Nonspecific adaptation of jejunal amino acid uptake in the rat

GASTROENTEROLOGY 1986;91:49-55

of Jejunal Amino GARY M. LEVINE Division of Gastroenterology Philadelphia, Pennsylvania; Pennsylvania

and Nutrition, Albert Einstein Medical Center-Northern and Temple University School of Medicine, Philadelphia,

Lurhinal nutrients are a major effector bf intestinal adaptation. Amino acids ard trophic to the intestine, but their role in regulating amino acid trhnsport is not well documented. The prbsence of several distifict amino acid transpdrt systems raises the question of whdther adaptation is class-specific. Studies were carried out in parenterally nourished rats receiving a it-day jejunal infusion of a 3% solutioq of either aminoisobutyric acid, aspartil: acid, ghitamine, histidine, lysine, of valine, While all amino acids were trophic tb the intestine, their effects on the in vitro uptake of 0.1, 1.0 alid i.O.0 mM aspartic acid, lysine, and valine (representative acid, basic, and neutral amino acids) were irariable and nonspecific. Compared to controls receiving either total parenterhl nutritiori alone or total $are$eral nutrition plus luminal saline, prioi lysine and aspartic acid infusion significantly increased in vitro uptake of all three amino acids tested, whereas valine had little effect on trarlspo$ No effect bn transport was seen with glutamine [actively metabdlized by the intestine as is aspartic acid), arhinoisobutyric acid (a nonmetabolizable qmino acid congendr), or histidin6 [the most trbphic amino acid). I~-Itionclusion, while individual amind acids cause an adaptation of amino acid uptake, the eff6cts are nonBpecific cind independent of their metabdlic or trobhfc potential. Received August 7, ,1965. Accepted December 19,1985. Address requests for reprints to: Gaiy M. BevinB, M.D., Head of Division of Gastroenterolagy and Nutriiion, Albert Einstein Medical Center, Northern Division, York ahd Tabor Roads, Philadelphia, Pennsylvania 19141. from This work was supiorted b a grant (lRdl-AM-31955-01) the National Institutei of Hea Tth. This work was presented in part at the National Meeting of the American Federation for Clinical Research, Washington, Q.C., May 1984, and at +e Annual Meetjig of the American Gastroenterological Association, New Oilcans, Louisiana, May 1984. The author th&nk$ Elizabeth Yezdimir for tixhnical assistance and Donna Black for manuscript prep&atibn. Q 1986 by the American Gastroenterblogical Association 0016~5085/86/$3.50

Division,

Nutrients play a major role in the regulation of intestinal structufe and function. Sugars sticli as glucosa, frutitose, sucrose, and galactose all maintain intestinal, mass wheli infused individually into parenterally fed rats (1,2). A similar saltitory trophic response has been reported for infusion of a hornplete niixture of amino acids, as well is certain inditiidtial amino acids (3,~). More reckntly, the characteristics of adaptation of nutrient gbsorption have begun to be unraveled. Itiusioi of glucose into tlie iat intestine not only increases intestinal mass in a dose-dependent fashion, but stimulates both in vivo ahd in Gitjro glucose trahsport (2,5,8). Metabolizable sqgars, r&her than nonmetaboiizable analogties,. Are necessary for stimulation of glucose uptak$ (2,5). Adaptation of absorption appbars td po’ssess certairi specificities. For vxample, infusion of gldcose into parenterallf fed rats does nbt affect leucine active transport (2). Rkcently, tw,o studies have reported that a high-prdiein diet stimulated amino acid absorption with a reciprochl decrease in sugar absorptioh,(‘/&). These data suggest that cotnplex interrelationships exist between the presetice of limiinal nutrients and regulatiori of nutrient absotption., .Stud) df the a$aptation of amin acid transport is komplioaied by the presence of at ledst three o$ four ipdividual actiye transport systems responsible for the uptake bf basic,.acidic, neutral, and imiao amino acids (9). No information is gvailable concerning bhether ari individual aminb acid of a spetiific class can affect its owxi absorption ,ot tihether it can affect ih@ absorptiov of amino acids transported by other tybed .of. carriers. A series of experiments was designed in which individual amino acids were infused into parehterally ndurished rats in order to deterdine (a) if a representative neutral, basic) or acidic aming acid stimulates its own in vitro uptake; Abbreviations used in this paper: AIB, aminoisobutyric TPN, total parenteral nutrition.

acid;

50 LEVINE

GASTROENTEROLOGYVol.91,No.l

(b] if an amino acid of one class affects the transport of amino acids of other classes; and (c) if amino acids such as aspartic acid and glutamine (actively metabolized by the intestine], aminoisobutyric acid, valine, and lysine (nonmetabolizable by the intestine) or histidine (highly trophic to the intestine) affect amino acid uptake.

Materials and Methods Experimental

Design

The primary purpose of these investigations was to determine whether or not there was any specificity in the adaptive response of the intestine to luminal amino acids. We used parenterally nourished rats in order to obviate any deleterious metabolic effects of negative nitrogen balance and weight loss or variation in caloric intake. Animal and tissue preparation. Male SpragueDawley rats weighing -250 g (Charles River Breeding Laboratorjes, Wilmington, Mass.) were fed pelleted rat diet and tap water until the afternoon before surgery. Under ketamine anesthesia, all animals underwent a neck dissection and laparotomy. Rats were prepared for total parenteral nutrition (TPN) by inserting a silastic catheter into the right jugular vein and for luminal infusion by inserting another silastic catheter into the midjejunum -20 cm distal to the ligament of Treitz (3). The catheters were secured by a harness, stainless steel spring, and swivel assembly (Spalding Medical Products, Arroyo Grande, Calif.), allowing the rat mobility within its metabolic cage. All rats received a TPN solution consisting of 35% dextrose, 4.25% amino acids (Travasol, Baxter-Travenol Laboratories, Deerfield, Ill.), vitamins, and electrolytes. Total parenteral nutrition was begun at 30 ml/day and gradually increased to an infusion rate of 50 ml/day by the beginning of the fourth postoperative day. One group received TPN alone, while all the remaining groups also received an enteral infusion. The enteral infusion rate was initially 10 ml/day, increasing to 20 ml/day by the fourth day. To control for the presence of i&alumina1 volume, a second control group received 0.9% saline infusion, whereas the experimental groups received a 3% solution of one of the following amino acids dissolved in distilled water: aminoisobutyric acid (AIB), aspartic acid, glutamine, histidine, lysine, or valine. Previous studies have shown that the calorie and nitrogen content of the TPN solution was sufficient to maintain nitrogen balance (2). Infusions were discontinued on the morning of the seventh day; the rats were removed from their harnesses, weighed, and killed 2 h later by decapitation. The abdomen was opened and the small intestine flushed with iced 0.9% saline and air. The infusion catheter was located and a 15-cm segment of small intestine distal to the catheter was removed. The first l-cm portion of the intestinal segment was discarded, and the next 10-12 cm was used for determinations. The proximal 2-cm portion of the segment was excised, suspended vertically, and its exact length was determined against a constant tension of 15 g. This segment was opened and blotted, and mucosal scrapings were prepared. Mucosal scrapings were weighed,

homogenized in 5 x wt/vol of 0.9% saline, and frozen at -70°C until analyzed for protein content (10). The remaining segment of midjejunum was everted over a glass rod, cut into rings weighing -10-20 mg each, and used for uptake studies. Preliminary observations. A series of preliminary experiments was performed to determine if the effects of luminal infusion were uniform over the 15-cm segment of intestine used for our studies. Two groups of 3 rqts each received TPN plus a luminal infusion of 3% valine or lysine for 1 wk. After the rats were killed, the midjejunal segment was divided into twelve l-cm segments. Uptake of 1 mM valine was determined in the first, fifth, and nirith segments, and 1 mM lysine uptake was determined in the second, sixth, and tenth segments. The six remaining 2-cm segments were used for measurement of mucosal weight. Amino acid uptake and mucosal weight were uniform throughout the length of intestine studied. Determination of intracellular uptake. Rings were incubated in 25-ml erlenmeyer flasks containing 5 ml of Krebs’ bicarbonate buffer, pH 7.4, pregassed with 5% CO,-95% O2 at 37°C in a shakei bath rotating at 100 cycles per minute. Nine pairs of erlenmeyer flasks were prepared for each rat. The incubation medium contained either 0.1, 1, or 10 mM concentrations of valine, aspartic acid, or lysine. Radipactive tracers consisted of L-[14C(U)]valine (250mCi/mmol), L-[14C(U)]aspartic acid (200mCi/mmol), L-[14C(U)]lysine (300 mCi/mmol) (New England Nuclear, Boston, Mass.). [1,23H]Polyethylene glycol, molecular weight 4000, 0.5-2 mCi/mmol (New England Nuclear), was used as an extracellular marker. The incubation mixture contained -25,000 dpm/ml of 14C and 60,000 dpm/ml of 3H. Preliminary experiments revealed that amino acid uptake was linear for 5 min and that [3H]polyethylene glycol permeated the extracellular space in 90-120 s. All incubations were performed for 3 min, after which time the rings were drained over gauze and immediately placed in acid saline (pH 1) to abolish metabolic activity. Rings were homogenized in 5 ml of acid saline, and 1 ml aliquots were removed for scintillation counting and protein analysis. Scintillation counting was performed after dispersion in a Triton-toluene scintillation fluid in a Beckman model 7600 liquid scintillation counter (Beckman Instruments, Inc., Fullerton, Calif.) using external standards for quench correction. Counting efficiency was >60% for 14C and >30% for 3H with
NONSPECIFIC JEJUNAL AMINO ACID UPTAKE

July 1986

Table

1, Effect of Luminal

Amino

TPN alone (n = 5) Initial weight (g) Final weight (g) Mucosal weight (g) Mucosal protein (mg/cm)

Acids on Body Weight, Mucosal Saline (n = 6)

AIB (n = 8)

Weight, and Mucosal

Content

Glutamine

Histidine

Valine

Aspartic acid

Lysine

(n = 6)

(n = 6)

(n = 7)

(n = 6)

(n = 7)

258 + 2.5 267 2 2.9 57.4 2 2.1“ 6.2 2 0.2d

261 t 5.2 263 t 2.4

261 2 5.2 267 rt 5.1

259 r 3

255 2 1.6 260 k 1.0

272 + 0.6’ 274 k 1.7’

272 k 1.7’ 274 lr 2.4”

34.1 ? 1.0 3.6 4 0.3

39.9 2 0.4b 4.6 k O.lb

50.7 ? 1.40 5.3 ? 0.1”

47.0 + 0.5” 5.5 2 0.1”

254 f 2

Protein

45.0 t 1.1” 5.4 r 0.1”

51

260 + 2.5 263 t 2.6

45.1 -+ 0.9O 51.3 * 0.7” 5.8 + 0.1” 5.2 + O.la

AIB, aminoisobutyric acid; TPN, total parenteral nutrition. 0 p < 0.01 vs. saline and TPN alone by t-test. b p < 0.01 vs. TPN alone. ’ p < 0.05 vs. AIB and lysine; p < 0.01 vs. all others by t-test. d p < 0.01 vs. all groups except lysine by t-test.

methyl ethyl ketoneipyridineiwateriglacial acetic acid (70:15:15:2). Plates were developed with Ninhydrin, and the amino acid spot was scraped and placed in scintillation vials for counting. Scintillation counting was also performed on a sample of each solution used for plating. The efficiency of recovery of each plate was measured by applying a known standard of radioactive amino acid. Determination of the actual number of [14C]amino acid dpm present after incubation was assessed by comparing the dpm recovered with the dpm plated after compensating for the efficiency of each plate. [14C]Amino acid recovery exceeded 92% in the aspartic acid group and from 95% to 97% in other groups. There were no significant differences in recovery between groups or between each of the three amino acids tested. Point-by-point analysis of difStatistical analysis. ferences between controls and each experimental group at each concentration tested was performed using Student’s t-test. The t-test also was used for comparing differences in body weight, mucosal weight, and mucosal protein content. Differences in the overall uptake of each of the three amino acids tested at all three concentrations were studied by using analysis of variance (12), and significance was assessed by Duncan’s multiple range t-test (13). This method allowed simultaneous comparison of uptake.

Results Effects of Luminal Weight

and

Mucosal

Amino Acids Mass

on Body

As shown in Table 1, the initial and final body weights were slightly higher in the AIB and glutamine groups. The group receiving TPN plus saline had a significantly higher mucosal weight and mucosal protein content than the group receiving TPN alone (p < 0.01). In comparison to the TPN plus saline group, all groups receiving luminal amino acids had a significantly higher mucosal weight and protein content (p < 0.01). In addition, the mucosal weight and protein content of the histidine group exceeded all other groups, confirming that histidine has a greater trophic potential than the other amino acids tested (4).

Comparison

of Amino

Acid

Uptake

For all groups tested and at all three concentrations examined, the in vitro uptake of valine was greater than lysine, which was greater than aspartic acid. This effect was significant (p < 0.01 by analysis of variance]. The three concentrations of amino acids used (0.1, 1 .O, and 10.0 mM) were selected to encompass the range normally encountered in the intestine (14). The lowest concentration might simulate the interdigestive period when small amounts of amino acid are present in the intestinal lumen from the digestion of mucous and exfoliated cells. A 1-mM intraluminal concentration of amino acid may occur after a low-protein meal, whereas the 10 mM concentration would be anticipated to be present after a high-protein meal. As previously reported, the “apparent K,” of amino acids is in the range of 0.5-5 mM (9). Although uptake data from only three concentrations do not allow accurate calculation of kinetic parameters, the two lower concentrations used should approximate the range at which most transport occurs through carrier-mediated processes, whereas at the highest concentration, 10 mM, much of the transport should occur through a nonsaturable process. The specific activity of in vitro amino acid uptake of all three amino acids was identical in the TPN alone [data not shown) and TPN plus saline groups. Therefore, the TPN plus saline group served as the control to which all other groups receiving TPN plus luminal amino acids were compared. Effects of luminal amino acids on 0.1 mM amino acid uptake. As shown in Figure 1, the prior

administration of lysine significantly increased aspartic acid uptake (p < O.Ol), whereas prior valine administration increased valine uptake (p < 0.01) compared to saline. Prior exposure to either histidine or valine significantly decreased lysine uptake (p < 0.05) compared to saline, and prior AIB administration decreased valine uptake (p < 0.05). Effects of luminal amino acids on 1 mM As shown in Figure 2, the prior amino acid uptake. administration of lysine significantly increased the

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\

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NONSPECIFIC

July 1986

ASPARTIC ACID

JEJUNAL AMINO ACID UPTAKE

LY SINE

53

VALINE

19 ** 8

.:.:.:.:.~.......s.. :.:.:.:.&#$~ .:.:.y.%y.%w4

:.:.:.:&$$$$g

6

JL

AMINO AiD INFUSED Figure

2. Effect of luminal infusion on 1 mM aspartic acid, lysine, and valine uptake. The format of this figure is identical to that of Figure 1. Lysine significantly increased aspartic acid, lysine, and valine uptake. Aminoisobutyric acid significantly decreased the uptake of all three amino acids, whereas glutamine decreased aspartic acid and valine uptake. Valine decreased lysine uptake.

LY SINE

ASPARTlC ACID

VALINE

+

36

30 +:. C$::: 8:

p. .

BQ i

HVAL

*B

AMINO A;D INFUSED Figure

3. Effect of luminal infusion on 10 mM aspartic acid, lysine, and valine uptake. The format of this figure is identical to that of Figure 1. Lysine and aspartic acid significantly increased the uptake of aspartic acid, lysine, and valine. Aminoisobutyric acid, histidine, and valine significantly decreased aspartic acid uptake, whereas AIB and glutamine significantly decreased valine uptake.

54

LEVINE

the 1.0 and 10 mM concentrations. Prior aspartic acid administration increased the uptake of all three amino acids at the 10 mM concentration. These data suggest that luminal exposure to lysine and aspartic acid induced a nonsaturable process, perhaps related to an increase in intestinal permeability. This hypothesis would confirm a previous observation from our laboratory. We found that intraluminal glucose administration increased the permeability of the jejunum to both glucose and leucine, suggesting that one of the mechanisms by which luminal nutrients enhance absorption is through a passive process (2). Conversely, in the present study, it was shown that intraluminal valine administration led to an increase only in the 0.1 mM uptake of valine. It may be concluded that valine was capable of stimulating its own high affinity, carrier-mediated transport, which was demonstrable at the 0.1mM incubation concentration. The method of data presentation in this study should be considered in interpreting conclusions. The specific activity of amino acid transport was used because it best demonstrates the relative ability of a given quantity of intestinal tissue to carry out transport. It is also feasible, however, to determine the effects of amino acid infusion on the total transport capacity simply by multiplying the specific activity by a measure of gut mass (i.e., protein content per centimeter). Any calculation of the data in terms of uptake per centimeter would have taken into account differences in mucosal mass produced by the various amino acids (Table 1). For example, although histidine generally did not increase transport specific activity, its salutory effect on gut mass led to an increase in overall segmental absorption of the three amino acids tested. In a similar manner, the effect of lysine infusion on total transport capacity per segment would be amplified, as it caused significant increases in transport specific activity as well as augmented intestinal mass. One of the factors that could influence adaptation is the ability of an amino acid to be metabolized by the intestine. Because aspartic acid stimulates amino acid uptake and is metabolized by the intestine to some extent (~3, we compared its effects to the infusion of AIB and glutamine. Aminoisobutyric acid, a nonmetabolizable amino acid congener, had disparate effects on amino acid transport and intestinal mass. Aminoisobutyric acid was as effective as the naturally occurring amino acids in maintaining intestinal mass; it moderately depressed the uptake of our test.panel of amino acids at both 1.0 and 10.0 mM concentrations. We also studied the effects of glutamine, which is actively metabolized by the intestine, providing approximately two-thirds of the intestine’s energy requirements in the interdigestive

GASTROENTEROLOGY

Vol. 91, No. 1

period (15). The trophic potential of glutamine was no greater than that of AIB, and it had no stimulatory effect on amino acid uptake. Glutamine significantly depressed aspartic acid and valine uptake at the 1.0 mM concentration and also depressed valine uptake at the 10 mM concentration. These studies demonstrate that lysine, an essential amino acid, was an effector of adaptation of its own uptake, as well as that of aspartic acid and valine. However, when we examined the effects of valine, another essential amino acid, we found it to have a minimal effect on adaptation, producing a significant stimulatory effect only on 0.1 mM valine uptake. It should be realized that the capacity of the small intestine for valine uptake exceeded that for lysine and aspartic acid. This inherently high transport capacity may reflect the fact that valine is an essential branched chain amino acid needed both for protein synthesis and muscle energy metabolism (16). It is unwise, however, to extrapolate the results from a limited number of experiments to general concepts of the overall needs of other amino acids. These data should be considered in light of previous work regarding the effects of fasting, semistarvation, and protein deprivation on amino acid transport. In general, it has been shown that catabolic states preserve or stimulate amino acid transport in the rat (17,lB). Other studies have shown that feeding a low-protein diet did not severely affect methionine (19) or proline (7) absorption. In contrast to the maintenance of amino acid absorptive capacity, fasting or a low-carbohydrate diet significantly depress the capacity for glucose assimilation. Teleologically, these data suggest that protein uptake must be preserved because of the critical need of amino acids. Karasov et al. (7) hypothesized that it would be impractical for the gut to maintain high levels of transport capacity for energy sources, because energy intake is much more variable and available from a variety of carbohydrate or lipid sources. In summary, these studies further define the role of individual amino acids in intestinal adaptation. Individual amino acids differ in their trophic potential, and they affect changes in the specific activity of in vitro uptake independent of their ability to stimulate intestinal growth. Studies are underway to determine whether in vivo amino acid uptake is affected after luminal infusion of individual amino acids.

References Weser E, Vandeventer A, Tawil T. Stimulation of small bowel mucosal growth by midgut infusion of different sugars in rats maintained by total parenteral nutrition. Pediatr Gastroenter01 Nutr 1982;1:411-6. Richter GC, Levine GM, Shiau YF. Effects of luminal glucose

July 1986

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versus non-nutritive i&sates on jejunal mass and absorption in the rat. Gastroenterology 1983;85:1105-12. Spector MH, Levine GM, Deren JJ. Direct and indirect effects of dextrose and amino acids on gut mass. Gastroenterology 1977;72:70&10. Spector MH, Traylor J, Young EA, Weser E. Stimulation of mucosal growth by gastric and ileal infusion of single amino acids in parenterally nourished rats. Digestion 1981;21:3340. Kotler DP, Levine GM, Shiau YF. Effects of luminal nutrition and metabolic status on in vivo glucose absorption. Am J Physiol 1981;240:G432-6. Weser E, Babbitt J, Vanderventer A. Relationship between enteral glucose load and adaptive mucosal growth in the small bowel. Dig Dis Sci 1985;30:675-81. Karasov WH, Pond RS III, Solberg DH, Diamond JM. Regulation of proline and glucose transport in mouse intestine by dietary substrate levels. Proc Nat1 Acad Sci USA 1983;80: 7674-7. Scharrer E, Wolfram S, Raab W, Amann B, Ange N. Adaptive changes of amino acid and sugar transport across the brush border of the rat. In: Robinson JWL, Dowling RI-I, Riecken EO, kds. Mechanisms of intestinal adaptation. Lancaster: MTP Press, 1982:123-37. Munck BG. Intestinal absorption of amino acids. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven, 1981:1097-122.

NONSPECIFIC JEJUNAL AMINO ACID UPTAKE

55

10. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-75. 11. Brenner M, Niederwieser A, Pataki G. Amino acids and derivatives. In: Stahl E, ed. Thin layer chromatography. New York: Academic, 1965:391-432. 12. Winer BJ. Statistical principles in experimental design. 2nd ed. New York: McGraw-Hill, 1971:514-603. 13. Bruning JL, Kintz BL. Computational handbook of statistics. Glenview, Ill.: Scott Foresman and Company, 1968:115-7. 14. Adibi SA, Mercer DW. Protein digestion in human intestine as reflected in luminal, mucosal and plasma amino acid concentrations after meals. J Clin Invest 1973;52:1586-94. 15. Windmueller HG, Spaeth AE. Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem 1974; 249:5070-g. 16. Fulks RM, Li JB, Goldberg AL. Effects of insulin, glucose and amino acids on protein turnover in rat diaphragm. J Biol Chem 1975;250:290-8. 17. Steiner M, Gray SJ. Effect of starvation on intestinal amino acid absorption. Am J Physiol 1969;217:747-52. 18. Hindmarsh JT, Kilbe D, Ross B, Wiseman G. Further studies in intestinal active transport.during semi-starvation. J Physiol 1967;188:207-18. 19. Lis TM, Crampton RF, Matthews DM. Effect of dietary changes on intestinal absorption of L-methionine and Lmethionyl+methionine in the rat. Br J Nutr 1972;27:159-67.