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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:1120-1123, May 2004

Nutrient Interactions and Toxicity
Research Communication

Lactobacillus casei Alters hPEPT1-Mediated Glycylsarcosine Uptake in Caco-2 Cells1,2

Brien L. Neudeck*,3, Jennifer M. Loeb* and Nancy G. Faith{dagger}

* The University of Wisconsin School of Pharmacy, Madison, WI 53705-2222; and {dagger} The University of Wisconsin School of Veterinary Medicine, Madison, WI 53706-1102

3To whom correspondence should be addressed. E-mail: blneudeck{at}pharmacy.wisc.edu.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Augmentation of the normal flora of the gastrointestinal tract with probiotic bacteria is currently under investigation as a therapeutic tool for several diseases. However, it is unknown whether probiotic bacteria such as Lactobacillus casei alter the expression and function of intestinal transport proteins such as hPEPT1. The effects of 24 and 48 h incubation of Caco-2 cells with 108/L L. casei on the hPEPT1-mediated uptake rate of 20 µmol/L [3H]glycylsarcosine were examined. Dipeptide uptake did not differ from the control at 24 h (15.9 ± 2.4 vs. 11.5 ± 1.4 cm · s–1 · mg protein–1); however, a significant increase in uptake occurred after 48 h of L. casei treatment (23.7 ± 1.5 vs. 12.0 ± 1.9 cm · s–1 · mg protein–1; P = 0.005). hPEPT1 involvement was confirmed in experiments using excess substrate. Increased uptake of [3H]glycylsarcosine appeared to be the result of the direct interaction of the bacteria with Caco-2 cells because conditioned medium had no effect on dipeptide uptake. hPEPT1 mRNA levels did not differ at any time point. These results show that prolonged incubation of Caco-2 cells leads to increased hPEPT1 activity and that this occurs by a mechanism distinct from increased gene expression.

KEY WORDS: • hPEPT1 • Lactobacillus casei • Caco-2 cells • glycylsarcosine

There is considerable interest in employing probiotic bacteria to treat a variety of gastrointestinal and infectious conditions. Indicative of this, numerous clinical trials are underway to investigate their therapeutic potential. Previous studies with probiotic bacteria demonstrated promising results for conditions including antibiotic-associated diarrhea, pouchitis, ulcerative colitis, and Crohn’s disease (1–4). These living, nonpathogenic bacteria are believed to enhance the equilibrium of the gut flora. Although numerous hypotheses have been proposed, the mechanisms underlying the beneficial effects of probiotic bacteria on the intestinal environment remain unclear. Decreased attachment and invasion of enteropathogenic bacteria, induction of epithelial cytokine responses, production of antimicrobial bacterocins, and induction of mucin gene expression have been documented (5–10).

Probiotic research has largely concentrated on the prevention or treatment of disease. As such, little is known regarding the effects of probiotic bacteria on intestinal physiology unrelated to disease. To date, the effects of probiotic bacteria on intestinal proteins important for nutrient and drug absorption have not been characterized. One such protein is the human small intestinal oligopeptide transporter, hPEPT1, which is responsible for the absorption of di- and tripeptides into cells via an inward H+ gradient. In addition to oligopeptides, hPEPT1 is arguably 1 of the most important carrier proteins involved in the absorption of drugs from the intestine. hPEPT1 is responsible for the absorption of a number of orally administered peptidomimetic drugs such as ß-lactam antibiotics, angiotensin-converting enzyme inhibitors, and renin-inhibitors (11–15). Therefore, characterization of the effects of probiotic bacteria on this transporter is required.

Information regarding the regulation of hPEPT1-mediated transport is evolving. Phosphorylation by protein kinase C as well as insulin, leptin, and luminal dipeptides has been shown to affect transporter activity; however, there are undoubtedly other endogenous or exogenous regulators (16–19). One intriguing mediator may be the bacterial flora present in the intestine. It is unknown whether supplementation of orally administered probiotic bacteria alters hPEPT1 expression or function. Understanding how bacteria affect these transporters is important for 2 reasons. First, discernment of how changes in intestinal flora affect nutrient absorption is integral to understanding how disease affects absorption. Second, consumer use of probiotic supplements is increasing and therefore the effects of these agents on intestinal drug transport proteins should be delineated. In the current study we characterized the effects of Lactobacillus casei, a common organism in probiotic formulations, on hPEPT1 expression and function in Caco-2 cells. The microtubule destabilizing agent colchicine was employed to determine whether changes were due to posttranscriptional modifications.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Cell culture. The hPEPT1 expressing cell line Caco-2 was obtained from the American Type Culture Collection (ATCC)4 and incubated in a humidified atmosphere of 5% CO2 at 37°C. Growth medium consisted of DMEM without antibiotics supplemented with 25 mmol/L glucose (Mediatech), 10% fetal bovine serum (FBS), 1% nonessential amino acids, 2 mmol/L L-glutamine, and 1 mmol/L sodium pyruvate (Sigma). Cell monolayers at 90% confluence were subcultured 1:5 using 0.25% trypsin and 0.2% ethylenediaminetetraacetic acid. Cells of passages 33–38 were used in the experiments. For uptake experiments, cells were seeded in 24-well cell culture plates. For RNA isolation, cells were seeded in 60-mm cell culture dishes. All experiments were performed using fully differentiated cells grown 18–21 d postseeding.

    Bacterial cultures. L. casei (ATCC 49178) was grown overnight in Lactobacilli MRS broth (BD Diagnostic Systems). Culture (2 mL) was centrifuged at 500 x g for 5 min. The supernatant was aspirated and the volume replaced with Caco-2 growth medium. Following the measurement of the optical density at 600 nm, a 108 bacteria/L solution was prepared by serial dilutions. A total of 108/L of L. casei was incubated in growth medium for 48 h to determine whether effects of L. casei on dipeptide uptake were due to an active, soluble mediator secreted by the bacteria over time The bacteria were then removed using a 0.22-µm calcium acetate filter and the resulting medium was designated "conditioned medium." The pH of the conditioned and growth media was not significantly different. For the control in experiments using conditioned medium, Caco-2 growth medium was also filtered once with a 0.22-µm filter. Serial dilutions of conditioned medium were plated on MRS Lactobacillus agar to confirm the absence of viable L. casei.

    Uptake studies. Prior to study, 1 mL of medium containing 108/L L. casei, conditioned medium, or control (Caco-2 growth medium) was placed on the Caco-2 cells (n = 12 wells per condition) for 24 and 48 h and incubated at 37°C (Fig. 1). Cell integrity was determined in a separate group of cells using Trypan blue dye exclusion. After 24 and 48 h, experimental medium was removed and the monolayers were washed 3 times with uptake buffer. Uptake buffer consisted of HBSS with 0.1% FBS with a pH of 6.0 (MES). Subsequently, 0.5 mL of uptake buffer containing [3H]glycylsarcosine (Gly-Sar) (Moravek Biochemicals) and unlabeled Gly-Sar at a final concentration of 20 µmol/L were added to each of the 12 wells and incubated at 37°C for 5, 15, or 30 min. After the 5-, 15-, and 30-min incubation periods the buffer was removed (n = 4 wells per time point) and the cells were washed 3 times with ice-cold uptake buffer to cease uptake. For the determination of intracellular [3H]Gly-Sar, cells were permeabilized using 0.5 mL of ice-cold Milli-Q water containing 1% Triton X-100. The cells were scraped, placed into 1.5-mL microcentrifuge tubes, and sonicated for 3 cycles of 10 s each. A 200-µL aliquot of this mixture was frozen at –80°C for future protein determination using a Bio-Rad protein assay kit. The remaining 300 µL was placed in a liquid scintillation vial containing 5 mL of scintillation cocktail (Scintisafe Econo 1, Fisher Scientific) and radioactivity was measured by liquid scintillation counting. To confirm that detected differences were due to hPEPT1, identical experiments were conducted with the exception that excess Gly-Sar (50 mmol/L) was added immediately prior to and throughout [3H]Gly-Sar–containing incubations to saturate hPEPT1-mediated transport. Additional experiments were conducted to determine whether the microtubule destabilizing agent colchicine (10 µmol/L) could alter Gly-Sar transport affected by L. casei. This was accomplished by incubating the cells (n = 12) with colchicine 20 min prior to and for the first 6 h of each 24-h period after addition of the bacteria. The uptake rate (Puptake) of [3H]Gly-Sar in Caco-2 cells treated under each of the experimental conditions was calculated using the following equation and expressed as centimeters per second per milligram of protein (15):

dQ/dt represents the initial rate of Gly-Sar uptake, which corresponds to the slope of the linear portion of the Gly-Sar uptake-time profile. A is the surface area of the cell culture well, C0 is the substrate concentration, and Pr is the protein amount of each sample.



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  		FIGURE 1 Experimental design.

 
    Quantitative PCR. Cells were treated under identical experimental conditions and hPEPT1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA were measured with quantitative real-time PCR (Light Cycler, Roche). Briefly, cells were washed with HBSS and total RNA was extracted using the Ultraspec II RNA isolation system (Biotecx) according to the manufacturer’s specifications. The RT reaction was conducted using 2 µg of extracted total RNA, 25 U avian myeloblastosis virus reverse transcriptase, 40 U RNAsin, and 4000 µmol/L deoxyribonucleoside triphosphates (dNTPs) (Promega) per 25-µL reaction for 60 min at 42°C. One microliter of cDNA was used for each PCR in the presence of Master SYBR Green 1 reagents according to the manufacturer’s instructions. Samples were run in duplicate and quantified using a standard curve of serially diluted template. Primers were synthesized by Integrated DNA Technologies and were as follows: hPEPT1 sense 5'-TCCACCGCCATCTACCATAC-3' and antisense 5'-GGACAAACACAATCAGGGCT-3'; GAPDH sense 5'-ACCACAGTCCATGCCATCAC-3' and antisense 5'-TCCACCACCCTGTTGCTGTA-3'. The relative concentration of hPEPT1 mRNA was normalized to GAPDH mRNA levels. Each sample was analyzed in duplicate.

    Statistical analysis. Comparisons of uptake permeabilities were performed using one-way ANOVA with SigmaStat Statistical Software 2.03 (SPPS). Tukey’s post-hoc test was performed for detection of individual differences between the groups. If data were not normally distributed or equal variance between the groups was achieved, a Kruskal-Wallis one-way ANOVA on ranks was employed. Significant difference was defined as P < 0.05. All data are shown as means ± SEM.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    3H-Gly-Sar uptake. Although no effect was documented at 24 h (15.9 ± 2.4 vs. 11.5 ± 1.4 cm · s–1 · mg protein–1, P = 0.343), incubation of Caco-2 monolayers with L. casei 108/L for 48 h increased [3H]Gly-Sar uptake (P = 0.005) (Fig. 2A). This corresponded to an almost 98% increase in [3H]Gly-Sar uptake compared to control cells. Changes in Gly-Sar uptake appeared to be due to altered hPEPT1 because the addition of excess Gly-Sar decreased uptake with no difference between L. casei and control cells (Fig. 2A). Conditioned medium had no effect, indicating that the presence of bacteria was necessary for changes in uptake to occur (Fig. 2B). Last, colchicine did not affect the L. casei–mediated increase in [3H]Gly-Sar uptake at 48 h (Fig. 3).



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  		FIGURE 2 [3H]Gly-Sar uptake rate at 48 h in L. casei–treated Caco-2 cells (A) and Caco-2 cells treated for 48 h with conditioned medium (B). Values are means ± SEM, n = 12 wells. *Different from control, P = 0.005.

 


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  		FIGURE 3 Effect of colchicine on [3H]Gly-Sar uptake rate in L. casei–treated Caco-2 cells. Values are means ± SEM, n = 12 wells. *Different from untreated control cells and control cells treated with colchicine, P < 0.05.

 
    hPEPT1 expression. Real-time PCR revealed no differences in hPEPT1 mRNA among control, L. casei–treated, and conditioned medium–treated cells (Fig. 4). This was consistent for both 24- (data not shown) and 48-h incubations with L. casei.



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  		FIGURE 4 hPEPT1 mRNA expression in control, L. casei–treated, and conditioned medium–treated Caco-2 cells. Values are means ± SEM of duplicate experiments.

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
The research of oligopeptide absorption via hPEPT1 has historically ignored the contributions of endogenous mediators such as bacteria. As a result of the growing attractiveness of using probiotic bacteria as a therapeutic tool and widespread use by consumers, characterization of the bacterial/hPEPT1 interaction is required. In the current study, we demonstrate that a 48-h incubation of Caco-2 cells with L. casei increased uptake of the dipeptide [3H]Gly-Sar. This effect could be quenched by adding excess substrate, confirming hPEPT1 involvement. Increased [3H]Gly-Sar uptake appears to be due to a direct interaction of the bacteria with the apical membrane of the enterocyte rather than via a secreted or soluble mediator since conditioned medium had no effect. This is in contrast to findings with probiotic mixtures, which indicate that soluble mediators are involved in probiotic-induced enhancement of barrier function (1). This illustrates the importance of evaluating probiotic bacteria under experimental conditions both alone and in combination with other organisms. Thus, our findings indicate that it is likely that L. casei activates specific receptors on Caco-2 cells leading to increased hPEPT1-mediated transport.

Of interest, increased dipeptide uptake was not associated with a concomitant increase in hPEPT1 mRNA expression. One potential explanation for this discordance is that L. casei treatment may lead to posttranscriptional modifications of hPEPT1. Thus, phenotypically, increased dipeptide transport is seen without changes in gene expression. One such modification may be altered intracellular trafficking, leading to increased membrane-associated hPEPT1. Increased translocation from a preformed cytoplasmic pool would result in increased protein available to transport Gly-Sar. Similar effects of insulin on hPEPT1-mediated transport in Caco-2 cells have been documented (18). Therefore, in an attempt to explain our findings, we treated cells with colchicine. Colchicine has been shown to disrupt microtubules, which are important for translocation of proteins targeted for membrane insertion (20,21). Increased dipeptide uptake was preserved despite colchicine treatment, suggesting that this is not a potential mechanism for the increased uptake (Fig. 2). Thus, other processes related to translation may be responsible for the detected changes.

With any in vitro study, extrapolation to similar conditions in the intact host should be performed cautiously. It is possible that some of the radioactivity measured in the assay reflects membrane-bound dipeptide rather than dipeptide absorbed intracellularly. Therefore, similar experiments in an intact host would need to quantify dipeptide binding as well as absorption. Our model was a bacteria naive system in that it was previously sterile and bacteria were added for study purposes. Therefore, this does not exactly reflect the supplementation of exogenous bacteria onto intestinal epithelial cells already colonized with bacteria. Unfortunately, an in vitro cell culture system complete with bacterial colonization has yet to be developed. Another potential limitation of our system was the use of a filter to remove bacteria for the conditioned medium studies. As depicted in Figure 2B, control [3H]Gly-Sar uptake at 48 h for conditioned medium studies increased compared to other conditions (Fig. 2A). This is most likely due to the unintentional removal of FBS (unpublished observations) from the medium during the filtering process, which may have created a stressed or pseudostarvation environment for the cells. As expected, this was detected to a much greater degree with the longer, 48-h time period. Previous investigations have shown that starvation leads to increased dipeptide transport (22,23). However, since identical conditions were employed for control and conditioned medium wells, we do not believe that this confounds the final interpretation that conditioned medium had no effect. Last, the control dipeptide uptake value for the colchicine experiments was slightly higher than in earlier experiments (Fig. 3). Although the precise reason for this is unknown, one possibility may be that transporter expression was slightly higher because these experiments were performed with cells of a later passage (P38). However, because the colchicine experiments were performed with cells from the same passage, we believe that this potential confounding effect was equalized among the treatment arms.

In summary, a 48-h incubation of Caco-2 cells with L. casei led to significant increases in hPEPT1-mediated [3H]Gly-Sar uptake compared to control cells. These effects occurred without increased hPEPT1 mRNA abundance and appear to be due to direct contact of the bacterium with the Caco-2 apical membrane. Interactions between the gastrointestinal epithelium and the microbiota are obviously complex. Future in vivo studies will undoubtedly yield additional information regarding the extent of this bacterial/intestinal transporter interaction. However, the current findings clearly indicate that additional research is required given the increased use of probiotic bacteria as a therapeutic tool.


   FOOTNOTES
 
1 Presented in part at the American Association of Pharmaceutical Scientists Annual Meeting, November 2002, Toronto, Canada. [Neudeck, B. L., Loeb, J. M., Faith, N. G. & Czuprynski, C. J. Effects of Lactobacillus casei on hPEPT1 and P-glycoprotein expression and function in Caco-2 cells] (http://www.aapspharmaceutica.com/scientificjournals/ pharmsci/am_abstracts/2002). Back

2 This work was supported with internal funds. Back

4 Abbreviations used: ATCC, American Type Culture Collection; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Back

Manuscript received 6 November 2003. Initial review completed 13 December 2003. Revision accepted 17 February 2004.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
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 DISCUSSION
 LITERATURE CITED
 

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