Epithelial growth and the postnatal development of the small intestine in humans remain poorly defined, mostly because of the ethical difficulties in obtaining tissue from healthy infants. Investigators studying intestinal development have therefore largely concentrated on rodents and other animals(1-8). However, there are marked differences between species in the pattern of intestinal development. Other approaches have included in vitro intestinal cell culture(9,10), explant culture of animal or human fetal intestine (11), and transplantation of intestine, either subcutaneously or underneath the kidney capsule, in rodents(12-14). There are limited studies in humans(15-17), but subject selection may have been biased toward infants with intestinal disease. Nevertheless, their results suggest that the epithelium of the small intestine in humans is more developed than that in rodents. The application of endoscopic study in infants has now allowed access to a larger population that coincidentally do not have any disease of the small intestine and yet provides a safe means of obtaining duodenal biopsy specimens for research.
Confusion exists on the timing of postnatal intestinal development in relation to breast feeding and weaning. Results of some animal studies of the trophic effect of breast milk would suggest that an accelerated phase of epithelial growth is associated with milk feeding(9,10,18-21), whereas in other animal studies, results have shown that epithelial growth occurs later during weaning, at a time when milk feeding is withdrawn(2-4). There is evidence from animal study results that mucosal T cells promote intestinal epithelial proliferation(4-8), extending the concept that if crypt proliferation is T-cell dependent in pathologic disease states, then crypt proliferation during weaning may also be T-cell dependent(7). We have shown that physiological inflammation in the small intestine in the rat peaks during weaning, with an increase in weight and cell number of mesenteric lymph nodes, with degranulation of mucosal mast cells (4), with expansion of eosinophils(5), with a peak at midweaning of interleukin-2 receptor(IL-2R) expression by T cells in the mesenteric lymph node(8), and with a peak of IL-2R expression in the lamina propria (unpublished data, Cummins, 1997). Treatment with cyclosporin A or anti-IL-2R antibody delays intestinal growth(6,8).
Most human infants are given solids between the ages of 4 and 6 months(22,23). We have previously shown that healthy human infants have elevated levels of soluble interleukin-2 receptor (sIL-2R) and γ-interferon in blood, which peak when the infant is 4 months old, in spite of low levels of IL-2R expression by blood lymphocytes(23). This is strongly suggestive of physiological inflammation during weaning in a sequestered site (e.g., mucosal tissues). Such physiological inflammation has been described in the small intestine of germ-free mice exposed to a conventional environment(24), a process that is somewhat analogous to weaning. Induction of HLA-DR expression on intestinal epithelium in humans during the first few weeks and months of life suggests physiological inflammation caused by food or bacterial antigens (25). If breast milk is trophic to the gut, then intestinal growth should occur in the first few months of life in those who are breast-fed; if the immunologic system is trophic from physiological inflammation, however, growth should occur later during and after weaning, as suggested by the results of our studies in the rat. An understanding of the factors that affect growth and maturation may give insights into how disease states occur and may help in their management(7).
Two epithelial compartments should be measured for growth studies, the intestinal villus, which is the functional unit of nutrient absorption, and the crypt, which is the proliferative unit (26). Villus area is correlated with the number of villus epithelial cells and is a better measure than villus length, because villi grow in width as well as in length(26). Intestinal crypts increase mainly in length, and so crypt length has a good correlation with the crypt cell population. Epithelial proliferation is estimated by recording mitotic figures per crypt, which is directly related to the gold standard, crypt cell production rate(26). A microdissection technique allows measurement of villus length and apical and basal widths (for calculation of villus area), crypt length, and mitotic count (26,27). Along with an increase in the number of epithelial cells, intestinal development includes maturation of individual enterocytes, which can be assessed by enterocyte height (28).
The purpose of this study was to define the characteristics of postnatal epithelial growth and development in the human small intestine. These were compared with changes in immunologic activity and feeding. Duodenal tissue was obtained from infants and young children undergoing upper gastrointestinal endoscopic examination as part of investigations for gastroesophageal reflux or for other medical indications not related to disease of the small intestine. Morphometric measurements were used for epithelial growth, mucosal mast cells (MMCs) and intraepithelial lymphocytes (IELs) were counted in the biopsy specimens, and immunologic activity was measured using sIL-2R andγ-interferon concentrations.
PATIENTS AND METHODS
Infants were recruited into this study if they were undergoing endoscopy for assessment of reflux esophagitis. Consent was obtained from parents for duodenal biopsies and a blood sample to be taken during endoscopic evaluation. Full feeding histories were obtained. All endoscopic studies were performed under general anesthesia, at The Royal Children's Hospital (Melbourne) or at the Women's and Children's Hospital (Adelaide). Two duodenal biopsy specimens were taken from the second part of the duodenum, which was identified by the presence of the ampulla of Vater. Ethical approval was obtained from the human ethics committees of The Queen Elizabeth Hospital (Adelaide), The Royal Children's Hospital, and the Women's and Children's Hospital. Patients were excluded if an enteropathic condition was diagnosed (e.g., celiac disease or cow's milk allergy). Seventy-four biopsy specimens and 57 blood samples were available for the study. Specimens from the second part of the duodenum were obtained from 77 adult subjects who had endoscopic examination for reflux esophagitis, nonulcer dyspepsia, or iron deficiency at The Queen Elizabeth Hospital. Their mean age was 36 years (range, 20 to 87). Endoscopic exploration showed no macroscopic esophagitis, and evaluation of biopsy specimens and results of subsequent investigations demonstrated no pathologic condition in the upper gastrointestinal tract. Some members of this adult group have been used as control subjects in other studies(29,30).
Morphologic Assessment of the Small Intestine
Each duodenal specimen was mounted on cardboard and shaken vigorously in Clarke's fixative (75% ethanol:25% acetic acid) for 5 seconds to remove mucus and was transferred after 1 to 7 days for storage in 70% ethanol(26,27). The intestinal specimen was later stained with Feulgen's reagent and microdissected. Villus area was calculated as a trapezoid approximation, using measures of apical and basal villus widths and villus length (29). Crypt length and mitotic count per crypt were also recorded. Generally, 5 to 15 villi and crypts were measured, depending on the size of the specimen. Enterocyte height was measured in the midvillus region from the basement membrane to the brush border as the average of 3 to 10 measurements.
Measurements of Mucosal Immune Activity
Intraepithelial lymphocyte and MMC counts were used as indicators of mucosal immune activity. A second duodenal specimen was mounted on cardboard and fixed in Carnoy's fixative (60% ethanol, 30% chloroform, and 10% glacial acetic acid) before embedding in paraffin. Histologic sections were cut (5μm), and IEL and MMC numbers were recorded after staining with hematoxylin-eosin or Alcian blue (pH 0.6)/safranin. Counts were expressed per millimeter of muscularis mucosae (5).
Soluble Interleukin-2 Receptor and γ-Interferon Concentrations
sIL-2R levels were measured in sera, using an enzyme-linked immunosorbent assay (CellFree IL-2R, T Cell Sciences, Cambridge, MA, U.S.A). Sera aliquots of 25 μl were diluted 1:2 before measurement. The lower limit of detection is 50 U/ml. We have previously measured sIL-2R levels in 25 healthy adults and have recorded mean values of 695 ± 359 U/ml (23). Serum γ-interferon levels were measured using an enzyme-linked immunosorbent assay kit (Factor-Test, Inter-Test-γ, Genzyme Corporation, Cambridge, MA, U.S.A.). Sera aliquots of 50 μl were diluted 1:2 before measurement. The lower limit of sensitivity was 50 pg/ml.
Data are expressed as the mean ± SD. The 95% limits of the reference range were calculated as the mean ± 2 SD. Group mean values were compared by Student's t-test for significant differences.
Age Range and Feeding History
There were 37 infants up to 6 months, 27 infants up to 12 months and 10 infants up to 24 months of age. The overall breast-feeding rate was 75%. The median duration of breast feeding was 2 months (range, 0.06-9) in the 33 infants who had begun breast feeding. This calculation excluded those infants who were currently breast fed as well as those in whom data were not available. The median age of first introduction of solid food, generally rice cereal, was 4 months (range, 0.8-9) in 33 infants (bottle- or breast-fed) in whom data were available.
Changes in Intestinal Morphometry During Infancy
Villus area and crypt length are given in Figure 1. Mean villus area was similar in the 74 infants (0.364 ± 0.108 mm2) to that of the 77 adults (0.336 ± 0.106 mm2). Mean crypt length was increased by 31% in infants (270 ± 56 μm) compared with increases in adults (206 ± 29 μm; p < 0.0001), and mean mitotic count per crypt was increased by 68% in infants (4.2 ± 2.8) compared with increases recorded in adults (2.5 ± 1; p< 0.0001). Thus, crypt hyperplasia, measured by crypt length and mitotic count, was present during infancy but was not present in adults. It has been suggested that trophic factors in breast milk promote epithelial growth of the small intestine(1,9,10,18-21,31). To examine this proposal, intestinal morphometry was compared in those infants less than 6 months old who were still totally breast fed or who had continued bottle feeding exclusively from birth. This excluded many subjects who had been breast fed for short periods before bottle feeding or in whom weaning onto solids had been initiated. In Table 1, intestinal morphometry in subjects who were breast fed is compared with that in those who were bottle fed. There was no detectable effect of breast milk in specifically promoting intestinal growth, when defined by morphometry, but bottle feeding resulted in relative crypt hyperplasia, with increased crypt length and mitotic count per crypt.
Changes in Epithelial Cell Height During Infancy
There was no apparent change in epithelial cell height during infancy. However, mean epithelial cell height was significantly less in infants (27.0± 3.0 μm; n = 62) compared with that in adults (30.9± 4.6 μm; n = 28; p < 0.0001). This may indicate that enterocytes in infants are less mature than are those in adults and that change in enterocyte height occurs later during childhood.
Changes in Intraepithelial Lymphocyte and Mucosal Mast Cell Counts
There was no apparent change in IEL numbers during infancy. However, the mean number of IELs was significantly less in infants (30 ± 12 per mm;n = 63) compared with counts in adults (64 ± 30 per mm;n = 27; p < 0.0001). This would mean IELs expand later during childhood. The MMC count did not change during infancy, and the mean number of MMCs was similar in infants (49 ± 23 per mm; n = 63) and adults (46 ± 16 per mm; n = 21).
Soluble Interleukin-2 Receptor and γ-Interferon Concentrations During Infancy
There was a peak of sIL-2R in early infancy from 2 to 4 months of age(Fig. 2). Mean levels of sIL-2R were elevated during infancy (1,820 ± 596 U/ml; n = 57) compared with mean levels in adults (695 ± 359 U/ml; n = 25; p < 0.0001). Mean levels of γ-interferon were also elevated during infancy (150± 33 pg/ml; n = 39) compared with mean levels in adults (98± 66 pg/ml; n = 26; p = 0.0013).
The purpose of the current study was to examine postnatal epithelial growth in human small intestine. The application of endoscopic exploration in human infants has meant that a larger population is accessible for duodenal biopsies than was available in studies that relied on Crosby capsule biopsy or partially autolyzed intestinal samples obtained at autopsy(15-17). The specimens may have been biased by intestinal diseases or confounded by major illness or trauma. Endoscopic evaluation is used increasingly to assess reflux esophagitis and other medical conditions that should not confound findings in a coincidental intestinal biopsy. In this study, infants were undergoing endoscopic investigation of irritability or other indications of reflux esophagitis; and although they could not be regarded as completely healthy, their intestinal specimens showed no pathologic conditions. The indications for endoscopic evaluation were not related to any disease of the small intestine, and there was very little added risk in performing duodenal biopsies for research purposes.
Duodenal specimens from infants with reflux esophagitis had morphometric changes of crypt hyperplasia with longer crypt length and increased mitotic count, compared with changes observed in those from adult subjects. Although it might be argued that these changes could be explained by subtle pathologic condition, the same argument would also apply to specimens from adult subjects who had similar indications for endoscopic study. There was some variability of data (e.g., villus area), that is usually not present in animal studies. It is very unlikely that this represents any age-related bias of the site of the duodenal biopsy, in that most of the variance between morphometry of biopsy specimens is between subjects, rather than between different sites of the biopsy (27,32). Presumably, this relates to differences in breast or bottle feeding, the composition of feedings, whether solid supplements had been initiated, and whether there had been prolonged fasting, as well as the innate variability among human subjects when compared with variability among inbred rats. The lower epithelial height in infants compared with that in adult subjects would be compatible with immaturity of enterocytes. We have noted that enterocyte height is low and yet lactase activity is high before weaning in rats (unpublished data, Cummins, 1994). This is compatible with the lower epithelial cell height observed in infants compared with that in adults and heightened lactase activity recorded during early infancy in humans (33).
Two successive stages of development have been distinguished in human and animal studies of growth of the small intestine(1,34). Initially, there is considerable absolute and relative organ growth of the small intestine in its longitudinal axis and diameter during fetal life, in which the intestine is considered a cylindrical organ (22). In humans, the intestinal length doubles prenatally during the third trimester and then growth decelerates after birth(34). Linear growth continues during neonatal life in rodents (2-5). This growth occurs with maintenance of a relatively immature mucosa, as the epithelium grows by longitudinal binary fission of crypts (1). In humans, this stage occurs primarily in the fetus. The second stage of development, as best described in rodents, is associated with an increased proliferation of individual intestinal crypts and growth of the mucosa toward the lumen(3-5). This second phase of growth results in amplification of the intestinal surface area into more than that of a cylinder. The epithelial surface area is amplified by the circular folds(plicae circulares) in humans (these are not present in rodents), by growth of villi, and by maturation of enterocytes with increased surface area of microvilli (35). The submucosal folds and villi increase the surface area approximately fourfold in the proximal intestine, decreasing to twofold in the distal small intestine (35). The interesting finding of the current study was that villus area was similar both in infants and adults, which would indicate that villus growth had already occurred fetally or perhaps in the immediate postnatal period, and therefore any increase in intestinal surface area is related to organ growth and possibly to an increase in microvilli of individual enterocytes. Changes in microvilli were not examined, but the lower enterocyte height in infants compared with that in adults in this study might indicate that enterocyte maturation will develop later in childhood and will include development of microvilli, which are known to amplify the epithelial surface area another 15-fold (36). Mucosal growth is associated with maturation of digestive functions to an adult pattern (5). Monosaccharide absorption, measured by the xylose test, also increases during the postnatal period, confirming an increase in intestinal surface area(36).
A variety of trophic factors have been suggested to control epithelial growth in the small intestine, including induction from the mesenchyme, genetic preprogramming, drive from luminal factors, and endocrine effects of systemic or local hormones(1,37-46). It still remains unclear which of these factors are physiologically relevant. A popular notion has been that breast milk has a specific trophic effect on the small intestine. We showed that breast feeding was not associated with increased epithelial growth. This agrees with results in other studies in rodents, in which it has been known for some time that the accelerated period of postnatal mucosal growth occurs during weaning and not during milk feeding(3-5). It has also been known for some time that artificial feeding of rat pups leads to precocious growth of the small intestine, rather than to delayed intestinal growth, as might be expected if no breast milk was given (47-49).
Results of our previous studies in rats have suggested that mucosal T cells also promote intestinal growth (6-8). We have shown that mucosal immunologic activity peaks at midweaning in the rat, and that inhibition with either cyclosporin A (6) or with anti-IL-2R antibody inhibits epithelial growth (8). We also showed in healthy infants that sIL-2R levels (indicating total T-cell activity) peak at midweaning (4 months); but these did not originate from systemic lymphocytes, suggesting that the activated lymphocytes reside in a sequestered site, the largest of which is in the gastrointestinal tract(23). Taken together, these results in rodent and human studies satisfy two important criteria for assigning a physiological role for any trophic factor that may promote intestinal growth(22): first, that the physiological activity of the trophic factor should be increased at the time of intestinal growth, and second that physiological blockade of the trophic factor reduces intestinal growth. A third criterion is also satisfied, in that supraphysiological stimulation by the trophic factor induces precocious growth, as is seen in neonatal graft-versus-host reaction in mice in which heightened immune activity initially induces precocious intestinal maturation before evolving into an enteropathic condition with unrestrained immunologic activity(50). Recent findings in studies suggest that there may be a three-way interaction between mucosal T cells, growth factors from pericryptal fibroblasts, and proliferation of intestinal crypts(44,45,51).
In the current study, we used sIL-2R and γ-interferon levels and IEL count as indicators of immune activity and compared these with adult levels. We showed that sIL-2R levels were high during infancy before 6 months of age, similar to findings in our previous human study that showed sIL-2R levels peak at 4 months of age (midweaning) in healthy infants (23). A similar peak of sIL-2R levels during early infancy was recorded by Chan et al. from infants undergoing endoscopic study (52).γ-Interferon levels in blood were also elevated during infancy compared with levels in adults. Further evidence for immunologic activity in the intestine is the induction of HLA-DR expression on intestinal epithelium during the first few weeks and months of life in humans(25), presumably because of local γ-interferon production that also increases systemic levels, as we observed. Expansion of IELs is also a marker of immune activation (53), although it lags behind other markers-for example, IL-2R expression of mesenteric lymph node cells or mucosal mast cell degranulation in rats (5). In the current human study, the finding of a lower IEL count during infancy and a higher IEL count in adults would indicate a similar lag in expansion of IELs, presumably during early childhood. Such postnatal expansion of IELs during childhood has been shown in results of a study using a combination of intestinal samples from autopsies, aspiration biopsies, and surgical resection specimens (54). We have postulated that this intense immunologic activity is related to exposure of the mucosa-associated immune system to food and bacterial and environmental antigens, as well as to withdrawal of the immunosuppressive effect of breast milk(8,23)
We conclude that postnatal maturation of the small intestine of human infants occurs with increased epithelial crypt proliferation and maturation of enterocytes. Although these changes were lower in magnitude than those observed in rodents, they were nevertheless significant. We found no evidence that breast milk is a specific trophic factor. In addition, we confirmed that infancy in humans is associated with heightened immunologic activity that would be compatible with this activity's acting as a trophic factor for the human small intestine (8,23).
Acknowledgment: The authors thank Drs. D. Cameron, R. Couper, and T. Pouras for allowing us to study infants under their care, and J. Ripper and D. Wright for their assistance in collecting and transporting samples.
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Keywords:© Lippincott-Raven Publishers
Epithelial growth; Mucosal immune system; Small intestine