Nutrient Digestion and Absorption

Carbohydrates, providing ~45% of total energy needs of Western diets, require hydrolysis to monosaccharides before absorption

We can classify dietary carbohydrates into two major groups: (1) the monosaccharides (monomers), and (2) the oligo­saccharides (short polymers) and polysaccharides (long polymers). The small intestine can directly absorb the monomers but not the polymers. Some polymers are digestible, that is, the body can digest them to form the monomers that the small intestine can absorb. Other polymers are nondigestible, or “fiber.” The composition of dietary carbohydrate is quite varied and is a function of culture. The diet of individuals in so-called developed countries contains considerable amounts of “refined” sugar and, compared with individuals in most developing countries, less fiber. Such differences in the fiber content of the Western diet may account for several diseases that are more prevalent in these societies (e.g., colon carcinoma and atherosclerosis). As a consequence, the consumption of fiber by the health-conscious public in the United States has increased during the past 3 decades. In general, increased amounts of fiber in the diet are associated with increased stool weight and frequency.

Approximately 45% to 60% of dietary carbohydrate is in the form of starch, which is a polysaccharide. Starch is a storage form for carbohydrates that is primarily found in plants, and it consists of both amylose and amylopectin. In contrast, the storage form of carbohydrates in animal tissues is glycogen, which is consumed in much smaller amounts. Amylose is a straight-chain glucose polymer that typically contains multiple glucose residues, connected by α-1,4 linkages. In contrast, amylopectin is a massive branched glucose polymer that may contain 1 million glucose residues. In addition to the α-1,4 linkages, amylopectin has frequent α-1,6 linkages at the branch points. Amylopectins are usually present in much greater quantities (perhaps 4-fold higher) than amylose. Glycogen—the “animal starch”—has α-1,4 and α-1,6 linkages like amylopectin. However, glycogen is more highly branched (i.e., more α-1,6 linkages).

Most dietary oligosaccharides are the disaccharides sucrose and lactose, which represent 30% to 40% of dietary carbohydrates. Sucrose is table sugar, derived from sugar cane and sugar beets, whereas lactose is the sugar found in milk. The remaining carbohydrates are the monosaccharides fructose and glucose, which make up 5% to 10% of total carbohydrate intake. There is no evidence of any intestinal absorption of either starches or disaccharides. Because the small intestine can absorb only monosaccharides, all dietary carbohydrate must be digested to monosaccharides before absorption. The colon cannot absorb monosaccharides.

Dietary fiber consists of both soluble and insoluble forms and includes lignins, pectins, and cellulose. These fibers are primarily present in fruits, vegetables, and cereals. Cellulose is a glucose polymer connected by β-1,4 linkages, which cannot be digested by mammalian enzymes. However, enzymes from colonic bacteria may degrade fiber. This process is carried out with varying efficiency; pectins, gum, and mucilages are metabolized to a much greater degree than either cellulose or hemicellulose. In contrast, lignins, which are aromatic polymers and not carbohydrates, are not altered by microbial enzymes in the colonic lumen and are excreted unaltered in stool.

As we discuss below, the digestive process for dietary carbohydrates has two steps: (1) intraluminal hydrolysis of starch to oligosaccharides by salivary and pancreatic amylases ( Fig. 45-3 ), and (2) so-called membrane digestion of oligosaccharides to monosaccharides by brush-border disaccharidases. The resulting carbohydrates are absorbed by transport processes that are specific for certain monosaccharides. These transport pathways are located in the apical membrane of the small-intestinal villous epithelial cells.

Luminal digestion begins with the action of salivary amylase and finishes with pancreatic amylase

Acinar cells from both the salivary glands (see pp. 893–894 ) and pancreas (see p. 882 ) synthesize and secrete α-amylases. Salivary and pancreatic amylases, unlike most of the pancreatic proteases that we discuss below, are secreted not in an inactive proenzyme form, but rather in an active form. Salivary and pancreatic α-amylases have similar enzymatic function, and their amino-acid sequences are 94% identical.

Salivary α-amylase in the mouth initiates starch digestion; in healthy adults, this step is of relatively limited importance. Salivary amylase is inactivated by gastric acid but can be partially protected by complexing with oligosaccharides.

Pancreatic α-amylase completes starch digestion in the lumen of the small intestine. Although amylase binds to the apical membrane of enterocytes, this localization does not provide any kinetic advantage for starch hydrolysis. Cholecystokinin (CCK; see pp. 882–883 ) stimulates the secretion of pancreatic α-amylase by pancreatic acinar cells.

α-amylase is an endoenzyme that hydrolyzes internal α-1,4 linkages (see Fig. 45-3 A ). α-amylase does not cleave terminal α-1,4 linkages, α-1,6 linkages (i.e., branch points), or α-1,4 linkages that are immediately adjacent to α-1,6 linkages. As a result, starch hydrolysis products are maltose, maltotriose, and α-limit dextrins. Because α-amylase has no activity against terminal α-1,4 linkages, glucose is not a product of starch digestion. The intestine cannot absorb these products of amylase digestion of starch, and thus further digestion is required to produce substrates (i.e., monosaccharides) that the small intestine can absorb by specific transport mechanisms.

“Membrane digestion” involves hydrolysis of oligosaccharides to monosaccharides by brush-border disaccharidases

The human small intestine has three brush-border proteins with oligo­saccharidase activity: lactase, glucoamylase (most often called maltase), and sucrase-isomaltase. These are all integral membrane proteins whose catalytic domains face the intestinal lumen (see Fig. 45-3 B ). Sucrase-isomaltase is actually two enzymes—sucrase and isomaltase (also known as α-dextrinase or debranching enzyme)—bound together. Thus, four oligosaccharidase entities are present at the brush border. Lactase has only one substrate; it breaks lactose into glucose and galactose. The other three enzymes have more complicated substrate spectra. All will cleave the terminal α-1,4 linkages of maltose, maltotriose, and α-limit dextrins. In addition, each of these three enzymes has at least one other activity. Maltase can also degrade the α-1,4 linkages in straight-chain oligosaccharides up to nine monomers in length. However, maltase cannot split either sucrose or lactose. The sucrase moiety of sucrase-isomaltase is required to split sucrose into glucose and fructose. The isomaltase moiety of sucrase-isomaltase is critical; it is the only enzyme that can split the branching α-1,6 linkages of α-limit dextrins. N45-2

N45-2

Oligosaccharidases

The oligosaccharidases are large integral membrane proteins that are anchored to the apical membrane by a transmembrane stalk; >90% of the protein is extracellular. Villous epithelial cells synthe­size the disaccharidases via the secretory pathway (see pp. 34–35 ). The proteins undergo extensive N-linked and O-linked glycosylation in the Golgi and then traffic to the apical membrane.

Sucrase-isomaltase is a special case. After the insertion of the single sucrase-isomaltase peptide (including its transmembrane stalk) into the brush-border membrane, pancreatic proteases cleave the peptide between the sucrase and isomaltase moieties. After this cleavage, the isomaltase moiety remains continuous with the transmembrane stalk, and the sucrase moiety remains attached to the isomaltase moiety by van der Waals forces. Thus, sucrase-isomaltase differs from the other two oligosaccharidases in that the mature protein consists of two peptide chains (encoded by the same mRNA nonetheless), each with a distinct catalytic site and distinct substrate specificities.

See eFigure 45-1 for a summary of the composition of sugars and oligosaccharides. As we saw in the text, sucrase is unique in splitting sucrose, and the isomaltase is unique in splitting the α-1,6 linkage of α-limit dextrins. The table lists the enzymatic specificities for each of the brush-border oligosaccharidases.

Specificities of Oligosaccharidases

	SUBSTRATES
ENZYME	LACTOSE (SPLITTING THE β-1,4 LINKAGE BETWEEN d -GALACTOSE AND d -GLUCOSE)	TERMINAL α-1,4 LINKAGES	INTERNAL α-1,4 LINKAGES IN OLIGOSACCHARIDES UP TO 9 MONOMERS IN LENGTH	SUCRASE (SPLITTING α-1,2 LINKAGES BETWEEN d -GLUCOSE AND d -GALACTOSE)	α-1,6 (BRANCHING) LINKAGES OF α-LIMIT DEXTRINS
Lactase	✓
Maltase		✓	✓
Sucrase *		✓		✓
Isomaltase *		✓			✓

* Sucrase and isomaltase are separate peptides, held together by van der Waals forces and anchored to the membrane via the transmembrane stalk of the isomaltase.

The action of the four oligosaccharidases generates several monosaccharides. Whereas the hydrolysis products of maltose are two glucose residues, those of sucrose are glucose and fructose. The hydrolysis of lactose by lactase yields glucose and galactose. The activities of the hydrolysis reactions of sucrase-isomaltase and maltase are considerably greater than the rates at which the various transporters can absorb the resulting monosaccharides. Thus, uptake, not hydrolysis, is the rate-limiting step. In contrast, lactase activity is considerably less than that of the other oligo­saccharidases and is rate limiting for overall lactose digestion-absorption.

The oligosaccharidases have a varying spatial distribution throughout the small intestine. In general, the abundance and activity of oligosaccharidases peak in the proximal jejunum (i.e., at the ligament of Treitz) and are considerably less in the duodenum and distal ileum. Oligosaccharidases are absent in the large intestine. The distribution of oligosaccharidase activity parallels that of active glucose transport.

These oligosaccharidases are affected by developmental and dietary factors in different ways. In many nonwhite ethnic groups, as well as in almost all other mammals, lactase activity markedly decreases after weaning in the postnatal period. The regulation of this decreased lactase activity is genetically determined. N45-3 The other oligosaccharidases do not decrease in the postnatal period. In addition, long-term feeding of sucrose upregulates sucrase activity. In contrast, fasting reduces sucrase activity much more than it reduces lactase activity. In general, lactase activity is both more susceptible to enterocyte injury (e.g., following viral enteritis) and slower to recover from damage than is other oligosaccharidase activity. Thus, reduced lactase activity (as a consequence of both genetic regulation and environmental effects) has substantial clinical significance in that lactose ingestion may result in a range of symptoms in affected individuals ( Fig. 45-4 A , Box 45-1 ).

SGLT1 is responsible for the Na ⁺ -coupled uptake of glucose and galactose across the apical membrane

The uptake of glucose across the apical membrane via SGLT1 ( Fig. 45-5 A ) represents active transport, because the glucose influx occurs against the glucose concentration gradient (see pp. 121–122 ). Glucose uptake across the apical membrane is energized by the electrochemical Na ⁺ gradient, which in turn is maintained by the extrusion of Na ⁺ across the basolateral membrane by the Na-K pump. This type of Na ⁺ -driven glucose transport is an example of secondary active transport (see p. 115 ). Inhibition of the Na-K pump reduces active glucose absorption by decreasing the apical membrane Na ⁺ gradient and thus decreasing the driving force for glucose entry.

The affinity of SGLT1 for glucose is markedly reduced in the absence of Na ⁺ . The varied affinity of SGLT1 for different monosaccharides reflects its preference for specific molecular configurations. SGLT1 has two structural requirements for monosaccharides: (1) a hexose in a d config­uration, and (2) a hexose that can form a six-membered pyranose ring (see Fig. 45-5 B ). SGLT1 does not absorb l -glucose, which has the wrong stereochemistry, and it does not absorb d -fructose, which forms a five-membered ring ( Box 45-2 ). N45-4

The GLUT transporters mediate the facilitated diffusion of fructose at the apical membrane and of all three monosaccharides at the basolateral membrane

Early work showed that fructose absorption is independent of Na ⁺ but has characteristics of both a carrier-mediated and a passive process. These observations show that the small intestine has separate transport systems for glucose and fructose. Subsequent studies established that facilitated diffusion is responsible for fructose absorption. Fructose uptake across the apical membrane is mediated by GLUT5, a member of the GLUT family of transport proteins (see p. 114 ). GLUT5 is present mainly in the jejunum. N45-5

The efflux of glucose, fructose, and galactose across the basolateral membrane also occurs by facilitated diffusion. The characteristics of the basolateral sugar transporter, identified as GLUT2, are similar to those of other sugar transport systems in erythrocytes, fibroblasts, and adipocytes. GLUT2 has no homology to SGLT1 but is 41% identical to GLUT5, which is responsible for the uptake of fructose from the lumen.

Proteins require hydrolysis to oligopeptides or amino acids before absorption in the small intestine

With the exception of antigenic amounts of dietary protein that are absorbed intact, proteins must first be digested into their constituent oligopeptides and amino acids before being taken up by the enterocytes. Digestion-absorption occurs through four major pathways. First, several luminal enzymes (i.e., proteases) from the stomach and pancreas may hydrolyze proteins to peptides and then to amino acids, which are then absorbed ( Fig. 45-6 ). Second, lumi­nal enzymes may digest proteins to peptides, but enzymes present at the brush border digest the peptides to amino acids, which are then absorbed. Third, luminal enzymes may digest proteins to peptides, which are themselves taken up as oligopeptides by the enterocytes. Further digestion of the oligopeptides by cytosolic enzymes yields intracellular amino acids, which are moved by transporters across the basolateral membrane into the blood. Fourth, luminal enzymes may digest dietary proteins to oligopeptides, which are taken up by enterocytes via an endocytotic process ( Fig. 45-7 ) and moved directly into the blood. Overall, protein digestion-absorption is very efficient; <4% of ingested nitrogen is excreted in the stool.

The protein that is digested and absorbed in the small intestine comes from both dietary and endogenous sources. Dietary protein in developed countries amounts to 70 to 100 g/day. This amount is far in excess of minimum daily requirements and represents 10% to 15% of energy intake. In contrast, dietary protein content in developing countries in Africa is often 50 g/day. Deficiency states are rare unless intake is markedly reduced.

Proteins are encoded by messenger RNA (mRNA) and consist of 20 different amino acids. Nine of these amino acids are essential (see Table 58-2 ); that is, they are not synthesized in adequate amounts by the body and thus must be derived from either animal or plant protein sources. In addition, cells synthesize some other amino acids by post-translational modifications: γ-carboxyglutamic acid, hydroxylysine, 4-hydroxyproline, and 3-hydroxyproline. Protein digestion is influenced by the amino-acid composition of the protein, by the source of protein, and by food processing. Thus, proteins rich in proline and hydroxyproline are digested relatively less completely. Cooking, storage, and dehydration also reduce the completeness of digestion. In general, protein derived from animal sources is digested more completely than plant protein.

In addition to protein from dietary sources, significant amounts of endogenous protein are secreted into the gastrointestinal tract, then conserved by protein digestion and absorption. Such endogenous sources represent ~50% of the total protein entering the small intestine and include enzymes, hormones, and immunoglobulins present in salivary, gastric, pancreatic, biliary, and jejunal secretions. A second large source of endogenous protein is desquamated intestinal epithelial cells as well as plasma proteins that the small intestine secretes.

Neonates can absorb substantial amounts of intact protein from colostrum (see p. 1146 ) through the process of endocytosis. This mechanism is developmentally regulated and in humans remains active only until ~6 months of age. In adults, proteins are almost exclusively digested to their constituent amino acids and dipeptides, tripeptides, or tetrapeptides before absorption. However, even adults absorb small amounts of intact proteins. These absorbed proteins can be important in inducing immune responses to dietary proteins.

Luminal digestion of protein involves both gastric and pancreatic proteases, and yields amino acids and oligopeptides

Both gastric and pancreatic proteases, unlike the digestive enzymes for carbohydrates and lipids, are secreted as proenzymes that require conversion to their active form for protein hydrolysis to occur. The gastric chief cells secrete pepsinogen. We discuss the pH-dependent activation of pepsinogen on pages 873–874 . Pepsin has a maximal hydrolytic activity between pH 1.8 and 3.5, and becomes irreversibly inactivated at above pH 7.2. Pepsin is an endopeptidase with primary specificity for peptide linkages of aromatic and larger neutral amino acids. Although pepsin in the stomach partially digests 10% to 15% of dietary protein, pepsin hydrolysis is not absolutely necessary; patients with either total gastrectomies or pernicious anemia N45-6 (who do not secrete acid and thus whose intragastric pH is always >7) do not have increased fecal nitrogen excretion.

Five pancreatic enzymes ( Table 45-2 ) participate in protein digestion and are secreted as inactive proenzymes. Trypsinogen is initially activated by a jejunal brush-border enzyme, enterokinase (enteropeptidase), by the cleavage of a hexapeptide, thereby yielding trypsin. Trypsin not only autoactivates trypsinogen but also activates the other pancreatic proteolytic proenzymes. The secretion of proteolytic enzymes as proenzymes, with subsequent luminal activation, prevents pancreatic autodigestion before enzyme secretion into the intestine.

Pancreatic proteolytic enzymes are either exopeptidases or endopeptidases and function in an integrated manner. Trypsin, chymotrypsin, and elastase are endopeptidases with affinity for peptide bonds adjacent to specific amino acids, so that their action results in the production of oligopeptides with two to six amino acids. In contrast, the exopeptidases —carboxypeptidase A and carboxypeptidase B—hydrolyze peptide bonds adjacent to the carboxyl (C) terminus, which results in the release of individual amino acids. The coordinated action of these pancreatic proteases converts ~70% of luminal amino nitrogen to oligopeptides and ~30% to free amino acids.

Brush-border peptidases fully digest some oligopeptides to amino acids, whereas cytosolic peptidases digest oligopeptides that directly enter the enterocyte

Small peptides present in the small-intestinal lumen after digestion by gastric and pancreatic proteases undergo further hydrolysis by peptidases at the brush border (see Fig. 45-6 ). Multiple peptidases are present both on the brush border and in the cytoplasm of villous epithelial cells. This distribution of cell-associated peptidases stands in contrast to that of the oligosaccharidases, which are found only at the brush border. Because each peptidase recognizes only a limited repertoire of peptide bonds, and because the oligopeptides to be digested contain 24 different amino acids, large numbers of peptidases are required to ensure the hydrolysis of peptides.

As we discuss below, a transporter on the apical membrane of enterocytes can take up small oligopeptides, primarily dipeptides and tripeptides. Once inside the cell, these oligopeptides may be further digested by cytoplasmic peptidases. The brush-border and cytoplasmic peptidases have substantially different characteristics. For example, the brush-border peptidases have affinity for relatively larger oligopeptides (three to eight amino acids), whereas the cytoplasmic peptidases primarily hydrolyze dipeptides and tripeptides. Because the brush-border and cytoplasmic enzymes often have different biochemical properties (e.g., heat lability and electrophoretic mobility), it is evident that the peptidases in the brush border and cytoplasm are distinct, independently regulated molecules.

Like the pancreatic proteases, each of the several brush-border peptidases is an endopeptidase, an exopeptidase, or a dipeptidase with affinity for specific peptide bonds. The exopeptidases are either carboxypeptidases, which release C-terminal amino acids, or aminopeptidases, which hydrolyze the amino acids at the amino (N)–terminal end. Cytoplasmic peptidases are relatively less numerous.

Absorption of whole protein by apical endocytosis occurs primarily during the neonatal period

During the postnatal period, intestinal epithelial cells absorb protein by endocytosis, a process that provides a mechanism for transfer of passive immunity from mother to child. The uptake of intact protein by the epithelial cell ceases by the sixth month; the cessation of this protein uptake, called closure, is hormonally mediated. For example, administration of corticosteroids during the postnatal period induces closure and reduces the time that the intestine can absorb significant amounts of whole protein.

The adult intestine can absorb finite amounts of intact protein and polypeptides. Uncertainty exists regarding the cellular route of absorption, as well as the relationship of the mechanism of protein uptake in adults to that in neonates. Enterocytes can take up by endocytosis a small amount of intact protein, most of which is degraded in lysosomes (see Fig. 45-7 ). A small amount of intact protein appears in the interstitial space. The uptake of intact protein also occurs through a second, more specialized route. In the small intestine, immediately overlying Peyer's patches (follicles of lymphoid tissue in the lamina propria), M cells replace the usual enterocytes on the surface of the gut. M cells have few microvilli and are specialized for protein uptake. They have limited ability for lysosomal protein degradation; rather, they package ingested proteins (i.e., antigens) in clathrin-coated vesicles, which they secrete at their basolateral membranes into the lamina propria. There, immunocompetent cells process the target antigens and transfer them to lymphocytes to initiate an immune response. Although protein uptake in adults may not have nutritional value, such uptake is clearly important in mucosal immunity and probably is involved in one or more disease processes.

The apical absorption of dipeptides, tripeptides, and tetrapeptides occurs via an H ⁺ -driven cotransporter

Virtually all absorbed protein products exit the villous epithelial cell and enter the blood as individual amino acids. Substantial portions of these amino acids are released in the lumen of the small intestine by luminal proteases and brush-border peptidases and, as we discuss below, move across the apical membranes of enterocytes via several amino-acid transport systems (see Fig. 45-6 ). However, substantial amounts of protein are absorbed from the intestinal lumen as dipeptides, tripeptides, or tetrapeptides and then hydrolyzed to amino acids by intracellular peptidases.

The transporter responsible for the uptake of luminal oligopeptides ( Fig. 45-8 A ) is distinct from the various amino-acid transporters. Furthermore, administering an amino acid as a peptide (e.g., the dipeptide glycylglycine) results in a higher blood level of the amino acid than administering an equivalent amount of the same amino acid as a monomer (e.g., glycine; see Fig. 45-8 B ). One possible explanation for this effect is that the oligopeptide cotransporter, which carries multiple amino acids rather than a single amino acid into the cell, may simply be more effective than amino-acid transporters in transferring amino-acid monomers into the cell. This accelerated peptide absorption has been referred to as a kinetic advantage and raises the question of the usefulness of the enteral administration of crystalline amino acids to patients with impaired intestinal function or catabolic deficiencies. The evidence for a specific transport process for dipeptides, tripeptides, and tetrapeptides comes from direct measurements of oligopeptide transport, molecular identification of the transporter, and studies of the hereditary disorders of amino-acid transport, cystinuria, and Hartnup disease.

Oligopeptide uptake is an active process driven not by an Na ⁺ gradient, but by a proton gradient. Oligopeptide uptake occurs via an H/oligopeptide cotransporter known as PepT1 (SLC15A1; see p. 123 ), which is also present in the renal proximal tubule. PepT1 also appears to be responsible for the intestinal uptake of certain dipeptide-like antibiotics (e.g., oral amino-substituted cephalosporins). As noted above, after their uptake, dipeptides, tripeptides, and tetrapeptides are usually hydrolyzed by cytoplasmic peptidases to their constituent amino acids, the forms in which they are transported out of the cell across the basolateral membrane. Because peptides are almost completely hydrolyzed to amino acids intracellularly, few peptides appear in the portal vein. Proline-containing dipeptides, which are relatively resistant to hydrolysis, are the primary peptides present in the circulation.

Amino acids enter enterocytes via one or more group-specific apical transporters

Multiple amino-acid transport systems have been identified and characterized in various nonepithelial cells. The absorption of amino acids across the small intestine requires sequential movement across both the apical and basolateral membranes of the villous epithelial cell. Although the amino-acid transport systems have overlapping affinities for various amino acids, the consensus is that at least seven distinct transport systems are present at the apical membrane (see Table 36-1 ); we discuss the basolateral amino-acid transporters in the next section. Whereas many apical amino-acid transporters are probably unique to epithelial cells, some of those at the basolateral membrane are probably the same as in nonepithelial cells.

The predominant apical amino-acid transport system is system B ⁰ (SLC6A19, SLC6A15; see Table 36-1 ) and results in Na ⁺ -dependent uptake of neutral amino acids. As is the case for glucose uptake (see p. 919 ), uphill movement of neutral amino acids is driven by an inwardly directed Na ⁺ gradient that is maintained by the basolateral Na-K pump. The uptake of amino acids by system B ⁰ is an electrogenic process and represents another example of secondary active transport. It transports amino acids with an l -stereo configuration and an amino group in the α position. System B ⁰⁺ (SLC6A14) is similar to system B ⁰ but has broader substrate specificity. System b ⁰⁺ (SLC7A9/SLC3A1 dimer) differs from B ⁰⁺ mainly in being independent of Na ⁺ .

Other apical carrier-mediated transport mechanisms exist for anionic (i.e., acidic) α amino acids, cationic (i.e., basic) α amino acids, β amino acids, and imino acids (see Table 36-1 ). Because these transporters have overlapping affinities for amino acids, and because of species differences as well as segmental and developmental differences among the transporters, it has been difficult to establish a comprehensive model of apical membrane amino-acid transport in the mammalian small intestine ( Box 45-3 ).

Box 45-3

Defects in Apical Amino-Acid Transport

Hartnup Disease and Cystinuria

Hartnup disease and cystinuria are hereditary disorders of amino-acid transport across the apical membrane. These autosomal recessive disorders are associated with both small-intestine and renal-tubule abnormalities (see Box 36-1 ) in the absorption of neutral amino acids in the case of Hartnup disease and of cationic (i.e., basic) amino acids and cystine in the case of cystinuria.

The clinical signs of Hartnup disease are most evident in children and include the skin changes of pellagra, cerebellar ataxia, and psychiatric abnormalities. In Hartnup disease, the absorption of neutral amino acids by system B ⁰ (SLC6A19) in the small intestine is markedly reduced, whereas that of cationic amino acids is intact ( Fig. 45-9 ).

The principal manifestation of cystinuria is the formation of kidney stones. In cystinuria, the absorption of cationic amino acids by system b ⁰⁺ (SLC7A9/SLC3A1 dimer) is abnormal as a result of mutations in SLC7A9 or SLC3A1, but absorption of neutral amino acids is normal.

Because neither of these diseases involves the oligopeptide cotransporter, the absorption of oligopeptides containing either neutral or cationic amino acids is normal in both diseases. Only 10% of patients with Hartnup disease have clinical evidence of protein deficiency (e.g., pellagra) commonly associated with defects in protein or amino-acid absorption. The lack of evidence of protein deficiency is a consequence of the presence of more than one transport system for different amino acids, as well as a separate transporter for oligopeptides. Thus, oligopeptides containing neutral amino acids are absorbed normally in Hartnup disease, and oligopeptides with cationic amino acids are absorbed normally in cystinuria.

These two genetic diseases also emphasize the existence of amino-acid transport mechanisms on the basolateral membrane that are distinct and separate from the apical amino-acid transporters. Thus, in both Hartnup disease and cystinuria, oligopeptides are transported normally across the apical membrane and are hydrolyzed to amino acids in the cytosol, and the resulting neutral and cationic amino acids are readily transported out of the cell across the basolateral membrane.