Absorption
of Protein
and Protein
Fragments
in
the Developing
Intestine:
Role in lmmunologic/
Allergic
Reactions
W. Allan Walker, MD
From the Department of Pediatrics, Harvard Medical School and the Combined Program in Pediatric Gastroenterology and Nutrition, The Children’s Hospital and Massachusetts General Hospital, Boston
ABSTRACT. An important adaptation of the gastrointes-tinal tract to the extrauterine environment is its
devel-opment of a mucosal barrier against the penetration of
proteins and protein fragments. To combat the potential
danger of invasion across the mucosal barrier the
new-born infant must develop within the lumen and on the
luminal mucosal surface an elaborate system of defense
mechanisms which act to control and maintain the
epi-thelium as an impermeable barrier to the uptake of
macromolecular antigens. As a result of a delay in the
maturation of the mucosal barrier, newborn infants are
particularly vulnerable to pathologic penetration by
harmful intraluminal substances. The consequences of
altered defense are susceptibility to infection and the
potential for hypersensitivity reactions and the formation
of immune complexes. With these reactions comes the
potential for developing life-threatening diseases such as necrotizing enterocolitis, sepsis, and hepatitis. Fortu-nately, “nature” has provided a means for passively
pro-tecting the “vulnerable” newborn against the dangers of
a deficient intestinal defense system, namely human
milk. It is now increasingly apparent that human milk
contains not only antibodies and viable leukocytes but
many other substances that can interfere with bacterial colonization and prevent antigen penetration. Pediatrics
1985;75(suppl):167-171; protein absorption, newborn host defense, intestinal immunity, gastrointestinal allergy, breast milk.
An important adaptation of the gastrointestinal tract to the extrauterine environment is its deveb-opment of a mucosal barrier against the penetration of harmful substances (bacteria, toxins, and anti-gens) present within the intestinal lumen. At birth, the newborn infant must be prepared to deal with
Read before the Workshop on Current Issues in Feeding the Normal Infant, Palm Springs, CA, April 8-11, 1984.
Reprint requests to (W.A.W.) Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Boston, MA 02114.
PEDIATRICS (ISSN 0031 4005). Copyright © 1985 by the
American Academy of Pediatrics.
bacterial colonization of the gut, with formation of toxin byproducts of bacteria and viruses (enteno-toxins and endotoxins) and with the ingestion of
antigens (milk proteins). These potentially noxious
substances, if allowed to penetrate the mucosab epithebial barrier under pathologic conditions, can cause inflammatory and allergic reactions, which may result in gastrointestinal and systemic disease states.’
To combat the potential danger of invasion across the mucosal barrier the infant must develop an elaborate system of defense mechanisms within the lumen and on the luminal mucosab surface; these mechanisms act to control and maintain the epithebium as an impermeable barrier to uptake of macromobecular antigens. These defenses include a unique immunologic system adapted to function in the complicated milieu of the intestine as well as other nonimmunobogic processes such as a gastric barrier, intestinal surface secretions, peristaltic movement, and natural antibacterial substances
(lysozyme, bile salts), which also help to provide
maximum protection for the intestinal surface. The purpose of this review is to summarize the evidence for an altered mucosal barrier to proteins and protein fragments in human newborns, to con-sider factors contributing to mature mucosal barrier function in the human, and finally to stress the consequences (intestinal allergic reactions etc) of antigen penetration across an immature mucosa during infancy.
PROTEIN TRANSPORT IN THE IMMATURE
INTESTINE
The neonatal mammalian small intestine, like the reticuloendothelial system in humans has a capacity to ingest macromolecules by an endocy-totic mechanism. During the peninatal period in all
mu-cosal barrier to antigen uptake and transport ne-mains immature for varying time periods. During this time, excessive quantities of antigens may be transported across the intestinal epithelium into the systemic circulation. At the time when intes-tinal immunologic and nonimmunobogic host defen-ses develop and intestinal epithebial cells mature functionally and morphobogicabby, the uptake of macromolecules decreases. The phenomenon, known as “closure” is the result of matunational events in gastrointestinal development.
Closure Phenomenon in the Human
The process of closure in the human is more subtle than in other mammals. The bulk of the evidence to be presented suggests that in contrast to the mature intestinal epithebium, excessive quan-tities of macromolecubar antigens can cross the mucosal barrier of the underdeveloped intestine. Excessive uptake appears to be related to an under-developed gbycocabyx and predominantly immature microvillus membrane surface area.
Antigen Absorption in the Human
Several clinical studies suggest that
macromole-cules can cross the mucosal barrier under normal
physiologic conditions in the human. Because the pinocytotic process of antigen absorption most likely represents a residual and premature absorp-tive mechanism in the alimentary canal, the capac-ity to absorb large molecules may be more extensive in the immature small intestine than in the highly developed mature intestine. In fact, this observa-tion is supported by evidence suggesting that pre-mature and newborn infants can absorb greater quantities of ingested food antigen than older in-fants or adult.2 Rothberg,3 for example, has mea-sured bovine serum albumin in the serum of pre-mature infants fed quantities of this protein non-mally present in the daily milk requirement. In contrast, circulating bovine serum albumin could not be detected in serum samples from olden chil-dren fed equivalent quantities of protein. We have also reported a larger percentage of serum samples containing antibodies to food antigens among in-fants aged less than 3 months than among infants exposed to antigen after age 3 months, a finding that suggests that food proteins are absorbed more readily into the circulation during the first 3
months of life.4 More recently, Robertson et ab5
suggested that the ability of the gastrointestinal tract to exclude antigenicably intact food proteins increases with gestational age. Cunningham-Run-dbes et al6 have measured circulating casein in milk protein immune complexes after ingestion of milk in patients with immunogbobin A deficiency.
The implication of these studies is that the neo-natal intestine may absorb antigenic quantities of ingested protein more readily than the more mature adult intestine. In support of this hypothesis, Lev and Orlic7 in recent morphologic studies with fetal monkeys, and Moxey and Trier8 with human fe-tuses, have shown excessive uptake of large mole-cubes by intestinal epithelial cells. They also de-scnibed morphologic features of epithelial cells sug-gesting structural immaturity. This same immatu-nity of gastrointestinal function and structure may persist beyond fetal life into the newborn period, at a time when the small intestine is exposed to in-creased quantities of both bacterial and food anti-gens. In addition to increased antigen uptake, it is also possible that a greaten quantity of protein ingested by intestinal epithelial cells escapes intra-cellular proteobysis as a result of immature lyso-somab function, and therefore more protein be-comes available for subsequent transport out of the cell and into the circulation.
Although infants may absorb greaten quantities of antigen, evidence also exists to suggest a limited but nonetheless measurable absorption of macro-molecular antigens from the small intestine of older children and adults. Korenblat et a19 showed that an appreciable percentage (15% to 30%) of normal adults developed milk precipitins after a physiologic load of milk proteins. In earlier studies, Wilson and Walzer’#{176}reported uptake and transport of undi-gested protein (egg albumin) using immunologic methods to measure circulating food proteins; they also demonstrated precipitins to food proteins in serum of adults fed physiologic quantities of the same proteins.
Development of Intestinal Host Defenses in the Human
Role of Human
Colostrum
in ClosureAs stated earlier, newborn infants lack many specific and nonspecific intestinal features that are
necessary to protect them adequately from the ex-trautenine environment. Fortunately, “nature” has provided an excellent substitute to protect the vub-nenable neonate passively during this critical pe-nod. This substitute, human milk, contains many factors that can compensate for processes lacking in the infant and at the same time stimulate the maturation of the gut toward independent function.
It is increasingly apparent that human milk con-tains not only important nutrients and protective factors for the newborn but also factors that can facilitate intestinal maturation. Heind and Hansen1’ have reported that the ingestion of cobs-trum can facilitate the maturation of mucosal epi-thelial cells, enhance absorption of digested foods, and perhaps accelerate the development ofan intact mucosal barrier. They have also shown that brush bonder enzymes (lactase, sucnase, alkaline phospha-tase) are enhanced after the ingestion of cobs-trum.” Udall et al’2 have actually demonstrated a decrease in antigen penetration in newborns after cobostrum feeding. These investigations have sug-gested that milk may contain a “mucosal growth factor” which facilitates the early maturation of the gut (closure).
In addition to actively accelerating closure in the newborn, human colostrum/milk provides a passive protection of the gut surface while it is maturing. Specific secretory IgA antibodies exist in milk and these exclude bacteria and luminab antigens. Also present, are additional protective factors that con-tribute to the protection of the newborn. However, a more prolonged discussion of this topic is beyond the scope of this paper.
Clinical Conditions Possibly Associated with Immature Mucosal Barrier
Clinical conditions known to be associated with pathologic uptake of antigens are shown in the Table. The pathophysiobogic mechanism(s) of rep-resentative conditions discussed in this section will illustrate the association between antigen transport and clinical disease. A comprehensive review of all clinical conditions is beyond the scope of this paper’3 (See Figure).
As a result of the pathologic transport of antigens across the small intestine, ingested antigens may traverse the mucosal barrier and predispose to ab-lergic and toxic reactions leading to a number of gastrointestinal diseases. The gastrointestinal dis-eases possibly associated with antigen absorption are gastrointestinal allergy,’4 inflammatory bowel
TABLE. Clinical Conditions Possibly Associated with
Immature Mucosal Barrier
Newborn and early childhood (immediate clinical
re-sponse)
Necrotizing enterocolitis Gastrointestinal allergy Sudden infant death syndrome Dermatitis
Toxigenic diarrhea Malabsorption
Later childhood and adulthood (delayed clinical re-sponse)
Inflammatory bowel disease Chronic active hepatitis Nephritis
Autoimmune (immune complex-mediated diseases)
disease,’5 celiac disease,’6 toxigenic diarrhea,’7 chronic hepatitis,’8 necnotizing enterocobitis, and autoimmune disease’8 Because the evidence cited to support the hypothesis that intestinal penmea-bibity to antigens is involved in the pathogenesis of human disease is largely indirect, one should realize that these comments are somewhat speculative and still remain to be proved by more direct evidence. For purposes of this report, only gastrointestinal allergy will be discussed in detail as a prototype condition.
Gastrointestinal Allergy
1
Patterns ofAbnormal Function
IMMATURE GUT DAMAGED GUT
#{149}Celiac Disease #{149}Gastroententis #{149}Milk Allergy (‘?)
DEVELOPMENT
OF GASTROINTESTINAL
FUNCTION
___________MATURE FIJNC77ONAL GIlT
#{149}Prematurity #{149}Malnutrition
Crypt
Figure. Development of gastrointestinal function. In normal physiologic conditions,
crypt-to-villus cell turnover proceeds at a rate allowing for appropriate functional surface
area (brush border and glycocalyx). When disruption of crypt-villus turnover occurs
(immature gut), as in prematurity or malnutrition, decreased cell turnover results in
inadequate cell surface function and host defense of the gut is disrupted. If a noxious
insult to the gut occurs (damaged gut), mature cells are destroyed at a greater rate than
they can be replaced, resulting in a decreased functional surface. (Reprinted with permis-sion from Walker.’)
protein. With reexposure at a time when much less macromolecular absorption is occurring, minute quantities of allergen may be absorbed and result in allergic symptoms. These symptoms can then be propagated by further uptake of allergens across a disrupted mucosab surface. In recent experimental studies from this laboratory, we have reported that intestinal anaphylaxis can lead to increased uptake
of nonspecific intestinal allergens which in turn can
evoke an IgG-mediated reaction leading to further propagation of disease. This secondary process oc-cunring with classic IgE-mediated disease may be important in converting a self-limited process into a chronic disease state.
SUMMARY
AND
CONCLUSIONS
An important adaptation of the gastrointestinal tract to the extrauterine environment is its devel-opment of a mucosal barrier against the penetration of proteins and protein fragments. To combat the potential danger of invasion across the mucosab barrier, the infant must develop within the lumen and on the luminal mucosal surface an elaborate system of defense mechanisms that act to control and maintain the epithelium as an impermeable
barrier to the uptake of macnomobecular antigens. These defenses include a unique local immunologic
system adapted to function in the complicated
mi-lieu of the intestine as well as other nonimmuno-logic processes such as a gastric barrier, intestinal surface secretions, penistabtic movement, etc, all of which help to provide maximum protection for the intestinal surface.
Unfortunately, during the immediate post-pan-turn period, particularly for premature infants and “small-for-dates” infants, this elaborate local de-fense system is incompletely developed. As a result of the delay in the maturation of the mucosab ban-nier, newborn infants are particularly vulnerable to pathologic penetration by harmful intnaluminal substances. The consequences of altered defense are susceptibility to infection and the potential for hypersensitivity reactions and the formation of irn-mune complexes. With these reactions comes the potential for developing life-threatening diseases such as necrotizing enterocolitis, sepsis, and hepa-titis. Fortunately, nature has provided a means for passively protecting the “vulnerable” newborn against the dangers of a deficient intestinal defense
appar-ent that human milk contains not only antibodies and viable leukocytes, but many other substances that can interfere with bacterial colonization and prevent antigen penetration.
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