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