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The Journal of Nutrition
Nutritional Immunology
Daily Intake of Heat-Killed Lactobacillus
plantarum L-137 Augments Acquired Immunity
in Healthy Adults1
Yoshitaka Hirose,2* Shinji Murosaki,2 Yoshihiro Yamamoto,2 Yasunobu Yoshikai,3 and Tomomi Tsuru4
2
Research and Development Department, House Wellness Foods, Itami 664-0011, Japan; 3Division of Host Defense, Medical Institute
of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; and 4PS Clinic, Medical LTA, Hakata-ku, Fukuoka
812-0025, Japan
Abstract
Heat-killed Lactobacillus plantarum strain L-137 (HK-LP) is a potent inducer of IL-12 in vitro as well as in vivo in mice. HK-LP
has been shown to suppress IgE production against food allergens, as well as tumor growth in mice, through IL-12
production, which induces the T helper (Th) 1 type immune response. To determine whether the intake of HK-LP influences
immune function and the quality of life (QOL), a randomized, double-blind, placebo-controlled, parallel study was conducted
Downloaded from jn.nutrition.org by on June 8, 2010
in healthy subjects. Sixty subjects (30 men and 30 women, mean age 56.3 y) were randomly assigned to receive a capsule
containing 10 mg of HK-LP daily or a matching capsule for 12 wk. Biomarkers for innate immunity such as the natural killer
activity of peripheral blood mononuclear cells, neutrophil phagocytosis, and cell surface expression of CD64 on monocytes
were measured every 4 wk. Biomarkers for acquired immunity such as concanavalin A (Con A)-induced proliferation,
percentages of INF-g and IL-4–producing cluster of differentiation (CD)41 T cells (Th1:Th2 ratio), and the serum IgG4:IgG
ratio were measured every 4 wk or at wk 0 and wk 12. Health-related QOL was assessed using a self-rating questionnaire
with 26 items. Among the measured biomarkers, the percent change in Con A-induced proliferation and the Th1:Th2 ratio in
the HK-LP group was greater than those in the control group (P ¼ 0.036 and P ¼ 0.002, respectively). The degree of
improvement in QOL was higher in the HK-LP group than in the control group at wk 8 (P ¼ 0.049) and tended to be higher at
wk 12 (P ¼ 0.092). These results suggest that a daily intake of HK-LP augments acquired immunity, especially Th1-related
immune functions in healthy subjects, thereby improving the health-related QOL. J. Nutr. 136: 3069–3073, 2006.
Introduction
These effects of HK-LP have been shown to be exerted
Probiotics have been defined as live microbial food components through the induction of IL-12, which leads to a T helper (Th)
that are beneficial for human health. Recently, because they 1 type immune response (5,6). Another study has also shown the
exhibited beneficial effects equal to those of live microbes, effectiveness of lactobacilli on the Th1 response, in which activa-
genetically engineered microbes and nonviable microbes have tion of human dendritic cells by lactobacilli skews T cells toward
been regarded as probiotics (1,2). Lactic acid bacteria, one of the Th1 polarization (7). Augmentation of the Th1 response may be
most common types of probiotic bacteria, have been reported to beneficial for individuals in Westernized societies, because the
exhibit beneficial effects on host homeostasis, including activa- better public hygiene and fewer infections in these societies may
tion of the immune function (3,4). We showed previously that reduce the Th1 response, thereby increasing the risk of devel-
heat-killed Lactobacillus plantarum L-137 (HK-LP),5 a strain oping allergies (8).
isolated from fermented food, is a potent inducer of IL-12 in Various lines of evidence in human studies have revealed
vitro as well as in vivo in mice (5). Administration of HK-LP that foods and their components can improve immune function
suppressed IgE production against naturally fed antigen in a in a wide range of human subjects whose immune function is
mouse model of food allergy (5). HK-LP also inhibited tumor poorer than expected. Systematically analyzing such evidence,
growth in mice transplanted with syngeneic tumor cells (6). Kaminogawa et al. (9) have concluded that the improvement of
immune function by food ingredients can be evaluated by mea-
1
Supplemental Table 1 is available with the online posting of this paper at suring the general biomarkers for innate immunity [phagocytic
jn.nutrition.org. activity and natural killer (NK) activity] and acquired immunity
5
Abbreviations used: CD, cluster of differentiation; Con A, concanavalin A; FITC, (delayed-type hypersensitivity, antigen-specific antibody pro-
fluorescein isothiocyanate; HK-LP, heat-killed Lactobacillus plantarum L-137; NK, duction, proliferative response of T cells, and T cell number).
natural killer; PBMC, peripheral blood mononuclear cell; QOL, quality of life; Th, T
helper.
Moreover, improvement of these biomarkers has been shown
* To whom correspondence should be addressed. E-mail: hirose_yoshitaka@ to correlate with reduction of the incidence of pathogenic infec-
house-wf.co.jp. tion (9).
0022-3166/06 $8.00 ª 2006 American Society for Nutrition. 3069
Manuscript received 21 June 2006. Initial review completed 16 July 2006. Revision accepted 24 September 2006.
Poor immune function likely results not only in high suscep- The results are expressed as the mean fluorescence intensity of CD64-
tibility to infections but also deterioration of the health-related positive monocytes.
quality of life (QOL). In fact, among patients with chronic fatigue
syndrome, individuals with lower T cell proliferation have been Biomarkers for acquired immune functions. PBMC (5 3 108 cells/L)
were cultured with or without suboptimal dose (2 mg/L) of concanavalin
reported to show poor health-related QOL scores (10). In ad-
A (Con A) for 72 h at 37°C and pulse labeled with 37 kBq of [3H]-
dition, we have previously reported that nigerooligosaccharide, thymidine during the last 8 h. DNA synthesis was assessed by measuring
which is an immunopotentiating agent, augments T-cell mitogen thymidine uptake. Percentages of INF-g and IL-4-producing CD41 T
response in association with improvement of the health-related cells (Th1:Th2 ratio) were determined by single-cell measurement of
QOL in the elderly (11). Therefore, enhancement of immune intracellular cytokines using flow cytometry as described (13). Serum
function may lead to improvement of the health-related QOL. IgG was measured quantitatively by the latex-agglutination method
The objective of this study was to examine whether intake of using N-assay TIA IgG-SH (Nittobo) and IgG4 was measured by
HK-LP affects innate and acquired immune functions and nephelometry using IgG subclass BS-NIA IgG4 (The Binding Site).
health-related QOL in healthy subjects.
Health-related QOL. Health-related QOL was assessed every 4 wk
using a self-rating questionnaire with 26 items, as shown in Supplemen-
tal Table1 (11). Each question was scored from 1 to 3; a higher score
Subjects and Methods indicated a better QOL. Increase in the total QOL score compared with
Subjects. Sixty healthy subjects (mean age 56.3 y) participated in this that of the baseline was defined as improved QOL, and unchanged and
study. They comprised 36 middle-aged (40–64 y, 18 men and 18 women) decreased total QOL scores were defined as unchanged and deteriorated
and 24 elderly subjects (.64 y, 12 men and 12 women). The eligibility of QOL, respectively. QOL changes were scored as follows: improved
the subjects was assessed by interviewing them and consulting with their QOL, 1; unchanged QOL, 0; and deteriorated QOL, 21.
health care providers. The inclusion criteria were general good health
and a willingness to follow the trial guidelines. Exclusion criteria were Statistical analysis. We compared baseline values between groups
any history of any illness, including allergic disease, currently being using the unpaired t test for age and immune functions or the Mann-
treated with a prescribed medicine, and intolerance of soy and milk Whitney U test for total QOL score. We calculated Spearman correlation
coefficients between age and immune functions. Because the methods for
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products. Eating habits were not considered for the criteria, but the
subjects were instructed to continue with their habitual diets during the assessing immune function are based on a highly complicated process in-
study. Approval of the protocol was obtained from the Institutional cluding cell culture, we thought that intra-assay variation would increase
Review Board of Medical Co. LTA (Fukuoka, Japan) and the study was over time. Therefore, we compared the measurements between groups at
conducted in accordance with the Declaration of Helsinki. The proce- the same time point but not within a single individual over time. Percent
dures had been fully explained to the subjects and written informed changes from the baseline in immune functions other than the IgG4:IgG
consent was obtained from each subject before the beginning of the study. ratio were analyzed by 2-way ANOVA, followed by comparison be-
tween groups at each time point using the unpaired t test. We compared
Preparation of HK-LP. LP20 (House Wellness Foods), which contains QOL change scores between groups by the Mann-Whitney U test. All
20% HK-LP and 80% dextrin, was used in this study. HK-LP was analyses were performed in all subjects as well as in subjects by age
prepared on the basis of the method previously described (5). (middle-aged, 40–64 y, and elderly, .64 y) and sex (male and female)
using Dr. SPSS software version 8.0J (SPSS Japan). Differences of P ,
Experimental design. Sixty healthy subjects were enrolled in a 0.05 were considered significant.
randomized, double-blind, placebo-controlled, parallel study. The sub-
jects were randomly assigned by age (middle-aged or elderly) and sex
into 2 groups using a sequential series of numbered, sealed envelopes, Results
each containing 1 food ingredient assigned in a computer-randomized
fashion. After the assignment, the subjects consumed a hard gelatin
Baseline characteristics. Before completing the study, 2
capsule containing 50 mg of LP20 (1 capsule/d) or a matching placebo subjects in the HK-LP group dropped out, 1 because of chronic
capsule in which dextrin was substituted for LP20 for 12 wk. Through- ulcerative colitis that had not been recognized as a disease by the
out the study, the general health of subjects was assessed every 4 wk via subject but was revealed by a medical checkup during the study,
direct interviews conducted by the health care provider. Subjects were and the other as a result of a herniated disk. In addition, 2
asked to confirm their compliance with the dietary regimens. Blood sam- subjects in the control group and 1 subject in the HK-LP group
ples were collected every 4 wk. Biomarkers for immune function were who completed the study were excluded from the analysis
measured by a clinical laboratory testing company, SRL, every 4 wk. The because the former contracted upper respiratory tract infections
IgG4:IgG ratio was measured at 0 and 12 wk. Safety assessments such as and the latter developed herpes labialis, both of which can
anthropometric measurements, biochemical examinations of blood, he-
considerably affect immune function. A total of 55 subjects was
matological assessments, and urine tests were done at 0 and 12 wk. The
study was conducted at PS Clinic (Fukuoka, Japan) from May to August
included in the statistical analysis. The data of proliferation of
2005. 1 subject in the control group was excluded from the analysis,
because no response was detected in Con A-stimulated and
Biomarkers for innate immunity. Peripheral blood mononuclear cells unstimulated PBMC. Baseline immune characteristics and QOL
(PBMCs) were isolated by the Ficoll-Conray centrifugation technique scores are shown in Table 1. Expression of CD64 on monocytes
(Ficoll-Conray, density ¼ 1.077; centrifuged at 400 3 g for 30 min). The (P ¼ 0.046) and the unstimulated proliferation of PBMC (P ¼
NK activity of PBMC was assessed by a standard chromium release 0.030) were higher in the HK-LP group than in the control
method using K562 tumor cells at an effector:target ratio of 20:1 for 3.5 group, and the IgG4:IgG ratio tended to be lower in the HK-LP
h (12). The neutrophil phagocytosis function was analyzed by flow group (P ¼ 0.077). The other characteristics did not differ
cytometry (FACSCalibur; Becton Dickinson) after uptake of fluorescein
between groups. Con A-induced proliferation decreased (r ¼
isothiocyanate (FITC)-labeled latex beads (Polyscience) by whole blood.
The results are expressed as the percentage of FITC-positive cells, which
20.287, P ¼ 0.028), whereas NK activity increased (r ¼ 0.381,
correspond to cells phagocytosing 1 or more beads, vs. total neutrophils. P ¼ 0.003) with age.
Cell surface expression of cluster of differentiation (CD)64 on mono-
cytes was analyzed by FACSCalibur after whole blood samples were Effects of dietary intervention on innate immunity. The
stained with FITC-conjugated CD64-specific mAb (Becton Dickinson). control and HK-LP groups did not differ in the percent change of
3070 Hirose et al.
TABLE 1 Baseline immune characteristics and QOL scores Safety assessments. Three adverse events in the control group
of subjects enrolled in this study1 and 6 in the HK-LP group were recorded during the study. The
adverse events other than mentioned above were knee arthralgia
Control HK-LP All subjects in the control group and Meniere’s syndrome, dizziness, and
n 30 30 60
acute urticaria in the HK-LP group. All adverse events were
Male, % 50 50 50
judged to be unrelated to the dietary intervention. Among the
Age, y 55.6 6 12.8 57.0 6 11.7 56.3 6 12.2
safety assessments that we performed, the percent change in
Innate immune function
lymphocyte count was greater in the HK-LP group than in the
NK activity, % cytotoxicity 35.8 6 13.9 33.2 6 12.3 34.5 6 13.1
control groups (P , 0.05), but the changes were within the range
Neutrophil phagocytosis 95.2 6 1.4 95.5 6 2.3 95.4 6 1.9
of reference values.
function, %2
CD64 expression on 304 6 57 339 6 77* 321 6 69 Discussion
monocytes, Ch3
Acquired immune function
In this study, the healthy subjects who took HK-LP daily
Unstimulated proliferation, 0.18 6 0.06 0.23 6 0.10* 0.20 6 0.08
sustained increases in Con A-induced proliferation of PBMC and
3103 cpm4
the Th1:Th2 ratio of CD41 T cells from 4 wk after the start of
Con A-induced proliferation, 13.5 6 7.9 14.1 6 8.0 13.8 6 7.9
dietary intervention. Subsequently, the health-related QOL also
3103 cpm
improved from wk 8 in the HK-LP supplemented group. HK-LP
INF-g-producing cells (Th1 cells), 23.5 6 10.0 21.4 6 7.7 22.5 6 8.9
has been shown to be a potent inducer of IL-12 in vitro as well as
% CD41 cells
in vivo in mice and is therefore effective for the prophylaxis and
IL-4-producing cells (Th2 cells), 2.2 6 0.9 2.6 6 1.3 2.4 6 1.1
treatment of the disease evoked by the weaker Th1 type immune
% CD41 cells
responses. Our results in this study illustrate the possibility that
Th1:Th2 ratio 12.4 6 6.3 10.0 6 5.4 11.2 6 5.9
the effects of HK-LP demonstrated in animal experiments may
IgG4:IgG ratio, 31022 3.85 6 3.07 2.68 6 1.82 3.26 6 2.57
also occur in humans.
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Total QOL score 72.6 6 5.5 71.9 6 4.4 72.3 6 5.0
Because there are many reports of improvement of immune
function by food-derived components in healthy individuals,
1
2
Values are means 6 SD unless otherwise noted. *Different from control, P , 0.05. systematic analysis of these reports enables us to advocate
FITC-positive cells relative to total neutrophils after the uptake of FITC-labeled latex
reliable biomarkers for assessing the immunomodulating effects
beads by whole blood.
3
Channel; fluorescense intensity. of food-derived substances. By doing this, Kaminogawa et al. (9)
4
Count per minute. have advocated general biomarkers for assessing immune func-
tion. To examine the effects of HK-LP intake on immune function
NK activity, neutrophil phagocytosis function, or the expression in healthy individuals, we measured such general biomarkers,
of CD64 on monocytes (Table 2). However, in men (P ¼ 0.028) including phagocytic activity, NK activity and the proliferative
and in middle-aged subjects (P ¼ 0.054), the percent change in response of T cells. Among these biomarkers, the proliferative
NK activity was greater in the HK-LP group than in the control response of T cells was considerably augmented by HK-LP. The
group (data not shown). On the other hand, in the elderly acquired immunity such as the proliferative response of T cells
subjects (P ¼ 0.005) and women (P ¼ 0.054), the percent change reportedly decreases as a result of aging and of stress (14–18). In
in CD64 expression was less in the HK-LP group than in the accordance with these observations, Con A-induced prolifera-
control group (data not shown). tion was decreased in association with aging in this study. The
poorer acquired immunity was reported to correlate with the
Effects of dietary intervention on acquired immune func- risk of various infectious diseases (14–18). Therefore, the fact
tion. The percent change in Con A-induced proliferation was that intake of HK-LP augmented the proliferative response of T
greater in the HK-LP group than in the control group (P ¼ cells during the dietary period suggests that HK-LP is beneficial
0.036), whereas the percent change of unstimulated prolifera- for the prevention of infectious diseases.
tion did not differ between groups (Table 2). A similar effect of Several lines of evidence show that dietary consumption of
HK-LP on Con A-stimulated proliferation was also observed in probiotic lactic acid bacteria can enhance the activity of NK cells
middle-aged subjects (P ¼ 0.077, data not shown). The percent in healthy adult subjects (19,20). Although the intake of HK-LP
change in the Th1:Th2 ratio was higher in the HK-LP group than did not affect NK activity in all subjects (Table 2), it did affect
in the control group (P ¼ 0.002) because of a higher percent NK activity in men and the middle-aged subjects. We do not
change in Th1 cells and lower percent change in Th2 cells in the know why other subjects did not respond to HK-LP, but the
HK-LP group than in the control group (Table 2). A similar reason may be related to the strong influence of the menstrual
effect of HK-LP on the Th1:Th2 ratio was also observed in cycle on NK activity in females (21) and to age-related changes
middle-aged subjects (P ¼ 0.001) and men (P , 0.001; data not in the responsiveness to external stimuli in the elderly. HK-LP
shown). The percent change in IgG4:IgG ratio did not differ did not enhance the neutrophil phagocytosis function, although
between groups (Table 2). However, in women, the percent lactic acid bacteria have been reported to enhance phagocytic
change was less in the HK-LP group than in the control group activity (19,20). We assessed the neutrophil phagocytosis func-
(P ¼ 0.070, data not shown). The time of sampling affected both tion by a conventional clinical method for assessing neutrophil
Con A-induced proliferation (P , 0.001) and the Th1:Th2 ratio dysfunction, in which functional neutrophils that could phago-
(P ¼ 0.001) (Table 2). cytose 1 or more beads exceeded 90% of the total neutrophils in
most healthy subjects. Thus, the method is not appropriate for
Effects of dietary intervention on health-related QOL. The evaluating the effect of immunomodulators on phagocytic
QOL change score, the degree of improvement in QOL, was activity in healthy subjects. To clarify the effects of HK-LP on
higher at 8 wk (P ¼ 0.049) and tended to be higher at 12 wk (P ¼ innate immunity in healthy subjects, further examinations are
0.092) in the HK-LP group than in the control group (Table 2). needed.
Effects of heat-killed Lactobacillus plantarum on immunity 3071
TABLE 2 Percent change from baseline in immune characteristics and QOL change scores in
subjects who took either a capsule containing 10 mg of HK-LP or a control capsule each day
for 12 wk1
2-Way ANOVA
4 wk 8 wk 12 wk Intervention Time Interaction
Innate immune function % P-value
NK activity
Control 17.7 6 28.6 17.5 6 31.9 12.8 6 29.8
0.131 0.841 0.997
HK-LP 27.7 6 68.3 27.9 6 45.2 24.0 6 50.5
Neutrophil phagocytosis function
Control 22.4 6 5.5 20.8 6 2.9 21.6 6 3.7
0.614 0.416 0.314
HK-LP 21.5 6 1.9 21.7 6 2.7 22.6 6 3.7
CD64 expression on monocytes
Control 9.7 6 22.9 10.7 6 31.9 9.6 6 23.8
0.164 0.968 0.956
HK-LP 4.8 6 11.8 5.6 6 15.8 6.6 6 14.5
Acquired immune function
Unstimulated proliferation
Control 21 6 52 214 6 73 60 6 119
0.531 0.001 0.909
HK-LP 23 6 42 23 6 54 53 6 142
Con A–induced proliferation
Control 213 6 53 220 6 60 53 6 88
0.036 ,0.001 0.894
HK-LP 9 6 69 18 6 116 84 6 136
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INF-g–producing cells (Th1 cells)
Control 5.0 6 18.7 5.1 6 21.6 3.0 6 19.3
0.014 0.563 0.886
HK-LP 14.5 6 18.8 12.8 6 21.1 8.8 6 19.3
IL-4–producing cells (Th2 cells)
Control 11.6 6 44.8 31.0 6 40.3 39.1 6 35.8
0.044 0.001 0.907
HK-LP 22.1 6 36.3 14.2 6 52.9 29.5 6 42.2
Th1:Th2 ratio
Control 8.2 6 48.5 210.8 6 43.3 221.4 6 25.4
0.002 ,0.001 0.721
HK-LP 33.4 6 58.1 14.8 6 46.0* 27.6 6 32.7
IgG4:IgG ratio
Control — — 4.2 6 21.9 — — —
HK-LP — — 20.8 6 17.6
QOL change scores2
Control 0.11 6 0.88 20.04 6 0.92 20.07 6 0.90
— — —
HK-LP 0.11 6 0.89 0.44 6 0.75* 0.33 6 0.83
1
Values are means 6 SD, n ¼ 27. HK-LP group, n ¼ 27. *Different from the control group at that time, P , 0.05.
2
The QOL change scores at each time point relative to baseline were graded as follows: 1, improved; 0, unchanged; 21, deteriorated.
We examined the effects of the intake of HK-LP on Th1- In the measurements of either Con A-induced proliferation
related immune function by determining the Th1:Th2 ratio of or the Th1:Th2 ratio, a time point effect was observed (Table 2).
CD41 T cells. Intake of HK-LP considerably augmented the Because the methods for measurement of these biomarkers are
Th1:Th2 ratio in healthy subjects, as was observed previously based on a highly complicated process including cell culture, mea-
in a study in which a number of lactic acid bacteria skewed T surement noise must be considered. Intra-assay variation is thought
cells toward Th1 polarization in vitro (7). This result suggests to be lower in measurements at the same time point than in those
that HK-LP may decrease risk for the development of infectious at different time points. In addition, measurement reliability can
and allergic disease associated with a low Th1:Th2 ratio. We be enhanced by measuring a control specimen. Therefore, we
also measured the expression of CD64 on monocytes and the considered that the comparison between groups at the same time
serum IgG4:IgG ratio as a candidate for a biomarker for Th1- point was reliable but that those over time were not. However,
related immune function on the basis of observation that in we could not exclude the possibility that Con A-induced prolif-
vivo treatment with INF-g in healthy human subjects led to an eration and Th1:Th2 ratio varied seasonally.
increased expression of CD64 (FcgRI) on monocytes (22) and QOL has been defined by the WHO as ‘‘the state of complete
that higher Th1:Th2 ratios enhanced IgG4 antibody production physical, mental, and social well-being and not merely the
from PBMC in subjects who responded to bee venom (23). How- absence of disease or infirmity.’’ Schipper suggested that QOL
ever, intake of HK-LP did not affect either the expression of has 4 components: physical and occupational functions, social
CD64 on monocytes or the serum IgG4:IgG ratio in all subjects interaction, psychological state, and somatic sensation (24). To
(Table 2). Therefore, it seems that these biomarkers are not ap- investigate the effects of HK-LP on health, we measured health-
propriate for assessing Th1-related immune function in healthy related QOL using a self-rating questionnaire aimed at both
subjects. physical and psychological states. The degrees of improvement
3072 Hirose et al.
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