neuroscience.

[80]  B. Gómez-González,et al.  Prenatal stress alters microglial development and distribution in postnatal rat brain , 2010, Acta Neuropathologica.

[81]  P. Gaspar,et al.  New perspectives on the neurodevelopmental effects of SSRIs. , 2010, Trends in pharmacological sciences.

[82]  T. Oberlander,et al.  Sustained Neurobehavioral Effects of Exposure to SSRI Antidepressants During Development: Molecular to Clinical Evidence , 2009, Clinical pharmacology and therapeutics.

[83]  T. Oberlander,et al.  Neonatal S100B Protein Levels After Prenatal Exposure to Selective Serotonin Reuptake Inhibitors , 2009, Pediatrics.

[84]  P. Scully,et al.  Early Life Stress Alters Behavior, Immunity, and Microbiota in Rats: Implications for Irritable Bowel Syndrome and Psychiatric Illnesses , 2009, Biological Psychiatry.

[85]  Tobias Plümpe,et al.  Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation , 2006, BMC Neuroscience.

[86]  K. Lohr,et al.  Perinatal Depression: A Systematic Review of Prevalence and Incidence , 2005, Obstetrics and gynecology.

[87]  B. Levy,et al.  Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. , 2004, The American journal of psychiatry.

[88]  B. McEwen,et al.  Stress and the individual. Mechanisms leading to disease. , 1993, Archives of internal medicine.

[89]  R. Pohland,et al.  Placental transfer and fetal distribution of fluoxetine in the rat. , 1989, Toxicology and applied pharmacology.

[90]  J. Cryan,et al.  The Microbiome-Gut-Brain Axis in Neurocognitive Development and Decline. , 2021, Modern trends in psychiatry.

[91]  J. Swain,et al.  Neurobiology of peripartum mental illness. , 2021, Handbook of clinical neurology.

[92]  T. Oberlander,et al.  The Microbiome-Gut-Brain Axis: A New Window to View the Impact of Prenatal Stress on Early Neurodevelopment , 2021 .

[93]  Prenatal Stress and Child Development , 2021 .

[94]  T. Oberlander,et al.  The Other Side of Prenatal Depression: Developmental Outcomes Associated with Antidepressant Medication Therapy , 2021 .

[95]  Steven P. Miller,et al.  Alterations in Resting-State Networks Following In Utero Selective Serotonin Reuptake Inhibitor Exposure in the Neonatal Brain. , 2019, Biological psychiatry. Cognitive neuroscience and neuroimaging.

[96]  Ou Stella Liang,et al.  Detecting Patterns of Prescription Drug Use During Pregnancy and Lactation with Visualization Techniques. , 2019, AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science.

[97]  O. Koren,et al.  The Pregnancy Microbiome. , 2017, Nestle Nutrition Institute workshop series.

[98]  S. Salzberg,et al.  FLASH: fast length adjustment of short reads to improve genome assemblies , 2011, Bioinform..

[99]  Robert C. Edgar,et al.  Search and clustering orders of magnitude faster than BLAST , 2010 .