Journal of the American College of Nutrition, Vol. 22, No. 1, 56-63 (2003)
Published by the American College of Nutrition
Randomized Controlled Trial of the Effect of Bifidobacteria-Fermented Milk on Ulcerative Colitis
Hideki Ishikawa, MD,
Ikuko Akedo, MD,
Yoshinori Umesaki, PhD,
Ryuichiro Tanaka, MD,
Akemi Imaoka, MS and
Toru Otani, MD
Department of Cancer Epidemiology, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka (H.I., I.A., T.O.), JAPAN
Yakult Central Institute for Microbiological Research, Tokyo (Y.U., R.T., A.I.), JAPAN
Address reprint requests to: Hideki Ishikawa M.D., Laboratory of Hereditary Tumor, Institute for Advanced Medical Sciences, Hyogo College of Medicine, 3-1 Kyomachibori 2-chome, Nishi-ku, Osaka 550-0003, JAPAN. E-mail: cancer{at}gol.com
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ABSTRACT
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Background: Alterations of intestinal flora, such as reduction in the concentration of bifidobacteria and increase in that of Bacteroides species, are apparently associated with the severity of ulcerative colitis.
Objective: We conducted a randomised clinical trial of the use of a bifidobacteria-fermented milk (BFM) supplement as a dietary adjunct in the treatment of ulcerative colitis.
Methods: The subjects were randomly divided into two groups: a group with BFM supplementation (BFM group, 11 subjects) and a control group (control group, 10 subjects). The BFM group was given 100 mL/day of BFM for one year. Colonoscopies, general blood markers and examinations of intestinal flora including the analysis of fecal organic acids were performed at the commencement of the study and after one year.
Results: Exacerbation of symptoms was seen in 3 out of 11 subjects in the BFM group and in 9 out of 10 in the control group. Log rank statistic analysis of the cumulative exacerbation rates showed a significant reduction in exacerbations for the BFM group (p = 0.0184). The analysis of microflora and the organic acids in the feces showed a significant reduction in the relative proportion of B. vulgatus in Bacteroidaceae and butyrate concentration, respectively, after supplementation with BFM, in comparison with before.
Conclusion: Supplementation with the BFM product was successful in maintaining remission and had possible preventive effects on the relapse of ulcerative colitis.
Key words: ulcerative colitis, Randomised controlled trial, Bifidobacteria, Bacteroides vulgatus, short chain fatty acid
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INTRODUCTION
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Ulcerative colitis is a non-specific colorectal erosive inflammatory condition, characterized by inflammation of the mucosa, erosion and ulceration [1]. Its prevalence is increasing in Japan, the number notified to the Ministry of Health, Labour and Welfare exceeding 57,000 by the end of 1998 [2]. It is relatively easy to induce remission of this condition using such agents as steroids and salazosulfapyridine, but exacerbations are frequent. It is therefore important to try to prevent exacerbations.
Such factors as upper respiratory tract infections, stress, overwork, change in the weather and the use of nonsteroidal anti-inflammatory drugs have been implicated in exacerbations of ulcerative colitis [3]. Intestinal bacteria have been also implicated in the development and/or exacerbation of ulcerative colitis [4], in clinical studies to investigate the effect of antibiotics on inflammatory bowel disease (IBD) patients [5] and many gnotobiotic studies using animal colitis models. For example, TCR alpha chain [6] or IL-10 deficient mice [7], HLA-B27/ß2m transgenic rats [8] and SAMP1/Yit mice [9] develop typical colitis or enteritis under conventional breeding conditions, but not in germ-free conditions. Application of a probiotic preparation containing bifidobacteria or lactobacilli to chronic pouchitis was recently reported to be successful in maintaining remission of the disease [10].
Microbiologically, it has been found that bifidobacteria exist in fewer numbers in the feces of patients with ulcerative colitis than in healthy subjects [11,12]. Accordingly, it is expected that probiotics or prebiotics which have the potential to enhance the growth of the indigenous bifidobacteria can aid in the treatment and/or prevention of UC. Prebiotic foodstuff prepared from germinated barley has been already shown to be effective in the treatment of ulcerative colitis [13]. In our study, we designed and conducted a randomised clinical trial to determine whether exacerbations of ulcerative colitis could be prevented by altering the intestinal flora through supplementation with BFM as a dietary adjunct in combination with the usual medication.
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SUBJECTS AND METHODS
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Subjects
Subjects were patients of this institution who had been diagnosed with ulcerative colitis at least one year previously. The diagnosis was made on clinical grounds and based on colonoscopic findings from April to September 1998. Of the 25 patients invited to participate, consent was obtained from 21. The reasons for refusal were as follows: three were already regularly consuming BFM and did not want to stop, and one did not want to participate in a clinical trial. The 21 participants drew lots and were assigned to a BFM group of 11 and a control group of 10.
Subject backgrounds are given in Table 1. No differences were seen between the two groups in age, gender, extent of disease or disease activity, though there was some difference in the total amount of salazosulfapyridine used for six months before this study.
Study Protocol
The protocol for this study was approved by the Ethics Committee of the Osaka Medical Center for Cancer and Cardiovascular Diseases. Following explanation of the study, written consent was obtained from each subject. The subjects then drew lots, randomly assigning themselves to either the group with BFM supplementation (BFM group) or without (control group). Subjects underwent colonoscopy at the conclusion of the one-year study period. Blood was taken at the time of recruitment and after one year, for blood counts and biochemistry.
Study Medication
Treatment for ulcerative colitis was given as usual on clinical grounds, using salazosulfapyridine, mesalazine and steroids. When data on medication dosages was collected, one mesalazine 250 mg tablet or one salazosulfapyridine 500 mg suppository was counted as one salazosulfapyridine 500 mg tablet, and one betamethasone 1 mg suppository was counted as one prednisolone 5 mg tablet. For the dietary adjuncts, the members of the BFM group were provided with the BFM product. All patients of both groups were instructed not to take any fermented milk products during the study period by handing them an explanation with photographs of commercially available dairy products containing bifidobacteria and lactobacilli (more than 10 items). At monthly outpatient appointments, compliance was checked using the patient diary. The commercially available BFM product was provided by Yakult Co., Ltd. (Tokyo, Japan) and contained live bifidobacteria Yakult strains of Bifidobacterium breve, and Bifidobacterium bifidum, and Lactobacillus acidophillus YIT 0168 in numbers of at least 10 billion per 100 mL bottle. This product was delivered to the homes of the BFM group members, who were instructed to drink 100 mL each day for one year.
Study Evaluation
The main endpoint was considered to be an exacerbation of clinical symptoms. At each outpatient monthly appointment, subjects were questioned as to whether, in comparison with one month earlier, there had been any increased frequency of bowel motions or abdominal pain, or if blood or mucus in the motions had appeared or increased. It was considered an exacerbation if even one of these symptoms had worsened. Compliance in the ingestion of the BFM product was confirmed by checking supplementation diary kept by the subjects throughout the test period (one year).
Microbiological Analysis
Anaerobic stool collections were performed immediately following subject recruitment and again after one year. Fecal pH, water content, short-chain fatty acids and bacterial flora were assayed. Stool collections were performed as follows: subjects were asked to defecate directly into a plastic bag, then place this, with an oxygen absorber (AGELESS, Mitsubishi Gas Chemical Co., Tokyo, Japan), immediately into an ice-cooled sealed container and to bring this to our institution. Part of the collection was placed in nitrogen and sent to the Yakult Central Institute for Microbiological Research (Tokyo, Japan) for culture. Bacterial counts were performed as follows: anaerobically prepared diluent was added to the fecal sample, and the solution was thoroughly homogenised. This was then cultured at 37°C using the roll tube method, with VL medium [14] for total anaerobes, VLMB medium (VL medium containing 80 mg/mL of kanamycin and 1 mg/mL of vancomycin) for Bacteroidaceae [15,16], and MPN medium (modified Petuely’s synthetic medium supplemented with nalidixic acid) [17] for bifidobacteria [15]. The relative counts of the various Bacteroidaceae and bifidobacteria species were determined using recently developed molecular methods by selecting and extracting DNA from 20 colonies from each of the VLMB and MPN media. In brief, differences between strains were confirmed with the RAPD (Randomized Amplified Polymorphic DNA) method, using primers (5'-GGCGTCGGTT-3') and (5'-AACGCGCAAC-3') [18]. Species were then identified at the Yakult Central Institute with PCR using species-specific primers, Bacteroidaceae according to the method of Miyamoto et al. [19] and bifidobacteria according to the method of Matsuki et al. [20]. The recovery of the administered Bif. bifidum strain Yakult and Bif. breve strain Yakult in the stool samples was measured by culturing on T-CPBC (Transgalctosylated oligosaccharide agar supplemented with 0.625 g/mL streptomycin sulfate and 1 mg/mL carbenicillin) and T-LCM plate media (Transgalctosylated oligosaccharide agar supplemented with 0.625 g/mL of streptomycin sulfate and 2 mg/mL of lincomycin hydrochloride), respectively, and confirmed using monoclonal anti-Bif. bifidum strain Yakult and anti-Bif. breve strain Yakult antibodies. Generally, 30% to 100% of colonies on each medium were formed from probiotic strains. The lower limit of detectable counts was 200 per gram of wet feces.
Organic Acid Analysis
Another portion of stool collected was deproteinated with perchloric acid and used for measurement of short-chain fatty acids. Measurement of fecal short-chain fatty acid content was performed as follows: following deproteinization, the sample was centrifuged, and the supernatant was analyzed using high performance liquid chromatography. The column used was a Shodex KC-811 (x2) (Showa Electronics), with the internal standard method.
Statistics
For statistical analysis of differences between the two groups, the unmatched t test and 
2 test were used. Log rank statistic analysis was used to determine the cumulative exacerbation rates. The matched t test was used for comparison of biochemical data before and after the study period. A degree of confidence of p < 0.05 was considered statistically significant.
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RESULTS
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Participation
Of 11 members of the BFM group, seven took 95% or more of the planned amount of BFM, and the remaining four subjects managed rates of 90%, 86%, 83% and 73%. During the one-year duration of the study, no members of the control group consumed any bifidobacteria-fermented dairy products.
In the second month of supplementation, one of the members of the BFM group developed a coryza-like illness accompanied by abdominal pains without diarrhea and vomiting, so supplementation was suspended for two weeks. Following treatment of the coryza-like illness, supplementation was recommenced with no further abdominal pain, so the abdominal pains were thought to have been unrelated to consumption of BFM. No adverse effects were seen in any other subjects that might have been related to BFM supplementation.
Clinical Findings
During the one-year duration of the study, exacerbation of ulcerative colitis symptoms was seen in three out of 11 subjects in the BFM group (27%), and in nine out of 10 subjects in the control group (90%) (Table 2). In all cases in the BFM group, the number of exacerbations over the one-year study period was two or one, whereas there were three cases of more than two exacerbations in the control group.
Cumulative exacerbation rates and the data on individual patients are shown in Fig. 1. Log rank statistical analysis shows that exacerbations of ulcerative colitis were significantly reduced in the BFM group in comparison with the control group, p = 0.018.
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Fig. 1. Frequency of exacerbation in individual patients of the BFM group and control group (A) and cumulative exacerbation rates in the two groups (log rank statistical analysis, p = 0.0184) (B). At each monthly outpatient appointment, clinical symptoms were evaluated in comparison with one month earlier, as described in the Methods section. Hatched tiles show the month of the exacerbation of the symptoms of UC.
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No difference was seen in the colonoscopic findings at one year between the two groups. Although there was some difference in total amount of salazosulfapyridine used for six months before this study, there was no significant difference in the amounts of salazosulfapyridine, mesalazine and steroids taken during the study. Three and five patients in the BFM group and control group, respectively, were treated with steroids during the study period (Fig. 1).
As shown in Table 3, significant rises in total protein and serum albumin levels were seen after BFM supplementation in the BFM group, whereas no change was seen in the control group in blood taken at the commencement and completion of the study.
Bacterial Analysis and Organic Acid Constituents in the Feces
No differences were seen between the two groups in total fecal bacterial counts or in Bacteroidaceae or bifidobacteria counts (Fig. 2). However, the relative number of B. vulgatus species among all the bacteria isolated on selective medium (VLMB) for Bacteroidaceae was significantly reduced in the BFM group, as shown in Fig. 3. There was no significant difference in the ratio of other Bacteroides species, such as B. ovatus, B. fragilis, B. eggerthii, B. thetaiotaomicron and B. uniformis (data not shown). We also investigated the composition of Bifidobacterium species at the commencement of this study and after one year. The percentages of major Bifidobacterium species such as Bif. longum and Bif. catenulatum were not changed (Fig. 4). Strains from the BFM were recovered from the feces of the BFM group, Bif. breve strain Yakult from nine out of 10 subjects and Bif. bifidum strain Yakult from all at one year (Fig. 2). Relative proportions of fecal concentrations of short chain fatty acids in UC patients at the commencement and completion of the study are shown in Table 4. A decrease in total short chain fatty acids was seen in the BFM group, with a particularly marked decrease in butyrate (p = 0.06).
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Fig. 2. The numbers of total bacteria, total Bacterodaceae, total Bifidobacterium, and the two probiotic strains (Bif. breve strain Yakult and Bif. bifidum strain Yakult) at the commencement of the study (B) and one year later (A). *p < 0.05 (paired t test).
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Fig. 3. Ratio of each Bacteroides species in the bacteria isolated from the selective medium for Bacteroidaceae in UC patients with or without BFM supplementation. Bacteroides species were determined at the commencement of the study (B) and one year later (A). *p < 0.05 (paired t test).
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Fig. 4. Ratio of Bifidobacterium species in the bacteria isolated from the selective medium for Bifidobacterium in UC patients with or without BFM supplementation. Bifidobacterium species were determined at the commencement of the study (B) and one year later (A). *p < 0.05 (paired t test).
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Table 4. Fecal Concentration of Organic Acids in UC Patients, with or without BFM Supplementation at the Commencement of the Study (before) and 1 Year After (after)
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DISCUSSION
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Through a randomized clinical trial, we were able to demonstrate that BFM supplementation may be effective in the prevention of exacerbations of ulcerative colitis. Recently, clinical trails were performed to test the benefits of pro/prebiotics to the treatment of UC. Among the probiotics, the preparation VSL#3 comprising bifidobacteria, lacotobacilli and streptococci significantly repressed chronic pouchitis following total colectomy and ileo-anal anastomosis [10]. It was reported that the concentrations of lactobacilli, bifidobacteria and St. salivalius subsp. thremophillus increased, while those of other genera did not change. Although the mechanism of repression in the clinical trial was not clear, an animal study using IL-10 deficient mice strongly suggested that a soluble factor released from the bacteria contained in VSL#3 plays a role in normalizing the function of the damaged intestinal barrier [21]. The ingestion of non-pathogenic E. coli was also reported to be effective for the remission of ulcerative colitis [22]. In our clinical trial, BFM supplementation may have reduced exacerbation of UC through the normalization of the intestinal flora. It has been reported that the number of B. vulgatus strains in the colonic mucosa [23] and blood levels of antibodies against B. vulgatus are increased in patients with ulcerative colitis [24]. BFM supplementation led to a significant decrease in the relative number of B. vulgatus (percentage) in Bacteroidaceae in feces. This change in B. vulgatus was thought to reflect a decrease in the concentration of B. vulgatus species, because RAPD typing showed the same strains of B. vulgatus to be present both at the commencement of the study and one year later (data not shown). We know of other successful clinical trials showing the normalization of intestinal flora on administration of B. breve preparations using the same strain in BFM to preterm infants [15] or B. bifidum and St. thermophilus preparations to patients with diarrhea [25]. Although we could not evaluate the immunological status of the patients before and after this trial, immunological analyses are very important for IBD studies. We have shown that supplementation with BFM clearly suppressed inflammation and the Th1 response in the IBD model mouse, SAMP1/Yit strain [26] and that B. bifidum used here has high antioxidative activity in the iron-overload mouse colonic mucosa [27]. The immunological modification by BFM in this clinical treatment remains to be clarified.
Prebiotics are also expected to apply to normalization of the intestinal flora, particularly enhancement of bifidobacteria, in disorders of the gastrointestinal tract. Prebiotic foodstuffs derived from germinated barley [13] and resistant starch [28] were suggested to be effective in the amelioration of colitis in the clinical trial and animal IBD model, respectively. In both cases, enhancement of butyrate production by the ingestion of prebiotic preparations is estimated to be a key factor for the positive effect. Generally butyrate is considered to contribute to not only the supply of energy source to colonocytes [29] but also immunological regulation in the clonic mucosa [30] including the repression of the proinflammatory cytokines through inhibition of the activation of NF-kB [31]. In this clinical study, the luminal butyrate concentration (relative proportion) was reduced after BFM treatment, in contrast with a study with prebiotics published previously [13]. Although there was a large difference in the basal SCFA concentration in individual patients as observed in healthy subjects (data not shown), the decrease in butyrate after BFM treatment became more evident on evaluating the relative proportions of SCFA (Table 4). If butyrate is a key molecule in the remission of colitis, it is possible that the reduction in its butyrate concentration after this supplementation with BFM reflects increased uptake or oxidation of short chain fatty acids by the improved colorectal mucosa [32]. This is because total fecal bacterial counts were largely unchanged (Fig. 2), so there was unlikely to have been any alteration in the production of short chain fatty acids caused by BFM. The decrease in the butyrate concentration and its percentage in the feces observed in this study raise questions on the dynamics and the role of short chain fatty acids, particularly butyrate, in the treatment of colitis with pro/prebiotics supplementation.
In this study using BFM, we showed a good recovery of probiotic strains in the stools and a reduction in the percentage of Bacteroides vulgatus and luminal butyrate. In addition, we observed increases in serum total protein and albumin levels after BFM supplementation, suggesting the reduced transudation of albumin and other proteins from the colorectal mucosa and also a general improvement in condition. It will be necessary to conduct a multi-centered double-blind randomized clinical trial with larger subject numbers to determine the effective ingredients in this BFM product.
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ACKNOWLEDGMENTS
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We would like to express our gratitude to Mrs. Reiko Yamamoto (Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan) for dealing with patients and patient data so efficiently, and also to Dr. G. D. Miller (National Dairy Council, USA) for his critical reading of this manuscript. Part of this study was supported by grants from the Yakult Bio-Science Foundation.
Received September 24, 2001.
Accepted July 23, 2002.
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ABSTRACT
INTRODUCTION
