Gut hormones and regulatory peptides in relation to enteral feeding, gastroenteritis, and necrotizing enterocolitis in infancy

Gut hormones and regulatory peptides in relation to enteral feeding, gastroenteritis, and necrotizing enterocolitis in infancy A. Aynsley-Green, MA, DPhil, MBBS, FRCP, A. Lucas, MB,BChir, MRCP, G. R. L a w s o n , MB,ChB, MRCP, DTMtH, a n d S. R. B l o o m , MA, MD, DSc, FRCP From the Department of Child Health, University of Newcastle Upon Tyne, Dunn Nutrition Unit, Cambridge, and the Royal Postgraduate Medical School, Hammersmith Hospital, London, England

T H E G U T A S AN E N D O C R I N E

ORGAN

On Jan. 16, 1902, at University College, London, W. M. Bayliss and E. H. Starling suggested that an internal secretion was made in the duodenum and that this chemical messenger circulated in the bloodsteam to affect the activity of the pancreas. They called this postulated messenger secretin, and in 1905 Starling proposed that such chemical messengers should be called hormones, from the Greek verb meaning to excite or to arouse. Although the gut was recognized early to be an endocrine organ, further progress in the field of gastrointestinal endocrinology during the next 60 years was greatly overshadowed by much more spectacular advances in the endocrinology of the discrete glands such as the pancreas, pituitary, adrenal, and thyroid glands. The gut is a much more difficult organ to study because the cells secreting the active peptides tie throughout the mucosa, making it impossible to extirpate the cells to cause defined hormone deficiency syndromes. There have also been substantial difficulties in extracting and purifying the products of gut endocrine cells, and although gastrin was discovered in 1905 and cholecystokinin postulated in 1928, little further progress was possible until the development of greatly improved chemical purification techniques during the 1960s and 1970s. Peptide-secreting cells in the gastrointestinal tract may exert their effects through endocrine, paracrine, or neurocrine mechanisms, with some peptides having more than one

Reprint requests: Professor A. Aynsley-Green, Department of Child Health, The Medical School, Framington Place, Newcastleupon-Tyne, NE2 4HH, England. 9/0/21432

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mode of action. Therefore it has been difficult to document precisely how individual peptide secreting cells are regulated and to determine their interaction and mechanism of action in the gut mucosa. Despite these difficulties, evidence has accumulated to indicate the principal actions of the various peptides that have been discovered and characterized in recent years, and it is clear that they have a fundamental role in the regulation of digestive physiology. In this article we present a brief review of the role of these agents in controlling the use of food in the adult, before considering what is potentially their important role in triggering the adaptation of the gut to postnatal enteral feed-

GIP PP PYY VIP

Gastric inhibitory polypeptide Pancreatic polypeptide Peptide tyrosine tyrosine Vasoactive intestinal polypeptide

ing. Current knowledge on the effects of some disease states on circulating concentrations of these peptides in older subjects will be presented before this information is used as background data to examine the consequences of acute infectious diarrhea in infancy and of enterocolitis in the newborn period. USE OF FOOD IN THE HUMAN

ADULT

After ingestion, food has to be propelled through the gut in a coordinated and sequential manner; local trauma leads to a continuous process of mucosal regeneration. Digestive secretions are released at the appropriate time, with changes in visceral blood flow to carry the nutrients through the visceral and then the systemic circulations. Metabolic hor-

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Gut hormones and regulatory peptides in N E C

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Table. Regulatory peptides and hormones isolated from the gastrointestinal tract Regulatory peptide

Main source(s)

Mode of action

Main action

Antrum Upper small intestine, CNS Upper small intestine Pancreas Ileum and colon Pancreas

Hormone Hormone/neurotransmitter

Gastric inhibitory polypeptide Motilin Vasoactive intestinal polypeptide

Upper small intestine Upper small intestine All tissues

Hormone Hormone Neurotransmitter

Bombesin Somatostatin

Gut, CNS, lung Gut, CNS

Neurotransmitter/paracrine Paracrine/neurotransmitter

Neurotensin

Ileum, CNS

Hormone/neurotransmitter

Substance P

Gut, CNS, skin

Neurotransmitter

Leu-enkephalin and met-enkephalin PYY

Gut, CNS

Neurotransmitter

Stimulates gastric acid secretion Gallbladder contraction and pancreatic enzyme secretion Pancreatic bicarbonate secretion Stimulates hepatic glucose output Gut mucosal growth, gut motility Inhibits pancreatic enzyme secretion and gallbladder contraction Enhancement of insulin secretion Stimulates gastrointestinal motility Neurotransmitter (secretomotor, vasodilator, and smooth muscle relaxation) Stimulates gut hormone release Inhibits hormone release and hormone target tissues Inhibits gastric emptying and acid secretion Sensory neurotransmitter (especially pain) Opiate-like (endorphin system)

Gut, CNS

Hormone

Gastrin Cholecystokinin Secretin Pancreatic glucagon Enteroglucagon Pancreatic polypeptide

Hormone Hormone Hormone Hormone

mones have to be secreted in relation to feeding and fasting to ensure metabolic homeostasis. The integration and coordination of these highly complex facets of physiology require an efficient regulatory system. Although several factors, including the autonomic nervous system, play a major role, there is evidence that the secretion of hormones and of regulatory peptides from the gut and from the classic endocrine organs contributes substantially to this regulatory process. The Table outlines the hormones and regulatory peptides that have been isolated from the grastr0intestinal tract, their main anatomic sources, and their modes of action. The distribution in the human adult of the cells secreting the classic gastrointestinal hormones is schematically represented in Fig. 1. Further information on the properties and actions of the individual peptides is found in references 1 to 4. ADAPTATION

TO P O S T N A T A L

FEEDING

Before birth a coordinated sequence of developmental changes of structure and function prepares the gut for postnatal nutrition. 5 This natural rate of development can be influenced profoundly by environmental triggers; prematurely born babies may adapt to enteral feeding as long as 12 weeks "too soon." Of course, the fetal gut has not been inactive; the fetus swallows substantial volumes of amniotic fluid, which has a significant protein content that can be di-

Inhibits gastric acid secretion and gut motility

gested and absorbed. 6 Regulatory peptides, together with their corresponding cell lines, have been identified in the human fetal gut from 6 to 16 weeks after conception, 78 , and with advancing gestation there appear to be changing spectra of molecular forms, with certain peptides appearing and disappearing from different regions of the gut during development. This description suggests that cells secreting regulatory peptides, through changes in anatomic localization and in the products and potencies of their secretions, may play a key role as local inducing agents regulating the growth and functional development of the fetal intestine. Moreover, substantial concentrations of hormones and peptides are present in amniotic fluid during the second trimester, 9 raising important questions on the role of amniotic fluid in the preparation of the gut for postnatal feeding. Enteral feeding postnatally leads to the introduction into the gut of food Of a very different composition, and there is evidence that enteral feeding may be a key environmental trigger. The changes in gut growth, activity, and function that follow the introduction of enteral feeding may be due to several factors, including hormones and growth-stimulating peptides in human milk, direct stimulation of mucosal development by the presence of food, and changes induced by alteration of intestinal secretions and bacterial colonization. 1~ This article, however, addresses the proposal that food-induced secretion of regulatory peptides has a particularly important role in regulating postnatal adap-

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Aynsley-Green et al.

/ secretin GiP CCK

motilin

\

ne,urcrter~sir

Fig. I. Distribution of location of cells secreting regulatory peptides acting as hormones in human adult.

tation by triggering a cascade of developmental changes that depend on the known effects of these substances. 13 Gastrointestinal peptides are found in significant concentrations in venous cord blood of infants born prematurely or at term. 14 Most of the measured hormone concentrations at birth are similar to those in healthy fasting adults, although term infants have higher concentrations of gastrin and vasoactive intestinal polypeptide than fasting adults have, whereas in prematurely born infants, although concentrations of plasma gastric inhibitory polypeptide, gastrin, and enteroglucagon are similar, there are differences in the cord levels of pancreatic polypeptide, motilin, and neurotensin. Infants born at term after fetal distress have a selective venous cord plasma elevation of motilin, VIP, pancreatic polypeptide, pancreatic glucagon, neurotensin, and enteroglucagon.15 The rise in plasma motilin in fetal distress is especially marked, and might account for the passage of meconium, an event pathognomonic of this condition. The significance of the changes in plasma VIP, PP, and neurotensin levels is uncertain, but collectively the peptides may have effects on the redistribution of visceral blood flow in distressed fetuses.

The Journal of Pediatrics July 1990

The first feeding of milk is the next event of considerable physiologic significance. In term infants the first feeding of human milk given by gavage feeding causes an immediate increase in the blood glucose level, together with significant increases in plasma levels of insulin, growth hormone, gastrin, and enteroglucagon.16m similar increase in the plasma level of gastrin, with failure to increase plasma enteroglucagon, occurs when the first feeding consists of 10% dextrose solution rather than milk, indicating that the gut is capable of differentiating between the nutrients delivered into it in terms of hormone secretion. 17 During the neonatal period, progressive increments in prefeeding concentrations of peptides are seen in normal term infants, but on the sixth postnatal day there are impressive differences in the postprandial hormone increments between human milk-fed and formula-fed infants. 18 There is a greater insulin response to the feeding at this age in formula-fed babies, compared with those who are fed human milk, and this difference appears to be related to differences in GIP secretion. There are also differences in the responses of the motor hormones of the gut, motilin and neurotensin. Even at 9 months of age there remain differences between the hormone responses to feeding in infants who have been formula fed and weaned and the responses in those who have been exclusively fed human milk for this period19; these findings suggest that early feeding practices may have both prolonged and subtle effects on programming of the pattern of hormone responses to feeding. In contrast to the impressive changes in intermediary metabolism and in hormone concentrations in term infants after the first feeding, no change occurs in the concentration of any substance measured after the first feeding in infants born prematurely. 2~ This indicates that developmental changes occur during the last few weeks of gestation that prepare the infant born at term to respond immediately. Nonetheless, within a few days of being fed regularly with milk, premature infants have greater preprandial surges of hormone concentrations than term infants have, 2l and a progressive change occurs in the pattern of postprandial hormone levels. 22-24 Thus regular "cycles" of feedingrelated increments in hormone concentrations are demonstrable within 21/2 days of birth. No similar increments are seen in infants who have never been fed enterally25 and who have received only intravenous fluids during the first 6 days after birth. These data suggest that it is food which, when introduced into the gut, is a powerful stimulus to the production of gut hormones. Moreover, very small amounts of milk appear to be able to induce these surges, and this finding has led to the concept of "minimal enteral feeding," particularly in very low birth weight infants. 26

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Further differences in the endocrine milieu are seen in the continuously fed infant compared with the intermittently fed baby, 27 and also in the latter babies in relation to being fed either human milk or a milk formula designed for the premature infant. 28 The mechanism and significance of these differences are unclear, but the differences suggest that not only the method of feeding but also the composition of the feeding may influence the development of postnatal circulating concentrations of some of the peptides. It is not possible to state which method or composition is to be preferred or recommended for prematurely born babies, and further work is needed to investigate the potential consequences of these differences in the endocrine milieu. Nonetheless, the data lead to the questioning of the current policy of routinely feeding small premature infants entirely by the intravenous route. These infants are deprived not only of enteral milk but also of the amniotic fluid they should have been swallowing in utero. Very small volumes of milk are needed to induce the surges, and it seems logical that milk should be given in small volumes to induce gut development, rather than purely for nutritional reasons. 26 Much further work is needed to determine the control of the development of gut function after birth, but studies investigating the interrelationships of intermediary metabolism and of regulatory peptides may be of practical importance, not only in defining more scientifically the nutritional management of newborn infants, but also in investigating and treating disorders that interfere with normal adaptation to postnatal nutrition. E F F E C T S O F D I S E A S E S T A T E S ON CIRCULATING CONCENTRATIONS OF GUT REGULATORY PEPTIDES The interested reader is referred to references 1 to 4 for reviews of the extensive literature on the measurement of circulating concentrations of gut regulatory peptides in a variety of diseases in adult subjects. It is beyond the scope of this article to explore these issues in detail, but it is important to consider how some gastrointestinal diseases in older subjects may affect regulatory peptide secretion, so that changes in infancy and childhood can be compared. Three circumstances will be considered, namely, acute infectious diarrhea, malabsorption secondary to celiac disease, tropical sprue and cystic fibrosis, and the watery diarrhea syndrome associated with "VIPomas" and ganglioneuromas. 29 Acute infectious diarrhea in adults. Significant advances have been made in understanding the pathogenesis of acute infectious diarrhea. 3~ Several mechanisms are responsible for the interaction of the infecting organism and the gut that

Gut hormones and regulatory peptides in N E C

S27

leads to the clinical syndrome of diarrhea. Although a subject of controversy, there is evidence that there are changes in the motility of the gut during acute infectious diarrhea, but whether these are primary phenomena caused by toxins acting either directly on gut muscle or through the effects of mucosal nerves or peptides remains uncertain. Besterman et al, 31 measured the effects on circulating hormone concentrations of a standard test breakfast in adult patients with acute diarrhea presumed to be infectious and in normal control subjects. Patients with diarrhea had reduced fasting levels of blood glucose with a decreased postprandial rise in comparison with control subjects; fasting plasma insulin concentrations were, however, high in the patients, although the postprandial rise was similar in both groups. The patients also had increased fasting levels of PP, motilin, and enter0glucagon; plasma VIP concentrations were greater both before and after the meal in the patients with diarrhea. No differences were seen in plasma gastrin, GIP, or glucagon levels. In these patients the elevated concentrations of motilin and enteroglucagon fell with recovery, but PP and VIP levels remained elevated. When cholera toxin is introduced into the feline small bowel, there is a marked increase in intestinal venous VIP concentrations. 32 It is likely, therefore, that the local activity of VIP in the gut wall is involved somehow in the pathogenesis of choleraic secretion, but other mechanisms, including the release of prostaglandins, may be of equal or greater importance) 3 Intestinal ischemia is associated with elevated plasma VIP levels.34 Hormone profiles in chronic diarrhea and malabsorption. Several reports have appeared on the circulating concentrations of hormoncs in ccliac discase, a condition localized to the small intestine. 2p, 35-4l The hormone profile in untreated celiac disease accurately reflects the anatomic distribution of the disease, with normalization of the endocrine response reflecting improvement in the mueosa with treatment. Thus basal and postprandial insulin concentrations arc reduced, and plasma sccrctin concentrations and GIP levels after a meal are both diminished, reflecting damage to the small bowel. In contrast, plasma enteroglucagon concentrations arising from an unaffected part of the gut showed a massivc postprandial increase, with a decrease in response to trcatmcnt. Plasma motilin levels were only marginally elevated above control postprandial values, and gastrin and PP levels were relatively unchanged. In contrast to celiac disease, tropical malabsorption affects thc cntire length of the gut. Some aspects of the hormone profile before and after feeding are similar in subjects with sprue and those with celiac disease; there is normal release of gastrin, PP, and neurotensin, with impaired insulin

S 28

Aynsley-Green et al,

and GIP secretion. On the other hand, although motilin and enteroglucagon levels are both elevated in basal samples, they do not change markedly after a meal. 42 The lack of change in postprandial enteroglucagon and motilin levels differs from that noted in patients with celiac disease. Restudy of these patients 4 years after successful treatment showed entirely normal preprandial and postprandial hormone profiles. There is some evidence that the severity of the underlying mucosal damage in disorders affecting the small bowel alters the circulating hormone profile.36 In contrast to the patients with celiac disease and tropical malabsorption, patients with cystic fibrosis have markedly decreased fasting plasma PP concentrations, with complete abolition of the postprandial increase. 43 Fasting plasma enteroglucagon concentrations are grossly elevated and remain so after a meal, but no differences are seen in the basal or postprandial responses of plasma levels of glucagon, gastrin, seeretin, VIP, or motilin. Thus yet another chronic malabsorptive disorder appears to have a specific hormonal profile. It can be concluded from these studies that the endocrine milieu reflects not only the nature of the underlying disease in chronic diarrhea but also the degree of mucosal damage and the response to treatment. Hormone profiles in the watery diarrhea syndrome. The role of VIP in the pathogenesis of choleraie diarrhea has been mentioned. This peptide is also the cause of the watery diarrhea syndrome in patients with non-beta islet cell tumors, ganglioneuroma, or neuroblastoma. The excessive release of VIP is responsible for all the clinical features of the disease.44, 45 It is probable that the mechanism is the action of VIP in stimulating intestinal epithelial cyclic adenosine monophosphate production and hence in increasing intestinal secretion. 46 Conspectus. The brief review presented above confirms that changes in circulating concentrations of hormones occur in patients with a variety of conditions causing diarrhea. The changes in motilin levels are of particular interest in view of the effects of this hormone on gut motility. Thus the finding of substantially elevated plasma motilin concentrations in patients with acute diarrhea may have relevance to the associated motility changes. In other chronic diarrheal states, motilin levels are also elevated. It is not clear whether the motilin changes are primarily or partially responsible for the pathogenesis of the diarrhea, or whether they are caused by secondary or adaptive changes in the gut mucosa. Plasma enteroglucagon levels are elevated in acute and chronic diarrhea and return to normal with resolution of the disease, indicating a role for the measurement of this hormone as an indicator of response to therapy. The physiologic role of the hormone is more difficult to assess, but indirect

The Journal of Pediatrics July 1990

evidence suggests that it may stimulate villous growth and slow intestinal transit, 47 and there is some clinical evidence to support its action as atrophic hormone. 48 Enteroglucagon may therefore may be acting as a key trophic agent in the gut in stimulating its response to injury. REGULATORY PEPTIDES DISEASE IN INFANCY

AND GUT

Against this background, studies will now be reviewed that address acute infectious diarrhea in infancy and necrotizing enterocolitis in prematurely born infants. Acute infectious diarrhea in infancy. We recently collected data on 11 infants (mean age 6.7 months) with acute gastroenteritis. 49 None of the babies had a previous history of gastrointestinal disease, and all had required admission to the hospital. Blood samples were drawn on admission and, after a period of oral rehydration therapy, before and after the first feeding of full-strength milk; a fasting sample was then drawn after an interval of 3 months, at a time of complete clinical recovery. The results were compared with data on 14 control infants of similar ages from whom a fasting blood sample had been obtained and, 1 hour after a milk feeding, a postprandial blood sample had been obtained. At presentation there was a massive elevation of enteroglucagon levels, with values approximately 15 times greater than in adult subjects with infectious diarrhea. Moreover, there was a further increase during the period of acute illness before the introduction of milk feedings, with no further postprandial increment at that time. When the infants were 3 months of age, the enteroglucagon concentrations had returned to normal. An elevation of the pancreatic glucagon concentration at presentation was more pronounced in the fasting concentrations on refeeding. Peptide tyrosine tyrosine (PYY) was also found in high concentrations at presentation and on refeeding, with return to normal on recovery. The motilin concentrations at presentation were elevated to a value similar to that seen in concentrations in adults with diarrhea, and yet the concentrations at recovery were still signifcantly elevated compared with control values, even though the infants at that time had no clinical symptoms. No significant differences were seen at any time between control subjects and infants with gastroenteritis in the concentrations of VIP, neurotensin, or pancreatic polypeptide. Two infants subsequently had diarrhea that lasted for 7 weeks and 4 weeks, respectively; the first of these children had particularly elevated preprandial and postprandial levels of enteroglucagon (2472 and 3106 pmol/L), pancreatic glucagon, and PYY; after apparent recovery the enteroglu-

Volume 117 Number 1, Part 2

cagon concentration was well above the mean value, but the pancreatic glucagon and PYY values had returned to norreal. The second infant had a markedly elevated preprandial fasting level of enteroglucagon (1671 pmol/L) before refeeding. The most dramatic finding from this study was the massive elevation of enteroglucagon in all infants at the time of acute gastroenteritis. This elevation may be due to a decreased plasma clearance mechanism for the hormone at this age, but it is more likely due to a more responsive gut endocrine system at a time of rapid growth and development of the gastrointestinal tract. It is possible that the degree of enteroglucagon rise may be related to the extent of mucosal damage and its repair; the two infants who subsequently had more prolonged diarrhea had particularly high concentrations early in the course. The elevation in plasma glucagon may be a manifestation of the generalized severe stress caused by gastroenteritis in these infants, in contrast to the more benign and less stressful illness in adults. Motilin was the only hormone that had not returned to normal concentrations 3 months after clinical recovery had occurred; these observations suggest that gastroenteritis has a persistent effect on this hormone. Further work is needed to determine the natural history and consequences of this phenomenon. These data suggest that the way an infant reacts during gastroenteritis, is different from the way adults react, and that the measurements of the peptides may give quantitative information on the magnitude of gut damage and may also act as markers of gut recovery or of ongoing pathologic changes. Necrotizing enterocolitis. It might have been predicted that infants with necrotizing enterocolitis would have profound abnormalities in circulating concentrations of regulatory peptides, particularly in view of the effects of gut ischaemia on plasma VIP levels. 34 Our cumulative data were recently analyzed to assess the effects of necrotizing enterocolitis on circulating concentrations of regulatory peptides in six infants (mean gestational age 30 weeks) with symptoms and signs of the disease. The mean age at which the necrotizing enterocolitis developed was 23 days. Fig. 2 shows the mean hormone data, with compararable data on the normal surges seen in healthy, intermittently fed premature babies and also on the levels in infants receiving only intravenous fluids for the first 6 days. The concentrations of neurotensin, GIP, enteroglucagon, and pancreatic polypeptide were lower than the mean values for control fed infants, whereas the concentrations of gastrin and motilin were higher; the concentrations of enteroglucagon were not elevated, The mean plasma VIP level was also not significantly elevated. These collective data are difficult to interpret further in

Gut hormones and regulatory peptides in N E C

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view of the spectrum of ages at which the necrotizing enterocolitis occurred and the ages at which the blood samples were drawn in relation to the onset of disease. One infant, at 6 days of age, had bloody diarrhea, a distended abdomen, and striking clinical deterioration. A blood sample drawn on that day revealed circulating concentrations of hormones, as indicated in Fig. 3. This infant had been clinically well until the day of clinical deterioration, but the pattern of hormone concentrations was much rnore suggestive of an infant who had never been fed, the study infant

Aynsley-Green et al.

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The JournalofPediatrics July1990

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having apparently failed to develop any postnatal hormone surges. This finding is surprising, but it is impossible to determine whether necrotizing enterocolitis developed in this infant as a result of a failure to trigger normal postnatal endocrine responses to feeding, or whether the low values were due to the illness. It would be interesting to document the progression of hormone surges during the prodromal phase before clinical symptoms of necrotizing enterocolitis appear, but this is logistically an extremely difficult task.

What can be said, however, is that an infant who had a serious systemic and gastrointestinal illness did not have a pattern of hormone responses similar to that seen in older infants with acute bowel abnormalities. Moreover, his plasma VIP level was in the range for normal, enterally fed infants. Necrotizing enterocolitis developed in the second infant at 28 days of age, the infant having received enteral feeding up until that time. During the next few days he became critically ill, and a perforated bowel with intraperitoneal gas and pus developed. A blood sample drawn 6 days into the illness revealed a profile of hormones as outlined in Fig. 3. Once again, there was no evidence for a massive enteroglucagon surge, as seen in older infants with gastroenteritis. The hormonal profile was remarkably "uninteresting" with the exception of the values for motilin, neurotensin, and VIP. The first two hormones are believed to play important roles in regulating the motor function of the gut, and the neurotensin value was very low. Motilin appears to have responded after disease lasting several days in a manner similar to that in other inflammatory and infectious illnesses in older children and in adults. Moreover, this particular infant's plasma VIP level was above the normal values for age-matched, fed infants, perhaps reflecting underlying ischemia in the gut. These vignettes underline the importance of further studies to document the ontogeny and chronology of hormonal changes in relation to symptoms in infants with necrotizing enterocolitis. The gut of the prematurely born infant with this disease appears to be behaving in a unique manner in comparison with that of normal premature infants and of older children and adults with a variety of intestinal diseases. CONCLUSIONS In the 80 or more years since Bayliss and Starling proposed that the gut was a simple endocrine organ, it has become clear that it is a highly complex structure secreting a myriad of regulatory peptides with important influences in ensuring the efficient use of food. This article reviewed the potential importance of these substances in the newborn period, and it may well be that at this time of life they have their greatest influence in controlling an orderly transition to postnatal life by affecting the growth and function of the gastrointestinal tract. Prematurity and the mode, composition, and route of feeding have major influences on the circulating profiles of these peptides, and these data have been used to challenge some established dogma and the empiricism of neonatal nutrition. The response of the prematurely born baby's gut differs from that of the term infant, but further studies are needed

Volume l 17 Number 1, Part 2

Gut hormones and regulatory peptides in N E C

to examine more carefully the relationship between circulating concentrations and tissue growth and function. Illnesses causing d i a r r h e a in older children and in adults result in characteristic profiles of hormones t h a t m a y be of diagnostic value a n d t h a t m a y also reflect mucosal regeneration and recovery. T h e effects of acute infectious gastroenteritis in adults differ from those in young infants, perhaps because of differences in the endocrine cell mass or in t h e function of peptides in a rapidly growing gut. Finally, preliminary results from the study of a small n u m b e r of infants with necrotizing enterocolitis suggest t h a t this disease is not associated with the markers of damage t h a t are seen in the older patient's gut (with a special reference to enteroglucagon), and yet motilin m a y be profoundly influenced in babies who have overwhelming gut abnormalities. F u r t h e r studies are needed to identify w h e t h e r the patterns observed are reproducible and whether they are associated with the cause of the disease or are due to the disease. These data should stimulate further investigation.

14. Lucas A, Bloom SR, Aynsley-Green A. Development of gut hormone responses to feeding in neonates. Arch Dis Child 1980;55:678-82. 15. Lucas A, Christofides ND, Adrian TE, Bloom SR, AynsleyGreen A. Fetal distress, meconium and motilin [Letter]. Lancet 1979;1:718. 16. Aynsley-Green A, Bloom SR, Williamson DH, Turner RC. Endocrine and metabolic response in the human neonate to the first feed of breast milk. Arch Dis Child 1977;52:291-5. 17. Aynsley-Green A, Lucas A, Bloom SR. The effect of feeds of different composition on entero-insular hormone secretion in the first hours of life in human neonates. Acta Paediatr Scand 1979;68:265-70. 18. Lucas A, Adrian TE, Sarson DL, Blackburn AM, AynsleyGreen A, Bloom SR. Breast vs bottle: endocrine responses are different with formula feeding. Lancet 1980;1:1267-9. 19. Salmenpera L, Perheentupa J, Slimes MA, Adrian TE, Bloom SR, Aynsley-Green A. Effects of feeding regimen on blood glucose levels and plasma concentrations of pancreatic hormones and gut regulatory peptides at nine months of age: comparison between infants fed with milk formula and infants exclusively breast-fed from birth. J Pediatr Gastroenterol Nutr 1988;7:651-6. 20. Lucas A, Bloom SR, Aynsley-Green A. Metabolic and endocrine events at the time of the first feed of human milk in preterm and term infants. Arch Dis Child 1978;53:731-6. 21. Lucas A, Bloom SR, Aynsley-Green A. Postnatal surges in gut hormones in term and preterm infants. Biol Neonate 1982; 41:63-7. 22. Lucas A, Sarson D, Bloom SR, Aynsley-Green A. Developmental physiology of gastric inhibitory polypetide and its role in the entero-insular axis in preterm neonates. Acta Paediatr Scand 1980;69:321-5. 23. Lucas A, Adrian TE, Bloom SR, Aynsley-Green A. Plasma motilin, gastrin and enteroglucagon and feeding in the human newborn. Arch Dis Child 1980;55:673-7. 24. Lucas A, Aynsley-Green A, Blackburn AM, Adrian TE, Bloom SR. Plasma neurotcnsin in term and preterm neonates. Acta Paediatr Scand 1981;70:201-6. 25. Lucas A, Bloom SR, Aynsley-Green A. Metabolic and endocrine consequences of depriving preterm infants of enteral nutrition. Acta Paediatr Scand 1983;72:245-9. 26. Lucas A, Bloom SR, Aynsley-Green A. Gut hormones and "minimal enteral feeding." Acta Paediatr Scand 1986;75:71923. 27. Aynsley-Green A, Adrian TE, Bloom SR. Feeding and the development of enteroinsular hormone secretion in the preterm infant: effects of continuous gastric infusions of human milk compared with intermittent boluses. Acta Paediatr Scand 1982;71:379-83. 28. Calvert SA, Soltesz G, Jenkins PA, et al. Feeding premature infants with human milk or preterm milk formula: effects on postnatal growth, intermediary metabolism and regulatory peptides. Biol Neonate 1985;47:189-98. 29. Aynsley-Green A, Bloom SR. Hormones in acute and chronic diarrhoea in infancy and childhood. In: Lebenthal E, ed. Chronic diarrhoea in childhood. New York: Raven Press, 1984:289-306. 30. Lebenthal E. Chronic diarrhoea in children; vol 6. (Nestl6 Nutrition Workshop Series.) New York: Raven Press, 1984. 31. Besterman HS, Christofides ND, Welsby PD, Adrian TE,

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