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IAPS Laboratory, University of Toulon, Toulon, FranceDepartment of Physiology, Faculty of Fundamental and Applied Sciences, University of Poitiers, Poitiers, France
In the absence of a well-established therapeutic approach, patients with irritable bowel syndrome seek alternative strategies such as probiotics.
Aims
The current trial named LAPIBSS aimed to demonstrate the efficacy of a 2-strain mixture of Lactobacillus acidophilus to improve irritable bowel syndrome symptoms.
Methods
Eighty patients diagnosed for irritable bowel syndrome were recruited to a multicentre, double-blinded, in parallel groups, placebo-controlled, randomized clinical trial. Patients were provided with a daily dose of two capsules containing either probiotics (5 × 109 cfu/capsule) or placebo for 8 weeks. The primary outcome was abdominal pain score assessed with a 100-mm visual analogue scale. Secondary outcomes included scores of bloating, flatus and rumbling assessed with a 100-mm visual analogue scale, a composite score and bowel habits.
Results
Abdominal pain score was significantly improved in both groups at weeks 4 and 8 (P < 0.0001), but no significant differences were found between groups at week 8 (19.0 ± 2.5 vs 25.1 ± 2.6, respectively; LS Means differences = 6.0 ± 3.2; P = 0.06). Significant differences between groups were observed for flatus score at week 4 (P = 0.04) and week 8 (P = 0.03) and composite score (P = 0.04) at week 8.
Conclusions
The consumption of the 2-strain mixture of L. acidophilus over 8 weeks is safe and decreases significantly flatus and composite scores.
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder with a worldwide global prevalence estimated at 6% in the general adult population [
]. IBS consists of abdominal pain or discomfort and altered bowel habits, especially constipation and/or diarrhea, criteria which have not been directly linked to structural or biochemical abnormalities [
]. The current consensus is that the pathophysiology of IBS is multifactorial and involves a dysfunction of the gut-brain axis linked to gut microbiota or “microbiome”, visceral hypersensitivity, abnormal gastrointestinal motility and secretion as well as a low-grade intestinal inflammation [
]. Dysbiosis is highly associated with the disruption of gut-brain axis in IBS patients, suggesting that microbiota influences these different pathophysiological targets [
]. Several food-associated Lactobacillus species have an excellent safety profile and have a “generally-regarded-as-safe” (GRAS) status, such as Lactobacillus acidophilus (L. acidophilus) [
]. While L. acidophilus is one of the most commonly dietary used bacteria, only 2 RCT performed with L. acidophilus strains and conducted with a high-quality method have been reported in the symptomatic treatment of IBS [
]. After 4 weeks of treatment, L. acidophilus-SDC 2012, 2013 significantly reduced abdominal pain compared with placebo in a pilot RCT including 40 patients [
]. Recently, a 12-week RCT performed with L. acidophilus NCFM showed significant improvement of abdominal pain in the subgroup of patients suffering from moderate to severe pain [
]. Although modest, this latter result is consistent with preclinical data demonstrating the strain-specific property of L. acidophilus NCFM to modulate and restore a normal perception of visceral pain [
]. Based on the higher magnitude of positive results observed with L. acidophilus-SDC 2012, 2013 strains, we have suggested an additional benefice of a combined treatment with two strains of the same species without known antagonist effects, and designed a tightly-controlled protocol to test this hypothesis [
]. This design was published as L. acidophilus versus placebo in the symptomatic treatment of irritable bowel syndrome (LAPIBSS study) and used to obtain the results of the present RCT [
]. The use of a second available L. acidophilus strain, i.e. L. acidophilus subsp. helveticus LAFTI L10, was based on preclinical and clinical evidence for its strain-specific gut immune-enhancing properties [
]. The aim of the LAPIBSS study was to test the assumption that the consumption of a 2-strain mixture of probiotic L. acidophilus species for 8 weeks could improve abdominal pain/discomfort as primary outcome and the others IBS symptoms such as bloating, flatus, rumbling and bowel habits, including stool frequency and consistency/appearance as secondary outcomes [
The study protocol refers to a multicentre, double-blind, placebo-controlled, two-armed, parallel design, individually randomized trial, comparing probiotics with placebo in patients with IBS. The current trial was performed for a maximum of 9 weeks with 4 visits planned (at points corresponding to screening, baseline, 2 control visits after 4 and 8 weeks of treatment). During the screening visit, investigators checked the eligibility of participants and obtained their informed consent. If the eligibility was confirmed within a maximum of 7 days from the date of the first visit, they were randomized to receive probiotics or placebo for 8 weeks, stratified by care centre. Regulatory approval was obtained September 11, 2008 from the ANSM (French National Agency for Medicines and Health Products Safety — Number B80623-40) and ethics approval of all procedures of the present study was obtained September 15, 2008 from the Ethics Committee in France (French Consultative Committee for the Protection of Persons in Biomedical Research of the South West with the number: CPP08-014a). Written informed consent was obtained from each participant. The present trial was registered in July 2008 under EudraCT number 2008-A00844-51 (European Union Drug Regulating Authorities Clinical Trial) in accordance with the European Union Clinical Trials Directive 2001/20/EC.
2.2 Patients
Patients who fulfilled the screening criteria were recruited by 10 office-based physicians located in France, and by a gastroenterologist of the Rangueil University Hospital of Toulouse, France. Eligible participants were screened among French patients already diagnosed with IBS and a total of 80 patients male and female were enrolled between January 2009 and April 2012. The trial was completed on May 19, 2012. Patients were eligible for the trial if they provided written informed consent and if they met all of the following criteria: aged between 30 and 60 years old; diagnosed for IBS according to Rome III criteria; presented with a negative coprological and inflammatory balance (negative CRP blood test) for over 6 months. Subjects were excluded from the trial if they presented with an organic intestinal disease, a severe or active disease with multiple treatments, intestinal parasitic infection in the last 6 months, inflammatory bowel disease or a history of previous abdominal surgery (except appendectomy, caesarean birth, tubal ligation, hernia). In addition, subjects were excluded if they changed their medication in the last 2 months, took probiotics in the last 2 months or antibiotic therapy in the last 30 days, received current antidepressant or antipsychotic treatment, and received antimycotic and antiseptic treatment or treatment affecting gastrointestinal transit as well as chronic use of antalgic and antispasmodic medications. Additional exclusion criteria are detailed in the LAPIBSS protocol [
The study was a double-blind trial. Neither investigators nor patients were aware of product allocation until the end of the trial. The type of randomization was the block randomization method and it was stratified by care centres with participants randomly allocated (1:1 basis) to either probiotics or placebo. An 88-case randomisation arrangement was performed by an independent statistician according to the sequence generated with SAS® software (SAS® 8.2 software (SAS®, Cary, NC, USA)). The study product was provided in the form of vegetable capsule containing a blend of two viable lyophilized L. acidophilus strains: L. acidophilus NCFM (FDA GRAS Notice 000357, strain number ATCC SD5221, Danisco Inc. Madison, Wisconsin, United States) and L. acidophilus subsp. helveticus LAFTI L10 (strain number CBS 116.411, Lallemand Health Solutions, Blagnac, France). This mixture of two probiotic strains provides for each 2.5 × 109 colony-forming unit (cfu) for a total of 5 × 109 cfu per capsule. Formulations of the indistinguishable investigational products are detailed in the supplementary material (Table S-1). These products were specially manufactured for the study by Laboratoire Denel-Codifra (Le Chesnay, France). The trial dose was 2 capsules/day taken orally; one in the morning and the other one in the evening with a full glass of water half an hour before eating. At the baseline visit, investigators provided a box containing 120 capsules to each included participant to ensure 8 weeks of consecutive supplementation (56 ± 2 days). Eligible participants also received a diary to report their bowel habits daily and their IBS symptoms weekly for 8 weeks. Compliance was evaluated by counting the return of unused capsules.
2.4 Outcomes and safety assessment
IBS symptoms of abdominal pain or discomfort, bloating, flatus and rumbling were recorded by the clinical investigator on the case report forms for each patient at the baseline visit and at both visits (weeks 4 and 8). Each IBS symptom score was assessed with a 100-mm visual analogue scale (VAS; 0: none; 100: very severe) [
]. The composite score was the sum of 4 VAS scores (abdominal pain/discomfort, bloating, flatus and rumbling) calculated for each patient. Stool frequency and consistency were recorded by each patient on the daily diary delivered at baseline visit and theirs scores were averaged over consecutive 7-day periods. Baseline scores were calculated over the 7 days before product consumption. Consistency/appearance of any bowel movement was assessed in accordance with the 7-point Bristol Stool Form Scale using the absolute difference from normal (score 4) [
The difference in score of abdominal pain/discomfort between groups at week 8 was defined as primary outcome. Secondary outcomes included differences in scores of bloating, flatus, rumbling, composite score and stool characteristics between groups at week 8. A medical history, including the presence of chronic diseases and regular medication were recorded before inclusion. Physical examinations were performed at each visit and vital signs were also monitored during the screening visit and at week 8.
2.5 Sample size calculation
According to the data from a previous trial performed by Nobaek et al. using a probiotic strain of the genus Lactobacillus to improve IBS symptoms, a difference of 10 points for the primary outcome of abdominal pain between the two groups of the trial was expected [
]. Assuming a standard deviation (s.d.) of 10 points, the sample size required was 23 patients in each group to observe these differences with α error of 0.05 and at a statistical power of 90%. By considering the risk that 40% of the patients included could not be assessed at the end of the study, it was necessary to include 40 patients per group [
The efficacy of Lactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndrome—a double-blind, placebo-controlled, randomized study.
]. Given the risk of failure at the selection, it was planned to include an additional 10% of subjects. Consequently, a maximum of 88 subjects was necessary to obtain 80 assessable subjects were recruited. This statistical sample size calculation was consistent with the EMA (European Medicines Agency) guidelines [
Statistical analysis was conducted based on the intention to-treat (ITT) population, which includes every subject who is randomized according to randomized treatment assignment. All treated subjects without any major protocol deviations comprised the per-protocol set (PPS). Statistical analysis was performed using the SAS® 8.2 software (SAS®, Cary, NC, USA) and the statistical significance was defined as a two-sided P-value <0.05. The Shapiro-Wilk test as well as measures of Skewness and Kurtosis indicators were performed in order to check the normal distribution of raw data and residuals. Demographics and baseline clinical outcomes data were compared between groups using χ2 test or Fisher’s exact and Student’s t-test or Mann–Whitney–Wilcoxon test, when appropriate. Primary and secondary outcomes were analysed using a mixed linear model including the fixed, categorical effects of group, investigative center, visit, and treatment-by-visit interaction as well as the fixed, continuous covariates of baseline score and baseline score-by-visit interaction. Baseline score was included in the analysis according to the statistical methods from previous trials conducted in patients with IBS as recommended by the EMA guidelines [
Effect of a fermented milk containing Bifidobacterium animalis DN-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care a multicentre, randomized, double-blind, controlled trial.
European Medicines Agency. Guideline on adjustment for baseline covariates in clinical trials. EMA/CHMP/295050/2013. Available from: http://www.ema.europa.eu/ema/.
]. The primary comparison was the contrast, i.e. the difference in least-squares means (LS Means) ± standard error of mean (SEM), between groups at week 8. An autoregressive covariance structure was used to model the within-patient errors and the Kenward-Roger approximation was used to estimate denominator degrees of freedom and adjust standard errors. The primary comparison was also performed on PPS. As required by the protocol, analysis of tolerability was conducted on the ITT population and missing data were not replaced.
3. Results
3.1 Subjects
In accordance with the CONSORT statement, the flowchart of patients through the protocol study is described in the Fig. 1 [
]. Of the 127 participants screened by investigators to check their eligibility, 80 patients were randomized, 1 patient from probiotics group discontinued and 79 completed the study leading to an ITT population of 80 patients and a PPS of 79.
Fig. 1Flowchart of patients through the study protocol in accordance with the CONSORT statement.
As shown in Table 1, no significant differences (from P = 0.49 to P = 0.93) between probiotics and placebo groups were seen in terms of age, weight, gender, severity scores of abdominal pain, bloating, flatus, rumbling and composite scores as well as stool frequency and consistency/appearance.
Table 1Patient demographic and clinical characteristics at baseline (n = 80).
Abdominal pain/discomfort scores shown in Table 2 improved significantly in both probiotics and placebo groups (P < 0.0001) after 8 weeks of treatment compared with baseline. No significant differences were found between groups at week 8 (19.0 ± 2.5 vs 25.1 ± 2.6, in probiotics and placebo groups respectively; LS Means differences = 6.0 ± 3.2; P = 0.06). As shown in Fig. 2, a greater reduction in abdominal pain/discomfort severity was observed for probiotics group compared with placebo group throughout the intervention period. Compared with the ITT population, the analysis on PPS did not show any significant difference.
Table 2Symptoms scores of irritable bowel syndrome and composite score at baseline, week 4 and week 8 of the study period (n = 80).
Comprised of the sum of 4 VAS scores calculated for each patient.
Baseline
195.2 ± 9.6
192.8 ± 9.8
2.4 ± 11.7
0.84
Week 4
110.3 ± 9.6
130.1 ± 9.8
19.8 ± 11.7
0.09
Week 8
79.2 ± 9.6
103.7 ± 9.8
24.5 ± 11.8
0.04*
Symptoms scores in each group and differences between groups at baseline, week 4 and week 8 are expressed as least-square mean (LS Means) ± SEM using a mixed linear model (*P < 0.05).
a Assessed with a 100-mm visual analogue scale (VAS; 0: none; 100: very severe).
b Comprised of the sum of 4 VAS scores calculated for each patient.
Fig. 2Evolution of abdominal pain score in probiotics and placebo groups throughout the trial. Abdominal pain scores assessed with a 100-mm visual analogue scale (VAS; 0: none; 100: very severe) at baseline, week 4 and week 8 are expressed as least-square means (LSmeans) ± SEM. Within groups changes from baseline to week 8 (†P < 0.0001) and between groups differences at each time point were done using a mixed linear model.
Symptom scores of bloating, flatus, rumbling and composite scores are shown in Table 2. Bloating scores improved significantly in both groups (P < 0.0001) after 8 weeks of treatment compared with baseline, but no significant differences between groups were found at week 8 (20.7 ± 2.8 vs 26.3 ± 2.8, in probiotics and placebo groups respectively; LS Means differences = 5.6 ± 3.5; P = 0.10) (Table 2). A greater reduction of bloating scores was observed in probiotics group in comparison with placebo group throughout the intervention period as shown in Fig. 3A. Compared with baseline, flatus, rumbling and composite scores were reduced significantly in both probiotics and placebo groups (P < 0.0001) at week 8 (Table 2). Fig. 3B–D shows respectively a greater reduction of flatus, rumbling and composite scores in probiotics group compared with placebo group throughout the trial. Significant differences between groups were found for flatus scores at week 4 (28.3 ± 3.0 vs 36.0 ± 3.1, in probiotics and placebo groups respectively; LS Means differences = 7.7 ± 3.7; P = 0.04) and week 8 (21.3 ± 3.0 vs 29.6 ± 3.1, in probiotics and placebo groups respectively; LS Means differences = 8.2 ± 3.8; P = 0.03), while no significant differences between groups were found for symptoms scores of rumbling at the end of the study (P = 0.21) (Table 2). Significant differences between groups were found for composite scores at week 8 (79.2 ± 9.6 vs 103.7 ± 9.8, in probiotics and placebo groups respectively; LS Means differences = 24.54 ± 11.84; P = 0.04) (Table 2). No significant differences between groups were observed for stool frequency (P = 0.73) and consistency (P = 0.89) at the end of the trial (Table 3).
Fig. 3Evolution of bloating (A), flatus (B), rumbling (C) and composite (D) scores in probiotics and placebo groups throughout the trial. Bloating, flatus, rumbling scores assessed with a 100-mm visual analogue scale (VAS; 0: none; 100: very severe) and composite scores comprised of the sum of 4 VAS scores at baseline, week 4 and week 8 are expressed as least-square means (LSmeans) ± SEM. Within groups changes from baseline to week 8 (†P < 0.0001) and between groups differences at each time point were done using a mixed linear model (*P < 0.05).
Stool characteristics in each group and differences between groups at baseline, week 4 and week 8 are expressed as least-square means (LS Means) ± SEM using a linear mixed model.
Apart from one patient from the placebo group who discontinued the trial due to a voluntary withdrawal after the 4th week, all patients complied with the protocol. According to the returned capsules, compliance with investigational product was high in both groups with no significant differences between probiotics and placebo groups (38/40 vs 39/40, respectively; P = 1.0).
3.6 Adverse events
One subject from the probiotics group reported transient adverse events (AE) including abdominal pain, bloating and diarrhea occurring at the first week of the trial, but he did not withdraw from the trial and complied with the protocol until the end of the study without any other AE. No serious AE were reported in this trial.
3.7 Use of rescue medication
The use of rescue medication was comparable in both groups with no significant differences between probiotics and placebo groups (12/40 vs 14/40, respectively; P = 0.63).
4. Discussion
The current trial has failed to demonstrate a significant improvement of the primary outcome of abdominal/pain discomfort and the secondary outcome of bloating although the reduction of the severity of these symptoms was greater in the probiotics group compared to the placebo group. Significant differences between groups were observed for secondary outcomes of flatus score at weeks 4 and 8 and composite score at week 8.
According to the FDA IBS clinical guidelines published after the start of the present trial, responders were defined as patients reporting a decrease ≥50% of abdominal pain [
Center for Drug Evaluation and Research (CDER). U.S. Department of Health and Human Services Food and Drug Administration. FDA Guidance for Industry. Irritable Bowel Syndrome—Clinical Evaluation of Products for Treatment. May 2012. https://www.fda.gov/downloads/Drugs/Guidances/UCM205269.pdf.
]. The placebo response rate (PRR) found in our study was 52.5%. Using the same response threshold, the PRR in IBS composite score was 40% which is consistent with results of a meta-analysis performed by Ford et al. investigating the magnitude of PRR in treatment trials for IBS and reporting a pooled PRR across all RCT of 37.2% (95% CI 34.4–40.6%) [
]. Interestingly, results of this meta-analysis showed a higher PRR in RCT performed in Europe, with physician-reported outcomes, and using shorter duration of treatment [
]. This important information could be an explanation of the weakness of our results, in particular for the clinical criteria of abdominal pain/discomfort and bloating.
According to the protocol that we have previously published, we expected a synergistic effect on abdominal pain of 2 strains of the same species without antagonist effects known regarding to positive results of a previous pilot RCT conducted with the 2-strain mixture of L. acidophilus SDC-2012, 2013 [
]. Modes of action such as strain-specific antinociceptive and immunoregulatory properties have been demonstrated for each strain of L. acidophilus used in our study [
]. Our results do not support this assumption that could be explained by an insufficient dosage and/or duration of the trial. Indeed, the consumption over 3 weeks of L. acidophilus NCFM alone at a daily dosage of 2 × 1010 cfu can induce the expression of μ1-opioid receptor that has a well-established physiological role in gut nociception, motility, and secretion [
]. Moreover, the involvement of the gut-brain axis dysregulation in the pathogenesis of IBS could also explain the limited effect on abdominal pain observed in our trial based on probiotic properties targeting the intestinal system [
]. A more relevant comparison could be done with results from the high-quality RCT investigating the dose response relationship with L. acidophilus NCFM alone on patients with IBS [
]. At two daily dosage of 109 and 1010 × cfu over 12 weeks, a significant improvement of abdominal pain severity at the end of intervention in active groups combined compared with placebo has been demonstrated [
]. However, this significant result was obtained by a post-hoc analysis performed among the subgroup of patients suffering from moderate to severe pain (n = 99; P = 0.046) thus limiting the weight of evidence [
]. Regarding to our results, it could be speculated that a study period of 12 weeks or more would result in a plateau effect for placebo response and an emphasis of probiotic response. Nevertheless, a longer study period above of 12 weeks, i.e. 6 months, corresponding to a long-term efficacy assessment would increase significantly the patient withdrawal rate according to the results of the unique 6-month RCT using a probiotic strain of the genus Lactobacillus in symptomatic treatment of IBS [
The efficacy of Lactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndrome—a double-blind, placebo-controlled, randomized study.
The current RCT was designed to enroll participants without distinction of IBS subtypes or threshold for baseline symptom severity. However, this heterogeneity of included participants would have contributed to the large variability of treatment responses observed in our trial which may have underestimated when choosing the standard deviation for the sample size calculation.
The significant effect on flatus could result from the species-specific homofermentative properties of L. acidophilus strains able to produce lactic acid without gas production [
]. This shared mechanism among L. acidophilus species could result in an additional effect in view of our results and its potential implications for general probiotic claims [
]. Although the survival of strains in the gastrointestinal tract is not considered as an evaluation criterion by the European Food Safety Authority (EFSA) in the scientific demonstration of the probiotic health claim, one of the main limitation of the current trial is the lack of a stool microbiome analysis that would have helped to ascertain compliance and a potential change in microbial composition to clarify this hypothesis [
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)
Guidance on the scientific requirements for health claims related to the immune system, the gastrointestinal tract and defence against pathogenic microorganisms.
]. The lack of significant effect of probiotics on stool characteristics changes is consistent with results of previous RCT performed with probiotics among general patient population and would confirm that bowel-related symptoms should be studied in RCT selecting participants according to IBS subtypes [
]. Probiotics were well tolerated and free from significant or serious AE confirming the GRAS status of Lactobacilli, in particular of probiotic species L. acidophilus [
Future trials in this area are required to investigate whether microencapsulation of L. acidophilus NCFM using polymerized whey proteins as wall material and/or cellobiose which ensures a prebiotic effect on this strain would increase the efficacy of the probiotic response [
The differential proteome of the probiotic Lactobacillus acidophilus NCFM grown on the potential prebiotic cellobiose shows upregulation of two β -Glycoside hydrolases.
]. The pathogenesis of IBS appears multifactorial without a well-established biomarker for its diagnosis, but nevertheless could be achieved with the introduction of the Rome IV criteria for improving the accuracy of diagnosis criteria [
]. Although our study reflects the methodology of years during which it was performed, the abdominal pain as the primary outcome for the current trial remains an essential component of diagnosis criteria [
In conclusion, the consumption of the 2-strain mixture of L. acidophilus over 8 weeks is safe and decreases significantly flatus and composite scores compared with placebo at the end of the trial. The beneficial and significant effect on flatus could result from the species-specific homofermentative properties of L. acidophilus strains able to produce lactic acid without gas production. The strong placebo effect and the potential heterogeneity of global population of patients with IBS may contribute to the lack of significant differences on abdominal pain and could warrant further study with probiotics targeting the gut-brain axis.
Funding
This study was funded by OSEO Innovation - Bpifrance (Maisons-Alfort, France) and Laboratoire Denel-Codifra (Le Chesnay, France).
Conflict of interest
Stéphane Sadrin is an employee of Laboratoire Denel-Codifra (Le Chesnay, France), which supplied probiotics and the placebo for the research. The remaining authors disclose no competing interests.
Aknowlegments
Pr Susan J. Whiting (College of Pharmacy and Nutrition, Saskatoon, Canada), Dr Raul Martínez-Zaguilán (Texas Tech University Health Sciences Center, Lubbock, USA), Dr Sandrine V. Pierre (Marshall Institute for Interdisciplinary Research, Huntington, USA), and Dr Thierry Coste (Novastell, Étrépagny, France) for the proofing of the manuscript.
Appendix A. Supplementary data
The following is Supplementary data to this article:
The efficacy of Lactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndrome—a double-blind, placebo-controlled, randomized study.
Effect of a fermented milk containing Bifidobacterium animalis DN-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care a multicentre, randomized, double-blind, controlled trial.
European Medicines Agency. Guideline on adjustment for baseline covariates in clinical trials. EMA/CHMP/295050/2013. Available from: http://www.ema.europa.eu/ema/.
Center for Drug Evaluation and Research (CDER). U.S. Department of Health and Human Services Food and Drug Administration. FDA Guidance for Industry. Irritable Bowel Syndrome—Clinical Evaluation of Products for Treatment. May 2012. https://www.fda.gov/downloads/Drugs/Guidances/UCM205269.pdf.
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)
Guidance on the scientific requirements for health claims related to the immune system, the gastrointestinal tract and defence against pathogenic microorganisms.
The differential proteome of the probiotic Lactobacillus acidophilus NCFM grown on the potential prebiotic cellobiose shows upregulation of two β -Glycoside hydrolases.
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