The physicochemical environment of the neonatal intestine1–3
Ian R Sanderson
ABSTRACT Dietary intake, bacterial metabolites, and the
secretion of factors (eg, proteins, electrolytes, lipid-soluble
molecules, and water) by the body each contribute to the
physicochemical environment of the gastrointestinal tract.
Peristalsis regulates the changes along the length of the intestine.
However, coordinated peristaltic responses develop as premature
infants mature. In addition, the physicochemical environment of
the center of the intestinal lumen differs from that of the epithelial
surface. The area adjacent to the small intestinal epithelium is
more acid than the bulk phase. Na+/H+ exchange antiporters in the
epithelial cell apical membrane generate this acidity. Mucus
maintains the acid microclimate by preventing free diffusion of
hydrogen ions into the bulk phase. Development also affects
these mechanisms. Changes in the lumenal environment may
alter the synthesis of signaling molecules expressed by the
intestinal epithelium. Thus, the epithelium, through changes in
gene regulation, may act as an active interface that transmits
information about the composition of the intestinal lumen to the
mucosal immune system. Premature neonates are at risk of
necrotizing enterocolitis, a disease almost exclusively associated
with oral feeds. The pathogenesis of this condition may, in part,
be due to the immaturity of the interactions between the
physicochemical environment of the lumen and intestine. Am
J Clin Nutr 1999;69(suppl):1028S–34S.
KEY WORDS Infant, peristalsis, unstirred layer, acid
microclimate, nutrient regulation of gene expression, epithelial
signaling, intestine
INTRODUCTION
The intestinal lumen is a space topologically outside the liv-
ing organism, the composition of which is regulated by the body.
The physicochemical environment of the intestine determines
how nutrients are absorbed and how potential pathogens are con-
trolled. The ability of the intestine to dominate this space is
therefore critical to life. The key evolutionary event in the devel-
opment of multiorgan animals was containment of this external
environment in a tube to gain effective control over it. The intes-
tine was then able to select from this area those things that were
beneficial while leaving behind those that were of no benefit or
even harmful. Unicellular organisms, sponges, and other collec-
tions of cells cannot regulate their absorptive surface. They,
therefore, have not solved the essential problem of allowing
other cells in the body to specialize into organs whose environ-
ment is bathed in more consistent surroundings than are found in
1028S Am J Clin Nutr 1999;69(suppl):1028S–34S. Printed in USA. © 1999 American Society for Clinical Nutrition
nature. The evolution of the intestine led to the evolution of
many different tissue types including muscles and nerves, which
ultimately resulted in intelligent life. This review will examine
how the intestinal environment is regulated, with particular ref-
erence to neonates.
The environment of the intestine is derived from 3 main fac-
tors: dietary intake, bacterial ecology, and factors such as peri-
stalsis and glandular secretions that are intrinsic to the intestine.
Regulation of the physicochemical environment therefore
depends on the body’s ability to control each of these areas effec-
tively. Control of the microbial ecology is the subject of another
review in this supplement. Dietary intake is controlled by active
ingestion. As the development of the gut led to the evolution of
complex organisms, so also the appearance of coordination in
multiorgan animals resulted in the control of ingestion. Animals
of higher order select what they eat. Thus, the ability of the intes-
tine to enable complex organisms to evolve in turn resulted in the
control of ingestion. Interplay therefore occurred between intesti-
nal evolution and phylogeny of the complex animal. This concept
of “evolutionary reinforcement” is an underinvestigated area of
biology. It occurs in other examples, notably the coevolution of
color sensing by insects and color display by flowers.
This article presents evidence that not only does the intestine
control the environment of the lumen but that the reverse also
occurs; namely that a change in the intestinal lumen can alter the
epithelial cell. Short-chain fatty acids will be used to illustrate
some of these points; both diet and bacterial flora alter their con-
centrations, and their uptake by the gut is subject to changes in
the environment of the epithelial cell surface. They also affect
the expression of genes within the epithelium.
PERISTALSIS
The intrinsic mechanisms that alter the intestinal environment
include many distinct components (Figure 1). Factors such as
1
From the Developmental Gastroenterology Laboratory, the Combined
Program in Pediatric Gastroenterology and Nutrition, Massachusetts General
Hospital, Harvard Medical School, Boston, and the Department of Paediatric
Gastroenterology, St Bartholomew’s and the Royal London School of Medi-
cine and Dentistry, London.
2
Supported by the National Institutes of Health (grant DK-47753).
3
Address reprint requests to IR Sanderson, Department of Paediatric Gas-
troenterology, St Bartholomew’s and the Royal London School of Medicine and
Dentistry, Dominion House, St Bartholomew’s Hospital, West Smithfield, Lon-
don EC1A 7BE, United Kingdom. E-mail: I.R.Sanderson@mds.qmw.ac.uk.
 INTESTINAL ENVIRONMENT IN THE NEONATE
FIGURE 1. The epithelium regulates the composition of the lumen by secretion of factors. The environment of each part of the intestine is main-
tained within defined limits by peristalsis.
proteins, electrolytes, lipid-soluble molecules, and water are
swept along the intestine together with digested food by peri-
stalsis. This longitudinal propulsion limits the variation in
intestinal contents at any one point along the gastrointestinal
tract. In health, the greatest changes occur in different distances
down the intestine. To a great extent, therefore, peristalsis
replaces temporal distinctions (as would be seen with reactions
in a static receptacle) with spatial differences. This fundamental
characteristic of the gut allows specialized activity, such as
absorption and glandular secretion, to be located at strategic
points along the length of the tract.
Peristalsis is developmentally regulated. In term infants, as in
adults, migrating motor complexes pass as waves along the gas-
trointestinal tract (1). Feeding results in further complexes super-
seding the background wave pattern. In preterm neonates, how-
ever, migrating complexes are not present until around 34 wk
gestation (2, 3). Thus, the mechanisms necessary for maintaining
a stable temporospatial relation in the intestine are not developed.
In fetuses, the environment of the intestine is mostly controlled
by the amniotic fluid and thus the role of peristalsis in regulating
lumenal homeostasis is correspondingly less important. In infants
born before term, however, the intestinal environment is affected
by the outside world. Thus the possibility of buildup of sub-
stances within the intestine exists because the propulsive action
of the intestine is not yet developed.
THE ENVIRONMENT OF THE EPITHELIAL SURFACE
The changes that occur in the gastrointestinal tract longitudi-
nally are determined to a large extent by peristalsis. However,
the environmental changes that occur transversely from the cen-
ter of the intestinal lumen are regulated by different factors.
Molecules passing from the bulk phase (ie, the contents of the
intestine that are propelled by peristalsis) of the intestine to the
epithelial cell apex encounter 2 specific regions, the unstirred
layer and the acid microclimate. Both are present in the neonatal
intestine. The effect of each entity on the absorption of mole-
cules depends on the chemical nature of the molecule in ques-
tion. For example, the unstirred layer is a significant barrier to
lipid-soluble molecules, whereas the acid microclimate has a
large effect on weak electrolyte uptake.
1029S
Unstirred layer
The unstirred layer may not be a distinct layer on the mucosal
surface, but a diffusion barrier in which molecules diffuse at a rate
different from that predicted by the diffusion coefficient of water.
Winne (4) has used the term preepithelial diffusion resistance to
describe this notion. However, the term unstirred layer better
expresses the idea that the greater the agitation of the bulk phase the
less resistant the diffusion barrier becomes. In preterm neonates, the
degree of mixing of lumenal contents may be small because of
immature peristaltic activity, and might result in an unstirred layer
of greater thickness than is present in neonates born at term.
Although the thickness of the unstirred layer has only been
estimated (5), we do know that it is a significant barrier to highly
lipid-soluble molecules. To a great extent the effect of the
unstirred layer on fat absorption is minimized by micelle forma-
tion, allowing lipids to be taken directly into the epithelial cell.
However, in premature neonates, pancreatic and biliary func-
tions are not as well developed as in adults, making the unstirred
layer a significant barrier to lipid absorption. The propensity for
lipids to remain in the bulk phase in preterm infants may make
long-chain fatty acids (6) possible factors in the etiology of
necrotizing enterocolitis, a disease with a high mortality (see
below). Water-soluble molecules are not greatly impeded by the
unstirred layer, and short-chain fatty acids are readily able to
reach the epithelial cell surface.
One component of the unstirred layer that has been difficult to
quantify in neonates is the role of mucus. Smithson et al (7)
measured the size of the unstirred layer in rat intestines by using
hydrolysis rates of sugars, resulting in a thickness estimate of
<700 mm, assuming that the fluid had the same diffusion coef-
ficients as water. These investigators concluded that this size
was untenable because such an unstirred layer would occupy
most of the intralumenal area. They suggested that the diffusion
barrier could have been thicker over a smaller volume by the
contribution of mucus. Mucus secretion is well developed in
neonates, although, as in rodents, its composition may change
during development (8).
Acid microclimate
The mucus coat and outer glycocalyx of the intestinal epithe-
lium are composed of negatively charged carbohydrate side
1030S SANDERSON
chains. This negative charge reduces the diffusibility of hydro-
gen ions within the surface layer of the cell. Any pH at the api-
cal surface of the epithelium will thus be maintained in the
region. In an absorption study on salicylic acid, a weak elec-
trolyte, uptake was much greater than expected when the bulk
phase of the intestine was alkaline (9). In fact, the absorption of
salicylate in experiments was equivalent to that expected if the
bulk phase had a pH value of 2 units lower than it was. Absorp-
tion rates of weak bases were altered in the opposite direction to
weak acids in rat small intestines (10). In a relation of absorption
against pH, the uptake of a weak electrolyte should be at 50% of
its maximum when the pH of the absorptive surface is equal to
the pKa of the electrolyte. These data resulted in the hypothesis
that the microclimate of the small intestinal surface is acidic.
Direct experiments measuring the pH of the surface with micro-
electrodes have confirmed this prediction in both humans and
rodents (11–14). In the proximal small intestine, the pH of the
microclimate was significantly more acidic than in the bulk
phase, but differences in pH in other parts of the intestine were
not significant. Indeed, in the stomach, the pH at the epithelial
cell surface was higher than in the bulk phase of the stomach.
Therefore, changes at the surface of the epithelium are less vari-
able than are those in the bulk phase in different parts of the gas-
trointestinal tract.
The pH of the intestinal microclimate changes during devel-
opment (15). In suckling rats the microclimate is even more
acidic than that in adult rats (Figure 2). Weak acids (such as
short-chain fatty acids) are particularly well absorbed under
these conditions. Studies by Said et al (15) showed that the pH
of the acid microclimate differed with age and was maintained
by mucus. The addition of a mucolytic agent (N-acetylcysteine)
reduced the acidity of the apical surface.
Mucus impedes the free diffusion of hydrogen ions into the
bulk phase but it does not generate the acidity. Hydrogen ions are
secreted by the epithelial cells in exchange for sodium ions by
Na+/H+ antiporters in the intestinal apical membrane. Sodium
passes readily into epithelial cells down its concentration gradi-
ent, causing hydrogen ions to be pumped into the apical space
where they are trapped by the negatively charged mucopolysac-
charide side chains, as discussed above. Removal of sodium
from the bulk phase causes a pH reduction in the microclimate
(16). For weak electrolytes (such as short-chain fatty acids),
sodium removal would indirectly alter absorption by increasing
FIGURE 2. The microclimate at the surface of the intestine is more
acidic than that in the bulk phase. In sucking rats the microclimate is
even more acidic than in adults. However, there are no data in the pre-
mature human neonate. Data from reference 15. Error bars indicate SE.
the pH, which normally maintains the weak acid in its more sol-
uble form. The acid microclimate has a direct effect on transport
of dipeptides (17) which, unlike amino acids, are transported
into the cell in association with hydrogen ions. On the basis of
studies in rodents (15), it appears that human neonates would
produce a microclimate sufficient for these absorptive functions.
However, little is known about the microclimate in preterm
neonates, and this remains and interesting area for further study.
LUMENAL MOLECULES AND GENE EXPRESSION IN
EPITHELIAL CELLS
The ability of the intestine to regulate its environment has
been acknowledged for decades. How this is achieved and how
it varies throughout development are more recently being under-
stood. On the other hand, the converse relation of how the lumen
might affect the intestinal epithelium has not been fully realized.
The possibility that the epithelium may respond to lumenal
molecules, signaling their presence to the mucosal immune sys-
tem, is only now being appreciated. The epithelium has mainly
been regarded as a passive barrier with points of selective filtra-
tion (Figure 3A), surveillance of the lumenal contents occurs
after this filtration has taken place (18).
It has long been known that nutrients may alter the expression
of genes whose actions are restricted to the confines of the epithe-
lial cell monolayer of the intestine (Figure 3B). As an example of
this cellular adaptation, changes in the lumenal milieu can cause
variations in the expression of disaccharidases and nutrient trans-
porters. The relevance of lumenal factors on gene expression of
proteins whose actions occur away from the epithelium, such as
that of cytokines and growth factors, is quite different. In this sit-
uation (Figure 3C) the epithelium acts as a mediator between the
lumenal contents of the intestine and target cells beyond the
epithelial barrier. Such target cells include immunocytes in the
mucosa and cells recruited from the circulation. This epithelial
signaling (Figure 3C) represents a higher level of evolutionary
complexity than does cellular adaptation (Figure 3B). Although
epithelial cellular adaptation is beneficial to the body as a whole,
it involves only 1 cell type. Epithelial signaling, on the other
hand, requires the cooperation of 2 different cell types, those of
the epithelium and of the mucosal immune system.
The epithelium of the small intestine interacts with other cells
of the mucosal immune system (20) by secreting cytokines,
which directly alter immune responses, and growth factors and
their binding proteins, which may affect the proliferation of
immune cells. Furthermore, the small-intestinal epithelium may
present antigens directly to T cells through class II major histo-
compatibility complex (MHC) molecules or through CD1 mole-
cules. The molecular mechanisms governing the expression of
these genes have features in common with those of other entero-
cyte genes (such as disaccharidases and nutrient transporters that
respond to dietary nutrients and factors in the lumen). For exam-
ple, the epithelial cell must still recognize the nutrient or other
lumenal factor, and other mechanisms must then transduce this
recognition into molecular changes that alter directly the expres-
sion of immunologic genes. The main difference in molecular
terms in this adaptive response (Figure 3B) is that the resulting
actions of the proteins escape from the influence of the epithe-
lium and interact with receptors on target cells (Figure 3C).
Epithelial signaling (Figure 3C) enables lumenal factors to
alter immune responses while the integrity of the epithelial bar-
 INTESTINAL ENVIRONMENT IN THE NEONATE 1031S

FIGURE 3. Possible interactions of molecules from the intestinal lumen with the epithelium. Traditionally, the epithelium has been seen as a selec-
tive barrier to molecules, admitting those required for energy intake or immunosurveillance and excluding others (A). However, nutrients can alter the
phenotype of the epithelium to adapt to changing nutritional needs (B). When changes in the intestinal lumen induce new proteins that interact with
mucosal immune cells, the epithelium can act as a membrane signaling information from the lumen to the immune system (C). Reproduced from ref-
erence 18 with permission.

rier is maintained. Although the transfer of lumenal molecules
across the epithelium (Figure 3A) is an important method by
which the mucosal immune system surveys the intestinal lumen,
it represents a breach (albeit a controlled one in most cases) of
the epithelial barrier (19). This provides a potential source for
invasion by pathogens. Poliovirus, for example, enters the body
by exploiting the normal uptake of macromolecules into the
intestine (21). The ability of the epithelium to signal information
between the lumen and mucosal immune system without the
need for a physical pathway linking the lumen to its serosal sur-
face offers obvious advantages in terms of epithelial protection.
The notion of epithelial signaling (Figure 3C) implies that the
epithelium can modulate the level of immune activity in the
mucosal immune system according to the environment of the
intestinal lumen. Because mucosal immune responses play a
large part in gastrointestinal diseases, the opportunity exists to
manipulate these responses by changing the milieu of the intesti-
nal lumen by alterations in diet. Such a strategy may enable us to
develop new treatments in the future.
Immunologically active proteins are known to be synthesized
by the intestinal epithelium. Such proteins were originally
thought to be produced only by other cell types. Diseases of chil-
dren are associated with the increased production of some of
these proteins in the circulation and gastrointestinal tract. Data
from our laboratory now show that the expression of some of
these proteins in the epithelium is influenced by dietary factors.
Chemotactic cytokines
Chemokines are a family of low molecular weight (8–12 kD),
basic, heparin binding proteins that are related by both primary
structure and position of 4 cysteines in the amino acid sequence.
They are involved in the multistep process of selective adhesion,
activation, and migration of leukocytes and can both initiate and
perpetuate inflammation. They are generally induced by proin-
flammatory signals [eg, interleukin (IL)-1 or lipopolysaccha-
ride]. In contrast with classic chemoattractants, chemokines can
direct the migration of defined leukocyte subpopulations. The
chemokine family has been divided into 2 subfamilies (a- and
b-chemokines) based on the arrangement of the first 2 cysteines
and the chromosomal location of their genes. In general, a-
chemokines are potent attractants and activators of neutrophils
but not monocytes; b-chemokines are potent attractants and acti-
vators of monocytes but not neutrophils. However, each specific
chemokine has its own spectrum of activity that includes an
array of different possible effects. Several chemokines are
expressed in the intestinal mucosa, by lamina propria leukocytes,
fibroblasts, and intestinal epithelial cells (22, 23). Intestinal
epithelial cells may therefore participate in the processes that
regulate the composition of the various leukocytes in the lamina
propria that control inflammation. Chemokines have a long half-
life in vivo relative to other cytokines, making them feasible
candidates for long-lasting control over mucosal immune
responses.
IL-8 is a member of the a-family of chemokines. It is a potent
chemotactic factor for neutrophils and may be important in
recruiting them into the gastrointestinal tract during inflamma-
tion. IL-8 also stimulates the release of superoxide radicals in
neutrophils as well as other potential mediators of damage in
intestinal inflammation. Furthermore, it increases the permeabil-
ity of vascular endothelium to albumin resulting in tissue edema.
It is increased in inflamed intestine in several conditions (24). Its
production in intestinal epithelial cells has been documented in
response to bacterial invasion and by other agents including
phorbol myristate acetate and IL-1 (25), but evidence is now
emerging that its expression is altered by dietary factors.
n-Butyrate is a short-chain fatty acid derived from the bacterial
metabolism of unabsorbed carbohydrate. The type of fiber con-
sumed in the diet alters the amount of butyrate produced in the
stool (26). In addition, the populations of butyrate-producing bac-
teria in the intestine may themselves vary with diet. Infants fed
casein-based artificial milk formulas (27, 28) produce large
amounts of butyric acid and propionic acid in the stool, whereas
the predominant short-chain fatty acid in breast-fed infants is
acetic acid. Furthermore, casein inhibits the bacterial flora (lacto-
bacilli) responsible for high acetate production (29). Butyrate con-
centrations, therefore, depend on both the type of bacteria in the
1032S SANDERSON
gut and the amount of substrate available for butyrate production.
Signaling alterations in butyrate production to the mucosal
immune system would provide information about events in the
intestinal lumen, in addition to being an epithelial nutrient.
Butyrate increases IL-8 secretion by cultured enterocytes and acts
in synergy with inflammatory stimuli, such as lipopolysaccharide
and IL-1b (30). The changes in the pattern of chemokine secretion
induced by butyrate show that lumenal factors may alter the
involvement of epithelial cells in mucosal immune responses. In
rodents, the family member that performs a comparable function
to IL-8 is macrophage inflammatory protein 2 (MIP-2). Cell lines
derived from rodent intestinal epithelium secrete MIP-2 in
response to lipopolysaccharides and sodium butyrate (31). Each
effect of butyrate was associated with corresponding changes in
chemokine messenger RNA (mRNA). Future studies are needed to
show whether, in vivo, epithelial cells secrete MIP-2 in response
to inflammatory mediators and what the effect of butyrate and
other dietary factors on this expression might be. However, the
effect of dietary factors on class II MHC and invariant chain
expression (32) has been examined in vivo in our laboratory.
Class II major histocompatibility complex and invariant
chain expression
The initiation of an immune response to protein antigen nor-
mally requires the help of T lymphocytes. Activation of T lym-
phocytes in turn depends on the processing and presentation of
peptides by an antigen presenting cell (APC) (33). Class II MHC
heterodimers (Ia in the rodent) are the molecules that present the
processed exogenous antigen to the T cell receptor. In addition to
classic APCs (dendritic cells, macrophages, B lymphocytes, and
Langerhans cells), several other cell types, including intestinal
epithelial cells, express class II MHC and may function as APCs.
Electron micrographs showing lymphocytes in contact with
enterocytes in vivo lend support to this possibility (34). The pro-
cessing and presentation of exogenous antigen require an addi-
tional protein, the invariant chain (Ii chain) (35).
Diet has a marked effect on the expression of class II MHC
and Ii chain in the mouse intestinal epithelium. The expression
of both genes is regulated developmentally (36) in the epithe-
lium, appearing normally in the first week of life (unlike in lam-
ina propria cells, where it is expressed from before birth). In
addition, the timing of expression can be altered by delaying the
age of weaning from mother’s milk to a normal feed diet (32).
The expression of class II MHC and Ii chain is normally appar-
ent 3–4 d after weaning onto normal feed. However, weaning
onto an elemental diet (containing chemically synthesized amino
acids, simple sugars, and fats) does not induce the expression of
class II MHC or Ii chain. Differences in the expression of these
2 molecules and their transcripts were observed in cells isolated
from intestinal epithelium at different time points after birth in
mice changed on day 17 from mother’s milk either to an ele-
mental diet or a normal feed diet (Figure 4). This experiment
shows that the expression of these genes in the intestinal epithe-
lium is influenced by dietary manipulation in vivo.
Insulin-like growth factor binding proteins
Immune responses depend not only on the activation of T
cells, but also on the ability of T cells to proliferate. One factor
involved in lymphocyte proliferation is insulin-like growth fac-
tor I (IGF-I). This agent is normally thought of as the primary
molecule responsible for nutrient control of body growth in
Figure 4. Dietary factors alter the expression of class II major histo-
compatibility complex and invariant chain expression in intestinal epithe-
lial cells. Shown is a Northern blot of RNA from epithelial cells taken
from individual mice of a single split litter weaned at day 17 onto ele-
mental diet (lanes 1–3) or normal mouse feed (lanes 4–7). The blot was
probed with invariant chain complimentary DNA and autoradiographed
for 48 h. Mice were examined at days 23, 25, 27, and 29. Blots were also
probed with g-actin complimentary DNA to verify uniformity of entero-
cyte extraction. Reproduced from reference 32 with permission. mRNA,
messenger RNA.
health (37, 38) and disease (39).
However, IGF-I also acts on cells of the immune system. Acti-
vated T cells and B cells possess receptors for IGF-I. IGF-I
increases the proliferation of both of these cell types and is
chemotactic for activated T cells. Treatment of adult mice with
recombinant human IGF-I induces striking modifications in
lymphocyte number and function (40). Fourteen days of treat-
ment with IGF resulted in increases in both CD4+ T cells and
splenic B cells. Mitogenic responses of T cells and B cells were
also enhanced, showing that IGF-I increases lymphocyte num-
bers and activity.
In extracellular fluids, IGF-I is bound to IGF binding proteins
(IGFBPs), of which 6 have been described and cloned (41).
Their biological functions include regulating the stability and
clearance of IGFs, acting as shuttles for IGF transport, and mod-
ulating the actions of IGFs at a cellular level. Cultured intestinal
epithelial cells (42, 43) secrete IGFBPs, and it is possible that
the epithelium can influence the proliferation of activated
mucosal lymphocytes by this means. Furthermore, data have
shown that nutritional factors affect the production of IGFBPs in
cell lines in vitro (44). Butyrate, for example, increases IGFBP-
2 (the protein with the greatest affinity for IGF-II) while reduc-
ing the secretion of IGFBP-3 (which binds avidly to IGF-I). Glu-
tamine, on the other hand, increases IGFBP secretion without
altering the relative secretion of one binding protein over
another. These changes in IGFBP secretion are correlated with
alterations in IGFBP mRNA. Thus, not only may nutritional fac-
tors influence IGF and IGFBP secretion by the liver into the cir-
culation (45), resulting in changes in growth of the whole indi-
vidual, but nutrients may also affect the IGF-IGFBP system in
the intestinal epithelium, leading to alterations in the prolifera-
tion of the mucosal immune system.
NECROTIZING ENTEROCOLITIS
Necrotizing enterocolitis is a disease that occurs almost exclu-
sively during the neonatal period. It is characterized by ulceration
and necrosis of the gastrointestinal tract, primarily the distal small
intestine and colon. It has an incidence of 1–3 cases per 1000 live
births (46). Infants weighing < 1000 g are at most risk for necro-
tizing enterocolitis. Despite the high degree of experience with
 INTESTINAL ENVIRONMENT IN THE NEONATE
this condition, its associated mortality rate is still <30% (47). The
disease has been well described (47) and this review provides
more information on its clinical features, treatment, and progno-
sis. Necrotizing enterocolitis is relevant to the present article
because the physicochemical environment is important in its
pathogenesis. At present the mechanisms responsible for develop-
ment of this disease are speculative. However, it is known that
almost all infants with necrotizing enterocolitis have received
milk feeds, pointing to changes in the intestinal lumen as central
to the disease process. Israel (46) compiled 6 studies with a total
of 537 infants and noted that all but 7% had been fed enterally.
Various possibilities exist as to which aspect of enteral feeds
causes the pathology. Because lactase activity is relatively low in
premature infants, undigested carbohydrate was proposed as a
possible agent (48). Bacteria metabolize carbohydrates in the
intestinal lumen to short-chain fatty acids. Whereas these mole-
cules serve as sources of nutrition for colonic epithelium, it is pos-
sible that in the small intestine they may increase the risk of necro-
tizing enterocolitis (49). Clarke et al (6, 50) showed that excessive
fermentation of carbohydrate in the small intestine may cause an
inflammatory condition resembling nectrotizing enterocolitis.
However, other nutrients have also been implicated in necrotizing
enterocolitis. Long-chain fatty acids in piglet small intestines
induce a nectrotizing enterocolitis–like condition (51, 52).
Although many theories could account for how changes in the
lumen of the intestine may alter inflammatory responses, one
possibility is that lumenal molecules alter the signaling between
the intestinal epithelium and the mucosal immune system. In
premature neonates, this interplay between lumen and intestine
may not be sufficiently developed to deal with molecules derived
from the extrauterine environment.
CONCLUSION
This article examined some of the factors that regulate the
physicochemical environment of the intestine and illustrated how
these factors may be altered in neonates. Changes in the lumenal
environment in preterm infants are likely to be important in the
pathogenesis of necrotizing enterocolitis. Finally, this article
described how variations in the environment of the intestine may
be signaled by the epithelium to the mucosal immune system
beneath, and speculated that in the immature gut this signaling
may be important in the pathogenesis of intestinal disorders.
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