The inflammatory event of birth: How oxytocin signaling may guide the development of the brain and gastrointestinal system

https://doi.org/10.1016/j.yfrne.2019.100794Get rights and content

Highlights

  • Oxytocin (OT) signaling at birth coordinates several adaptive functions.

  • OT is a potent anti-inflammatory molecule in the neonatal gut and brain.

  • Birth interventions that alter OT signaling may increase vulnerability to neurodevelopmental disorders.

  • Sex differences in OT signaling may contribute to the male bias in disorders like autism.

Abstract

The role of oxytocin (OT) as a neuropeptide that modulates social behavior has been extensively studied and reviewed, but beyond these functions, OT’s adaptive functions at birth are quite numerous, as OT coordinates many physiological processes in the mother and fetus to ensure a successful delivery. In this review we explore in detail the potential adaptive roles of oxytocin as an anti-inflammatory, protective molecule at birth for the developing fetal brain and gastrointestinal system based on evidence that birth is a potent inflammatory/immune event. We discuss data with relevance for a number of neurodevelopmental disorders, as well as the emerging role of the gut-brain axis for health and disease. Finally, we discuss the potential relevance of sex differences in OT signaling present at birth in the increased male vulnerability to neurodevelopmental disabilities.

Introduction

The role of oxytocin (OT) as a neuropeptide that modulates social behavior has been extensively studied and reviewed in recent years (Carter, 2017a, Carter, 2017b, Carter et al., 1995, Carter et al., 2008, Young et al., 2011, Young and Wang, 2004). Beyond these functions, some of OT’s most important functions are associated with the delivery process, including the stimulation of uterine contractions and milk letdown for lactation. Moreover, OT’s adaptive functions at birth are quite numerous, as OT appears to coordinate many physiological processes in the mother and fetus to ensure a successful delivery, such as fetal analgesia, fetal lung maturation, expulsion of the placenta, and enhanced mother-infant bonding for first feeding. In this review we focus on the functions of OT at this critical time-point and explore in detail the potential adaptive roles of oxytocin as an anti-inflammatory, protective molecule at birth for the developing fetal brain and gastrointestinal system. For offspring, birth is an inflammatory/immune event characterized by hypoxic-like conditions during delivery (Lagercrantz and Slotkin, 1986, Maron et al., 2010, Tyzio et al., 2006), a surge in stress hormones (Lagercrantz and Slotkin, 1986), elevated fetal cytokines (Castillo-Ruiz et al., 2018a, Golightly et al., 2011), antigen stimulation through microbial colonization (Castillo-Ruiz et al., 2018a, Costello et al., 2012) and amino acid insufficiency stress (Klein et al., 2017). OT is a potent anti-inflammatory molecule (Li et al., 2016, Wang et al., 2015) that reduces gut inflammation in models of colitis (Cetinel et al., 2010, Welch et al., 2014) and cellular stress in gut epithelial cells (enterocytes) following bacterial endotoxin exposure (Klein et al., 2017, Klein et al., 2014). Thus, we explore the possible adaptive roles of OT for the developing gut, including the modulation of inflammatory processes during microbial colonization at birth (Klein et al., 2016) and amino acid insufficiency stress that occurs in enterocytes before the first feeding of colostrum (Klein et al., 2017). Within the brain, parturition is associated with a surge in brain pro-inflammatory cytokines and widespread modulation of neuronal cell death (Castillo-Ruiz et al., 2018b). Because OT has been shown to reduce brain inflammation in postnatal and adult animals by limiting oxidative stress and cytokine release from microglia (Amini-Khoei et al., 2017, Karelina et al., 2011, Yuan et al., 2016), OT may be similarly protective for the brain at birth during the hypoxic-like conditions of delivery and natural elevation of brain cytokine levels. Importantly, OT receptors (OTRs) are expressed in the fetal brain (Tyzio et al., 2006) and gut (Welch et al., 2009) during the perinatal period, suggesting important roles for OT signaling during this critical event.

We next consider what is known about the alteration of OT signaling at birth and the risk for various neurodevelopmental disorders. As part of this discussion, we describe the emerging role of the gut-brain axis since alterations in this axis have the potential to shift developmental trajectories and influence disease processes. The gut-brain axis refers to the bidirectional signaling that occurs between the gastrointestinal tract and the nervous system and is characterized by neural, hormonal, biochemical and immunological routes of communication (Cryan and Dinan, 2012). If we consider the microbial organisms within the gut, it is referred to as the microbiome-gut-brain-axis and accounts for the role that these microorganisms play in this bidirectional signaling. It is becoming increasingly recognized that disturbances of the gut microbial ecosystem can create intestinal dysfunction and inflammation that gives rise to abnormal social behavior and cognition (Cryan and Dinan, 2012). One mechanism by which the brain and gut communicate with each other is via the vagus nerve and we discuss recent studies that demonstrate that OT is an integral player within this signaling pathway that gives rise to normal social behavior (Buffington et al., 2016, Sgritta et al., 2019).

Finally, we discuss how sex differences present at birth may make males particularly vulnerable to the hypoxic-like conditions of delivery, particularly if the hypoxia is prolonged or elevated due to adverse events of labor. Compared to males, females may be more resilient based on their hormonal milieu at birth and an inherently greater antioxidant capacity within their brains.

Section snippets

Introduction to OT and its receptors

The neuroendocrine hormone OT is a highly conserved nine amino acid peptide (“nonapeptide”) that arose through a duplication event of the ancestral gene, arginine vasotocin, more than 600 million years ago (Acher and Chauvet, 1995). The present day canonical form of OT (Leu8-OT) dates back to eutherian mammals and was first well described by Du Vigneaud (Du Vigneaud et al., 1953) and Archer (Acher and Fromageot, 1955). OT is primarily produced by magnocellular and parvocellular neurons within

Well-known protective functions of OT at birth (outside of the brain and gastrointestinal system)

Perhaps two of the most well known functions of OT are the stimulation of uterine contractions during parturition and milk letdown during lactation. However, additional studies suggest that OT plays a significantly greater adaptive role at birth and serves to coordinate multiple physiological processes within the fetus to maximize physiological and behavioral outcomes. For instance, OT released during labor facilitates fetal lung maturation by contributing to epinephrine secretion. This

OT’s potential neuroprotective effects for the brain at birth

OT’s remarkable adaptive and neuroprotective effects for the fetal brain at birth were demonstrated by Tyzio et al. (2006), in which OT was shown to protect neurons from the hypoxic-like conditions of delivery by switching the action of GABA signaling. In addition to providing neuroprotection at birth via a GABA switch, additional adaptive functions of OT may include microglia inhibition and a reduction in oxidative stress. For instance, within postnatal and adult models of hypoxia-ischemia, an

OT’s potential protective effects for the gastrointestinal system at birth and beyond

Parturition involves changes in inflammatory signaling since the fetal gastrointestinal tract must adapt to significant antigen stimulation via the introduction of thousands of species of bacteria at birth. Because OT (1) is a potent anti-inflammatory molecule for the gastrointestinal system (Cetinel et al., 2010, Welch et al., 2014, Iseri et al., 2008), (2) has several adaptive functions at birth and (3) is involved in signaling within the microbiome-gut-brain axis (Buffington et al., 2016,

Administration of Pitocin (synthetic OT)

Given all the protective effects of endogenous OT signaling at birth, one might imagine that the administration of synthetic OT (sOT; Pitocin) to pregnant women for labor induction and/or augmentation might provide similar or even enhanced protection to the developing fetal brain and gastrointestinal tract. This is an especially important concept to consider given that 23–50% of pregnant women in the United States currently receive sOT to induce or augment labor (Declercq et al., 2014, Hamilton

Factors influencing sex-specific risks versus resilience in relation to OT signaling at birth

ASD is more prevalent in boys than girls, with 3–4 males affected for every female (Baio, 2010, Loomes et al., 2017), suggesting that boys may be more vulnerable to genetic and/or environmental risk factors. Here we discuss how sex differences may create an enhanced vulnerability for males during birth, compared to females, particularly in reference to OT’s functions at birth. As described earlier, elevations in OT just before birth protects the fetal brain from the hypoxic-like conditions of

Conclusions

Birth is a highly adaptive yet stressful experience and is perhaps one of the most significant life events for both a mother and child. Humans and other species of animals have evolved complex, integrated physiological mechanisms to facilitate the transition of the fetus to an extrauterine environment. In the present review, we examined the specific functions of oxytocin signaling at birth beyond its well-known roles of the stimulation of uterine contractions and milk letdown, describing how it

References (144)

  • A. Castillo-Ruiz et al.

    The microbiota influences cell death and microglial colonization in the perinatal mouse brain

    Brain Behav. Immun.

    (2018)
  • M. Ceanga et al.

    Oxytocin is neuroprotective against oxygen-glucose deprivation and reoxygenation in immature hippocampal cultures

    Neurosci. Lett.

    (2010)
  • S. Cetinel et al.

    Oxytocin treatment alleviates stress-aggravated colitis by a receptor-dependent mechanism

    Regul. Pept.

    (2010)
  • C.E. Cho et al.

    Cesarean section and development of the immune system in the offspring

    Am. J. Obstet. Gynecol.

    (2013)
  • J.M. Conway et al.

    Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome – a systematic review

    Early Hum. Dev.

    (2018)
  • V. Du Vigneaud et al.

    The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin

    J. Biol. Chem.

    (1953)
  • E. Friedlander et al.

    Social impairments among children perinatally exposed to oxytocin or oxytocin receptor antagonist

    Early Human Dev.

    (2017)
  • E.C. Fuchs et al.

    Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior

    Neuron

    (2007)
  • C. Fulling et al.

    Gut microbe to brain signaling: what happens in Vagus

    Neuron

    (2019)
  • J.B. Furness et al.

    Intrinsic primary afferent neurons and nerve circuits within the intestine

    Prog. Neurobiol.

    (2004)
  • E. Golightly et al.

    Endocrine immune interactions in human parturition

    Mol. Cell. Endocrinol.

    (2011)
  • M.A. Gulpinar et al.

    Anti-inflammatory effect of acute stress on experimental colitis is mediated by cholecystokinin-B receptors

    Life Sci.

    (2004)
  • A. Hartsock et al.

    Adherens and tight junctions: structure, function and connections to the actin cytoskeleton

    BBA

    (2008)
  • K. Horvath et al.

    Gastrointestinal abnormalities in children with autistic disorder

    J. Pediatr.

    (1999)
  • E.Y. Hsiao

    Immune dysregulation in autism spectrum disorder

    Int. Rev. Neurobiol.

    (2013)
  • S.O. Iseri et al.

    Oxytocin ameliorates skin damage and oxidant gastric injury in rats with thermal trauma

    Burns: J. Int. Soc. Burn Injur.

    (2008)
  • R.J. Kelleher et al.

    The autistic neuron: troubled translation?

    Cell

    (2008)
  • A.M. Kelly et al.

    Social functions of individual vasopressin-oxytocin cell groups in vertebrates: what do we really know?

    Front. Neuroendocrinol.

    (2014)
  • R. Khazipov et al.

    Effects of oxytocin on GABA signalling in the foetal brain during delivery

    Prog. Brain Res.

    (2008)
  • B.Y. Klein et al.

    Oxytocin modulates mTORC1 pathway in the gut

    Biochem. Biophys. Res. Commun.

    (2013)
  • B.Y. Klein et al.

    Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells

    Cell Stress Chaperones

    (2014)
  • B.Y. Klein et al.

    Oxytocin opposes effects of bacterial endotoxin on ER-stress signaling in Caco2BB gut cells

    BBA

    (2016)
  • B.Y. Klein et al.

    Colostrum oxytocin modulates cellular stress response, inflammation, and autophagy markers in newborn rat gut villi

    Biochem. Biophys. Res. Commun.

    (2017)
  • H.S. Knobloch et al.

    Evoked axonal oxytocin release in the central amygdala attenuates fear response

    Neuron

    (2012)
  • R. Landgraf et al.

    Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication

    Front. Neuroendocrinol.

    (2004)
  • M. Leonzino et al.

    The timing of the excitatory-to-inhibitory GABA switch is regulated by the oxytocin receptor via KCC2

    Cell Rep.

    (2016)
  • R. Loomes et al.

    What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis

    J. Am. Acad. Child Adolesc. Psychiatry

    (2017)
  • M.P. Mamidala et al.

    Prenatal perinatal and neonatal risk factors of Autism Spectrum Disorder: a comprehensive epidemiological assessment from India

    Res. Dev. Disabilit.

    (2013)
  • G. Marchini et al.

    Fetal and maternal plasma levels of gastrin, somatostatin and oxytocin after vaginal delivery and elective cesarean section

    Early Hum. Dev.

    (1988)
  • J.L. Maron et al.

    Cord blood genomic analysis highlights the role of redox balance

    Free Radical Biol. Med.

    (2010)
  • M.M. McCarthy et al.

    Getting excited about GABA and sex differences in the brain

    Trends Neurosci.

    (2002)
  • I.D. Neumann

    The advantage of social living: brain neuropeptides mediate the beneficial consequences of sex and motherhood

    Front. Neuroendocrinol.

    (2009)
  • C. Nicolini et al.

    The valproic acid-induced rodent model of autism

    Exp. Neurol.

    (2018)
  • D. Ocampo Daza et al.

    The oxytocin/vasopressin receptor family has at least five members in the gnathostome lineage, inclucing two distinct V2 subtypes

    Gen. Comp. Endocrinol.

    (2012)
  • L. Palmieri et al.

    Mitochondrial dysfunction in autism spectrum disorders: cause or effect?

    BBA

    (2010)
  • P. Polo-Kantola et al.

    Obstetric risk factors and autism spectrum disorders in Finland

    J. Pediatr.

    (2014)
  • R. Acher et al.

    Chemistry of posterior-pituitary hormones

    Ergeb. Physiol.

    (1955)
  • M.B. Azad et al.

    Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months

    CMAJ

    (2013)
  • M.B. Azad et al.

    Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study

    BJOG

    (2016)
  • J. Baio

    Prevalence of autism spectrum disorder among children aged 8 years – autism and developmental disabilities monitoring network, 11 sites, United States, 2010

    MMWR Surveill. Summ.

    (2014)
  • Cited by (0)

    View full text