Eskesen et. al. Biotherapy Journal Review Summer 2016

Reviewer: Ronald Sherman, MD

Journal Citation

Eskesen D, Jespersen L, Michelsen B, Whorwell PJ, Müller-Lissner S, Morberg CM. Effect of the probiotic strain Bifidobacterium animalis subsp. lactis, BB-12®, on defecation frequency in healthy subjects with low defecation frequency and abdominal discomfort: a randomised, double-blind, placebo-controlled, parallel-group trial. Br J Nutr. 2015 Nov 28;114(10):1638-46.

Published Abstract

The aim of the present study was to investigate the effect of Bifidobacterium animalis subsp. lactis, BB-12®, on two primary end points - defecation frequency and gastrointestinal (GI) well-being - in healthy adults with low defecation frequency and abdominal discomfort. A total of 1248 subjects were included in a randomised, double-blind, placebo-controlled trial. After a 2-week run-in period, subjects were randomised to 1 or 10 billion colony-forming units/d of the probiotic strain BB-12® or a matching placebo capsule once daily for 4 weeks. Subjects completed a diary on bowel habits, relief of abdominal discomfort and symptoms. GI well-being, defined as global relief of abdominal discomfort, did not show significant differences. The OR for having a defecation frequency above baseline for ≥50% of the time was 1·31 (95% CI 0·98, 1·75), P=0·071, for probiotic treatment overall. Tightening the criteria for being a responder to an increase of ≥1 d/week for ≥50 % of the time resulted in an OR of 1·55 (95% CI 1·22, 1·96), P=0·0003, for treatment overall. A treatment effect on average defecation frequency was found (P=0·0065), with the frequency being significantly higher compared with placebo at all weeks for probiotic treatment overall (all P<0·05). Effects on defecation frequency were similar for the two doses tested, suggesting that a ceiling effect was reached with the one billion dose. Overall, 4 weeks' supplementation with the probiotic strain BB-12® resulted in a clinically relevant benefit on defecation frequency. The results suggest that consumption of BB-12® improves the GI health of individuals whose symptoms are not sufficiently severe to consult a doctor (ISRCTN18128385).

Context

Gastrointestinal (GI) microbiota are now recognized to play an integral role in such functional bowel disorders as irritable bowel syndrome (IBS) and constipation. Therefore, it is reasonable to investigate whether administered microbes (probiotics) could alleviate the symptoms of functional bowel disorders or even the mild symptoms in otherwise “normal” individuals.

In prior studies, the administration of Bifidobacterium animalis subsp. lactis (BB-12®) has already been shown to improve abdominal distress and defecation irregularity in certain patient groups.

In this study, the authors “set out with the primary objective to investigate the effect of the probiotic strain BB-12® in different dosages on defecation frequency and global relief in healthy subjects with low defecation frequency and abdominal discomfort. The secondary objective was to investigate the effect on abdominal pain and bloating. As little is known about healthy populations with minor GI complaints, we also wanted to explore whether certain subgroups were more likely to benefit from treatment with the probiotic strain BB-12®

The study was designed as a randomized, double-blind, placebo-controlled, multicenter clinical trial, conducted in two parts: a 2-week baseline (“run-in period”) followed by a 4 week intervention period. The intervention consisted of administering 1 capsule of BB-12® to subjects each day, in doses of either 1 or 10 billion colony-forming units (CFU) per capsule. The control group received identical placebo capsules. Subjects were allowed to continue all other medications and their normal activities, except excessive physical exercise or the consumption of probiotics or fermented dairy products.

Subjects were recruited voluntarily if they were between 18 – 70 years old, with a low defecation frequency (defined as 2 - 4 days/week) and complaints of general abdominal discomfort. Subjects were excluded if they had a history or diagnosis of specific GI disease such as IBS, prior complicated GI surgery, depressive disorder, or the use of oral antibiotics within the preceding 4 weeks. The use of drugs or large doses of vitamins and minerals or food or herbal supplements, even for digestive symptoms, was permitted as long as the substance and dose was stable.

After enrollment and randomization, subjects began the 6 week study, completing a daily and weekly diary assess study outcomes, their symptoms, their self-assessment of any changes over the past week, and their compliance with the study regimen. Subjects also completed questionnaires regarding their physical activity and adverse events.

Primary end points were defecation frequency and GI well-being. Responders were defined as subjects with an average weekly defecation frequency above baseline for at least 50% of the time (at least 2 weeks of the 4-week intervention period); GI well-being responders were defined as subjects who achieved “relief” for at least 50% of the time. Secondary end points were symptom severity scores for abdominal pain and bloating. Data was analyzed with rigorous standard statistical methodology. Before completion of the study, data was submitted for two interim analyses.

Findings

A total of 1248 subjects were randomized into the study and analyzed in the intent-to-treat analysis. Attrition was less than 1%. The characteristics of the three study groups were similar at

Baseline. Subject compliance with study protocol was reported as 100%. The low dose (1 million CFU) arm of the study was closed early, as the result of the interim analysis.

The odds ratio (OR) – which can be likened to statistical probability – for having a defecation frequency above baseline for ≥50% of the time was 1·31 (95% CI 0·98, 1·75), P=0·071, for probiotic treatment overall. However, when looking only at those subjects who increased their bowel frequency by at least ≥1 day/week for ≥50% of the time, there was a significant difference between subjects who received the probiotic supplements and those who did not: OR of 1·55 (95% CI 1·22, 1·96), P=0·0003. Defecation frequency increased for subjects in all three treatment groups, though it increased more for those in the probiotics arms than in the control arm (P=0·0065). Defecation frequency increased most for thos subjects whose baseline frequency was ≥3 day/week. No dosage-related difference was seen with defecation frequency nor with any other finding of benefit or harm.

There were no statistically significant differences in symptoms of GI well-being between the three treatment groups. Abdominal pain and bloating decreased by about 40% for subjects in all treatment groups during the study period (no significant difference between different interventions). Stool consistency became softer for subjects in all study groups, though maybe more so for those in the There was evidence of softer stool in one billion group (P= 0·056).

While 337 adverse events were reported in 233 subjects (18·7 %), all but 17 events in 14 subjects were considered unrelated to the study. Most of these were GI related, and there was no difference between the number or severity of adverse event and the treatment group.

Discussion

The authors are to be commended for executing a rigorous scientific study, complete with randomization and controls, a baseline observational period, extensive statistical analyses (including intent-to-treat analysis and intermediate analysis), and a large enrollment of over 1,200 subjects. Their study demonstrated a clear increase in defecation frequency in patients with baseline stooling of only 3 – 4 days per week, if they received the daily BB-12® probiotic supplement (either 1 billion or 10 billion CFU dose). Although the probiotic was not definitely associated with increased defecation frequency for those with baseline stooling of <3 days / week (since most patients increased their defecation frequency during the study, regardless of treatment group), those who increased their frequency by at least one more day per week, for at least 2 weeks out of the 4-week intervention period, were more likely to have received the probiotic than not. Why were the benefits less visible in subjects with lower defecation frequency? This could be a result of a difference in severity, or even a difference in etiology. Clearly the subject population was not a uniform group, even though the distribution among the three treatment arms appears to have been homogeneous. Then again, one can always blame probability – a reality whose effects are minimized only by studying larger and larger sample sizes.

It is interesting that there was no dose effect seen with the BB-12®. This suggests that the benefits of this organisms are reached at some minimal level of consumption (presumably < 1 million CFU / day). Higher doses were associated with no greater benefits and no greater harms.

The authors claim that “the results suggest that consumption of BB-12® improves the GI health of individuals whose symptoms are not sufficiently severe to consult a doctor.” But I would temper that statement because – while there were clearly benefits in defecation frequency for many of the subjects – increased defecation frequency should not be interpreted as improved GI health overall. Indeed, all other measurements of GI health, such as symptoms of abdominal discomfort, stool consistency, etc., improved in subjects from all intervention groups, with no clear statistically significant association with the probiotics intervention arms.

Still, the study demonstrated BB-12® to be safe, with no more adverse events than those seen in the placebo-controlled arm. The results suggest that it is reasonable for individuals with infrequent defecation and GI symptoms who have no specific etiology identified and/or who have not felt their symptoms warranted consulting a doctor might benefit from a trial of BB-12®, and have little to lose from doing so.