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O. BRUNSER*, J. ESPINOZA and M. ARAYA
* Instituto de Nutricion y Tecnologia de los Alimentos (INTA), Casilla 138-11, Santiago, Chile.
1. Introduction
2. Cell and protein turnover
3. Nutrient absorption
4. Protein synthesis
5. Restriction of energy and protein intake
6. Fat absorption and exocytosis
7. Chronic environmental enteropathy
References
The digestive tract
constitutes an interface between the outer environment,
represented by the lumen, and the rest of the body. It plays an
important role in the metabolism of energy and protein because of
its anatomical and functional characteristics. Among its main
tasks are the digestion of the large molecules of foodstuffs into
smaller, simpler ones that can be absorbed by the enterocytes.
During this process, macromolecules lose their immunologic
identity.
The anatomical substrates
for these functions in the small intestine are a surface area
that has been calculated in the adult to be approximately 40 m2
and an epithelium that has one of the highest turnover rates in
the body (WILSON, 1962). In experimental animals, up to 40% of an
intravenously administered dose of tritiated thymidine becomes
incorporated in the epithelial lining of the small intestine,
with an additional 20% incorporated by the gastric and the
colonic mucosae; the whole rest of the organism incorporates the
remaining 40% (HINRICHS, PETERSEN and BASERGA, 1964).
The cell mass of the adult intestinal epithelium has been estimated to be approximately 600 g; since it turns over in 5 days, 120 g of cells with a protein content of approximately 20% are shed into the lumen daily; this means that 25 g of high-quality protein are delivered to the lumen every day (NASSET, 1965; FREEMAN and KIM, 1978; MACDONALD, TRIER and EVERETT, 1964)). To this must be added the protein content of saliva (2-12 g of protein per day), gastric (8-18 g of protein per day) and pancreatic juice (12-30 g of protein per day) and bile (2-3 g of protein per day) (ALPERS, 1987; RINDERKNECHT, 1986; FREEMAN, SLEISENGER and KIM, 1983). As a result, daily endogenous protein secretion in the gastrointestinal tract may equal or even exceed the amounts provided by the diet (about 1 g/kg body weight/d).
This
endogenous protein secretion is incremented by glycoproteins from
the glycocalix, the mucus of goblet cells, and by the digestive
enzymes of the brush border of the gastric epithelium, of the
liver and of the pancreas (ALPERS, 1987; ITO, 1974; BENNET,
LEBLOND and HADDAD, 1974; NEUTRA and FORSTNER 1987; NAIM et
al., 1988). Furthermore, approximately 1% of the
radioactivity associated with a close of intravenously
administered labeled serum albumin appears in the
gastrointestinal lumen; because the half-life of serum albumin is
10 days, one tenth of the turnover of serum albumin is explained
by its intraluminal digestion (approximately 2 g/d) (FREEMAN and
KIM, 1978; LaRUSSO, 1984).
The intestinal absorption
of glucose, galactose, amino acids and di- and tripeptides is
accomplished by specific carriers which have an absolute
requirement for Na+ in a stoichiometric proportion of
two Na+ for each molecule of non-electrolyte (CRANE,
1962; LUECKE, HAASE and MURER, 1977; MATTHEWS et al., 1979).
Absorbed Nat is transported to the intercellular space of the
epithelium against a gradient by the Na+ - K+
dependent ATPase (sodium pump) which requires the expenditure of
ATP (HARMS and WRIGHT, 1980).
Brush-border disaccharidases are turned over several times during the lifespan of enterocytes (JAMES et al., 1971; ALPERS and TEDESCO, 1975), which have the capacity to synthesize these complex glycoproteins at a high rate. Adaptation of the sucrase-isomaltase and the maltase activities to the presence of their specific substrates in the diet further increases the need for protein synthesis in the epithelium (ROSENSWEIG, HERMAN and STIFEL, 1971; ROSENSWEIG and HERMAN, 1969). Unabsorbed carbohydrates, including non-starch polysaccharides, are fermented in the large intestine by the resident bacterial flora (TOPPING, 1991). This results in the formation of short-chain fatty acids (SCFA) (acetic, propionic and butyric) whose transport by the colonic mucosa stimulates water and Na+ absorption.
Butyric
acid is one of the main fuels for the colonic epithelium. This
fermentative process, followed by absorption of the SCFA, is
known as colonic salvage and may account for 5 to 6% of the
energy intake when the diet provides 2000 kcal/d, including 30 to
40 g of non-starch polysaccharides (TOPPING, 1991). This salvage
of energy and the salvage of nitrogen derived from the metabolism
of the gut increase the economy and efficiency of
gastrointestinal absorptive functions (LANGRAN et al., 1992).
Protein synthesis is very
active in the intestinal epithelium. Proteins with higher
molecular weight are metabolized at faster rates than smaller
molecules (ALPERS, 1972a; 1977). Incorporation of amino acids
into cell proteins depends to a large extent on the route of
administration. Intravenously administered labeled leucine is
incorporated into cells of the crypt-villus junction whereas
intraluminal administration results in heavy labeling of cells
near the villus tip. This suggests that villus cells synthesize
protein at rates that exceed those of the crypts (ALPERS, 1972b).
The recycling of amino acids in the intestinal epithelium must be
very high to meet the rates of protein synthesis. Since protein
concentration in the epithelium remains constant, the synthesis
of new protein must be equilibrated by export and breakdown.
The
hyperplasia of the mucosa following extensive resection is also
indicative of a considerable capacity for protein synthesis. For
hyperplasia or recovery of intestinal mass to occur, adequate
amounts of monosaccharides, amino acids and long-chain fatty
acids are necessary (TOPPING, 1991; WESER, VANDEVENTER and TAWIL,
1982; SAKATA, 1986).
Starvation is followed by
atrophy of the intestinal wall, especially of the mucosa, and
similar changes occur during exclusive feeding by the parenteral
route (ALTMAN, 1972; JOHNSON et al., 1975; FORD et al.,
1984; ROEDIGER, 1986). Reversal of this atrophy is
accomplished only by nutrients administered by the enteral route
(NASSET, 1965; JOHNSON et al., 1975).
Enterocytes use a variety of fuels, some provided by the diet during absorption; however, the largest proportion is endogenous. In studies in vivo in rats it has been shown that glutamine is the main source of the energy used by the intestinal mucosa in the postabsorptive state (WINDMUELLER and SPAETH, 1975; 1978; 1980). Part of the ammonia generated by the metabolism of glutamine in the intestinal epithelium is released to the lumen, from where it is utilized by bacteria or salvaged for synthesis of non-essential amino acids in the colon (WIND-MUELLER and SPAETH, 1980; MORAN and JACKSON, 1990). Furthermore, glutamine and other polyamines stimulate mitotic activity in the crypts (LUK and BAYLIN, 1983).
Restriction of protein and energy intake in marasmic malnutrition, induces a slowing of cell renewal as evidenced by the decrease in mitotic activity in the crypt cells both in humans and in experimental animals (BRUNSER et al., 1966; 1968; BROWN, LEVINE and LIPKIN, 1963). In infantile protein and energy malnutrition leading to kwashiorkor, the mitotic index in the crypts of Lieberkühn is only slightly decreased; this is similar to findings in protein-malnourished rats in whom the mitotic index remains very close to normal despite prolonged periods of decreased protein intake (BRUNSER et al., 1966; 1968).
In marasmic
infants the architecture of the intestinal mucosa is close to
normal, while histological alterations are more severe in
kwashiorkor (BRUNSER et al., 1968). The reason for these
differences is not known; in marasmus, the preservation of
mucosal histology may be due in part to the capacity of the
enterocytes to recycle some of the molecules of their cytoplasm.
In marasmic infants, enterocytes frequently have large
autophagosomes in which the sequestered organelles are degraded
by Iysosomal enzymes until only undigested structures remain as
residual bodies (BRUNSER, CASTILLO and ARAYA, 1976). Molecules
released by this process may be recycled by the enterocytes and
contribute to maintain a more normal mucosal function and
structure. Furthermore, kwashiorkor is an acute condition, while
marasmus is chronic and allows adaptations of metabolic
activities to low levels of protein and energy intake (SUSKIND,
MURTHY and SUSKIND, 1990).
The absorption of dietary
fat also involves expenditure of energy and synthesis of protein.
Absorption of fatty acids and their transport to the endoplasmic
reticulum in the enterocytes requires the synthesis of Z protein
and of intestinal 'fatty acid-binding' protein (GORDON et al.,
1982), while their activation to acyl-CoA for intracellular
resynthesis of triglycerides or phospholipids requires
expenditure of ATP (SENIOR, 1964). The glycerol backbone for
resynthesis of neutral fat may originate from 2-monoglycerides
liberated by the lumenal hydrolysis of triglycerides, or it may
be produced by the anaerobic metabolism of glucose during which
ATP is synthesized (SENIOR, 1964).
Exocytosis
of fat resynthesized in the endoplasmic reticulum of enterocytes
requires the synthesis of apolipoproteins, especially of
apolipoprotein AI and AIV (GREEN et al.,
1980). The rate of synthesis of apoAIV during fat
transport is probably greater than for apoAI,
suggesting that this is a specific response and meets functional
requirements of the absorptive cells. The fact that apoCIII
is not secreted is further indication of a highly selective and
regulated process (BLAUFUSS et al., 1984). ApoAI
and apoAIV increase considerably in the plasma during
neutral fat absorption. Despite this, their concentration in the
cytoplasm of the enterocytes remains almost unchanged, suggesting
that considerable amounts of these polypeptides are secreted into
the lymph (ALPERS, LANCASTER and SCHONFELD, 1982). Intestinal
alkaline phosphatase is also secreted during a fatty meal
although, in absolute terms, the quantities are small (YOUNG,
YEDLIN and ALPERS, 1981).
Disturbances of digestive
and absorptive function may induce considerable losses of
nutrients and result in variable degrees of malnutrition, both in
children and adults. Their discussion, however, is beyond the
scope of this commentary. We will refer instead to a condition
that affects a large segment of the world population living in
the less developed countries, where environmental sanitation is
unsatisfactory. This condition was first described in
morphological studies of the small intestine of apparently
healthy individuals living in the tropics (LINDENBAUM, KENT and
SPRINZ, 1966; LINDENBAUM, 1968; KEUSCH, 1972).
The histological changes consisted of some blunting of the villi, a more basophilic staining of the cells at the tip of the villi, a mild-to-moderate increase of crypt depth, and an increase of lymphocytes and plasma cells in the lamina propria (BAKER, 1973; BRUNSER, EIDELMAN and KLIPSTEIN, 1970). Because of the geographic area where this condition was first described, it was originally called tropical enteropathy. This was an acquired condition, because the histologic changes were not seen in fetuses that miscarried shortly before term. Furthermore, in people moving to these areas from developed countries, the same morphological changes of the intestinal mucosa appeared after a few months, if they lived in conditions similar to those of the local residents; these changes regressed when they returned to well-sanitated environments (LINDENBAUM, KENT and SPRINZ, 1966; LINDENBAUM, GERSON and KENT, 1971).
The morphologic changes also improved when inhabitants from tropical areas moved to well-sanitated environments. The malabsorption associated with this condition affected all nutrients in variable degrees. Some individuals went on to develop a more severe course, with chronic diarrhea, severe malabsorption and macrocytic anemia (tropical sprue) (KLIPSTEIN, 1968a; b).
Individuals with tropical enteropathy were found to have an abnormal flora in the upper small intestine, mainly aerobes or microaerophilic bacteria (GORBACH et al., 1970; 1971). It is thought that the main cause of all these alterations is the passage of bacteria, viruses, and parasites along the gastrointestinal tract with contaminated foodstuffs and fluids. Most likely it is not necessary for the bacteria to have enteropathogenic capabilities to induce these effects.
It was later shown that people living in temperate areas may develop similar histological and functional changes if they live in environments with high levels of microbiological contamination (THOMAS, CLAIN and WICKS, 1976; PEREA et al., 1978; BRUNSER et al., 1987). For these reasons we feel that the expression 'chronic environmental enteropathy' is a more accurate description of this condition than 'tropical enteropathy'.
In the studies carried out in Chile we demonstrated that affected individuals have mild histologic changes and minor degrees of malabsorption. Along with increased fecal losses of nitrogen and fat, a decrease of the transport capacity of the small intestine for glucose was demonstrated, with a lower Vmax and saturation of its transport capacity occurring at lower concentrations. Fecal losses of nitrogen increased disproportionately when the diet provided moderate amounts of fiber, to levels far above those reported for individuals living in well-sanitated environments on similar levels of fiber intake (BRUNSER et al., 1987).
It was also shown that when the diet provided protein at maintenance levels, any change in intestinal absorptive capacity that resulted in greater fecal losses of nitrogen, such as those produced by increased dietary fiber intake, resulted in a compensatory decrease of urinary nitrogen losses (ESPINOZA et al., 1984). Microaerophilic and anaerobic bacteria were detected in increased numbers in the first loops of the jejunum. Three months of living in the well-sanitated environment of a metabolic ward resulted in the complete reversal of the morphologic changes (BRUNSER et al., 1987).
Chronic
environmental enteropathy has to be taken into account when
calculating the protein and energy requirements of people who
live in areas where microbiological contamination is highly
prevalent and where the fiber content of the diet is high.
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