Gastrointestinal Tract in Newborns and Appropriate Nutrition

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This entry is adapted from the peer-reviewed paper 10.3390/nu14071405

The maturation of the gastrointestinal (GI) system in full-term and preterm human infants is an area of great interest from both a nutritional and medical practice standpoint. Particularly in preterm infants less than 28 gestational weeks (GW), delivery constitutes a nutritional emergency in which the infant has high and difficult-to-meet nutritional needs. A contributing factor to the nutritional emergency is the relatively underdeveloped GI system of premature neonates, which limits their ability to utilize enteral nutrition.

gastrointestinal development preterm infants digestion intestinal motility microbiota gut–brain axis microbiota

1. Development of Digestion and Absorption in the Neonate

1.1. Proteins

Protein sources for term and preterm infants are comprised of two major components, whey and casein. Digestion of these proteins is initiated in the stomach, where parietal cells secrete hydrochloric acid which, in combination with activation of the proenzyme pepsinogen, denatures some of these proteins. Parietal cells are present by the late first trimester of pregnancy, and they actively secrete gastric acid by the second trimester. ^[1]^[2]. After preterm birth, gastric acid production is limited in comparison to infants born at 40 gestational weeks (GW). During the first two months after birth, gastric acid production doubles ^[3]. The proenzyme pepsinogen can be detected in the fetal stomach by 17–18 GW. After birth, pepsin activity is in line with the infant’s maturity ^[4].

Other major enzymes are produced by the pancreas during this time. These include trypsinogen, chymotrypsinogen, and carboxypeptidase, all of which are zymogens that require activation by enterokinase, which is produced by the upper intestinal epithelial cells. By 24 GW, enterokinase is active at 25% of the level found in older infants ^[5]. These enzymes break large protein molecules into oligopeptides, dipeptides and single amino acids. As these molecules move distally, the absorptive process into the small intestinal epithelial cells occurs. This is accomplished by several transporter mechanisms. There are limitations of these processes in preterm infants. ^[6].

1.2. Carbohydrates

Salivary and pancreatic amylases are involved in the luminal digestion of complex sugars. Digestion into oligosaccharides is then complemented by absorptive hydrolysis into monosaccharides at the epithelial brush border by enzymes that include lactase, sucrase, maltase, isomaltase, and glucoamylase. Sucrase, maltase, and isomaltase have been shown to be fully active in preterm infants. Lactase activity, which hydrolyzes lactose, which is the most abundant disaccharide, into glucose and galactose, is low in preterm infants. ^[5].

Salivary amylase, which digests complex carbohydrates of 18–29 glucose units, is an initiator of carbohydrate digestion ^[7]. Pancreatic amylase, the secretion of which is limited, not reaching adult levels until about 2 years of age, is responsible for most initial carbohydrate hydrolysis. ^[8]^[9]. Due to suck–swallow incoordination, enteral feeding in many preterm infants necessitates the use of feeding tubes. These bypass the oral cavity, hence also bypassing the activity of salivary amylase.

Undigested carbohydrates pass into the distal intestine. Here, microbial fermentation results in the production of short chain fatty acids (SCFAs), which subsequently are absorbed. These can be utilized as energy sources, but butyrate has been also shown to serve as an important fuel for colonocytes as well as having properties that alter proliferation, differentiation, and turnover of colonic cells. ^[10]^[11].

Lactose is especially interesting from this perspective. Being the primary carbohydrate source in milk, lactose intolerance rarely occurs in the preterm population. Unabsorbed lactose conversion to SCFAs provides an efficient salvage pathway. It was suggested that lactase activity can be induced in preterm infants with enteral feedings of human milk ^[12].

Most lactase activity is found at the middle to the top of the villus, while sucrase, maltase and glucoamylase are found at the mid-villus ^[13]. During time of intestinal mucosal injury, the lactase-rich cells at the villus tip are the first to be injured and the last to be fully restored through the process of cell migration from crypt to the villus tip.

Insulin plays an important role in intestinal maturation and may also contribute to improve lactase activity following preterm birth. Amniotic fluid contains carbohydrates, protein, fat, electrolytes, immunoglobulins, and growth factors. Insulin is present in the amniotic fluid (up to 20 μU/mL) and after skin keratinization completed (around 26 weeks’ gestation), amniotic fluid is the main source of insulin exposure to the GI tract and plays a role in development. Preterm birth abruptly interrupts these important fetal life processes and the local insulin exposure of the GI tract with detrimental consequences ^[14].

Oral insulin administration in preterm infants up to 28 days after delivery has proved effective in doubling the lactase activity ^[15].

1.3. Lipids

Triglycerides constitute half of the non-protein energy content in human milk and formula ^[16]. The digestion of triglycerides is initiated by bile acid micellar emulsification, which produces smaller droplets of triglycerides. This results in greater surface area for interaction with lipases, which hydrolyze long chain triglyceride into monoglycerides and free fatty acids, which in turn are absorbed into the small intestinal epithelium. Pancreatic lipase is one of the most important of these lipases.

The absorbed free fatty acids and 2-monoglycerides are re-esterified within the epithelial cell and subsequently converted to chylomicrons, which are transported from the basal region of the epithelial cell via the thoracic duct, from which they enter the blood circulation.

The digestion and absorption of medium chain triglycerides (MCTs) is less complex than that of long chain triglycerides. They do not require bile acid emulsification, are absorbed into the enterocyte without re-esterification and travel directly into the portal venous system. MCTs are frequently recommended for patients with lymphatic obstructions ^[17].

Different sources of lipase include lingual, gastric, pancreatic, and epithelial cells. Human milk contains a lipase termed bile-salt stimulated lipase. After activation in the small intestine in the presence of bile acids, it facilitates long-chain triglyceride digestion. Lingual lipase is secreted from glands at the base of the tongue; its activity is lower at birth in infants at 26 weeks’ gestation, peaks at 30–32 weeks, and declines near term ^[18]^[19]. Pancreatic lipase insufficiency is more prevalent in preterm infants when compared to older children. Adult levels are often not reached until 6 months after birth ^[20].

Another limitation of fat digestion relates to bile acids, which are synthesized and excreted from the liver via the biliary system at relatively low levels in very low birth weight (VLBW) preterm infants when compared to term infants. Bile ileal reabsorption is also lower in preterm infants, which results in less efficient lipid digestion when compared to term infants ^[21]^[22].

2. The Development of Intestinal Motility

2.1. Anatomy and Physiology of Gastrointestinal Motility

The movements of the GI tract are different for each region. They also show marked differences in relation to prematurity ^[23]^[24].

Gastric motility is ruled by myoelectrical activity that consists of rhythmically occurring transmembrane potential variations, called slow waves, that are independent of the presence of motor activity ^[25]. These waves that slowly travel through the GI tract are defined motor migratory complexes (MMCs) and occur every 2–4 h with the purpose of clearing the tract of undigested material, mucus, and debris ^[26]. MMCs initially occur due to vagal input and the release of motilin in the duodenum. Their propagation, on the other hand, is coordinated by enteric neurons. MMCs occur in humans only during periods of fasting and in the small intestine as opposed to other species. Phasic contraction is related to a different kind of electrical activity, called electrical response activity, characterized by spikes superimposed on gastric slow waves. The origin of electrical activity is found on the greater curve, approximately in the proximal corpus, from where the slow waves propagate towards the pylorus ^[26]^[27].

Different motor patterns occur in the proximal and distal stomach. In the proximal stomach, receptive relaxation and accommodation occur, which are both mediated by neurons in the brainstem via vagal reflexes. The distal stomach exhibits different motor patterns during feeding and fasting. In the feeding state, the distal stomach grinds and mixes. Extrinsic neurons are not essential for this contractile activity, but it can be modulated by vagal pathways.

Intestinal motor activity is also correlated with gestational age and motor development, which is defined by phases I, II, and III of the migration of the motor complex between 37 GW and term age ^[28]. In particular, the frequency of duodenal contractions, the number of duodenal contractions per impulse, and the peak intraluminal pressure of duodenal motility in preterm versus full-term infants are different ^[29]. Clustered phasic contractions are more frequent but of shorter duration and lower amplitude; duodenal clusters are less common and antro-duodenal coordination is more immature in preterm infants ^[30].

A role of insulin on gut motility has also been supported by Shulman et al., who demonstrated significantly reduced gastric residuals within the first month in preterm infants treated with oral insulin compared to untreated peers ^[15].

2.2. The Enteric Nervous System

By 12 GW, the fetal colon has a dense neuronal network in the myenteric plexus with expression of excitatory neurotransmitter and synaptic markers. Instead, the markers of inhibitory neurotransmitters appear no earlier than 14 GW. However, electrical train stimulation of internodal strands did not evoke activity in the the enteric nervous system (ENS) of 12- or 14-GW tissues ^[31].

Onset of evoked electrical activity in the human fetal ENS appears at approximately 16 GW. Such activity appears to coincide with increases in gene expression of various ion channels known to modulate enteric action potentials. The temporal development of several neural subtypes and enteric glia occurs between 12 and 16 GW ^[32]^[33]. The ENS consists of three parts: enteric neurons, enteric glial cells (EGCs), and interstitial cells of Cajal (ICCs). They form two major ganglionated structures and functional subunits—submucosal plexus (or Meissner’s plexus) and myenteric plexus (or Auerbach’s plexus). Meissner’s plexus is located in the connective tissue of submucosa, and innervates muscularis mucosae, intestinal neuroendocrine cells, glandular epithelium and submucosal blood vessels, while Auerbach’s plexus is located between the circular and longitudinal muscle layers and is associated with the contractility of the circular and longitudinal muscles ^[34]^[35].

Cdh19 is a direct target of Sox10 during early sacral NCC migration towards the hindgut and forms cadherin–catenin complexes which interact with the cytoskeleton in migrating cells ^[36]. The migration phase is followed by the proliferation of NCCs which will form millions of ENS cells. The NCCs then assemble into groups (myenteric ganglia or submucosal ganglia) and then differentiate into a range of enteric neurons and glia cells and form complex neuronal networks necessary for controlled intestinal activity ^[37]^[38]^[39].

Diverse populations of fibroblast-like interstitial cells are present in the adult gut. Loss or dysfunction of these cells has been linked to a wide variety of GI disorders. This broad group of cells comprises various subpopulations of Kit-positive ICCs and fibroblast-like cells expressing PDGFRα. ICCs located at the level of the myenteric plexus (ICC-MY) mediate slow waves, the electrical events that time the occurrence of phasic contractions ^[40]^[41], while evidence is accumulating that ICC and PDGFRα-expressing cells located within and surrounding GI muscle bundles serve as intermediaries in both excitatory and inhibitory neuromuscular transmission.

2.3. The Microbiota-Gut–Brain Axis

During the early postnatal period, infants undergo consistent gut development, which is parallel and interdependent, even if not always synchronous, with brain development. In the first years of life, the gut experiences huge changes of the resident microbiota and a substantial maturation of both the enterocytes and of the ENS. Meanwhile, the brain and the central nervous system (CNS) grow rapidly, both in terms of brain volume and neural function.

The interdependency of the two developmental processes is mediated through the so-called gut–brain axis, which constitutes a bidirectional communication between the gut and the brain, made of several interrelated components ^[42]. In recent years, the role of microbiota in the gut–brain axis has been studied extensively, so that the GBA is now commonly referred to as the microbiota-GBA (MGBA) ^[43]. Gut microbiota alterations have been directly linked to physical and mental health through a series of mechanisms which are yet to be fully elucidated ^[44].

The connection between gut and brain during early development involves both top-down and bottom-up mechanisms, with signals from the brain modulating GI functions, and GI-derived molecules influencing brain processes through different pathways. Even if the features of the MGBA in health and disease have been thoroughly described, the knowledge of the exact mechanisms through which the gut and the brain communicate in young infants is, at present, limited.

The mechanisms involved in the interplay between the brain and the gut include neural, endocrine, immune, and metabolic mediators ^[45].

Neural connections include the CNS, the ENS, and the autonomic nervous system (ANS). The ENS receives inputs from the brain and, in turn, provides ascending information through neural circuits. The ANS comprises sympathetic and parasympathetic nerves: the sympathetic system exerts mainly an inhibitory influence on the gut, while the vagus nerve (VN) appears to be able to sense hormones, cytokines, and metabolites from the GI tract, leading to afferent signals to the brain. The development and myelination of the VN is not complete at birth and continues until adolescence, with a peak in the myelination rate observed in the first months of life, when consumption of human milk, and human-milk-derived bioactive components, is the highest ^[46]. The ANS is connected to the limbic system of the brain, whose main components are the hippocampus, the amygdala, and the limbic cortex, and which is responsible for a variety of brain processes in health and disease ^[45].

As for humoral components of the MGBA, they mainly consist in the hypothalamic–pituitary–adrenal axis (HPA), the enteroendocrine system and the immune system. Stress responses are modulated through the HPA, via the release of corticosterone, adrenaline, and noradrenaline. The enteroendocrine cells (EECs) in the gut produce GI hormones such as ghrelin, glucagon-like peptide (GLP-1), cholecystokinin, and peptide YY (PYY); these hormones regulate food intake and satiety and are also involved in the regulation of emotions and mood ^[42].

The resident immune cells in the brain, known as the microglia, act as a neuroimmune component of the MGBA, by finely tuning neurogenesis and synaptogenesis. The maturation and function of the microglia appear to be related to changes in the gut microbiota, and also influenced by SCFAs ^[47], which are end-products of bacterial fermentation of dietary fibers and resistant starch in the colon. Furthermore, immune signaling molecules, whose production is also driven by gut microbiota, can play a role in the MGBA, by binding to VN receptors or by crossing the blood–brain barrier. In this respect, recent studies have suggested a potential role of bacterial peptidoglycans (PGNs), which are components of the bacterial cell wall, released not only by exogenous bacteria, but also by the resident gut microbiota. It has been proposed that PGNs could enter the systemic circulation and reach the developing brain, where PGN sensing molecules are expressed abundantly during specific time windows of perinatal development, thus potentially exerting a direct effect on brain function and development ^[48].

Finally, a central role in the MGBA is played by metabolic mediators, including tryptophan metabolites such as serotonin (5-hydroxytryptamine, 5-HT), melatonin, SCFAs, and other neurotransmitters. 5-HT is involved in most branches of the MGBA; for instance, it acts as a neurotransmitter both in the CNS and ENS, and 5-HT receptors have a critical function in the HPA ^[49]. The production of host 5-HT in the gut is regulated by microbiota, as indigenous spore-forming bacteria, derived from mouse and human microbiota, have been shown to promote 5-HT biosynthesis from enterochromaffin cells in the colon, thus impacting GI motility and homeostasis ^[50]. SCFAs (acetate, propionate, and butyrate) are thought to influence gut–brain communication through different potential pathways, either directly or indirectly. Once produced by colonic fermentation, SCFAs can exert a direct effect on the intestinal mucosal immunity and can modulate the integrity and function of the gut barrier. Furthermore, by interacting with the EECs, SCFAs promote a direct gut–brain signaling through the secretion of gut hormones, such as GLP-1 and PYY, and other metabolic mediators such as γ-aminobutyric acid and 5-HT. In addition, they can induce systemic inflammation through differentiation of T regulatory cells and secretion of interleukins and can probably also act centrally in the CNS by modulating neuroinflammation ^[51].

There are several factors which could have a specific impact on the MGBA development in early life; one of the most relevant might be prematurity, as preterm birth interrupts the physiological growth and development of both the GI tract and the nervous system and leads to a certain degree of microbial dysbiosis. Despite that, at present there are no studies specifically designed to describe the unique features of the MGBA in preterm infants ^[52]. In addition, nutrition during sensitive developmental time windows is thought to have a major impact on the microbiota-gut–brain crosstalk ^[53]^[54], either through an effect of single nutrients (for example, milk fat globule membranes ^[55], human milk oligosaccharides ^[56], or through the well-known benefits of exclusive human milk feeding compared to other feeding sources ^[57].

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