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Daily Intake of Probiotic as well as Conventional Yogurt Has a Stimulating Effect on Cellular Immunity in Young Healthy Women

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Abstract

The aim of this work was to study the effects of daily yogurt consumption on the cellular immunity of young healthy women and to compare a conventional with a probiotic product. 33 young healthy women (22-29 years) consumed 100 g/day of either probiotic or conventional commercially available yogurt for 2 weeks and 200 g/day for another 2 weeks followed by a 2-week washout period with no fermented food at all. Before the intervention and after each phase, a complete white blood count was done, the percentage of activated CD69+ T lymphocytes after stimulation of whole blood with pokeweed mitogen was determined as well as the natural cytotoxicity of peripheral blood mononuclear cells against a human erythroleukemic target cell line (K562). All analyses were done by flow cytometry. In the probiotic group only, the numbers of cytotoxic T lymphocytes (CD3+CD16+CD56+) increased significantly (+30.8% with p = 0.001, +22.1 and +32.7% with p = 0.002, for T2, T3 and T4 compared to T1). There were no major changes for other cell populations, and all remained within the physiological range. In both groups, the expression of CD69 on T lymphocytes increased after yogurt consumption, especially on CD8+ (conventional: T2 +23%, T3 +27.2%, probiotic: T2 +15.7%; T3 +10.8% compared to T1) and to a lesser extent on CD4+ (conventional: T2 +7.7%, T3 +14.9%, probiotic: T2 +4% compared to T1. The cytotoxic activity also augmented following the intake, this effect persisting after cessation of consumption. However, there were no significant differences between the probiotic and the conventional yogurt group. Daily yogurt intake has a stimulating effect on cellular immune functions, but in this study the probiotic product did not perform better than the traditional one.
Fax +41 61 306 12 34
E-Mail karger@karger.ch
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Original Paper
Ann Nutr Metab 2006;50:282–289
DOI: 10.1159/000091687
Daily I n t ake of Pr o b i o tic a s w e l l as Co nventi o n a l
Yogurt Has a Stimulating Effect on
Cellular Immunity in Young Healthy Women
Alexa L. Meyer
a
Michael Micksche
b
Irene Herbacek
b
Ibrahim Elmadfa
a
a
Department of Nutritional Sciences of the University of Vienna, and
b
Institute for Cancer Research of the
Medical University of Vienna, Vienna , Austria
all remained within the physiological range. In both
groups, the expression of CD69 on T lymphocytes in-
creased after yogurt consumption, especially on CD8+
(conventional: T
2
+23%, T
3
+27.2%, probiotic: T
2
+15.7%;
T
3
+10.8% compared to T
1
) and to a lesser extent on CD4+
(conventional: T
2
+7.7%, T
3
+14.9%, probiotic: T
2
+4%
compared to T
1
. The cytotoxic activity also augmented
following the intake, this effect persisting after cessation
of consumption. However, there were no signifi cant dif-
ferences between the probiotic and the conventional yo-
gurt group. Conclusion: Daily yogurt intake has a stimu-
lating effect on cellular immune functions, but in this
study the probiotic product did not perform better than
the traditional one.
Copyright © 2006 S. Karger AG, Basel
Background
Regular intake of lactic acid bacteria is able to enhance
the function of the immune system and reduce the inci-
dence of infectious diarrhea, acute gastroenteritis, allergic
symptoms and lactose intolerance [1, 2]
. In anorectic fe-
male adolescents and malnourished children, the produc-
tion of the cytokine interferon-
(IFN-
) increased fol-
Key Words
Probiotics Yogurt Cellular immunity NK cells
Abstract
Background/Aims: The aim of this work was to study the
effects of daily yogurt consumption on the cellular im-
munity of young healthy women and to compare a con-
ventional with a probiotic product. Methods: 33 young
healthy women (22–29 years) consumed 100 g/day of
either probiotic or conventional commercially available
yogurt for 2 weeks and 200 g/day for another 2 weeks
followed by a 2-week washout period with no fermented
food at all. Before the intervention and after each phase,
a complete white blood count was done, the percentage
of activated CD69+ T lymphocytes after stimulation of
whole blood with pokeweed mitogen was determined as
well as the natural cytotoxicity of peripheral blood mono-
nuclear cells against a human erythroleukemic target cell
line (K562). All analyses were done by fl ow cytometry.
Results: In the probiotic group only, the numbers of cy-
totoxic T lymphocytes (CD3+CD16+CD56+) increased
signifi cantly (+30.8% with p = 0.001, +22.1 and +32.7%
with p = 0.002, for T
2
, T
3
and T
4
compared to T
1
). There
were no major changes for other cell populations, and
Received: September 15, 2005
Accepted: December 5, 2005
Published online: February 23, 2006
Prof. Dr. Ibrahim Elmadfa
Department of Nutritional Sciences, University of Vienna
Althanstrasse 14, AT–1090 Vienna (Austria)
Tel. +43 1 4277 54901, Fax +43 1 4277 9549
E-Mail ernaehrungswissenschaften@univie.ac.at
© 2006 S. Karger AG, Basel
0250–6807/06/0503–0282$23.50/0
Accessible online at:
www.karger.com/anm
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Stimulation of Cellular Immunity by
Daily Yogurt Intake
Ann Nutr Metab 2006;50:282–289 283
lowing the intake of yogurt, but not after milk consump-
tion [3] . Yogurt also induced an increase of IgA-secreting
cells in malnourished mice [4] . However, the target group
for probiotic products is not especially immunodefi cient
people or risk groups, but mainly healthy adults wishing
to enhance their natural immune system and obtain a
better resistance against infections. Although some au-
thors could show a stimulating effect on various immune
parameters in healthy humans, others found no changes
during yogurt consumption. An extensive number of im-
mune parameters were analyzed by Spanhaak et al. [5] in
1998 in healthy adult men who consumed either milk
fermented with Lactobacillus casei Shirota or unferment-
ed milk for 4 weeks. None of the parameters changed
during and after the intake and there were no differences
between the test and control group. A comparable study
also failed to show any effect of yogurt intake on the mea-
sured immune parameters by itself and in comparison to
unfermented milk [6] . In a study by Trapp et al. [7] , no
effect of daily yogurt consumption on production of IFN-
and IgE after appropriate stimulation with the mitogen
phytohemagglutinin (PHA) or various inhalant allergens,
respectively, could be found.
On the other hand, there are a number of publications
suggesting an effect of yogurt intake especially on the nat-
ural and cellular immune function in healthy subjects.
After consumption of Bifi dobacterium lactis in milk the
production of IFN-
by peripheral blood mononuclear
cells (PBMC) stimulated with PHA was signifi cantly en-
hanced compared to the consumption of unfermented
milk. The same was found with regard to the phagocytic
activity of polymorphonuclear cells [8] . Natural killer
(NK) cell activity was increased after the intake of milk
containing different probiotic lactic acid bacteria [9–
11] .
The above-mentioned results suggest an impact of lac-
tic acid bacteria intake on the immune function not only
in immunodefi cient but in healthy humans as well. The
aim of this study was therefore to look for this effect in a
commercially available probiotic milk product contain-
ing the probiotic strain Lactobacillus casei defensis (DN
114 001). The product was consumed by the study par-
ticipants as it is on the market and not in the form of a
preparation especially generated for this study. In previ-
ous investigations, immunostimulation could be obtained
with probiotic as well as traditional cultures, but the con-
trol product was always unfermented milk. We were
therefore interested in comparing the probiotic yogurt to
a conventional (regular) non-probiotic one, because this
has, to our knowledge, not been done so far.
Subjects, Materials and Methods
Characteristics of the Yogurt and Subjects Diet
The conventional yogurt, provided by the Niederösterreichische
Milchgenossenschaft (NÖM, Baden, Austria) contained the tradi-
tional yogurt cultures Lactobacillus delbrueckii subsp. bulgaricus
with 6.4 ! 10
7
and 3.9 ! 10
7
CFU/ml of Streptococcus thermophi-
lus . The yogurt was not heat-treated after the fermentation process
so that the microorganisms were living.
The probiotic yogurt was a commercially available probiotic
yogurt drink (provided by Danone Austria, Vienna, Austria). In
addition to the traditional living starter cultures mentioned above,
that were found in amounts of 2.0 ! 10
8
CFU/ml for S. thermophi-
lus and 10
7
CFU/ml for L. delbrueckii subsp. bulgaricus , it con-
tained 3.7 ! 10
8
CFU/ml of live probiotic Lactobacillus casei
(DN 114 001).
Study Population and Design
The sample encompassed 33 young, apparently healthy women
between 22 and 29 years of age (mean 24.4). All were non-smokers,
neither pregnant nor suffering from any chronic or contagious dis-
ease and gave written informed consent. The study protocol was
approved by the Ethical Committee of the City of Vienna.
The total duration of the study was 7 weeks. The sample was
divided in two groups: a probiotic group comprising 17 and a con-
ventional group of 16 subjects. Assignment of subjects to these
groups was done randomly, but it was nevertheless assured that
women taking contraceptives were evenly distributed between the
groups. There were no signifi cant differences between the two
groups concerning height, weight or age.
To obtain baseline values of the analyzed parameters and for
equilibration, participants had to refrain from consuming any fer-
mented products for 1 week. After this time, the fi rst blood sample
was taken, and the yogurt was distributed to the subjects according
to their group. During the following 2 weeks they consumed one
portion of 100 g/day of the respective product. After these 2 weeks,
the portions of either product were doubled: participants consumed
two bottles of 100 g/day, i.e. a total of 200 g of the respective yogurt
for another 2 weeks. For the last 2 weeks, the subjects were again
requested not to consume fermented products. Blood samples were
taken at the end of each period, so that fi nally the following four
samples from each woman were obtained: (a) T
1
as a baseline sam-
ple before intake of yogurt (sampled at the end of week 1); (b) T
2
after
the rst 2 weeks of intake (sampled at the end of week 3);
(c) T
3
after another 2 weeks of intake of two yogurt portions (at the
end of week 5), and (d) T
4
at the end of the washout phase with no
fermented food (at the end of week 7).
The blood was drawn in heparinized (for immune status: EDTA-
containing) sterile sample tubes (Vacuette, Greiner Bio-One
GmbH, Kremsmünster, Austria) and processed the sampling day.
Immune Status
The absolute and relative numbers of the different leukocyte
and lymphocyte subpopulations were determined in a FACSCali-
bur dual laser system fl ow cytometer from Becton Dickinson (BD
Biosciences, San Jose, Calif., USA). Lymphocytes, monocytes and
granulocytes were distinguished according to their size and granu-
larity. A more detailed characterization was done by labeling the
cells with specifi c monoclonal murine antibodies conjugated with
uorescein isothiocyanate (FITC), phycoerythrin (PE), perinidin
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Ann Nutr Metab 2006;50:282–289
284
chlorophyll protein (PerCP) or allophycocyanin (APC). Four dif-
ferent antibody combinations were used as follows, each containing
anti-CD45-PerCP (CD45: common leukocyte antigen): (1) anti-
CD3-FITC/anti-CD8-PE/anti-CD4-APC for suppressor/cytotoxic
and helper T cells; (2) anti-CD3-FITC/anti-CD16+CD56-PE/anti-
CD19-APC for NK and B cells; (3) anti-CD3-FITC/anti-CD8-
APC/anti-HLA-DR-PE for activated T cells, and (4) anti-CD8-PE/
anti-CD14-APC/anti-CD57-FITC for monocytes (CD14) and
CD57+ T or NK cells.
CD45 is displayed on all leukocytes, but shows different densi-
ties hence offering a further means of differentiation [12] .
All of these antibody conjugates were purchased from Becton
Dickinson Immunocytometry Systems (BDIS, San Jose, Calif.,
USA). Whole blood was incubated with the respective labeled an-
tibodies, then lysed and washed to remove the erythrocytes and
analyzed. Relative numbers are expressed as percentage of a given
cell subtype of the total leukocytes or lymphocytes.
Activation of T Lymphocytes
To study the reaction of T lymphocytes to stimulation, 50
l
whole blood were incubated with 20
g pokeweed mitogen (PWM;
Sigma, Vienna, Austria) (corresponding to a fi nal concentration of
400
g/ml) for 4 h at 37 ° C and 5% CO
2
. After this time the number
of helper (CD4+) and cytotoxic or suppressor T cells (CD8+) ex-
pressing the activation marker CD69 on their surface was deter-
mined through fl ow cytometry by adding the corresponding conju-
gated antibodies (BDIS).
Natural Cytotoxicity
Lymphocytes were isolated from the fresh heparinized whole
blood by centrifugation over a Ficoll Paque Plus gradient (Amers-
ham Biosciences AB, Uppsala, Sweden) and washed twice in RPMI
1640 medium with 10% fetal calf serum (Sigma). NK-sensitive hu-
man acute myelogenous leukemia K562 cells (CCL-243, ATCC)
labeled with 5(6)-carboxyfl uorescein diacetate N-succinimidyl es-
ter (Cell Technology Inc., Mountain View, Calif., USA) were taken
as targets. Both effector and target cells were counted, mixed in
ratios of 25:
1, 50: 1 and 100: 1 (E:T) and incubated at 37 ° C and 5%
CO
2
for 4 h. The percentage of lysed target cells was then deter-
mined by fl ow cytometry after adding the live/dead stain 7-amino-
actinomycin D (7-AAD, Cell Technology Inc.) to assess NK cell
activity against the target cells.
All the fl ow cytometric measurements were done in the Institute
for Cancer Research of the Medical University of Vienna whose
analyses are subject to a quality control by recurrent round robin
tests according to the standards of the Austrian Society for Quality
Assurance and Standardization of medical diagnostical analyses
(ÖQUASTA).
Statistical Analysis
Data were evaluated with SPSS software 12.0 (SPSS Inc., Chi-
cago, Ill., USA) using analysis of variance (ANOVA) for repeated
measures with between-subject effects testing and least signifi cant
differences multiple pairwise comparison tests for within-subject
effects. When assumptions like normal distribution or homogene-
ity of variance were not met by the data, the non-parametric Fried-
man test was applied. In addition to the between-subject effects,
testing comparisons between the sample groups were done with the
Mann-Whitney U-test. Values are given as mean 8 SD.
Results
Immune Status
For most leukocyte and lymphocyte subsets, there were
only minor changes in the absolute and relative numbers,
most of which were not signifi cant ( table 1 ). All cell sub-
sets remained within their normal physiological ranges. It
Table 1. Absolute numbers of leukocyte and lymphocyte subpopulations during the study in both groups (cells/
l whole blood)
Cells/
l whole blood Probiotic group Conventional yogurt group
T1 T2 T3 T4 T1 T2 T3 T4
Total leukocytes (CD45+) 5,04081,222 4,85281,064 4,91681,003 5,18681,345 5,80981,199 5,43281,076 5,83581,336 5,33181,278
Granulocytes 2,8318965 2,6788977 2,7158838 3,02381,238 3,04081,004 2,9088877 3,25881,054 2,7958660
Monocytes (CD45+/CD14++) 3498114 317883 331892 327879 3818117 340895 3858104 3488111
Total lymphocytes (CD45++) 1,6678411 1,6818341 1,7498392 1,6668277 1,9218469 1,8328451 1,8558451 1,7668466
T lymphocytes (CD3+) 1,2098291 1,2418283 1,3008277 1,2768199 1,3308314 1,2898404 1,3608451 1,3358410
Helper T cells (CD4+) 7468216 7958267 8438228 7668118 8538197 8588217 8708226 8348228
Regulatory T cells (CD8+) 4208119 406890 443899 417883 4908151 4778207 4808198 4708154
CD4/CD8 ratio 1.8180.38 1.9180.5 1.9180.49 1.8980.35 1.8780.52 1.9580.59 1.9680.53 1.8680.46
Cytotoxic T cells 104840 136854 127877 138864 101857 103862 111873 107859
(CD3+CD16CD56+) (p = 0.001)* (p = 0.002)*
Activated T cells (HLA-DR+) 115845 104843 108836 112834 112830 101857 109851 112874
NK cells (CD16CD56+) 2058115 2158114 180889 2108104 195857 197878 182855 160870
Data are mean 8 SD of all the subjects of the respective group, obtained in a single measurement. Lymphocytes, monocytes and granulocytes were distin-
guished by size, granularity and specifi c surface antigens in a fl ow cytometer. The expression of the common leukocyte antigen CD45 shows different densities
depending of the leukocyte subset: it is most abundant on lymphocytes, who are therefore termed 45++, whereas expression is lower on monocytes (CD45+)
and lowest on granulocytes. Statistical results: * Differences as compared to the baseline.
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Stimulation of Cellular Immunity by
Daily Yogurt Intake
Ann Nutr Metab 2006;50:282–289 285
is notable though that the numbers of cytotoxic T lym-
phocytes (CD3+CD16+CD56+) increased signifi cantly in
the probiotic group: by 30.8% between T
1
and T
2
(p = 0.001), by 22.1% between T
3
and T
1
and by 32.7%
between T
4
and T
1
(p = 0.002). The numbers of CD4+
helper T lymphocytes and total T lymphocytes also aug-
mented slightly, but this effect failed to reach signifi cance
( table 1 ).
In contrast, the numbers of NK cells that bear CD16
and CD56 but not CD3 (CD16+CD56+) and also have
cytotoxic activity, did not increase, but on the contrary
showed a decrease ( table 1 ). However, none of the cell
populations showed statistically signifi cant differences
between both groups.
Activation of T Lymphocytes
The percentage of T cells, CD4+ helper as well as CD8+
cytotoxic/suppressor, displaying the activation marker
CD69 on their surface following activation with PWM
increased after 2 weeks of yogurt consumption (T
2
) and
maintained this higher level over the entire period of in-
take. However, this effect was signifi cant only in the con-
ventional group. With conventional yogurt, a greater in-
crease in activation was observed on both cell subtypes
than with probiotic. The effect was stronger in the CD8+
T lymphocytes, where CD69 expression was signifi cantly
higher at T
2
(+23%) and T
3
(+27.2%) when compared to
baseline and to each other (+3.4%), whereas with CD4+
T-helper cells, the increase was signifi cant only between
T
2
and T
3
(+6.6%) and T
1
and T
3
(+14.9%). A comparable
trend could be seen in the probiotic group, but there was
no further augmentation (+15.7% between T
1
and T
2
and
+10.8% between T
1
and T
3
) with the doubled yogurt por-
tion, and the differences between the timepoints failed to
reach signifi cance. After cessation of yogurt consumption,
the percentage of activated cells of both subtypes declined
below the baseline (T
1
) in both groups ( table 2 ). However,
the observed differences between the conventional and
the probiotic group were not statistically signifi cant.
Natural Cytotoxicity
With effector:target cell (E:T) ratios of 50:
1 and 100:1,
a signifi cant increase in cytotoxic activity could be seen.
In both study groups the number of lysed target cells was
signifi cantly higher after 2 weeks of yogurt consumption
as compared to the baseline. At T
3
a slight decrease oc-
curred, but the percentage of killed K562 target cells was
still higher than at baseline and increased again at T
4
. The
activity at this time (T
4
) was signifi cantly higher com-
pared to baseline ( g. 1 ). Due to a higher mean killer cell
activity in the probiotic group, that was present from the
beginning of the study, the results were expressed as per-
cental changes compared to the baseline. It can be seen
that the relative increase was greater in the conventional
group (with an E:T ratio of 50:
1 245.1, 195 and 228.4%,
with E:T 100:
1 268.2, 197.1 and 276.5% of the T
1
value
at T
2
, T
3
and T
4
, respectively). With probiotic yogurt, the
number of lysed target cells reached 142.1, 120.0 and
190.7%
(E:T 50: 1) and 133.1, 129.7 and 184.8% (E:T
100:
1) of the baseline value at T
2
, T
3
and T
4
, respective-
ly ( g. 2 ). The slight decrease at T
3
coincided with lower
numbers – absolute as well as relative – of NK cells at this
Percentage of CD69+ cells of the respective total T cells
T1 T2 T3 T4
CD8+
Probiotic yogurt group 20.489.6 23.6812.5 22.688.5 18.588.5
Conventional yogurt group 19.185.8 23.5810.1
a, b
24.388.0
a, b
16.583.3
CD4+
Probiotic yogurt group 17.687.6 18.389.7 17.789.2 16.786.4
Conventional yogurt group 16.884.2 18.186.2 19.386.1
a, b
15.684.1
Data are mean 8 SD of all the subjects of the respective group, obtained in a single
measurement. Repeated measures ANOVA with least signifi cant difference test for mul-
tiple pairwise comparisons.
a
Statistically signifi cant compared to T1 (CD8+: T2 p = 0.045; T3 p = 0.024; CD4+:
T3 p = 0.043);
b
statistically signifi cant compared to T4 (CD8+: T2 p = 0.006; T3 p < 0.001;
CD4+: T3 p = 0.003).
Table 2. Percentage of CD69+
T lymphocytes (CD4+ and CD8+)
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286
same timepoint. The correlation between the relative NK
cell number and the cytotoxic activity against K562 tar-
gets was nevertheless rather weak with Spearman
coef-
cients of 0.404, 0.457 and 0.453 for E:T ratios of 25:
1,
50:
1 and 100: 1, respectively, even if it was highly signifi -
cant (p ^ 0.01). The menstrual cycle is known to have an
infl uence on cytotoxic activity [13] , but the correlations
between the menstrual cycle and the natural cytotoxicity
were very weak and not signifi cant (Spearman
= 0.229,
0.242 and 0.321 for E:T ratios of 25:
1, 50: 1 and 100: 1,
respectively).
Discussion
In this study, intake of yogurt over a total period of
4 weeks had a stimulating effect on the cellular immune
system in young healthy women, and for the majority of
parameters this was already visible after the daily intake
of a single portion for 2 weeks, while the doubling of the
consumed amount caused no further alterations. Never-
theless, the absolute and relative cell numbers were not
profoundly altered, with the mean values remaining in
their physiological reference ranges. This is in accordance
with previous studies failing to show any impacts of yo-
gurt consumption on leukocyte numbers [5, 6, 10, 14] . In
this study, there was however an increase of the cytotox-
ic (CD3+/CD16+/CD56+) T cells that was signifi cant
only in the probiotic group. Though a slight increase was
seen in the conventional group as well, it was much small-
er and failed to reach statistical signifi cance, suggesting
that the probiotic product may have a greater effect on
this cell population. Nevertheless no signifi cant group dif-
ferences were observed (p = 0.331 for between-subject
effects, repeated measures ANOVA).
Small but statistically signifi cant increases of relative
T (CD3+), helper T (CD4+) and NK (CD3–CD56+) cells
(percentages of total lymphocytes) were also reported in
elderly subjects, who consumed milk containing B. lactis
for 3 weeks, but again, the numbers remained within the
physiological range [15] . While deep modifi cations of the
physiological equilibrium of the different cell populations
would indeed be rather undesirable, a light stimulation
of the cytotoxic cell system could play a role in cancer
defense.
This stimulation is also mirrored in the enhanced ex-
pression of CD69, an early activation marker, on CD4+
as well as CD8+ T cells following incubation with PWM
after yogurt intake in both groups, suggesting a stronger
reaction of the cells to external threats. Although its exact
function still remains unclear, CD69 is associated with
and regarded as a good marker for T-cell activation that
is expressed by these cells within hours upon stimulation
[16–18] .
The increase in mitogen-stimulated CD69 expression
after yogurt consumption was more pronounced in CD8+
T cells than in CD4+. Besides its suppressory function,
this T-lymphocyte subpopulation also shows cytotoxic
activity, so that the activation correlates with the in-
creased number of cytotoxic (CD3+/CD16+/CD56+) T
cells that was observed following yogurt intake.
–10
0
10
20
30
40
50
60
70
80
vs. 1
vs. 1
vs. 1,3
vs. 1,3
vs. 1
vs. 1
Percentage of
lysed target cells
T1 T2 T3 T4
Conventional 50:1
Conventional 100:1
Probiotic 50:1
Probiotic 100:1
Fig. 1. Natural cytotoxicity of isolated PBMC against K562 leuke-
mic cells. Data are mean 8 SD of all the subjects of the respective
group, obtained in a single measurement. Statistically signifi cant
differences: E:T 50:
1: T
2
and T
4
vs. T
1
in both groups (p ! 0.001
and p = 0.018, respectively, in the conventional group, and 0.037
and 0.004, respectively, in the probiotic group); E:T 100:
1: T
2
and
T
4
vs. T
1
in the conventional group (p ! 0.001 and p = 0.004, re-
spectively), T
4
vs. T
1
and T
3
in the probiotic group (p = 0.007 and
0.035, respectively).
100.0
130.0
160.0
190.0
220.0
250.0
280.0
210.0
Percentage of the baseline
cytotoxicity (= 100%)
T1 T2 T3 T4
Conventional 50:1
Conventional 100:1
Probiotic 50:1
Probiotic 100:1
Fig. 2. Percent changes in the natural cytotoxicity of isolated PBMC
against K562 leukemic cells relative to the baseline (pre-interven-
tion) values. The baseline values were set at 100%.
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Stimulation of Cellular Immunity by
Daily Yogurt Intake
Ann Nutr Metab 2006;50:282–289 287
In elderly subjects, expression of another early activa-
tion marker, the low-affi nity IL-2 receptor
chain (IL-
2R
) CD25 on T cells increased signifi cantly after con-
sumption of milk supplemented with B. lactis for 3 weeks.
This increase occurred without previous stimulation [15] .
Together with our own results presented here, this suggests
that intake of lactic acid bacteria can stimulate T lympho-
cytes to react more readily to an external threat. The bac-
teria also have a direct effect on immune cells. When co-
cultivated with Lactobacillus johnsonii or sakei , the T cells
showed an increased expression of CD69 on their surface,
and here as well, CD8+ T cells were more susceptible to
this stimulus than CD4+ that were not activated [19] .
The greater alertness of the immune cells towards ex-
ogenous threats and the increase in cytotoxic activity are
also refl ected in the increased cytotoxicity against K562
leukemic cells incubated with PBMC from the subjects,
that still remained elevated 2 weeks after cessation of in-
take. These fi ndings are in accordance with previous stud-
ies where the ability of PBMC to kill cancer cells was
enhanced after consumption of milk containing lactic
acid bacteria and where this effect also persisted after ces-
sation of intake [9–11] . In the study already mentioned
above, Haller et al. [19] could show that co-cultivation
with Lactobacillus johnsonii and sakei had a stimulating
effect especially on NK cells, on which the expression of
the activation markers CD69 and CD25 increased sig-
nifi cantly. For both markers, the effect was more pro-
nounced in NK cells than in T lymphocytes. CD25 ex-
pression after stimulation by bacteria was only weak in T
cells, whereas in NK cells it was strongly increased. This
could be of particular interest considering the fact that
cytotoxic lymphocytes, especially NK cells, play an im-
portant role in the defense against cancer cells. There is
some evidence that lactic acid bacteria and fermented
milk may have protective effects. Although most of this
evidence comes from animal trials with isolated microor-
ganisms or bacterial components, some epidemiological
studies found a negative correlation between fermented
milk or yogurt consumption and cancer incidence, espe-
cially colon cancer. The mechanisms behind these obser-
vations are not entirely clear, but enhanced immune
function in the host could be involved [20] . Indeed, the
feeding of L. casei strain Shirota to mice with 3-methylchol-
anthrene-induced cancer delayed the onset of tumorigen-
esis and reconstituted immune functions in the animals
that were impaired by the malignant cells. This effect
seemed to be at least partly borne by NK cells, whose ac-
tivity was signifi cantly higher in the group supplemented
with the probiotic bacteria [21, 22] . A reduction of chem-
ically induced intestinal tumor growth was also obtained
in mice fed yogurt [23, 24] .
On the other hand, as already mentioned, there are
also a number of studies failing to demonstrate any effects
of lactic acid bacteria on immune functions. An interven-
tion in young healthy women, that was conducted with
regard to the reduction in breast cancer incidence associ-
ated with consumption of fermented milk in certain epi-
demiological surveys, showed no enhancement of cellular
immune functions like natural cytotoxicity and lympho-
cyte proliferation or IL-2 production following mitogenic
stimulation [25] . The divergence between these studies
and our own results could be caused by the fact that dif-
ferent bacteria strains were used. Immune responses were
indeed shown to depend on the bacterial strain [26] . How-
ever, three of the above-mentioned studies [6, 7, 25] with
negative results used traditional yogurt fermented by
L. bulgaricus and S. thermophilus as we did in the con-
ventional group.
As with other oral antigens, the fi rst interactions be-
tween the ingested lactobacilli and the host’s immune sys-
tem occur in the gastrointestinal tract. In mice fed yogurt
or different isolated lactic acid bacteria, the number of
cells producing sIgA increased in the small intestine as
did the concentration of this immunoglobulin in the in-
testinal fl uid. An augmentation was also observed for the
T lymphocytes in the small intestine [23] . Interestingly,
the non-pathogenic lactic acid bacteria seem to need an
additional signal to activate intestinal epithelial cells that
are immunocompetent and able to present antigens to
T cells, like IFN-
, produced by activated T cells in re-
sponse to antigen challenge [27] . Conforming to these
ndings, in the present study, immunological functions
were only enhanced after exposure to adequate stimuli
like PWM, LPS and PHA.
Considering the fact that the intervention lasted for
almost 2 months and that there was no control group who
got no yogurt at all, a time effect cannot be ruled out com-
pletely. Seasonal effects on the immune system have been
described in many different species [28] , and appear to
be mediated by the pineal hormone melatonin through
its role in the regulation of seasonal and circadian rhythms.
During winter, food shortage and low temperature impair
immune function in wild animals, but this decrease is
counteracted by a stimulation by melatonin, whose pro-
duction is enhanced under short-day conditions [28–30] .
Our intervention began in mid-April and went on until
early June. As subjects living in modern industrialized
societies are no longer affected by food shortage and able
to protect themselves from low temperatures, immune
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Meyer /Micksche /Herbacek /Elmadfa
Ann Nutr Metab 2006;50:282–289
288
function during the cold season should be rather potent
and decline with the lengthening of days, when melatonin
secretion decreases. Therefore it is unlikely that the en-
hancement of immune function found in this study was
caused by a mere seasonal effect.
Although some differences in the effects of probiotic
and conventional yogurt on particular immune functions
could be observed, both were able to stimulate the body’s
defenses. Conventional yogurt tended to be even more
effective, although the increase in the cytotoxic T lym-
phocytes was greater in the probiotic group. The differ-
ences between both products did however not reach sta-
tistical signifi cance for any of the parameters. It is inter-
esting that the conventional yogurt, though containing
lower cell numbers than the probiotic, provoked a great-
er rise in activated (CD69+) T cells and in natural cyto-
toxicity than this latter. Despite the fact that their greater
ability to survive in the gastrointestinal tract has been
repeatedly stressed as one of the main advantages of pro-
biotic lactic acid bacteria over the traditional ones, it
could be shown that various cell wall components [31, 32]
as well as oligonucleotides [33] are as effective stimulators
of the immune system as are the living microorganisms.
The results of this study suggest that lactic acid bacte-
ria as contained in fermented milk products have a stim-
ulatory effect on cellular immune functions, and that con-
ventional strains are equally effective in producing this
outcome as are probiotic ones.
Acknowledgements
This study was partly supported by the Institut Danone für
Ernährung, Germany, and Danone Austria.
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It is possible accurately to distinguish lymphocytes from other leukocyte populations in peripheral blood using the combination of fluorescence associated with CD45/CD14 and forward and orthogonal light scatter. By identifying the cell population of interest based on immunofluorescence, a light scattering window can then be drawn to include all (greater than or equal to 98%) of the lymphocytes. In this manner, maximal recovery of the lymphocytes within a sample can be consistently obtained. The combination of light scattering and immunofluorescence can also be used to define the purity of the gate. The identification of nonlymphocytes within the light scattering gate can then be used to establish an accurate denominator for the percent lymphocytes stained. Once the optimal data acquisition gate has been established and characterized, it is possible to correct subsequent analyses with that particular sample since the reactivity of monoclonal antibodies on monocytes and granulocytes can be accounted for once the nonlymphocytes have been identified as being within the acquisition gate.
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The immune system consists of organs and several cell types. Antigen interaction with these cells induces a cellular immune response mediated by activated cells and a humoral immune response mediated by antibodies. The cellular interactions are enhanced by adhesion molecules, and the activated cells release different cytokines. These complex cellular interactions induce a systemic immune response. If the antigen penetrates by the oral route, a secretory immune response is obtained, which is mediated by secretory IgA. The determination of the number of T or B cells, the quantitative or qualitative measure of the cytokines, antibody levels, or the study of cellular function such as phagocytic activity is used to evaluate the state of the immune system. The effects of lactic acid bacteria on the systemic immune response and on the secretory immune system are described. Potential health benefits of lactic acid bacteria include protection against enteric infections, use as an oral adjuvant, the immunopotentiator in malnutrition, and the prevention of chemically induced tumors. The results showed that Lactobacillus casei could prevent enteric infections and stimulate secretory IgA in malnourished animals, but could produce bacteria translocation. Yogurt could inhibit the growth of intestinal carcinoma through increased activity of IgA, T cells, and macrophages.
Article
Because of the lack of data that convincingly show immunomodulatory properties of lactic acid bacteria in humans, a study was performed in which healthy volunteers were divided into two groups and given a fermented milk product supplemented with Lactobacillus acidophilus strain La1 or Bifidobacterium bifidum strain Bb 12 for 3 wk. Blood was sampled throughout the study to assess changes in lymphocyte subsets or leukocyte phagocytic activity following consumption of the fermented products. No modifications of lymphocyte subpopulations were detected. In contrast, phagocytosis of Escherichia coli sp. in vitro was enhanced after the administration of both fermented products. The increment in phagocytosis was coincident with fecal colonization by the lactic acid bacteria and persisted for 6 wk after ingestion of the fermented products. By this time, the fecal lactobacilli and bifidobacteria had returned to concentrations prior to consumption. Nonspecific, anti-infective mechanisms of defense can be enhanced by the ingestion of specific lactic acid bacteria strains. These strains can be used as nutritional supplements to improve the immune function of particular age groups, i.e., the neonate or the elderly, for which these functions are diminished.
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Winter is energetically demanding. Physiological and behavioral adaptations have evolved among nontropical animals to cope with winter because thermoregulatory demands increase when food availability decreases. Seasonal breeding is central within the suite of winter adaptations among small animals. Presumably, reproductive inhibition during winter conserves energy at a time when the adds of producing viable young are low. In addition to the well-studied seasonal cycles of mating and birth, there are also significant seasonal cycles of illness and death among many populations of mammals and birds in the field. Challenging winter conditions. such as low ambient temperatures and decreased food availability, can directly induce death via hypothermia, starvation or shock. In some cases, survival in demanding winter conditions puts individuals under great physiological stress, defined here as an adaptive process that results in elevated blood levels of glucocorticoids. The stress of coping with energetically demanding conditions can also indirectly cause illness and death by compromising immune function. Presumably, the increased blood concentrations of adrenocortical steroids in response to winter stressors compromise immune function and accelerate catabolic mechanisms in the field, although the physiological effects of elevated glucocorticoids induced by artificial stressors have been investigated primarily in the laboratory. However, recurrent environmental stressors could reduce survival if they evoke persistent glucocorticoid secretion. The working hypothesis of this article is that mechanisms have evolved in some animals to combat seasonal stress-induced immunocompromise as a temporal adaptation to promote survival. Furthermore, we hypothesize that mechanisms have evolved that allow individuals to anticipate periods of immunologically challenging conditions, and to cope with these seasonal health-threatening conditions. The primary environmental cue that permits physiological anticipation of season is the daily photoperiod; however, other environmental factors may interact with photoperiod to affect immune function and disease processes. The evidence for seasonal fluctuations in lymphatic organ size, structure, immune function, and disease processes, and their possible interactions with recurrent environmental stressors, is reviewed. Seasonal peaks of lymphatic organ size and structure generally occur in late autumn or early winter and seasonal minima are observed prior to the onset of breeding. Although many of the field data suggest that immune function and disease processes are also enhanced during the winter, the opposite seasonal pattern is also observed in some studies. We propose that compromised immune function may be observed in some populations during particularly harsh winters when stressors override the enhancement of immune function evoked by short day lengths. Because so many factors covary in field studies, assessment of our proposal that photoperiod mediates seasonal changes in immune function requires laboratory studies in which only photoperiod is varied. A review of the effects of photoperiod on immune function in laboratory studies reveals that exposure to short day lengths enhances immune function in every species examined. Short day exposure in small mammals causes reproductive inhibition and concomitant reduction in plasma levels of prolactin and steroid hormones, as well as alterations in the temporal pattern of pineal melatonin secretion. These hormones affect immune function, and influence the development of opportunistic diseases, including cancer: however, it appears that either prolactin or melatonin secretion is responsible for mediating the effects of photoperiod on immune function. Taken together, day length appears to affect immune function in many species, including animals that typically do not exhibit reproductive responsiveness to day length.
Article
Studies of the effects of yogurt on immunity and atopic diseases have suggested improvements in cytokine (interleukin-2 and interferon-gamma) responses and clinical scores in patients with allergic rhinitis. This study compares prospectively immune parameters of participants who received 16 oz of yogurt versus 16 oz of milk/day in a randomized cross-over design. Yogurt that contained live, active Lactobacillus bulgaricus and Streptococcus thermophilus or 2% milk was consumed for one month each. Twenty otherwise healthy adults with atopic histories documented by skin testing were enrolled. Immune studies were performed at the beginning and end of the two 1-month study phases, separated by a 2-week washout period. These studies included measurements of cellular, humoral, and phagocytic function. No adverse events were noted in either group. No significant improvements in any immune parameter were noted. The consumption of yogurt that contained the live active bacteria L bulgaricus and S thermophilus does not appear to enhance immune function in atopic individuals at the dosage and duration used in this study.