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Gut Protein Uptake and Mechanisms of Meal-Induced Cortisol Release

Departments of Neuroendocrinology (C.B., M.H., D.N., J.B.) and Internal Medicine I (B.S., V.M., H.L.F., W.K.), University of Lübeck, 23538 Lübeck, Germany; and Fresenius Kabi (J.S.), 61532 Bad Homburg, Germany

Address all correspondence and requests for reprints to: Christian Benedict, Department of Neuroendocrinology, University of Lübeck, Ratzeburger Allee 160, Haus 23a, 23538 Lübeck, Germany. E-mail: benedict{at}kfg.uni-luebeck.de.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The enhanced cortisol release after protein-rich meals might represent a neuroendocrine response to food allergens. We tested whether the antigenicity of proteins contributes to this effect. Twelve healthy men nasogastrically received casein, its less allergenic hydrolysate, and placebo. Contrary to expectations, secretion of cortisol (area under the curve, 742.70 ± 73.48 vs. 542.95 ± 70.31 µmol/liter·min, P < 0.03) and ACTH (2020.21 ± 251.10 vs. 1649.82 ± 241.23 µmol/liter·min, P < 0.05) was stronger on casein-hydrolysate than casein. Systemic immune activity remained unaffected as indicated by unchanged IL-6 plasma concentrations. This finding indicates that the grade of hydrolysis of a protein and the presence of particular amino acids, rather than its antigenicity, are crucial for the pituitary-adrenal response to nutrients. To further examine whether this response is triggered at the gastrointestinal mucosa or after the substance has reached the circulation, in a supplementary experiment, amino acids were given either nasogastrically or iv to healthy men (n = 4). Only the nasogastric infusion of amino acids induced a significant rise in cortisol concentrations. Serum concentrations of tryptophan, which is known to directly excite the hypothalamo-pituitary-adrenal axis, were comparable for both conditions. We conclude that the meal-related hypothalamo-pituitary-adrenal axis response to amino acids results from a signal that rather acts at the gastrointestinal mucosa than directly via the circulating blood.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
FOOD INTAKE ENHANCES serum cortisol concentrations in humans, especially at noontime (1, 2, 3, 4, 5), but the functional significance of this quite robust response of the hypothalamo-pituitary-adrenal (HPA) system is unclear. Interestingly, there is some evidence that cortisol secretion is stronger after intake of protein-rich meals than after intake of carbohydrate-rich meals (6, 7, 8, 9). Considering the fact that proteins have a distinctly greater antigenicity than carbohydrates and that food intake in general represents a fundamental immune challenge to the organism, we supposed that the meal-related cortisol release could serve an immunological function. Specifically, the increase in cortisol release in response to meal intake could counteract the development of an antigen-specific response to food that would prevent any regular uptake of nutrients with antigenic potential. The initial immune response to food is known to be local and primarily restricted to the gut (10, 11, 12). Nevertheless, it could involve some systemic components such as the induction of proinflammatory cytokines like IL-6 that are potent stimulators of HPA secretory activity (13, 14, 15, 16, 17). If the meal-related rise in cortisol is a response to an immune challenge, a protein-rich meal, due to its greater antigenicity, should result in a stronger activation of the HPA system than a meal of the same volume but composed solely of amino acids (18, 19).

To test to what extent the antigenicity of proteins determines the magnitude of the cortisol secretion, we administered casein, which is known to be the major allergen of cow milk (20, 21) and its less allergenic hydrolysate (22) via a nasogastric tube at noontime. We also measured plasma concentrations of IL-6, a most sensitive indicator of innate immune activity that is immediate and not local but via the circulation grasps the entire organism. Contrary to our expectations, this main experiment indicated that the hydrolysate induced a distinctly greater increase of cortisol concentrations than did casein. Plasma IL-6 levels remained unaffected in both conditions. This finding clearly rejects our hypothesis and suggests that the hydrolysis of the protein and some of its amino acid compounds are the crucial factors that drive HPA secretory activity after meal intake. In fact, certain amino acids like tryptophan are known to be potent stimulators of HPA secretory activity (23, 24, 25, 26). Because intestinal amino acids are absorbed into the circulation, the stronger rise in cortisol on casein hydrolysate than casein administration might be the consequence of a more rapid and stronger increase in the blood concentration of amino acids, with some of these molecules exerting a greater influence than others on the HPA system. To further explore this hypothesis, in a supplementary study, cortisol secretory responses to an amino acid solution were compared after enteral administration (via a nasogastric tube) and after parenteral (i.e. intravenous) administration. Also, serum tryptophan concentrations were monitored because several studies have consistently shown an increase in HPA secretory activity after oral administration of tryptophan (23, 25). In these supplementing experiments, an increase in cortisol was selectively observed after the enteral administration of amino acids, which speaks for a mediation of the meal-related rise in cortisol by a signal that is already generated within the gastrointestinal tract.

	Subjects and Methods

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Nonsmoking healthy male volunteers of normal weight [body mass index (BMI) < 25 kg/m²] participated in the studies. They were not under medication at the time of the experiments and had no histories of any metabolic disorder. The study was approved by the local ethics committee, and the volunteers gave written informed consent before participation.

In the main experiment, subjects participated in three sessions; in the supplementary study, subjects participated in two sessions. All sessions were at least 8 d apart. Throughout the sessions, subjects remained in a supine position. The experiments were conducted according to a double-blind, crossover design, and the order of conditions was balanced across subjects in both experiments.

Procedure of the main experiment

Twelve men (mean ± SEM, BMI, 23.64 ± 0.80 kg/m²; age, 26.0 ± 0.69 yr) were nasogastrically administered casein (Sigma, Taufkirchen, Germany), casein-hydrolysate (Amicase, Sigma), and saline. Casein is a compound of 18 different amino acids containing (in milligrams per gram casein) alanine (55.7), arginine (35.7), aspartic acid (50.1), cysteine (0.2), glutamic acid (187.5), glycine (21.3), histidine (28.4), isoleucine (46.9), leucine (75.6), lysine (90.1), methionine (22.0), phenylalanine (41.3), proline (83.5), serine (24.6), threonine (34.6), tryptophan (0.5), tyrosine (28.8), and valine (64.3). The hydrolysate infusion contained exactly the same amounts of the respective amino acids as the protein infusion.

At the start of the experimental session at 1145 h, a polyvinyl catheter was inserted into a forearm vein of each subject, and the subject was intubated with a nasogastric tube. Sessions ended at 1415 h. For the determination of serum cortisol, plasma ACTH, and plasma IL-6 concentrations, blood was collected every 15 min from 1200 to 1415 h. Immediately after the third blood drawing at 1230 h, the test phase started by nasogastrically infusing casein (50 g, diluted in 500 ml saline), casein-hydrolysate (50 g in 500 ml saline), or saline solution (500 ml) at a constant rate. The infusion ended after 30 min at 1300 h.

Procedure of the supplementary experiment

On two occasions, four healthy men (BMI, 23.33 ± 1.26 kg/m²; age, 23 ± 0.81 yr) iv and nasogastrically received an amino acid solution (Aminoplasmal 5%, Braun Melsungen AG, Melsungen, Germany). Aminoplasmal is a compound of 20 different amino acids containing (in milligrams per gram Aminoplasmal) alanine (137.0), arginine (92.0), aspartic acid (13.0), cysteine (5.0), glutamic acid (46.0), glycine (79.0), histidine (52.0), isoleucine (51.0), leucine (89.0), lysine (56.0), methionine (38.0), phenylalanine (51.0), proline (89.0), serine (24.0), threonine (41.0), tryptophan (18.0), tyrosine (13.0), valine (48.0), asparagine (32.8), and ornithine (25.0). The compound is free of carbohydrates.

To keep the design double blind, at the beginning of each session, a nasogastric tube and two iv catheters were inserted. Blood was collected every 15 min between 1200 and 1315 h. Infusion of the amino acid solution started immediately after the second blood drawing at 1230 h. The amino acids were infused nasogastrically within 30 min (50 g amino acids dissolved in 1000 ml) and within 60 min in the iv condition (10 g amino acids dissolved in 200 ml). The different durations of parenteral and enteral administration as well as the different amounts were chosen based on preliminary examinations to make sure that the time course of the increase in blood amino acid concentrations was comparable in both conditions within the first 30 min, when HPA secretory activity and cortisol start to rise. Comparable temporal dynamics of the rise in plasma amino acid concentrations were additionally assured by serum measurements of L-tryptophan during the first 45 min of the infusion period. On the nasogastric condition, saline was simultaneously infused iv at the same amount as on the iv condition; likewise, on the iv condition, saline was administered simultaneously nasogastrically at the same amount as on the nasogastric condition.

Blood parameters

Blood samples were immediately centrifuged, and the supernatant was stored at –20 C until assay determination. Plasma ACTH was measured by electroluminescence immunoassay (LUMI test ACTH, Brahms Diagnostica, Berlin, Germany; interassay coefficient of variation, <12%, intraassay coefficient of variation <8%). Cortisol concentrations were measured by ELISA (Immulite Cortisol, DPC Biermann, Bad-Nauheim, Germany; sensitivity: 5.5 nmol/liter, intra- and interassay coefficients of variation: <7.8 and <7.7%, respectively). Plasma IL-6 concentrations were also measured by ELISA kits (R&D Systems, Minneapolis, MN; sensitivity, 0.70 pg/ml; intra- and interassay coefficients of variation, <4.2% and <6.4%, respectively). Serum L-tryptophan concentrations were determined by standard HPLC (Eppendorf-Biotronik, Netheler, Germany) with photometric detection (sensitivity, 2 nmol/ml).

Statistical analyses

Data are means ± SEM. Statistical testing relied on ANOVA for repeated measures (within-subject factors: substance, time). Values were baseline-adjusted by subtracting the mean value during the 30-min baseline from the posttreatment values. Single time-point comparisons were calculated with pairwise t tests. For the supplementary experiments, within-subject comparisons were performed by means of one-tailed Wilcoxon tests. In addition, area under the curve (AUC) analysis was performed for selected time ranges of experimental sessions as derived in the Resultssection. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The effects of casein, casein-hydrolysate, and saline on serum cortisol concentrations after nasogastric administration are shown in Fig. 1. Increases in cortisol concentrations after substance administration emerged on an overall decreasing level of cortisol reflecting the typical circadian dynamics during this time period. Nasogastric administration of saline solution did not induce a significant rise in serum cortisol concentrations, indicating that the infused volume itself does not represent a substantial stimulus of HPA secretory activity. Administration of casein induced a distinct rise in cortisol concentration as indicated by AUCs, which were significantly greater after casein than after saline infusion (542.95 ± 70.31 vs. 219.56 ± 39.12 µmol/liter·min, P < 0.002). The increase in cortisol concentrations was most consistent between 45 and 75 min after the onset of casein infusion. During this interval, cortisol concentrations averaged 9.62 ± 1.00 µmol/liter on the casein condition and 6.93 ± 0.65 µmol/liter on the placebo condition (P < 0.07). Administration of casein hydrolysate, however, induced a distinctly greater rise in cortisol levels than infusion of casein, also peaking around 60 min after the onset of infusion (casein-hydrolysate vs. saline: 13.36 ± 1.10 vs. 6.91 ± 0.70 µmol/liter, P < 0.001; vs. casein: 9.68 ± 1.12 µmol/liter, P < 0.02). Considering the whole 105-min period of blood sampling starting with the onset of substance administration at 1230 h, the AUC likewise indicated a cortisol response that was most pronounced after casein-hydrolysate (742.70 ± 73.48 µmol/liter·min), compared with saline (P < 0.001), as well as to casein infusion (P < 0.03). Correspondingly, measurements of plasma ACTH concentrations yielded a distinctly stronger increase after infusion of casein-hydrolysate than after casein infusion as indicated by the AUC for the whole postadministration period (casein-hydrolysate vs. casein: 2020.21 ± 251.10 vs. 1649.82 ± 241.23 µmol/liter·min, P < 0.05), with both treatment conditions exceeding placebo values (1243.21 ± 106.52, P < 0.01 and P < 0.05, respectively; see Fig. 1). Plasma IL-6 concentrations appeared to increase slightly after nasogastric administration of casein and casein-hydrolysate. However, this change remained marginal and variable and did not reach any statistical significance (P > 0.2 for all comparisons, Fig. 1, bottom panel).

View larger version (14K): [in this window] [in a new window]   FIG. 1. Mean (±SEM) serum cortisol, plasma ACTH, and plasma IL-6 concentrations before (–30 to 0 min) and after nasogastric administration of saline solution (500 ml, solid lines), casein (50 g, diluted in 500 ml saline, dashed lines), and casein-hydrolysate (50 g in 500 ml saline, dotted lines). Substances were infused within 30 min (0–30 min). P values are indicated for pairwise comparisons between the effects of casein-hydrolysate vs. saline [a, aa, P < 0.05, P < 0.01], casein vs. saline [(b), b, P < 0.1, P < 0.05], and casein vs. casein-hydrolysate [(c), c, P < 0.1, P < 0.05]. Values are baseline adjusted.

The supplementary study compared the rise in serum cortisol after iv and nasogastric administration of amino acid solution. The nasogastric administration of amino acid solution in this study induced a distinct rise in cortisol concentrations that was, as expected, comparable with that seen in the main study after nasogastric administration of casein-hydrolysate. AUC for the 0- to 60-min postadministration period averaged 502.44 ± 40.56 µmol/liter·min after infusion of amino acids (supplementary study) and 514.81 ± 43.04 µmol/liter·min after infusion of casein-hydrolysate (main study; P > 0.77, Mann-Whitney U test). However, in the supplementary experiment, there was no substantial increase in cortisol concentrations during the first 60 min post infusion when the amino acids were infused iv (Fig. 2). Accordingly, the rise in cortisol after nasogastric administration of amino acid solution distinctly exceeded the levels after iv administration, as indicated by comparisons of AUC 0–60 min post administration (nasogastric vs. iv: 502.44 ± 40.56 vs. 297.32 ± 30.35 µmol/liter·min, P < 0.04) and cortisol levels at 15 min (10.15 ± 0.60 vs. 7.3 ± 0.21 µmol/liter, P < 0.04), 30 min (11.15 ± 0.84 vs. 6.82 ± 0.22 µmol/liter, P < 0.04), and 45 min (12.6 ± 1.37 vs. 7.13 ± 0.92 µmol/liter, P < 0.04). The L-tryptophan concentrations increased on both conditions during the first 45 min after the onset of infusions. The increase was closely comparable during the first 30 min of infusion when cortisol concentrations already started to rise in the nasogastric condition (Fig. 2). The L-tryptophan levels at 45 min were higher after nasogastric than iv infusion (119.28 ± 7.70 vs. 83.59 ± 3.26 µmol/liter, P < 0.04). However, at this time the cortisol response to the nasogastric infusion of amino acids was already declining.

View larger version (11K): [in this window] [in a new window]   FIG. 2. Top panel, Mean (±SEM) serum cortisol concentrations during a baseline interval and after nasogastric (dashed lines) and iv (solid lines) administration of an amino acid solution (Aminoplasmal, nasogastric: 50 g amino acids dissolved in 1000 ml; iv: 10 g amino acids dissolved in 200 ml). The amino acids were infused within 30 min (0–30 min) on the nasogastric condition and within 60 min (0–60 min) on the iv condition. The different times and rates of amino acid infusion were chosen to induce roughly comparable rises in blood amino acid concentrations particularly in the beginning of the administration period when the HPA system becomes activated. Bottom panel shows serum L-tryptophan concentrations during the baseline interval and at 15 and 30 min after the onset of amino acid infusions, i.e. in the time interval when cortisol concentrations distinctly increased after nasogastric administration. Note that the increase in serum tryptophan concentrations was closely comparable between both conditions during this time. *, P < 0.05. n.s., Nonsignificant for pairwise comparisons between the effects of enteral and iv administration of the amino acid solution.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

This view is further supported by our measurements of IL-6 that quite sensitively reflect inflammatory organismic responses. Although nasogastric infusion of both casein and casein-hydrolysate appeared to induce a slight and transient increase in plasma IL-6 concentrations, this effect was highly variable and did not reach statistical significance, indicating that the intake of protein-rich meals is not accompanied by a substantial systemic immune response. This has been likewise observed in previous studies (5). Together it can be excluded that IL-6, which is a highly potent stimulator of HPA secretory activity (13, 14, 15, 16, 17), contributes to the mediation of the cortisol response to food intake.

Because in all three conditions in the main experiments, the total volume infused and the rate of infusion were held constant, these factors cannot explain the distinct differences between the cortisol responses. Also, infusing pure saline solution in the placebo control condition was accompanied by only a rather marginal and transient elevation in cortisol that did not reach statistical significance. Thus, the magnitude of food intake in conjunction with the evoked mechanical dilatation of the stomach and with cephalic stimuli, if at all, plays only a minor role in the meal-related regulation of the HPA system. The cortisol response being distinctly stronger to casein-hydrolysate than to casein indicates that the degree of hydrolyzation of ingested proteins is an important factor in the regulation of HPA secretory activity. Hydrolyzed single amino acids per se as well as certain types of amino acids might generate a signal that triggers cortisol release in dependence on their concentration. It may be argued that the cortisol increase is not mediated via the hypothalamic-pituitary system but via direct hormonal and neural effects at the level of the adrenal gland. Contributions of the vegetative nervous system to the regulation of adrenocortical function by splanchnic and vagal inputs are well documented and cannot be fully ruled out here (27, 28, 29). However, on the background of our finding that infusion of casein-hydrolysate and casein also increased plasma ACTH concentrations, an activation of the hypothalamo-pituitary system is most likely to be the primary mechanism behind the meal-related cortisol peak (3).

Because amino acids are absorbed from the intestinal tract into the bloodstream, the question arises whether the amino acid-induced cortisol response is triggered before or after these molecules have reached the circulation. Results of our supplementary study indicate a stronger rise in cortisol on enteral (i.e. nasogastric) than iv infusion of amino acids. This observation suggests that the stimulating effect of amino acids on cortisol release is triggered by a signal generated at the gastrointestinal mucosa before the amino acids enter the hepatic blood stream. In principle, the stronger rise in cortisol after nasogastric than iv administration may also be due to the quick passage of some selected amino acids that are known to activate the HPA system into the blood stream. The amino acid most potently stimulating cortisol release is tryptophan. To control for influences originating from blood-borne tryptophan, tryptophan concentrations were measured. When cortisol concentrations in the nasogastric condition showed the most pronounced increase, concentrations of tryptophan were virtually identical for the nasogastric and iv conditions, which safely exclude any substantial contribution of this amino acid to the observed difference in the cortisol response. This conclusion fits well with previous studies showing that tryptophan stimulates HPA secretory activity only when administered orally (25, 26) but not after iv administration (30). In the latter study, the iv infusion of tryptophan at doses between 5.0 and 10.0 g induced distinct increases in plasma concentrations of GH and prolactin, whereas cortisol levels remained unchanged.

In summary, our experiments indicate that the cortisol response to protein-containing meals originates from an amino acid-dependent activation of the gastrointestinal mucosa. How this signal is reported to the HPA system to stimulate cortisol release is not yet clear. Afferent neurons of the vagus nerve, which is known to enable gut-brain communication, may serve this function. The vagus nerve could also be the target of neuropharmacological agents like cholinergic and adrenergic agonists that have been shown to reinforce the meal-related increase in cortisol release (3, 31). Also, vagal stimulation effectively stimulates HPA secretory activity (32). Alternatively, the intake of proteins and the accumulation of amino acids in the gut might stimulate the release of enteric hormones like cholecystokinin and gastrin-releasing peptide that, in turn, stimulate HPA secretory activity (33, 34).

	Acknowledgments

 
The authors thank Anja Otterbein, Christiane Otten, and Ingrid von Lützau for their skilled technical assistance.

	Footnotes

 
First Published Online December 7, 2004

Abbreviations: AUC, Area under the curve; BMI, body mass index; HPA, hypothalamo-pituitary-adrenal.

Received September 10, 2004.

Accepted November 23, 2004.

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