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Nestlé Research Center, Nutrition and Health Department, Lausanne, Switzerland
1To whom correspondence should be addressed. E-mail: magali.faure{at}rdls.nestle.com.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • mucins • threonine • protein synthesis • intestine • rats
The mucous layer is an important component of the nonimmune gut barrier. It is a complex mixture containing large amounts of secreted mucin glycoproteins, which form a viscoelastic gel covering, protecting the gastrointestinal epithelium against various injuries (1–3). The mucous layer and mucin production are qualitatively and quantitatively altered in many situations of intestinal stress, including the inflammatory bowel diseases (IBD)2 [ulcerative colitis (UC) and Crohn’s disease (CD), reviewed in (4)]. For example, in the active phase of the disease, UC patients exhibit reductions in the thickness of the colonic mucous layer, in the number of mucus-containing goblet cells, and in ex vivo analyzed MUC2 production (the main secreted-colonic mucin) (5–9). Because no changes in MUC2 gene expression were reported (10), the decrease in MUC2 production may be due to changes at the translational level.
The integrity of the mucous layer is associated with the nutritional state. For example, protein-energy malnutrition, starvation, or total parenteral nutrition all alter the mucous layer by decreasing mucosal mucin content (11–16) and increase intestinal permeability and susceptibility to endotoxins (17,18). However, although the nutritional state appears to be a key factor in regulating the mucous layer and gut barrier integrity, the effect of specific nutrients on mucin synthesis and expression has been addressed infrequently [reviewed by (19)]. Certain milk peptides were shown recently to stimulate mucin secretion in ex vivo intestinal sections from rats (20,21). However, the effects of specific amino acids have never been investigated.
Among the essential amino acids, threonine is particularly important for maintenance of the gut. Indeed, compared with other essential amino acids, a large proportion of dietary threonine (up to 60%) is retained by the healthy pig (22) or human (23) intestine. Because intestinal mucins are particularly enriched in threonine [up to 30% of their amino acid composition (2)] compared with other intestinal proteins, the high retention of dietary threonine by the gut may reflect the demand for this amino acid in the synthesis of these proteins. In both animals and humans, many pathological situations, such as sepsis, surgery, or IBD, are associated with an increase in protein turnover in the gut (24–28). Intestinal mucin turnover is also stimulated in some of these conditions (29). Our hypothesis is that under such pathologic situations, there is an increased requirement for threonine that is not met by the normal diet, and that intestinal mucins, compared with other intestinal proteins, are particularly sensitive to dietary threonine availability.
Before investigating this in animal models of intestinal stress (such as IBD) or in patients, it is important to determine whether the level of threonine in the diet can regulate the synthesis of mucins. The main goals of our study were to compare mucin synthesis in healthy rats as a function of the dietary threonine supply and to determine whether these proteins, which are particularly enriched in threonine, are more sensitive to the level of dietary threonine than other intestinal proteins.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Groups of rats were fed diets that were deficient in (group 30 and group 60, diets containing 30 or 60%, respectively, of the rat’s threonine requirement for growth), balanced for (group 100, control rats fed a diet containing 100% of the threonine requirement), or supplemented with L-threonine (group 150, diet containing 150% of the threonine requirement). These diets were isonitrogenous (adjusted with alanine). Rats were adapted to their respective diets for 5 d. The end of this adaptation period was defined as d 0 and the experiment was terminated on day 14. During the experiment, rats had free access to tap water. The threonine requirements for groups 30, 60, 100, and 150 were calculated on the basis of the theoretical threonine requirements of rats of this age and weight consuming food ad libitum. All groups of rats were pair-fed to the mean intake of group 30 (see results).
During the experiment, body weight was measured 3 times each week and food intake determined daily. At the end of the experiment, in vivo protein synthesis rates in tissues and mucins were measured using the flooding dose method, as described previously for intestinal proteins (30) and mucins (31), with a few modifications. Briefly, in each experimental group, 7 rats were administered within 30 s a flooding dose injection of L-[1-13C]-valine (150 µmol/100 g body weight, 99 atom% excess, Mass Trace) in the lateral tail vein. At 35, 38, 41, 44, 47, 50, and 53 min after injection of the tracer 1 rat/group was killed by exsanguination via the abdominal aorta while under isoflurane anesthesia. One rat per group was administered an injection of physiologic saline for determination of the basal L-[1-13C]-valine enrichment. Plasma was separated from whole blood by centrifugation (3000 x g for 5 min) and kept at –20°C until analysis of plasma amino acids. After exsanguination, the small and large intestines were rapidly removed. The duodenum (first 10 cm of the small intestine), jejunum (proximal half of the remaining small intestine), ileum, and colon were quickly isolated, flushed with cold physiologic buffered saline, gently dried, and weighed. Aliquots from these segments (100 mg) were immediately frozen in liquid nitrogen and stored at –70°C for subsequent analysis of mucin gene expression. The mucosa was recovered from the remaining tissue by scraping, immediately frozen in liquid nitrogen, and stored at –70°C for the subsequent analyses of mucosal and mucin protein synthesis rates and mucin amino acid composition. The liver and tibialis anterior muscle were also quickly excised, weighed, and frozen in liquid nitrogen. The protein concentration in all tissues was measured according to the method of Smith et al. (32).
Amino acids in plasma and mucins. Plasma amino acid concentrations were measured with a Beckman 6300 amino acid analyzer. Plasma samples (200 µL) were deproteinized with 20 µL of sulfosalicylic acid (400 g/L) and centrifuged at 10,000 x g for 3 min. Supernatants were frozen at –80°C after the addition of internal standards (50 µmol/L D-glucosaminic acid and 50 µmol/L S-(2-aminomethyl)-L-cysteine · HCl). Analyses were performed using a lithium buffer system. To avoid glutamine degradation, samples were kept at 10°C before injection. Amino acid concentrations (µmol/L) were calculated from individual peak areas, an external standard, and S-(2-aminomethyl)-L-cysteine · HCl. Intestinal mucins were purified and their amino acid composition was determined as described previously (31).
Protein fractional synthesis rates in tissues and mucins. 13C enrichments of free (intracellular) and protein- or mucin-bound valine were measured (30). Briefly, frozen tissue samples (100 mg) were homogenized for 30 s at 4°C in 1 mL of 1 mol/L perchloric acid solution using a polytron (16,000 rpm). Proteins were separated from acid-soluble amino acids as described previously (31). Free L-[1-13C]-valine enrichment was determined by GC-MS after N(O,S)-ethoxycarbonyl ethyl ester derivatization (31). L-[1-13C]-valine enrichments bound to intestinal proteins and purified mucins were measured by GC-combustion-isotope ratio MS after N-acetyl-N-propyl ester derivatization (31). The fractional synthesis rate (FSR) of tissue proteins or mucins, defined as the percentage of tissue protein or mucin synthesized per day (%/d), was calculated as follows: FSR = [Sb (t) – Sb (0)] x 100/(S'a t), where Sb (0) and Sb (t) are the basal enrichment and enrichment in 13C-valine in mucosal proteins or mucins, respectively, at the end of the incorporation period, S'a is the mean enrichment of tissue free 13C-valine between times 0 and t, t is the time elapsed between the bolus injection of 13C-valine and killing of the rats (min). Thus, S'a t represents the area under the curve of the enrichment of the precursor pool between time 0 and t (33). The individual S'a were determined by multiplying the Sa (t1/2) obtained at time t1/2 from the linear regression of Sa against time, by S'a (t)/Sa (t), where S'a (t) is the individual value of Sa at time t and Sa (t) is the Sa value of the regression at time t (33).
Muc2 and Muc3 mRNA levels. Total RNA extraction and RT-PCR experiments were performed as described previously (29), using specific primers for rat MUC2, MUC3, and ß-actin genes (29). PCR amplifications were performed using Taq Polymerase provided by Promega (29). The internal standard ß-actin was coamplified with mucins. PCR products (10 µL) were separated by agarose gel electrophoresis and visualized by ethidium bromide staining. Quantification of the PCR products was performed using the densitometry program NIH Imager. The ratio between MUC2 or MUC3 and ß-actin was calculated and expressed in arbitrary units (AU).
Statistical analyses. Data are means ± SEM. A one-way ANOVA was performed to analyze the effect of the diet. When an effect was detected, differences among groups were identified using the Tukey-Kramer Multiple Comparison Test and considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Fractional synthesis rates of intestinal mucins and tissue proteins. In all groups, the FSR of mucosal proteins decreased with a lower position in the gut and were not changed by any of the threonine-imbalanced diets (Fig. 2). In contrast, the FSR of mucin remained rather constant along the length of the small intestine and was slightly lower in the colon. In addition, extreme restriction of dietary threonine in group 30 profoundly affected the intestinal mucin FSR along the length of the gut. In this group, the mucin FSR was significantly lower than that of the control group 100, reaching a maximum reduction of 40% in the duodenum. In contrast, the mucin FSR did not differ from group 100 in groups 60 and 150. In the tibialis anterior, the protein FSR was relatively low in all experimental groups (6.3 ± 0.2, 7.7 ± 0.5, 6.9 ± 0.2, and 6.9 ± 0.2%/d in groups 30, 60, 100, and 150, respectively), probably due to the dietary restriction; furthermore, it did not differ among the groups.
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MUC2 and MUC3 mRNA levels. At the transcript level, MUC2 and MUC3 were expressed all along the gut. In the small intestine, MUC2 mRNA expression was not modified by the restriction or supplementation of threonine. MUC3 mRNA levels in the duodenum and ileum did not differ among groups, but in the jejunum of groups 30 and 150, MUC3 mRNA was significantly lower (0.80 ± 0.04 AU and 0.87 ± 0.02 AU for groups 30 and 150, respectively) than in group 100 (1.19 ± 0.07 AU) and group 60 (1.02 ± 0.03 AU). In the colon, MUC2 mRNA expression was greater in groups 30 (1.72 ± 0.06 AU) and 150 (1.72 ± 0.11 AU) compared with groups 60 (1.13 ± 0.11 AU) and 100 (1.13 ± 0.05 AU), whereas MUC3 mRNA expression did not differ among the groups.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Rats were fed semisynthetic, isonitrogenous diets containing 30, 60, 100, or 150% of the theoretical threonine requirement necessary for normal growth. Rats fed diets with an imbalance in essential amino acids (this includes threonine) immediately reduce their food intake (34). It was therefore essential in our study that all groups ate the same amount of food; for this reason all groups were pair-fed to the group that consumed the least (group 30). This pair-feeding forced a reduction of 25% in the intake of all amino acids other than threonine. This reduction probably affected protein turnover, and likely attenuated differences between protein and mucin synthesis levels among groups. In comparison to the normal requirement of threonine for growth in rats, the actual restriction of threonine imposed by pair-feeding in this study was 77% for group 30, 55% for group 60, and 25% for group 100, whereas the actual threonine supplementation was 12% for group 150.
The dietary intake of threonine and its subsequent level in the plasma were positively correlated (r = 0.93) as was reported previously in rats fed diets with an imbalance in threonine (35,36). Due to the restriction of food availability induced by pair-feeding, rats from all groups exhibited a low growth rate (between 1.7 g/d for group 30 and 2.8 g/d for group 150) compared with similarly aged rats consuming their food ad libitum (
5 g/d). At the end of the experiment, the body weight in group 30 was reduced significantly (by 20%) compared with all other groups, reflecting the lower feed efficiency. Group 30 also had a reduced absolute gut weight compared with all other groups but no changes in the gut weight expressed as a proportion of body weight. The weight of the tibialis anterior muscle in group 30 rats was reduced similarly (data not shown). Thus, although we did not detect impaired gut function after restricting threonine intake, we cannot exclude that more specific compartments of the gut, which we did not analyze, were affected.
The mucosal protein synthesis rate was not modified by restriction or supplementation of threonine in any of the intestinal segments studied. On the contrary, mucin synthesis was highly sensitive to dietary threonine restriction. Mucin production was likely limited at the translational level because globally, MUC2 and MUC3 mRNA levels were similar among groups. The threonine content of intestinal mucins produced by group 30 did not differ from that of group 100 (data not shown). This suggests that no changes in the relative production of the different mucin types occurred, i.e., no decrease in the synthesis of those mucin types that are more highly enriched in threonine (e.g., MUC2). The dramatic effect of threonine restriction on intestinal mucin synthesis in group 30 rats suggests that no compensatory mechanism was operating at the whole-body level to mobilize threonine and thereby supply the gut. In our study, the tibialis anterior muscle did not serve as a reservoir for the specific mobilization of amino acids because its relative weight and protein synthesis were not specifically impaired.
The situation was completely different when the reduction of threonine in the diet was less extensive as in group 60; in that group, intestinal goblet cells were able to maintain mucin synthesis at the normal level. It is possible, however, that the hypometabolism induced by the deficiency in all amino acids masked any effect of threonine restriction. Moreover, the feed efficacy in group 60 rats increased during the course of the experiment (from 11.2% between d 0 and 9 to 21.6% between d 9 and 14), suggesting that these rats were able to adapt to this diet. Also, by d 12, their cumulative body weight change became significantly greater than that in group 30 and similar to those of groups 100 and 150. This late adaptation of group 60 rats could be linked to a compensatory mechanism enabling a supply of threonine to the gut to maintain important gut functions such as mucin synthesis (37). Based on our results, and as mentioned above, muscles are unlikely to be the donor of threonine because the weight and protein content of the tibialis anterior muscle did not differ between groups 60 and 100 (data not shown). Other tissues and/or organs may be involved and should be identified.
Finally, supplementation of dietary threonine induced no major change in any of the variables investigated. Intestinal mucin synthesis was not stimulated in supplemented rats, suggesting again that the hypometabolism induced by pair-feeding with group 30 masked any effect of threonine supplementation. Nevertheless, our results indicate that when threonine requirements are adequately met by the diet in healthy rats, a higher intake of threonine does not stimulate the synthesis of mucins.
In conclusion, these results clearly indicate that the synthesis of intestinal mucins will be dramatically and specifically impaired in the case of a limited dietary supply of threonine. In clinical situations associated with increased utilization of threonine, threonine availability could become limiting for the synthesis of intestinal mucins, resulting in a reduction in gut barrier function. Further studies are warranted to determine whether, in such pathological situations, supplementation with threonine can protect gut function.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 2 August 2004. Initial review completed 2 September 2004. Revision accepted 14 December 2004.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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