Study Consipation Howaru-Transit
Study Consipation Howaru-Transit
Study Consipation Howaru-Transit
ORIGINAL ARTICLE
Accurate Clinical Research, Houston, TX, USA, 2Digestive and Immune Health, Fonterra Research Centre, Palmerston
North, New Zealand, 3Danisco USA, Health and Nutrition, Madison, WI, USA, 4Danisco Finland, Health and
Nutrition, Kantvik, Finland, and 5Sprim Advanced Life Sciences, San Francisco, CA, Sprim, USA
Abstract
Objective. To assess the impact of Bidobacterium lactis HN019 supplementation on whole gut transit time (WGTT) and
frequency of functional gastrointestinal (GI) symptoms in adults. Material and methods. We randomized 100 subjects
(mean age: 44 years; 64% female) with functional GI symptoms to consume a proprietary probiotic strain, B. lactis
HN019 (Fonterra Research Centre, Palmerston North, New Zealand), at daily doses of 17.2 billion colony forming units
(CFU) (high dose; n = 33), 1.8 billion CFU (low dose; n = 33), or placebo (n = 34) for 14 days. The primary endpoint of WGTT
was assessed by X-ray on days 0 and 14 and was preceded by consumption of radiopaque markers once a day for 6 days. The
secondary endpoint of functional GI symptom frequency was recorded with a subject-reported numeric (1100) scale before
and after supplementation. Results. Decreases in mean WGTT over the 14-day study period were statistically signicant in
the high dose group (49 30 to 21 32 h, p < 0.001) and the low dose group (60 33 to 41 39 h, p = 0.01), but not in the
placebo group (43 31 to 44 33 h). Time to excretion of all ingested markers was signicantly shorter in the treatment groups
versus placebo. Of the nine functional GI symptoms investigated, eight signicantly decreased in frequency in the high dose
group and seven decreased with low dose, while two decreased in the placebo group. No adverse events were reported in any
group. Conclusions. Daily B. lactis HN019 supplementation is well tolerated, decreases WGTT in a dose-dependent manner,
and reduces the frequency of functional GI symptoms in adults.
Key Words: Bidobacterium lactis HN019, gastrointestinal, probiotic, whole gut transit time
Introduction
Functional gastrointestinal symptoms are nonspecic conditions with no identiable structural or
biochemical cause [1] that often present concomitantly [2]. The burden of functional gastrointestinal
symptoms is enormous as 4269% of the population
report at least one of these disorders [3,4]. Treatment
is complicated by the non-specic presentation of
symptoms and by the fact that 75% of people do
not seek medical care when symptoms arise [5].
Therefore, management of functional gastrointestinal
symptoms is generally self-prescribed and directed at
Correspondence: Larry E. Miller, PhD, Sprim Advanced Life Sciences, 235 Pine Street, Suite 1175, San Francisco, CA 94104, Sprim, USA. Tel: +928 607-9657.
Fax: +928 268-3563. E-mail: larry.miller@sprim.com
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P. A. Waller et al.
Participants
Eligible subjects included males and females aged 25
65 years; self report of stool type 24 on the Bristol
Stool Chart; and average of 13 bowel movements per
week. Exclusion criteria were use of any probiotic
product intended to improve gastrointestinal function
within the 2 weeks preceding study entry; major
chronic and uncontrolled systemic medical conditions; severe gastrointestinal conditions known to
prolong WGTT; lactose intolerance; chronic diarrhea; gastric bypass surgery or lap band insertion
for weight loss; regular laxative use; and pregnant
or breast-feeding women.
Interventions
Study products (B. lactis HN019 and placebo powders) were supplied in capsules by Danisco USA, Inc.
(Madison, Wisconsin, USA). The capsules contained
either B. lactis HN019 at one of two dose levels
(17.2 billion colony forming units (CFU) or 1.8 billion
CFU) or placebo. The excipient used to adjust the
bacteria count per capsule and to serve as the placebo
was rice maltodextrin. All products were stored refrigerated at the study site until time of use and were
refrigerated by the participants throughout the supplementation period. Product stability was monitored
during the study and no signicant reduction in viable
counts was observed.
A timeline of study activities is presented in
Figure 1. Following screening procedures, subjects
began a 1-week run-in period during which the normal diet was consumed without taking any study
product. During this period, subjects were asked to
discontinue the consumption of laxatives, dietary
ber supplements, probiotics including B. lactis,
and any other products that might affect WGTT.
Following the run-in period, subjects were randomized into one of three study groups: 17.2 billion
CFU B. lactis HN019 per day (high dose, n = 33),
1.8 billion CFU B. lactis HN019 per day (low dose,
n = 33), or placebo (n = 34). Over 14 consecutive days,
study products were consumed once daily with breakfast by adding the entire contents of a capsule to
commercial yogurt that was free from probiotics
(product contained standard yogurt starter cultures
Lactobacillus bulgaricus and Streptococcus thermophilus).
The classic single lm estimate was utilized to
quantify WGTT [14]. Each subject ingested 24
radiopaque markers per day for six consecutive
days prior to abdominal X-rays on days 0 and 14.
The number of markers present in the right, left, and
rectosigmoid colon were summed to yield a total
marker count. Marker counts were identied by a
Day-7
Day-6
1059
Intervention period
Day 0
Daily consumption of
capsules with
radiopaque markers
Day 14
Day 8
Daily consumption of
capsules with
radiopaque markers
Figure 1. Timeline of study activities. DDQ = digestive discomfort questionnaire; FFQ = food frequency questionnaire.
Outcomes
Randomization
The primary endpoint of WGTT was assessed by
abdominal X-ray on days 0 and 14. A food frequency
questionnaire was completed on days 0 and 14 to
determine diet consistency during the study period.
Data were collected on the frequency of ingestion of
17 food categories over the previous week including
dairy products (milk, cheese, yogurt, and ice cream);
meat, sh, or poultry; eggs; peanut butter or nuts;
citrus fruits or juices; dark green leafy or deep orange
vegetables; other fruits or vegetables; bread, cereal,
rice, or pasta; sweets; salty snacks; soft drinks; alcohol;
coffee or tea; and fast food. The frequency of food
consumption in each category was self-rated on a
5-point Likert scale (0 = never, 1 = seldom, 2 = 2
3 times per week, 3 = once a day, and 4 = more than
once a day). A questionnaire was administered on
study days 0 and 14 to evaluate the frequency of nine
upper (vomiting, regurgitation, abdominal pain, nausea, and gurgling) and lower (constipation, diarrhea,
irregular bowel movements, and atulence) gastrointestinal symptoms experienced over the previous
week. The frequency of each symptom was subjectreported using a numeric scale anchored at 1 (never)
and 100 (always). Adverse events were dened as any
untoward medical occurrence that occurred during
the trial, regardless of the relationship with the administered study product.
Sample size
Statistical methods
A total required sample size of 100 subjects equally
distributed among the three treatment groups was
calculated based on an anticipated 33% reduction
1060
P. A. Waller et al.
Placebo (n = 34)
Discontinued (n = 0)
Discontinued (n = 7)
Discontinued (n = 5)
Analyzed (n = 33)
Analyzed (n = 26)
Analyzed (n = 29)
Figure 2. CONSORT patient ow diagram. High dose, 17.2 billion CFU Bidobacterium lactis HN019; Low dose, 1.8 billion CFU B. lactis
HN019. CFU = colony forming unit.
1061
Placebo (n = 29)
43 12
20 (61)
44 11
16 (62)
45 11
20 (69)
0.78
0.76
0.64
19
7
6
1
32
(58)
(21)
(18)
(3)
8
16 (61)
7 (27)
3 (12)
0
30 7
18 (62)
4 (14)
7 (24)
0
32 8
0.73
17
17
15
49
11
15
14
30
22
23
16
60
15
17
11
33
13
17
11
42
9
19
12
31
0.04
0.18
0.19
0.13
14.8
30.7
34.6
28.6
47.7
21.7
27.7
26.6
24.7
30.9
11.0
24.9
43.8
29.9
45.1
20.2
28.7
30.6
26.8
29.4
8.0
18.4
36.0
23.2
38.3
18.6
22.6
29.6
26.8
26.4
0.44
0.20
0.44
0.60
0.45
68.7
14.8
61.7
59.7
22.0
20.0
28.8
32.8
75.7
9.8
61.7
49.0
30.4
21.9
32.0
32.6
60.9
23.2
53.8
46.7
32.5
31.0
36.3
34.0
0.16
0.13
0.57
0.26
Abbreviations: GI = gastrointestinal; sd = standard deviation; *self-rated on a numeric scale anchored at 1 = never and 100 = always.
Numbers analyzed
1062
P. A. Waller et al.
100
CTT (hours)
0
Study day 14
10
20
High dose
Day 0 vs. Day 14
30
Low dose
Day 0 vs. Day 14
40
Placebo
Day 0 vs. Day 14
10
90
High dose
80
Low dose
70
Placebo
60
50
40
30
20
10
0
20
40
60
80
100
120
140
Hours
Figure 4a. Time to radiopaque marker excretion at pretreatment by study group. High dose, 17.2 billion CFU Bidobacterium lactis HN019; Low dose, 1.8 billion CFU B. lactis HN019.
CFU = colony forming unit.
Harms
Aside from functional gastrointestinal symptoms
reported on the questionnaire, no adverse events
were reported in any group during the study.
Discussion
This randomized, triple-blind, placebo controlled,
dose-ranging study provides Level I evidence that
dietary consumption of B. lactis HN019 shortens
WGTT in a dose-dependent manner and reduces
Table II. Whole gut transit time by treatment group and study day.
High dose
(n = 33)
Low dose
(n = 26)
Placebo
(n = 29)
Day 0, mean h
95% CI
Min, median, max
Day 14, mean h
95% CI
Min, median, max
Absolute change,
mean h*
95% CI
Min, median, max
Relative change,
mean %*
95% CI
Min, median, max
49.2
39.2 to 59.2
0, 49, 135
21.0
0, 5, 131
-28.1
59.5
46.7 to 72.3
9, 68, 111
41.0
0, 26.5, 141
-18.5
42.5
31.3 to 53.7
0, 35, 131
43.8
0, 46, 131
1.3
-38.9 to -17.3
-87, -33, 65
-32.6
-32.3 to -4.6
-84, -18, 67
-24.5
-5.7 to 8.3
-35, 5, 39
16.7
-100, -94,
600
-100, -48,
214
-100, 11,
286
100
High dose
90
80
Low dose
70
Placebo
60
50
40
30
20
10
0
0
20
40
60
80
100
120
140
Hours
Figure 4b. Time to radiopaque marker excretion at 14 days posttreatment by study group. High dose, 17.2 billion CFU B. lactis
HN019; Low dose, 1.8 billion CFU B. lactis HN019. CFU = colony
forming unit.
1063
High dose
(n = 33)
Low dose
(n = 26)
Placebo
(n = 28)
-9.8*
-14.9*
-17.9
-13.8*
-12.9*
-7.4
-11.3*
-26.6
-13.8
-23.9
-2.2
-2.3
-8.2
-3.5
-4.7
-29.0
-2.9
-19.0
-14.0*
-35.8
0.0
-22.8
-15.3*
-14.2*
-9.4*
-9.5
-5.9
p < 0.001.
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P. A. Waller et al.