Effects of a Probiotic Fermented Milk on Functional Constipation

A Randomized, Double-blind, Placebo-Controlled Study

Mena Mustapha Mazlyn; Lee Hun-Leong Nagarajahl Arshad Fatimah; A Karim Norimah; Khean-Lee Goh

J Gastroenterol Hepatol. 2013;28(7):1141-1147.

Discussion

Studies conducted in Japan and Europe have shown that LcS improves self-reported severity and stool consistency in chronic idiopathic constipation,^[13] reduces incidence of hard lumpy stools among healthy subjects,^[14] and increases stool frequency among subjects with low stool frequency.^[15] In the present study, however, within a 4-week treatment period, administration of 3.0 × 10¹⁰ CFU per day of LcS in adults with functional constipation did not bring about statistically significant improvement in any of the four efficacy outcomes when compared with a placebo nutrient drink at α = 5% level. The α = 5% level is conventionally used for clinical trials of medical prescriptions. The present study involved a fermented milk beverage that is not a prescribed pharmaceutical agent, and the purpose of supplementation is for long-term effect. Thus, α = 10% level is not considered critical, and re-evaluation at this α level was attempted, which revealed statistically significant improvement in constipation severity score at week 4 of treatment. It should be noted that the probiotics improved stool consistency significantly compared with baseline, while the placebo did not, and the magnitude of the probiotic treatment effect on stool consistency was small but statistically significant. This effect size also grew larger over time. These findings provide an indication that time could have been a limiting factor in the observation of the full effects of the probiotics on the earlier mentioned parameters. Further investigation with a longer duration of treatment of between 6 and 8 weeks is warranted in order to obtain conclusive results.

Previous studies found significant improvement in certain constipation-related parameters with 4-week administration of a variety of probiotic strains, which was the basis for deciding the present study's duration of intervention. However, the duration of time required for probiotics to exert their effects are still uncertain. There are studies that show significant results with a longer intervention period of 6 weeks.^[10] In an 8-week intervention study with prebiotic isomalto-oligosaccharides in constipated elderly people, it was observed that the effects of the prebiotic on defecation was time-dependent.^[23] An increase in frequency of spontaneous defecation occurred only in the 4th to 8th week of intervention and not in the first 4 weeks. As both probiotics and prebiotics are thought to exert their beneficial effects on bowel movement through modulation of the gut microflora, it is possible that in the case of probiotics as well, a certain amount of time is needed for the changes in gut microflora to translate to changes in bowel movement. In fact, many recent chronic constipation studies apply intervention periods of between 8 and 12 weeks,^[24,25] which is in line with recommendations for trial design in functional gut disorders.^[26,27]

Besides the duration of intervention, the positive response toward the placebo drink in control group was another limitation of the present study. Versus baseline values, the control group showed sustained significant improvement in terms of constipation severity score and stool frequency. Whether this response was due to variations in day-to-day diet, a laxative effect of the placebo drink itself or a placebo effect, is not known. Malaysians typically consume spicy food containing capsaicin on a regular basis that may irritate the digestive system resulting in a laxative effect. Both probiotic and placebo drink contained approximately 1 g of lactose. Although lactose intolerance is common among Malaysians, the low levels of lactose in the study drinks would not normally cause digestive disturbances in the lactose-intolerant. However, there is a possibility that even low amounts of lactose could produce a mild softening of stools not amounting to diarrhea that the subjects may have regarded as improvement to their constipation. For future studies, use of a lactose-free probiotic preparation and placebo is recommended. Nevertheless, placebo effect has been noted to be particularly strong in gut-related conditions^[28] and can sometimes persist for the first 2–3 weeks of intervention.^[13] This presents an ongoing challenge to researchers in evaluating treatments in functional gut disorders.

The present study is the first to test LcS as treatment in otherwise-healthy subjects with Rome-defined functional constipation, as well as in non-Japanese Asian sample. It is unclear whether the vastly different diets of South East Asian subjects compared with the Japanese or Europeans would have bearing on the effects of this probiotic in constipation, although diet has been shown to influence gut microflora composition^[29] that may be part of the mechanism through which probiotics exert their effects.

Volunteers in the present study were not actively seeking treatment for their condition and thus could be considered as having relatively mild constipation, also reflected by their low severity scores at baseline (5.06 and 5.21 points in probiotics and control groups, respectively), which was close to the 5-point cut-off between healthy and constipated subjects.^[19] The relatively low severity scores may have also contributed partly to the failure to achieve statistical significance.

Post-hoc exploratory analysis showed improvement in severity of incomplete evacuation in probiotic group that might suggest that this symptom may improve with LcS intake, although further investigation is necessary to verify this. Improvement in severity of incomplete evacuation has been previously reported with interventions using LcS^[15] as well other strains of probiotics.^[10] The sensation of incomplete evacuation is an integral component of constipation. Efficacy parameters involving the measurement of "completeness" of evacuation in each defecation combined with stool frequency, namely complete, spontaneous bowel movements (CSBMs), has been acknowledged to have clinical importance in chronic constipation and Irritable Bowel Syndrome with constipation.^[26] The effect of LcS on CSBM has yet to be investigated and thus remains a focal issue for future studies involving not only LcS but other probiotic strains as well.

The present study is the first to use a severity scoring tool as an outcome measurement in an intervention with LcS in constipation. The tool used, CCQ,^[19] was assessed in a review of self-report measures for constipation severity,^[19] where out of seven tools evaluated, only CCQ and Patient Assessment of Constipation—Symptom^[30] were found to be satisfactory in terms of validity and reliability. Results of the present study support utilization of CCQ^[19] severity score as a useful indicator to detect changes in severity of constipation over time with an intervention.

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Table 1. Subjects' demographic and anthropometric data at screening
Parameter	Probiotics	Control
Total no. of subjects	47	43
Males	5	7
Females	42	36
Age (years)a	31.8 ± 9.4	31.7 ± 9.4
Ethnicity (no. of subjects)
Malays	22	17
Chinese	20	24
Indian	5	2
Body weight (kg)^a	56.8 ± 9.3	58.1 ± 9.5
Height (m)^a	1.60 ± 0.06	1.59 ± 0.09
Body mass index (kg/m²)^a	22.3 ± 3.4	22.9 ± 3.2
Waist-to-hip ratio^a	0.81 ± 0.06	0.82 ± 0.08

^aMean ± standard deviation.
Discrete and continuous data were analyzed using χ² test and Mann–Whitney U-test, respectively.

Table 2. Subjects' constipation-related data at screening
Parameters	Probiotics	Control
Severity of constipation (CCQ score)^a	10.5 ± 3.4	10.1 ± 3.1
Frequency of constipation symptoms^bc (%)
Hard or lumpy stools	89.4	74.4
Feeling of incomplete emptying after defecation	85.1	86.0
Straining during defecation	85.1	74.4
Fewer than three defecations a week	68.1	69.8
Sensation of blockage when defecating	83.0	69.8
Abdominal fullness, bloating	63.8	55.8
Need to press on or around anus or vagina to try to remove stool in order to complete defecation	46.8	44.2
Duration of constipation^bd
Less than 5 years	25.5	18.6
Between 5 and 25 years	42.6	48.8
Others (unaware, etc)	31.9	32.6

^aMean ± standard deviation, assessment period was the 3 months preceding screening.
^bPercentage of subjects.
^cSymptom was present at least one-fourth of the time in the preceding 3 months.
^dSelf perceived based on subjects' own understanding of constipation.
Discrete and continuous data were analyzed using χ² test and Mann–Whitney U-test, respectively.
CCQ, Chinese Constipation Questionnaire.¹⁹

Table 3. Mean comparisons of end-point measures between probiotics and control groups and their effect sizes
End-points	Probioticsa	Controla	P value	Effect sized (95% CI)
Primary end-point measures
Severity of constipation (CCQ score)
Baseline	5.06 ± 2.75	5.21 ± 2.82	0.955	–
Week 2 of treatment	3.83 ± 3.29*	3.96 ± 3.40*	0.856	0.04 (−1.00–0.98)
Week 4 of treatment	2.33 ± 2.62,*	3.38 ± 2.78*	0.058	0.39 (−0.47–1.18)
Withdrawal period	3.78 ± 3.46*	3.73 ± 3.04*	0.966	−0.02 (−0.96–1.04)
Weekly stool frequency
Baseline	3.84 ± 1.78	3.91 ± 1.94	0.919	–
Week 2 of treatment	4.21 ± 1.78	5.22 ± 2.52,*	0.035	−0.46 (−0.98–0.30)
Week 4 of treatment	4.56 ± 1.99*	4.83 ± 2.24*	0.737	−0.13 (−0.72–0.57)
Withdrawal period	4.20 ± 2.18	4.55 ± 2.32*	0.528	−0.16 (−0.83–0.56)
Secondary end-point measures
Stool consistencyb
Baseline	2.61 ± 0.60	2.63 ± 0.62	0.842	–
Week 2 of treatment	2.62 ± 0.72	2.67 ± 0.72	0.594	−0.06 (−0.27–0.16)
Week 4 of treatment	2.97 ± 0.64*	2.86 ± 0.51	0.483	0.19 (0.00–0.35)***
Withdrawal period	2.92 ± 0.61*	2.73 ± 0.73	0.188	0.29 (0.11–0.52)***
Weekly stool quantityc
Baseline	10.09 ± 5.33	11.90 ± 7.11	0.340	–
Week 2 of treatment	11.82 ± 6.02*	14.90 ± 9.43*	0.163	−0.39 (−2.12–2.49)
Week 4 of treatment	13.36 ± 6.54*	14.80 ± 9.74	0.830	−0.17 (−2.13–2.84)
Withdrawal period	12.43 ± 7.38	13.60 ± 9.57	0.737	−0.14 (−2.40–2.83)

Student's t-test (paired samples) or Wilcoxon signed-rank test; *P < 0.05, versus baseline.
Student's t-test (independent samples) or Mann–Whitney U-test **P < 0.10, versus control or versus treatment.
***P < 0.05, versus control.
^aMean ± standard deviation.
^bAssessed by a 5-point scale modified according to Bristol stool form scale:²⁰ 1 indicates hard lumps; 2 lumpy, hard sausage; 3 normal sausage; 4 soft blobs; and 5 watery or mushy.
^cExpressed as number of balls (40-mm diameter) to the first decimal place using ping-pong ball as reference.
^dCohen's d.
CCQ, Chinese Constipation Questionnaire;¹⁹ –, not applicable.

Table 4. Post-hoc exploratory analysis of CCQ component symptoms
CCQ component scores^a	Baseline	Week 4 of treatment	P value
i) False alarm^a
Probiotics	0.89 ± 0.87	0.28 ± 0.63	0.518
Control	0.71 ± 0.70	0.35 ± 0.66	0.518
ii) Less than three defecations per week^b
Probiotics	0.89 ± 1.31	0.65 ± 1.49	0.883
Control	1.12 ± 1.53	0.70 ± 1.54	0.883
iii) Incomplete defecation^b
Probiotics	1.19 ± 0.74	0.40 ± 0.58	0.003*
Control	1.28 ± 0.91	1.05 ± 1.11	0.003*
iv) Lumpy/hard stoolsb
Probiotics	1.29 ± 0.89	0.67 ± 0.94	0.8
Control	1.22 ± 0.84	0.83 ± 0.81	0.8
v) Frequency of laxative usagec
Probiotics	0.02 ± 0.15	0.00 ± 0.00	1.000
Control	0.02 ± 0.15	0.00 ± 0.00	1.000
vi) Abdominal bloatingb
Probiotics	0.78 ± 0.90	0.33 ± 0.64	0.362
Control	0.86 ± 0.90	0.45 ± 0.71	0.362

Student's t-test (independent samples) or Mann–Whitney U-test; *P < 0.05 versus control.
^aMean ± standard deviation.
^bAssessed with 5-point ordinal scale; for (i), (iii), (iv) and (vi): 0 indicates none, 1 mild, 2 moderate, 3 severe, and 4 very severe; for (ii): 0 indicates never, 1 less than half the time, 2 half the time, 3 more than half the time, and 4 all the time.
^cCalculated based on number of times used averaged over a 2-week period.
CCQ, Chinese Constipation Questionnaire.¹⁹