The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal (GI) tract, is embryologically derived from the neural crest. Early in development, vagal (hindbrain) neural crest cells (NCC) migrate into the foregut, colonize the entire length of the gut, and differentiate into enteric neurons and glia. Although these enteric precursors and other components of the neuromuscular apparatus (eg, smooth muscle cells, interstitial cells of Cajal [ICC]) are appropriately arranged by weeks 12 to 14 of human development, the first coordinated gut motility patterns do not occur until approximately birth. This indicates that a significant amount of ENS modification occurs during the foetal period such that appropriate neuronal subtypes, functional interconnections, and coordinated electrical activity become established. There also is significant evidence that the ENS is modified postnatally. This may be a normally occurring process that allows the ENS to adapt to postnatal changes such as growth or dietary modifications, to external stresses such as maternal separation, or to gut injury/inflammation/disease. Studies have suggested that enteric neurons can respond to the changing intestinal environment by changing their expression of receptors and/or neurotransmitters, or their associations with other cell types. Interestingly, evidence that certain early life events are risk factors for the subsequent development of visceral hypersensitivity highlights the idea that early adverse experiences may permanently alter the neurobiological systems involved in pain perception. The ENS is, therefore, a key component of a fluid neuromuscular system that can be altered in a number of ways, some of which can be detrimental, some potentially therapeutic.
EMBRYOLOGIC DEVELOPMENT OF THE ENS
The many and diverse functions of the GI tract are influenced by a range of systems, including the central nervous system, the neuroendocrine and neuroimmune systems, the sympathetic and parasympathetic branches of the autonomic nervous system (ANS), the intestinal microbiota, and the ENS. Together, these components form an integrated network that allows signals from the brain to influence local gut functions and signals from the gut to influence brain function. This bidirectional communication, vital for homeostasis, is commonly referred to as the brain–gut axis (1) or, more recently, the brain–gut–enteric microbiota axis, recognising the importance of the gut microbiome (2).
Although each of the above systems plays important roles in regulating the activity of the gut, this article focuses attention on the ENS, a key component of the above circuitry that is an integrative target directly controlling the function of the GI tract. The ENS consists of an extensive network of neurons and glia cells that are arranged in interconnected plexuses (myenteric or Auerbach's plexus, and submucosal or Meissner's plexus) distributed between the smooth muscle layers of the gut wall. Neurons within the myenteric plexus are primarily involved in the control of gut motility, whereas neurons within the submucosal plexus are mainly involved in controlling mucosal functions, such as electrolyte and hormone secretion and exchange of fluids across the mucosal surface (3). Although the gut receives extrinsic innervation from the parasympathetic and sympathetic nervous systems, the intrinsic circuits of the ENS are capable of generating reflex gut contractile activity entirely independently. This sets the ENS apart from other branches of the ANS and has led to the ENS being referred to as the “second brain” (4).
Studies in animal models have demonstrated that the neurons and glial cells that make up the ENS are embryologically derived from the neural crest, a group of highly migratory, multipotent cells that also give rise to a wide variety of other cell types throughout the body, including melanocytes, the skeletal and connective tissues of the face, and neurons and glia of the sensory and sympathetic nervous systems (5). Vagal (hindbrain)-level NCC give rise to the majority of ENS cells along the entire length of the gut (6). They migrate from the hindbrain into the developing foregut and then colonise the growing gut, progressing in an oral-to-anal direction to ultimately reach the terminal hindgut. A second, more caudal region of the neural crest, the sacral neural crest, also contributes a smaller number of cells that are restricted to the hindgut ENS (7,8). To colonise the gut and form a functional ENS, NCC must undergo a number of key processes, including migration, survival, proliferation, differentiation, and axon formation. A large number of transcription factors, signalling pathways, and neurotrophic factors are involved in controlling the processes underlying normal ENS development, some of which are summarised in Figure 1; however, a detailed description of these molecular mechanisms is beyond the scope of this article and they are comprehensively reviewed elsewhere (9–12).
The initial colonisation of the gut by NCC is a relatively rapid process that occurs during the embryonic period of development, from weeks 4 to 7 in humans (13). In addition, the cell types necessary for coordinated neuromuscular activity, such as neurons and glia arranged within myenteric and submucosal plexuses, smooth muscle, and ICC, are present in the appropriate gut locations as early as week 14 of development (13); however, work in animals suggests that coordinated neuromuscular activity does not occur until the late foetal stages (14). This also appears to be the case in humans: intestinal contents have been shown to be propelled anally in late-stage foetuses (15), suggesting the presence of coordinated gut activity at this time; and at or around birth, migrating motor complexes and mixing motor patterns have been reported to be present in the small intestine (16,17). Although the cellular components necessary for coordinated neuromuscular activity are anatomically in place early in development, around week 14, it is not until many weeks later that coordinated gut motility patterns occur. It is unlikely that the cells that make up the neuromuscular components are “dormant” for the intervening weeks and months, waiting to become active with the intake of food after birth, but rather that a significant amount of neuromuscular maturation occurs during the mid- to late gestation period. Such maturation is likely to include differentiation of a comprehensive range of appropriate neuronal subtypes, formation of axonal projections, and establishment of intricate functional interconnections between nerves, smooth muscle, and ICC. Even in animal models, however, little is known about the development of functional neurons and even less about how circuits underlying motility reflexes are formed. Hence, the relationship between ENS development and the neutrally mediated control of gut motility is an important area of research that is only beginning to receive attention in the literature, and as a consequence is not addressed further in this review. Rather, the remainder of this article focuses on changes that occur in the ENS after birth. Although the majority of the studies cited have been carried out in animal models, where possible, human investigations are discussed.
POSTNATAL DEVELOPMENT AND CHANGES IN THE ENS
ENS Changes Caused by Normal Structural and Functional Growth
Maturational changes occur not only within the ENS before birth but also are ongoing in the postnatal gut as intestinal motility patterns become established and as the gut continues to grow and lengthen during infancy and childhood. Such postnatal changes have been seen in animal models as changes in colonic morphology (increased length and muscle thickness), motility patterns, myenteric plexus organization, myenteric neuron morphology, and myenteric neuron phenotypes during the birth to weaning period in young rats (18). There is evidence that as rhythmic spontaneous contractions become established, there is a significant increase in neuronal surface area and a decrease in cell density over time. Furthermore, the proportion of neuronal subtypes, namely excitatory cholinergic (ChAT) and inhibitory nitrergic immunoreactive neurons, increase in a time-dependent manner, highlighting a key role for cholinergic myenteric pathways in the development of postnatal motility (18).
Although such comprehensive investigations as those described above are difficult to replicate using human tissues, a study of the myenteric plexus of small bowel and colon specimens from 20 children, aged 1 day to 15 years, demonstrated that the density of ganglion cells decreased significantly during the first 3 to 4 years of life (19). These data support the idea that ENS development is an ongoing process in the postnatal period. Initially the ENS continues to enlarge in the period immediately after birth as the bowel grows in length and diameter, but then begins to decline in neuron number thereafter. This decline is likely to be the result initially of trophic regulation by target tissues, whereby functionally active neurons promote the synthesis of neurotrophic factors in target cells that in turn stimulate growth, survival, and synthesis of neurotransmitters within neuronal cell bodies, whereas functionally inactive neurons do not receive such support and die. In addition to this classic model for trophic support of neurons (20), it is also well known that degeneration of the ENS occurs during aging (21), although this characteristic is more prevalent later in life and not in the early postnatal period.
What factors could be involved in affecting postnatal changes in the ENS? A strong candidate is the neurotrophic factor glial cell line–derived neurotrophic growth factor (GDNF), which, acting through its REceptor rearranged during Transfection (RET) and co-receptor GDNF family receptor α-1 (22), is well known to play key roles in the migration, survival, proliferation, and differentiation of NCC during embryonic development (11) and is thus essential for the development of the embryonic ENS. Recent studies in the rat postnatal ENS demonstrated that GDNF, derived from intestinal smooth muscle, increased neuronal survival and numbers of neurites and induced morphological changes in the structure and organization of neurons and axons (23). Other studies using wild-type and 5-HT4 knockout mice suggested that 5-HT4 receptors are required postnatally for ENS growth and maintenance (24). These results from animal studies provide insight into at least a few mechanisms that are likely to be involved in ENS growth and maintenance postnatally, although again, this is an area that requires further research, particularly in humans.
ENS Changes Caused by Diet-Derived Factors
The control of gut motility by the intrinsic ENS is relatively complex, with different neuronal subtypes playing different roles. Within the myenteric plexus, excitatory neurons contain ChAT and substance P, and inhibitory motor neurons mainly contain vasoactive intestinal peptide (VIP) and nitrergic immunoreactive neurons; therefore, factors that have an impact on the proportions of these and/or other neuronal subtypes within the ENS also are likely to have a significant impact on gut motility. For example, short-chain fatty acids (SCFA), which are generated in the large intestine as a result of bacterial fermentation of dietary fiber and resistant starch (25), have been shown to affect both neuronal excitability and neuronal phenotype. In a study in which rats were fed a resistant starch diet (RSD) or had intracaecal perfusion of SCFAs (butyrate), it was found both in vivo and in vitro that RSD and butyrate significantly increased the proportion of ChAT myenteric neurons. Corresponding functional changes in the gut also were observed because RSD increased colonic transit and butyrate increased the cholinergic-mediated colonic circular muscle contractile response (26). These authors suggested that their findings support a role for butyrate as a “physiologic” modulator of the ENS phenotype, which could be of therapeutic interest for GI disorders associated with inhibition of colonic transit, the pathophysiology of which may result from a reduction in ChAT neurons. During early postnatal development, when there is a correlation between the acquisition of a cholinergic phenotype and the development of colonic motility, in a dysmotile setting butyrate could potentially be used to accelerate cholinergic maturation and thus augment colonic transit (26).
Not only can factors such as dietary SCFAs affect changes in the ENS but, interestingly, certain nutritional factors given in the maternal diet also have been shown to affect changes in the ENS of the offspring of the mothers who were fed a modified diet. For example, n-3 polyunsaturated fatty acids (n-3PUFAs) are known to have a number of beneficial effects on gut function: in intestinal inflammatory disorders (27), in necrotizing enterocolitis (28), and in food allergy (29). When sow pigs were given, during gestation and lactation, n-3PUFAs and the gut of their piglets subsequently analysed from birth up to 28 days, the n-3PUFA diet was shown to increase the proportion of ChAT neurons and to decrease the proportion of VIP neurons in the submucosal plexus of the piglet jejunum compared with controls (30). In this study, the changes in neuronal subtypes also were associated with increased mucosal barrier permeability. Although the consequences of this increased permeability were not determined, such changes could have an impact on the development of the immune system in newborns and the maintenance of gut homeostasis.
ENS Changes Caused by Stress/Inflammation
Early life stress is known to induce alterations in a number of gut functions, including increased visceral sensitivity, increased mucosal permeability, altered balance in enteric microflora, and increased mucosal mast cell density (31–33). Interestingly, such changes are common features of irritable bowel syndrome (IBS), a stress-related brain–gut axis disorder characterised by abdominal pain or discomfort, altered bowel habit, and absence of reliable biomarkers. Physical and psychological stresses also are accepted as playing a role in a number of GI disorders, including IBS (34).
Neonatal maternal deprivation, in which young rodents are removed from their mother for variable amounts of time before the weaning period, is a well-known model of early life stress. A number of studies have used this model to investigate how phenotypic changes in the gut can result from a stress event. For example, Barreau et al demonstrated that long-term alterations in colonic nerve–mast cell interactions were induced by neonatal maternal deprivation in rat pups (35). In this study, a combination of colonic mast cell hyperplasia, increased mucosal nerve fibre density, and increased synaptogenesis was observed. The number of mast cells in association with nerve fibres also increased following maternal deprivation (35). Mast cells, located in close proximity to mucosal nerve fibres, can be activated by neuropeptides to secrete mediators (eg, mast cell tryptase, histamine) that stimulate sensory neurons and thus play an important role in abdominal pain perception. Interestingly, the severity and frequency of abdominal pain has been significantly correlated with the number of mast cells closely apposed to colonic nerves in patients with IBS (36). Such changes in mast cell number/association with nerve fibres may involve nerve growth factor, which was found to be overexpressed in the colonic wall at the end of a period of maternal deprivation (37).
Inflammation of the gut also is known to have dramatic effects on gut structure and function, altering patterns of motility, secretion, and visceral sensation even after the recovery from the inflammatory response (38). Within the ENS, morphological alterations, for example, in the neurochemical content of some functional classes of neurons, can vary according to the site and type of inflammation, whereas the functional consequences depend on the nature of the inflammatory stimulus. The trinitrobenzene sulfonic acid (TNBS) model of chronic inflammation has been used in laboratory animals to assess changes in gut structure and function after recovery from an inflammatory response. Treatment with TNBS causes damage to the mucosa, inflammatory responses in the mucosa and enteric ganglia, and changes in myenteric neuron number and properties. Using such an approach, Lomax et al (39) demonstrated in the guinea pig that 8 weeks after TNBS treatment, although colonic inflammation had resolved, the electrical activity of enteric neurons was altered and neutrally mediated colonic secretory function was significantly reduced. In a similar study using the TNBS model in the guinea pig, Nurgali et al (40) demonstrated that despite mucosal repair and reinnervation of the mucosa after induction of inflammation, neuronal hyperexcitability persisted. These and other studies suggest that sustained alterations in enteric neural signalling, accompanied by gut functional changes, occur in the absence of active inflammation and may provide a potential mechanism underlying postinflammatory gut dysfunctions.
ENS Changes Caused by Damage/Injury
As outlined above, enteric neurogenesis mostly occurs in embryonic and early postnatal stages of development (41,42), although some neurogenesis in adult mice has been described (24). In addition to this pre- and postnatal neurogenesis that is essential for the development and maturation of a functional ENS, the postnatal ENS appears to have considerable capability for regeneration and plasticity. This idea is based on studies in which experimentally induced damage to the ENS (eg, with topical application of benzalkonium chloride, irradiation, inflammation, partial stenosis) results in neuronal hypertrophy and/or nerve cell regrowth into the damaged gut region (43,44). Because the gut can be exposed to a variety of insults during injury or disease (eg, inflammatory bowel disease, infection) that lead to the destruction of or damage to the ENS, the ability of the ENS to self-repair may be a key property of gut homeostasis. What is the source of the cells that recolonise the gut following denervation? One possibility is enteric neurons that undergo cell division; however, because no neuronal cell division was observed in studies of the adult mouse ENS (24,42), a more likely candidate is the population of neural crest–derived, self-renewing, multipotent progenitors (ENS stem cells) that have been identified in cultures of postnatal mouse and rat gut (45,46) and in cultures of gut obtained from children and adults (47,48). A large body of work has investigated not only the biology of these stem cells but also their therapeutic potential for the rescue of absent enteric neurons in patients with Hirschsprung disease, in whom ENS cells are absent in a variable length of the colon (49,50). The transplantation of ENS stem cells into aganglionic gut may represent an attractive alternative to surgery (the current treatment for Hirschsprung disease), and the ability to replenish absent enteric neurons within experimental models of gut aganglionosis has been demonstrated (10,51,52). Although the identity, localization, and physiological functions of the cells with neurogenic potential that reside in the adult gut are still unclear, studies in mice suggest that mature glial cells have the capability of generating enteric neurons when placed in culture and in response to gut injury in vivo (53). This suggests that glia, within a gut disease/insult setting, may be capable of dedifferentiating, becoming more progenitor-like, then differentiating into neurons. In a similar study, however, such neurogenic potential of glial cells in vivo was not found, and these latter authors concluded that their primary physiological function is to form new glia under steady-state conditions, and to regenerate glia that are lost to injury (54). These conflicting findings highlight the need for further research to determine the extent of neurogenesis that occurs following ENS damage and the origin and phenotype of cells that give rise to new neurons. These are important questions because this knowledge could be applied to help develop novel therapies for the manipulation/enhancement of postnatal neurogenesis in a disease setting, which could in turn repair the ENS and restore normal gut function.
LONG-TERM IMPLICATIONS OF ABDOMINAL DISCOMFORT/PAIN IN EARLY LIFE
As mentioned above, early life stress and/or inflammation is known to induce alterations in a number of gut functions, including increased pain perception (visceral hypersensitivity). Such changes in pain perception are believed to increase susceptibility to the development of functional GI disorders (where normal gut function is impaired in the absence of evident structural abnormalities). Based on this idea and on a number of established associations between perinatal complications and atypical behaviour later in life, it has been postulated that early adverse experiences may lead to long-term GI consequences. For example, there is some evidence to suggest that certain factors that predispose children to develop functional GI disorders can be traced to even the first hours or days of life. An interesting study by Anand et al (55) suggested that gastric suction (common in neonatal intensive care units) in infants at birth appears to lead to long-term visceral hypersensitivity, resulting in an increased prevalence of functional intestinal disorders in later life. In this study of Swedish patients, these disorders were listed as “symptoms from the intestines” denoting “abdominal pain, colic: not otherwise specified, infantile, intestinal” (55). It was suggested that the GI conditions may arise from stress because the authors postulated that gastric suctioning could cause physiological stress and noxious stimuli originating from the oropharynx and upper GI tract just after birth. Saps and Bonilla (56) further underscore the importance of early life events in the development of chronic abdominal pain in children. They hypothesised that children who underwent surgery for pyloric stenosis (hypertrophy of the pylorus leading to gastric outlet obstruction) are at greater risk for developing chronic abdominal pain because of the combination of various risk factors: an early stressful event, gastric surgery, and perioperative nasogastric tube placement. The authors speculated that nerve remodeling may have occurred in this group of children, predisposing them to visceral hyperalgesia, because nerve remodelling has been reported following gastric surgery in rats (57).
In addition to the above data from human studies, similar findings regarding visceral hypersensitivity have been reported in animal models: neonatal rats subjected to orogastric suctioning were reported to develop visceral hyperalgesia as adults (58), and in a rat colonic irrigation model, colon irritation in neonates but not in adults resulted in chronic visceral hypersensitivity (59). The above evidence and other studies support the idea that significant and long-lasting physiological consequences may follow painful insults in the very young. Underlying mechanisms may include local alterations in neurotransmitters, receptors, ion channels, and afferent neurons, with an important role for the TRP channel family (TRPV1, TRPV4, TRPA1) in visceral hypersensitivity in particular (60,61).
SUMMARY AND FUTURE DIRECTIONS
Development of the ENS is a complex process that occurs from the early embryonic period into postnatal life. To form the ENS, during early embryogenesis NCC colonise the entire length of the growing gut, proliferate extensively, and differentiate into neurons and glia. A significant period of maturation occurs during the foetal stages, such that a functional network of interconnected neurons, ICC, smooth muscle cells, and other target cells becomes established around birth. After birth, the ENS continues to change and adapts to various challenges. As the gut continues to grow and increase in size, the ENS also changes in size and composition; ENS stem cells may be mobilised to replace enteric neurons that are lost as a result of gut damage or insult; dietary factors may also cause changes in the ENS, such as changing the proportion of neuronal subtypes, which in turn affects gut motility; stress and inflammation can cause changes in enteric nerve–mast cell interactions and in enteric neuron number and properties, respectively. Interestingly, early adverse life events such as gastric surgery or orogastric suctioning may have long-term consequences for the development of functional GI disorders by changing the profile of enteric sensory nerves and/or receptors, resulting in visceral hypersensitivity.
Gaining insight into the mechanisms underlying ENS changes is a challenge, partly because of the diverse and numerous factors that impinge upon the ENS (eg, CNS and ANS input, stress, inflammation) and the gut microbiota. Many of the studies that have shed light on these topics come from animal models, with human studies being in the minority. The challenge, then, for the coming years is to better understand, not only in animals but also in humans, the mechanisms underlying postnatal changes in the ENS in normal (growth/repair) and “disease” (stress/inflammation/adverse events) states. Such understanding could allow translation of this knowledge into novel therapies for the treatment of a range of diseases affecting the ENS and/or elucidate ways to affect the ENS in a beneficial way, for example, through dietary changes or with prebiotics or probiotics.
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