Abstract
Gastrointestinal motility in human infants is a complex function and is dependent on sensory and motor regulation of the intrinsic enteric nervous system integrated and modulated by the central and autonomic nervous systems. Proper development of gastrointestinal motility reflexes is necessary for the coordinated movement of the gut, and these reflexes develop during mid- and late gestation and continue to mature in evolution frequency, magnitude, response sensitivity, and associated responses with advanced postnatal maturation. In preterm infants, this process is interrupted and often complicated by the influence of hypoxia, inflammation, sepsis, and other comorbid conditions. In this chapter, we review and summarize the developmental aspects of pharyngo-esophageal motility, gastrointestinal motility, and colonic motility.
Keywords
Aerodigestive reflexes, Neonatal gut motility, Prematurity
Introduction
Gastrointestinal motility in human infants is a complex function, and the development of the elements to facilitate this is a much more complex process. Briefly, by the 14th week of development, all the cellular components necessary for coordinated neural and muscular activities exist in the fetal gut. However, maturation of neuromuscular functions occurs during mid- and late gestation, and this translates to fully functional coordinated gut motility patterns in the full-term healthy neonate capable of independent feeding, aerodigestive protection, and small and large intestinal peristalsis, besides cyclical regulation of hunger, satiety and feeding. This process continues to mature postnatally and is influenced by the maturational changes in the central and enteric nervous system, gut muscle and interstitial cell of Cajal (ICC), as well as by the diet and rapidly changing anatomy and physiology during infancy. In the vulnerable high-risk preterm infants in neonatal intensive care units (NICUs) the influence of hypoxia, inflammation, sepsis, and other comorbid conditions complicate and alter the postnatal development of gastrointestinal motility. Coordinated movements of gut are crucial for the primary function of the neonatal foregut (to facilitate safe feeding process so as to steer the feedings away from the airway), midgut (gastrointestinal transit of luminal contents to modulate absorption and propulsion), and hindgut (evacuation of excreta to maintain intestinal milieu homeostasis). In this chapter, we will review and summarize the developmental aspects of (1) pharyngo-esophageal motility, (2) gastrointestinal motility, and (3) colonic motility.
Embryologic Aspects of Motility Development
The human gut initially arises as a primitive tube from the endoderm of the trilaminar embryo (week 3) and later receives contributions from all the germ cell layers. The endoderm gives rise to the epithelial lining and glands, the ectoderm gives rise to the oral cavity and the anus, and the mesoderm-derived splanchnic mesenchyme gives rise to the smooth muscle and connective tissue. During week 4, the gut differentiates into three distinct regions (foregut, midgut, and hindgut). The foregut later develops into the airway and lung buds, pharynx, esophagus, stomach, and proximal portion of the duodenum; the midgut gives rise to the remainder of the duodenum, small intestine, and portions of the large intestine up to the distal transverse colon; and the hindgut develops into the distal part of the transverse colon, descending colon, rectum, and proximal part of the anal canal.
The smooth muscles are innervated by the intrinsic neurons of the enteric nervous system (ENS), which consists of interconnected ganglia, containing neurons and glial cells. The ENS arises from precursor cells derived from the vagal (hindbrain) neural crest that enter the foregut and advance rostrocaudally in the intestine. They colonize the gut through a complex process of migration, proliferation, and differentiation along defined pathways and reach the midgut by week 5 of development and the entire length of the gut by week 7. A second, more caudal region of the neural crest, that is, the sacral neural crest, also contributes a smaller number of cells that are restricted to the hindgut ENS. The ganglia of the ENS are organized in two plexus layers that span the length of the gut—an outer myenteric plexus, situated between the longitudinal and circular muscle layers, and an inner submucosal plexus lying between the circular muscle and the muscularis mucosae. 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. The ENS neurons may be classified according to their function as afferent sensory neurons, interneurons, and motor neurons. Activation of afferent neurons is the first step in the triggering of motor reflexes as they translate stimuli from the intestinal lumen into nerve impulses that are transmitted to interneurons and motor neurons. Interneurons form circuitry chains running both orally and aborally within the myenteric plexus. The orally running interneurons activate excitatory motor neurons, resulting in smooth muscle contraction, and the aborally running interneurons activate inhibitory motor neurons, resulting in smooth muscle relaxation. The excitatory motor neurons release acetylcholine, and the inhibitory motor neurons release nitric oxide or vasoactive intestinal polypeptide. This sequential enteric reflex pattern of ascending contraction and descending relaxation, called peristalsis , forms the basis for Starling’s Law of the Intestine ( Fig. 2.1 ), which facilitates bolus propulsion in the peristaltic direction. The initiation and regulation of peristalsis is a complex process that involves pacemaker cells (ICCs), in addition to the smooth muscle cells and enteric nerves. ICCs generate spontaneous electrical slow waves, which constitute the basic electrical rhythm in the gut. ICCs develop independent of neural crest–derived enteric neurons or glia and originate mainly from Kit-positive mesenchymal mesodermal precursors.
The ENS is remarkably independent, but its neuronal activity can be modified or modulated by the central nervous system (CNS) via the autonomic nervous system (ANS; parasympathetic and sympathetic nervous systems). Much of the parasympathetic innervation to the gut travels via the vagus nerve and the sacral nerves and is primarily excitatory to gut function by promoting secretion and peristalsis. In contrast, sympathetic innervation travels along the mesenteric blood vessels from the prevertebral ganglia and is primarily inhibitory to gut function by decreasing peristalsis and reducing perfusion of the gut.
The human fetal gut, by week 14, has the longitudinal, circular, and muscularis mucosal layers of smooth muscle, submucosal and myenteric plexuses, and ICC networks that are associated with the ENS. However, the first coordinated gut motility patterns do not occur until birth or about that time. By 11 weeks, swallowing ability develops, by 18 to 20 weeks sucking movements appear, and by full-term gestation, the fetus can swallow and circulate nearly 500 mL of amniotic fluid. ENS-mediated contractile activity is prominent in function by full-term birth and is essential for propulsive activity. Variations in gut motility and peristaltic patterns occur in prematurely born neonates and are discussed in the latter part of this chapter.
Pharyngo-esophageal Motility Reflexes in Human Neonates
Maturation of Esophageal Peristalsis and Upper Esophageal Sphincter and Lower Esophageal Sphincter Functions
Deglutition refers to the whole process of propulsion of a food bolus from the mouth into the stomach and involves the complex coordination of rhythmic sequences of sucking, swallowing, and breathing, followed by well-timed relaxations of the upper and lower esophageal sphincters (UES and LES, respectively) and sequential esophageal contractions. Using micromanometry methods, pharyngeal, UES, esophageal body, and LES functions have been characterized in neonates. The UES and the LES maintain a resting tone irrespective of age or activity states, thus protecting the airway from luminal contents. With growth and maturation, the muscle mass and therefore the tone and activity of the UES increase. The average resting UES pressure (mean ± standard deviation) in preterm-born neonates at 33 weeks postmenstrual age (PMA) was 17 ± 7 mm Hg, and in full-term born neonates was 26 ± 14 mm Hg, whereas in adults it was 53 ± 23 mm Hg. Similarly, changes in LES length and tone have been observed with growth. Additionally, esophageal lengthening occurs in a linear fashion during postnatal growth in both premature and full-term infants.
Maturation of Basal and Adaptive Esophageal Motility
Pharyngeal swallowing and esophageal peristalsis constitute the principal methods used to drive the bolus from the oral cavity to the stomach, at the same time protecting the airways from aspiration or penetration. Pharyngeal swallowing is triggered when a bolus moves from the oral cavity to the pharynx or by direct pharyngeal or esophageal stimulation. Esophageal response to pharyngeal swallowing is termed primary peristalsis (triggered by the bolus moving from the oral cavity to the pharynx) or pharyngeal reflexive swallow (PRS, by direct pharyngeal stimulation), or esophageal deglutition response (EDR, by direct esophageal stimulation) ( Fig. 2.2 ). All three responses are characterized by sequential reflexes that include relaxation of the UES, restoration of UES tone, ordered esophageal body peristalsis, coordinated relaxation of the LES, and restoration of LES tone, all of which ultimately clear the pharynx and propagate the bolus distally into the stomach. This sequence is normally associated with a respiratory pause called deglutition apnea (inspiratory or expiratory) suggesting cross-communications between the pharynx and the airway. This occurs because of the physical closure of the airway by elevation of the soft palate and larynx, by tilting of the epiglottis, and by the neural suppression of respiration in the brain stem. Evaluation of consecutive spontaneous solitary swallows in preterm infants at 33 weeks, preterm infants at 36 weeks, full-term infants, and adults has shown significant age-dependent maturational changes in the sphincter kinetics and in the amplitude and velocity of esophageal peristaltic contractions. Importantly, primary esophageal peristalsis exists by 33 weeks PMA; however, it undergoes further maturation and differentiation during postnatal growth and is significantly different from that of adults.
The esophagus is a frequent target for retrograde bolus from the stomach as in gastro-esophageal reflux events, which causes mechanosensitive, chemosensitive, or osmosensitive stimulation of the esophagus. The esophagus clears such luminal contents back into the stomach either by a swallow-dependent EDR or by a more mature, swallow-independent peristaltic sequence response called secondary peristalsis . Secondary peristalsis comprises a coordinated sequence of proximal esophageal contraction and distal esophageal relaxation, coordinated relaxation of the LES, and restoration of LES tone ( Fig. 2.3 ). Similar to the occurrence of secondary peristalsis, esophageal provocation can result in an increase in UES pressure, which increases the pressure barrier against entry of refluxate into the pharynx (see Fig. 2.3 ). This reflex, referred to as esophago-UES-contractile reflex , is mediated by the vagus nerve. Concurrently, the LES relaxes to facilitate bolus clearance. This is called LES relaxation reflex response . These reflexes prevent the ascending spread of the bolus and favor descending propulsion to ensure esophageal clearance.
Although the nature and composition of the bolus within the pharyngeal or esophageal lumen can vary, peristalsis remains the single most important function that must occur to favor luminal clearance away from the airway. These reflexes advance during maturation in premature infants. A study of pharyngeal provocation responses in healthy premature infants at 34 weeks and 39 weeks PMA has shown a higher recruitment frequency of PRS and pharyngeal LES relaxation responses at 39 weeks. Secondary peristalsis upon mid-esophageal provocation has been described as occurring as early as 32 weeks PMA. When premature infants were studied at 33 weeks and 36 weeks PMA for esophageal provocation characteristics, the occurrence of secondary peristalsis and the frequency of completely propagated secondary peristalsis were significantly higher at 36 weeks PMA, with increment in dose volumes of air or liquid esophageal provocation. The occurrence of UES contractile reflex was also volume dependent, and its characteristics showed improvement with advancing maturation. Similarly, the aerodigestive defense mechanisms during the sleep state also mature with time in preterm infants, as evidenced by the greater ability to remain asleep with less cortical arousal, during esophageal provocation. During this maturation process, the peristaltic response becomes faster and more efficient with faster esophageal clearance and greater intraluminal esophageal pressure. These findings are suggestive of the existence of vago-vagal protective reflex mechanisms that facilitate esophageal clearance in healthy premature neonates and indicate that these mechanisms mature with increasing gestational age.
Safe and efficient nutritive sucking in infants requires synchronization of sucking, swallow processing (pharyngeal swallow and esophageal peristalsis), and breathing. Functional immaturity in these components, at either an individual level or an integrated level, is associated with oral feeding difficulties. Many components within each of these levels mature at different times and rates and may explain why infants of similar gestation age demonstrate wide variation in oral feeding skills. A recent study of neonates with significant oral feeding difficulties showed that ability for full oral feeding at NICU discharge was associated with less long-term neurodevelopmental impairment relative to full or partial gastrostomy tube feeding.
Gastrointestinal Motility Reflexes in Human Neonates
Although fetal peristalsis is recognized, local neural transmission and integration of peristalsis mature throughout fetal life and continue to develop during the first postnatal year. These local contractions are coordinated throughout the length of the intestine by neural regulation modulated by the ENS, the ANS, and the CNS. The gut has a network of specialized intrinsic pacemaker muscle cells (ICCs) that also play a role in triggering these coordinated contractions. Intestinal myoelectrical activity consists of slow waves and spike bursts. ICCs at the level of the myenteric plexus (ICC-MY) mediate the slow waves whose function is to regulate the maximum rate of muscular contraction. The frequency of slow waves varies along the gut, but each part of the gut has a characteristic frequency. The stomach has the lowest frequency of slow waves, occurring at 3 to 5 times/min, whereas it is fastest in the duodenum (9-11 times/min) and then diminishes distally in the midgut (6-8 times/min). The spike bursts are fast action potentials that only appear on the slow-wave plateau when the small intestine contracts and determine the intensity of the intestinal contractions. Finally, motor function can be modulated by gastrointestinal hormones and peptides, which may exert endocrine, paracrine, or neurocrine activity, resulting in inhibitory (e.g., peptide YY, nitrergic, vasoactive intestinal peptide) or excitatory (e.g., cholinergic–muscarinic, cholecystokinin, substance P) modulation. All of the neural and muscular elements are present by 32 weeks’ gestation, but full neural and neuroendocrine integration is not achieved until late in infancy.
Gastric Motor Functions
Anatomically, the stomach can be divided into the fundus, corpus (body), antrum, and pylorus, whereas, functionally, the proximal stomach (fundus and proximal corpus) acts as a gastric reservoir and the distal stomach (distal corpus and antrum) as a gastric pump where the peristaltic waves occur. The gastric fundus accommodates the ingested nutrients by receptive relaxation reflex. This is largely mediated by the vagus nerve as stimulation of the mechanoreceptors in the mouth and pharynx and of the distal esophagus induces vago-vagal reflexes that cause relaxation of the gastric reservoir by nitrergic pathways. Fundus relaxation is a prerequisite for antral contraction and gastric emptying. However, receptive relaxation in neonates and infants is not well studied. In contrast to the fundus, the antrum has tonic and phasic activity and is responsible for the churning of nutrients with secretions to initiate early digestion and to empty the stomach contents into the duodenum. Contractile activity in the antrum is coordinated with that in the duodenum to promote emptying of contents into the upper small intestine. Hence, the physical and chemical characteristics of the nutrients entering the duodenum trigger feedback signals to the antrum to hasten or slow emptying. Ultrasonographic studies of the fetal stomach detected gastric emptying occurring as early as 13 weeks of gestation, and the length of gastric emptying cycles in fetuses increases just before birth. The rate of gastric emptying is not influenced by nonnutritive sucking but is influenced by caloric density and osmolality of milk and stress—calorically denser formula accelerates gastric emptying, high milk osmolality, and extreme stress, such as that caused by the presence of systemic illness, delays gastric emptying. The administration of drugs for clinical care, such as opioids or mydriatics, may also impair gastrointestinal functioning. Interestingly, bolus feedings appear to delay gastric emptying in some preterm infants, presumably via rapid distention.
Small Intestine Motor Functions
Like in the stomach, there is an ICC network located in the intestinal wall between the internal circular and the external longitudinal muscle layers that initiate the slow waves. Peristaltic waves are far spreading and rapid at the proximal small intestine and become shorter and slower toward the distal gut. The intrinsic contractile rhythm of the stomach, duodenum, and small intestine are present as early as 24 weeks’ gestation. Full neural integration is inadequate at birth, and gastric emptying and the overall intestinal transit are slower in the preterm infant than in the full-term infant. Overall gut transit can vary from 7 to 14 days and depends on gestational maturation.
The small intestine exhibits two basic patterns of motor activity: (1) fed response and (2) fasting response. During fed response, the muscle layers contract in a disorganized fashion, resulting in active, continuous mixing and churning of nutrients and secretions resulting in chime ( Fig. 2.4 ). Fed response facilitates transport of nutrients distally to facilitate digestion and absorption. Although an adult-like fed response is seen in most full-term infants in response to bolus feeding, only about 50% of the preterm infants exhibit such a response. In contrast, in the fasting state, the small intestine does not stay quiescent but experiences muscular contractions organized into patterns known as the interdigestive migrating motor complex (IMMC) ( Fig. 2.5 ). Depending on the intensity of motor activity, the IMMC cycle can be divided into four periods: phase I, or period of smooth muscle quiescence, during which the intestine is at rest; phase II of random and unorganized motor activity; and phase III (migrating motor complex, MMC), in which bowel contractions occur at maximum frequency and intensity when >90% of slow waves are accompanied by spike bursts. It is usually generated at the duodenum, although it can be generated at any point between the stomach and the ileum. MMCs are responsible for about 50% of the forward movement of nutrients and are considered the “intestinal housekeeper.” This robust well-organized pattern is replaced by randomly occurring contractile waveforms that terminate in the reappearance of quiescence (phase IV). The MMC is interrupted by feeding, and the subsequent fed response is characterized by irregular muscle contractions.
