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.

Abstract and Introduction

Abstract

Background and Aim Evidence suggests that probiotics reduce certain constipation-related symptoms. Lactobacillus casei strain Shirota has never been tested as treatment for functional constipation in otherwise-healthy subjects. To evaluate the efficacy of this probiotic among adults with functional constipation was aimed.

Methods Subjects with functional constipation (Rome II-defined) were randomized to intake L. casei strain Shirota fermented milk or placebo once daily for 4 weeks under double-blind condition. Primary outcomes were constipation severity and stool frequency; secondary outcomes were stool consistency and quantity.

Results In intent-to-treat population, compared with baseline, constipation severity and stool frequency improved in both probiotic (n = 47) and control groups (n = 43), but improvements were comparable in both groups at week 4 (α = 5% level). In probiotic group, stool consistency and quantity at week 4 improved significantly versus baseline but not versus control. Considering that the study agent is non-pharmaceutical and the purpose of supplementation is for long-term effect, re-evaluation at α = 10% was conducted, which showed significant improvement in constipation severity at week 4 (P = 0.058). Magnitude of the probiotic effect on stool consistency was small but grew over time, d = 0.19, 95% confidence interval 0.00–0.35 (Week 4), d = 0.29, 95% confidence interval 0.11–0.52 (postintervention). Post-hoc exploratory analysis suggests incomplete evacuation may decrease with probiotic intake.

Conclusions Four-week administration of L. casei strain Shirota did not alleviate constipation severity or stool frequency, consistency, and quantity when compared with control. With re-evaluation at α = 10% level, improvement in constipation severity was significant at week 4. To obtain conclusive results, further studies with longer intervention are warranted.

Introduction

Chronic constipation is a common^[1] gastrointestinal complaint associated with infrequent, difficult defecation^[2] adversely affecting quality of life.^[3] Standard therapies do not always bring about satisfactory relief.^[4] Thus, there is a need to explore other approaches to manage this disorder that are safe and deliver long-term efficacy.^[4]

Probiotics are viable microorganisms that when administered in sufficient quantity deliver beneficial affects to the host^[5] and are generally considered safe.^[6,7] Studies have found probiotics useful in alleviating certain symptoms of constipation among adults,^[8–10] although clinical application is still considered investigational.^[11] There is a need to accumulate further evidence with well-designed trials.^[12] Lactobacillus casei strain Shirota (LcS) has shown some beneficial effects in constipation-related conditions.^[13–15] Yet, its efficacy has never been tested in Rome-defined functional constipation, a standard definition used in constipation research in recent years.^[16] In our placebo-controlled trial, we aimed to determine the effectiveness of 4-week intervention of LcS among otherwise-healthy adults with Rome II-defined functional constipation.^[2] Rome II criteria^[2] and not Rome III^[17] have been validated in Asian populations.^[18]

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Abstract and Introduction
Methods
Results
Discussion
References

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