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© 2007 American Society for Nutrition J. Nutr. 137:2742-2746, December 2007

Nutrient Requirements and Optimal Nutrition

Administration of Folate-Producing Bifidobacteria Enhances Folate Status in Wistar Rats1,2

Anna Pompei3, Lisa Cordisco3, Alberto Amaretti4, Simona Zanoni3, Stefano Raimondi4, Diego Matteuzzi3 and Maddalena Rossi4,*

3 Department of Pharmaceutical Sciences, University of Bologna, Bologna, 40100 Italy and 4 Department of Chemistry, University of Modena and Reggio Emilia, Modena, 41100 Italy

* To whom correspondence should be addressed. E-mail: rossi.maddalena{at}unimore.it.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
To develop a probiotic that provides the host with folate, we administered folate-overproducing bifidobacteria (Bifidobacteria adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116) to Wistar rats with induced folate deficiency. Four groups of rats were fed a solid, low-folate diet with no supplements, folate-producing bifidobacteria [probiotic (PRO)], oligofructose [prebiotic (PRE)], or PRO plus PRE [symbiotic (SYM)] for 14 d. The SYM group also had a significantly higher (16.4 ± 3.7 nmol/L) than in the PRO group (9.1 ± 0.3 nmol/L), which was greater than in the control (4.8 ± 0.5 nmol/L) and PRE groups (5.3 ± 1.4 nmol/L). The SYM group also had a significantly higher hepatic folate concentration than in the other groups, whereas the kidney folate concentration did not differ among the groups. In the unsupplemented group, the pH of feces did not change during the trial, whereas diets containing bifidobacteria and/or oligofructose led to significant acidification due to enhanced saccharolytic metabolism. As a consequence of feeding rats PRE, PRO, and SYM diets, lactobacilli and bifidobacteria were significantly greater than in controls, whereas coliforms and enterococci were lower. This experiment showed that B. adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116 exert both the beneficial effects of probiotics and produce folate in vivo, positively affecting the folate status of rats. The simultaneous administration of oligofructose and folate-producing bifidobacteria enhance their effectiveness on folate status. This study provides new perspectives on the specific use of probiotics to deliver important vitamins such as folate.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Folates are water-soluble vitamins that function as cofactors in 1-carbon transfer reactions occurring in purine and pyrimidine biosynthesis. They are required for efficient DNA replication, repair, and methylation. For this key role in the cellular cycle, tissues with a high cell growth rate or turnover, such as hemopoietic cells and intestinal mucosa, have a high requirement for folate. Furthermore, folates play an important role in the reduction of cancer risk, are involved in regulation of rectal cell proliferation, and are recommended for patients with inflammatory bowel diseases (1,2). Folate deficiency has been associated with neural tube defects during embryonic development, increased cancer risk, and elevated plasma homocysteine concentration, representing a risk factor for coronary heart disease (3–6).

Although natural folates occur in a wide variety of foods (yeast, organ meats, legumes, and green leafy vegetables), the absorption efficiency is ~50% of folate content (7). Because folates have poor chemical stability and bio-availability, many studies have assessed the possible contribution of intestinal microflora to the folate intake of the host animal (8–11). The need for an effective exogenous supply of this vitamin to reduce proliferation of colonic mucosal cells in a high-risk group for colon cancer (12) kindled an interest in probiotic bacteria as colonic sources of this vitamin (13).

Bifidobacteria are regarded as probiotics and are used in dietary supplements because they exert many in situ benefits for human health. They constitute an integral part of the gastrointestinal micro-ecology and are involved in healthy gut function and wellbeing (14). In bifidobacteria, the saccharolytic metabolism of indigestible carbohydrates produces mostly lactic and acetic acids, which acidify the large intestine and restrict growth of potential putrefactive pathogens (15–17). Bifidobacteria also play an important role in vitamin and amino acid production, immunostimulation, anticarcinogenic activity, competition with pathogens for nutrients and adhesion sites, and reduction of the conversion of primary bile salts to secondary bile salts (14,15,18–23). Because they exert such desirable health effects, bifidobacteria are increasingly being used as probiotics in functional foods and pharmaceutical products (24–26).

In a previous study, the ability of 76 strains of bifidobacteria to produce folate was studied to select strains that combine the intrinsic probiotic activities of the genus Bifidobacterium with a considerable production of folate (13). Three strains (Bifidobacterium adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116), which grew in a folate-free medium and produced a high concentration of vitamin, were identified. The presence in the medium of folate or of the vitamin precursor p-aminobenzoic acid did not affect folate biosynthesis in these strains. Moreover, folate production did not depend on the pH or carbon source and also occurred in fecal cultures (13). B. adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116 have been recently accepted for deposit by the German Collection of Microorganisms and Cell Cultures (DSMZ)5 and named B. adolescentis DSMZ 18352, B. adolescentis DSMZ 18350, and B. pseudocatenulatum DSMZ 18353, respectively.

In this work, we administered B. adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116 to rats to investigate their ability to improve folate status in serum, kidneys, and liver. Lyophilized bifidobacteria were used alone as probiotic supplements or were added to bifidogenic fructans in a symbiotic formulation. Fecal pH, coliforms, enterococci lactobacilli, and bifidobacteria were monitored during the trial to check the predominance of saccharolytic or proteolytic metabolism and to determine whether the probiotic strains survived through the gastrointestinal tract and persisted in feces. As controls, we also studied rats fed prebiotic-supplemented and unsupplemented diets.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Bifidobacterium strains and growth conditions. B. adolescentis MB 227 (DSMZ 18352), B. adolescentis MB 239 (DSMZ 18350), and B. pseudocatenulatum MB 116 (DSMZ 18353) (13) were obtained from the Collection of the ex-Institute of Agricultural Microbiology of the University of Bologna (V. Scardovi collection). Bifidobacteria were subcultured anaerobically at 37°C for 24 h in de Man, Rogosa, Sharpe broth (MRS, Difco Laboratories) containing 2.85 mmol/L L-cysteine · HCl and were cultivated in the folate-free synthetic medium (SM7) (13). Anidral/Probiotical produced the lyophilized biomass of the probiotic strains.

To determine whether B. adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116 were able to ferment the commercial mixture of fructo-oligosaccharides (FOS)5 used for symbiotic preparation, batch cultures were carried out in SM7 medium that contained 10 g/L Beneo P95 (Orafti) as the sole carbon source (13). All the growth experiments were carried out in triplicate.

    In vivo trial. The Animal Care Committee of the University of Bologna approved this study. The experiment was carried out on 34 male Wistar rats (200–210 g, 7 wk old). To minimize coprophagy, the rats were housed in individual wire-bottomed cages and feces were collected daily (27). The cages were kept in a room maintained at 23°C with a 12-h-light/-dark cycle. The rats were made deficient in folate by feeding for 7 d a solid, low-folate diet (Table 1) supplied by Mucedola. After 1 wk, blood samples were collected and analyzed to confirm depletion of serum folate. Folate-deficient rats were randomly assigned to 4 groups of 8–10 rats. For 14 d, the rats were fed the solid, low-folate diet by stomach tube with a basic liquid diet (6 mL of 10 g/L skim milk) containing the appropriate supplements. The control diet (n = 10) contained no supplements; the probiotic diet (PRO, n = 8) was supplemented with 2 · 108 live cells of each B. adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116; the prebiotic diet (PRE, n = 8) was supplemented with 10 g/L FOS; and the symbiotic diet (SYM, n = 8) contained 10 g/L FOS and 2 · 108 live cells of each probiotic strain. The amount of orally administrated bacteria was established based on the dose consumed by humans during probiotic or symbiotic treatments. Rats consumed water ad libitum throughout the study. Feces were collected at 0, 7, and 14 d of the treatment for analysis of pH and fecal microbial composition.


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  		TABLE 1 Composition of low-folate diet

 
At the end of dietary treatment, 5 mL blood was sampled by intra-cardiac withdrawal from ether-anesthetized rats. Blood was allowed to clot at room temperature. The clot was removed by centrifugation (5000 x g; 10 min at 4°C) and the serum was stored with 0.05 mol/L sodium ascorbate at –20°C. Kidneys and livers were excised from rats and frozen in liquid nitrogen at –80°C. Excised organs (1 g) were homogenized in a Potter Elvehjem homogenizer at 4°C with 9 mL of extraction buffer (0.1 mol/L Tris-HCl, 0.1 mol/L sodium ascorbate, pH 7.85). The samples were placed in a boiling water bath for 15 min, cooled in an ice bath, and then centrifuged to remove solids (5000 x g; 10 min at 4°C). The supernatants were stored at –20°C in Thumberg tubes under nitrogen until assayed.

    Folate analysis. Folate concentrations in serum, kidney, and liver samples were evaluated by microbiological assays of folate and its derivatives. For the bioassay, we used Bacto Folic Acid Casei Medium (Difco Laboratories) according to the manufacturer's protocol (28) using Lactobacillus casei subspecies rhamnosus ATCC 7469 as the test organism (29). All analysis were carried out in triplicate.

    Analysis of fecal pH and microflora. The pH of feces was measured with a pH-meter (Radiometer) in the freshly collected fecal samples diluted 1:10 (w:v) with distilled water (30).

Intestinal bacterial groups were enumerated using specific fluorescence in situ hybridization commercial kits (Microscreen B.V., Microbial Diagnostics) for the Lactobacillus group (Lactobacillus 10-ME-H006), the Bifidobacterium genus (Bifidobacterium 10-ME-H001), the Escherichia coli group (Escherichia coli 10-ME-H004) and E. faecalis (Enterococcus faecalis 10-ME-H015). Depending on the number of fluorescent cells, 30–100 microscopic fields were counted and averaged. All analysis were carried out in triplicate.

    Statistical analysis. All values are expressed as means ± SD. Differences in specific growth rate and biomass yield between FOS and glucose were evaluated using Student's t-test for independent samples. Differences were considered significant at P ≤ 0.05. Differences in folate levels among treatments were evaluated using 1-way ANOVA followed by Tukey's post hoc comparisons. Differences were considered significant at P ≤ 0.05. Differences in the pH and the concentration of bifidobacteria, lactobacilli, coliforms, and enterococci in feces were analyzed using 2-way ANOVA with repeated measures with diet as the first factor and time as the second factor, followed by Bonferroni post hoc comparisons. Differences were considered significant at P ≤ 0.05. Statistical analysis was performed using GraphPad Prism 4.0 (Graphpad Software).


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Fermentation of FOS by Bifidobacterium folate-producing strains. B. adolescentis MB 227, B. adolescentis MB 239, and B. pseudocatenulatum MB 116 were cultivated in the carbon-limited SM7 medium that contained glucose or FOS as the sole carbon source. The strains were incapable of growing in SM7 medium without adding carbohydrate. Cells grown on FOS had higher (P ≤ 0.05) specific growth rates and cell yields than cells grown on glucose (Table 2).


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  		TABLE 2 Maximum specific growth rate (µ) and stationary phase turbidity (cell yield) of Bifidobacterium strains growing on glucose or FOS12

 
    Changes in folate levels after dietary treatments. The serum folate concentration in all rats at the beginning of the dietary treatment was 4.1 ± 0.7 nmol/L. During the trial, all rats were healthy and survived until termination. Body weight gains did not differ among groups.

Serum folate concentration was similar in the control and PRE groups, whereas it was higher in the PRO group (P ≤ 0.05) and higher than in the PRO group in the SYM group (P ≤ 0.05) (Fig. 1). Hepatic folate concentration did not differ in the rats in the PRE and PRO groups, whereas it was higher in those fed SYM (P ≤ 0.05) and lower in the control group (P ≤ 0.05). Kidney folate concentration did not differ among the groups.


Figure 1
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  		FIGURE 1  Folate concentrations in serum, liver, and kidney of rats fed control, PRO, PRE, or SYM diets for 2 wk. Values are means ± SD. Within a tissue, means without a common superscript differ, P ≤ 0.05.

 
    Kinetics of microbial groups and pH in feces. The concentrations of bifidobacteria, lactobacilli, enterococci, and coliforms in rat feces were monitored at 0, 7, and 14 d (Table 3). Bifidobacterium counts were low after 14 d of the unsupplemented control diet, whereas PRO, PRE, and SYM diets increased the final counts of bifidobacteria (P ≤ 0.05). Bifidobacterium counts increased with different kinetics: after 7 d of feeding PRO, PRE, and SYM diets, bifidobacteria numbers had increased by 4.0, 2.6, and 4.4 orders of magnitude (P ≤ 0.05), respectively. After 14 d, only PRO caused a further significant increase in bifidobacteria. At the end of the trial, the concentrations of lactobacilli in rats fed PRO, PRE, and SYM diets increased by 2.4, 3.0, and 3.2 orders of magnitude (P ≤ 0.05), respectively, and were higher (P ≤ 0.05) than in the control group but not different from one another (Table 3). The E. coli concentration increased (P ≤ 0.05) after 7 d in the control group. At 7 and 14 d, it was higher in the control group than in the PRO, PRE, and SYM groups (P ≤ 0.05), which had maintained the original levels (Table 3). In groups fed PRO and SYM diets, enterococci counts decreased by 1.2 and 1.7 orders of magnitude (P ≤ 0.05) after 7 d, respectively, and remained low until termination (Table 3). In PRO and SYM groups, the fecal concentrations of enterococci were higher (P ≤ 0.05) than in PRO and SYM groups at d 7 and 14.


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  		TABLE 3 Microbial counts of feces in rats fed control, PRO, PRE, and SYM diets for 2 wk1

 
In rats fed the control diet, the fecal pH did not change (Table 4). After 7 d, the PRO, PRE, and SYM diets decreased the fecal pH (P ≤ 0.05) by 2.4, 1.8, and 2.7 pH units, respectively. After 7 and 14 d, the pH of PRO, PRE, and SYM groups did not differ and was lower than in controls (P ≤ 0.05).


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  		TABLE 4 pH in rats fed control, PRO, PRE, and SYM diets for 2 wk1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
This study investigated whether the wild-type strains B. adolescentis MB 227 (DSMZ 18352), B. adolescentis MB 239 (DSMZ 18350), and B. pseudocatenulatum MB 116 (DSMZ 18353), which synthesized high levels of folate in vitro (13), produced the vitamin in vivo, leading to improved folate levels in deficient rats.

These bifidobacteria were administered alone as probiotics and in a symbiotic formulation that contained the bifidogenic oligofructose mixture (FOS) (31), which was as an excellent carbon source. In fact, in growth experiments, higher specific growth rates and cell yields were attained on FOS than glucose, indicating the preference of these Bifidobacterium strains for oligosaccharides over monosaccharides. This fermentative behavior indicates the adaptation of this genus to a special ecological niche of the colonic environment, where monosaccharides are naturally absent and indigestible oligo- and polysaccharides are the major carbon source for saccharolytic bacteria (32).

The simultaneous addition of a prebiotic carbohydrate further increased the level of the administered probiotic strains in the intestine and resulted in the highest level of serum folate. This observation confirms the hypothesis that the availability of a preferred indigestible carbon source advantages the growth and the metabolic activity of probiotic bacteria (31).

The serum folate concentrations were lower in the PRE group than in the PRO and SYM groups. This result demonstrates that the increased folate concentrations is markedly due to the effective growth of the folate-producing bifidobacteria. Although both PRE and SYM increased fecal total bifidobacteria, the final serum concentration of folate was 2-fold higher in rats fed the SYM diet than in the PRE group. Most strains of Bifidobacterium cannot synthesize folate and only a few strains of B. adolescentis and B. pseudocatenulatum produce high amounts of folate. Furthermore, the strains supplied to the PRO and SYM groups are the best folate producers among the strains screened in our previous study (13).

Liver and kidney are involved in folate metabolism and homeostasis (33,34). Accumulation of folate in liver resulted from administration of PRE, PRO, and SYM diets. As for serum folate, the hepatic folate concentration was the highest in rats fed the SYM diet. Significantly greater accumulation in kidney did not occur after feeding the PRE, PRO, and SYM diets. It is conceivable that folate would accumulate in this organ in longer trials, when serum folate concentrations are elevated for a longer time. The folate produced by folate-producing bacteria can be utilized by the intestinal bacteria that are unable to synthesize it and can be absorbed by the colon as well. In fact, the intestinal microbiota form a complex ecosystem in which metabolic and cross-feeding interactions occur among the microbial groups and between the microflora and the animal host.

The marked decrease of fecal pH in the treated groups, which did not occur in the control group, indicates that the diets containing bifidobacteria and/or FOS result in saccharolytic metabolism. Acidification of feces was due to the fermentation of carbohydrates to short chain fatty acids and confirmed the predominance of healthy saccharolytic microbial processes over the harmful proteolytic/putrefactive ones. Moreover, Zimmerman (11) provided evidence that the uptake of folic acid in the colon proceeds by facilitated diffusion of the neutralized, nonionized form of the vitamin through a low affinity carrier and accumulation in colonic mucosa was significantly higher at pH 5.5 than at 7.5. Therefore, an acidic pH is important for the uptake of colonic folate and saccharolytic metabolism in rats fed PRO, PRE, and SYM diets. This could be responsible for the enhanced accumulation of the folate produced by the intestinal microflora.

In agreement with the decreased fecal pH, both bifidobacteria and lactobacilli counts significantly increased as a result of PRE, PRO, and SYM diet treatments. Coliform counts increased only in rats fed the unsupplemented diet, likely because of protein metabolism. Enterococci diminished only in rats fed bifidobacteria (PRO and SYM groups), indicating a competitive advantage of these probiotic strains against enterococci.

This study reports favorable effects of the administration of wild-type folate-overproducing bifidobacteria to enhance serum folate status in rats with induced folate deficiency. Folate is highly susceptible to oxidative destruction and 50–95% of that in food is estimated to be lost in storage, preparation, or the manufacturing processes (7). Therefore, oral administration of folate-producing probiotic strains may provide the host with a constant vitamin supply in cases of inadequate folate intake. Moreover, folate-producing bifidobacteria may efficiently confer protection against colon inflammation and cancer by exerting both the beneficial effects of probiotics and by continuously and contiguously supplying the colonocytes with this vitamin. In fact, localized folate deficiency is associated with premalignant changes in colonic epithelia.

New perspectives are now emerging regarding the specific use of probiotics to deliver important vitamins such as folate.


   FOOTNOTES
 
1 Supported by a grant from Anidral/Probiotical Ltd, Novara, Italy. Back

2 Author disclosures: A. Pompei, L. Cordisco, A. Amaretti, S. Zanoni, S. Raimondi, D. Matteuzzi, and M. Rossi, no conflicts of interest. Back

5 Abbreviations used: DSMZ, German Collection of Microorganisms and Cell Cultures; FOS, fructo-oligosaccharides; PRE, prebiotic-supplemented diet; PRO probiotic-supplemented diet; SYM, symbiotic-supplemented diet. Back

Manuscript received 31 July 2007. Initial review completed 21 August 2007. Revision accepted 1 October 2007.


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 Introduction
 Materials and Methods
 Results
 Discussion
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