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A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble Yeast Beta-Glucan to Improve the Immune Defense System


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Purpose: In a placebo-controlled, double-blind, randomized clinical trial, the effect of an insoluble yeast beta-glucan preparation on the incidences of common colds and its effect on common cold symptoms were compared to placebo. Methods: 100 healthy participants with recurring infections were randomly assigned to receive either placebo or yeast beta-glucan (Yestimun ® ; n = 50 each group) over a period of 26 weeks. The subjects had to document each common cold episode in a diary, and rate 6 predefined infections symptoms on a 3-point rating scale during an infection period, resulting in an infection score. The common cold episodes were confirmed by the investigators. Results: A total of 171 common cold episodes were documented. Of these, 76 were experienced by 38 subjects in the beta-glucan group and 96 were experienced by 48 subjects in the placebo group (p = 0.406). The beta-glucan group had significantly more sub-jects without incidences of common cold than the placebo group (15.6% vs 2.0%; p = 0.019). During the most intense infection season (first 13 weeks of the study), the beta-glucan group had significantly less infections compared to pla-cebo (p = 0.02). Beta-glucan significantly reduced the typical cold symptoms ("sore throat and/or difficulty swallow-ing", "hoarseness and/or cough" and "runny nose") as opposed to placebo. Conclusion: The present study demonstrates a prophylactic effect of yeast beta-glucan on the occurrence of common colds as opposed to placebo. In addition, when these episodes occurred, they were from the beginning less pronounced and subsided faster.
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Food and Nutrition Sciences, 2012, 3, 738-746
doi:10.4236/fns.2012.36100 Published Online June 2012 (
A Double-Blind, Randomized, Placebo-Controlled
Nutritional Study Using an Insoluble Yeast Beta-Glucan
to Improve the Immune Defense System
Hans-Joachim Graubaum, Regina Busch, Heike Stier, Joerg Gruenwald
Analyze & Realize AG, Berlin, Germany.
Received February 21st, 2012; revised April 5th, 2012; accepted April 13th, 2012
Purpose: In a placebo-controlled, double-blind, randomized clinical trial, the effect of an insoluble yeast beta-glucan
preparation on the incidences of common colds and its effect on common cold symptoms were compared to placebo.
Methods: 100 healthy participants with recurring infections were randomly assigned to receive either placebo or yeast
beta-glucan (Yestimun®; n = 50 each group) over a period of 26 weeks. The subjects had to document each common
cold episode in a diary, and rate 6 predefined infections symptoms on a 3-point rating scale during an infection period,
resulting in an infection score. The common cold episodes were confirmed by the investigators. Results: A total of 171
common cold episodes were documented. Of these, 76 were experienced by 38 subjects in the beta-glucan group and 96
were experienced by 48 subjects in the placebo group (p = 0.406). The beta-glucan group had significantly more sub-
jects without incidences of common cold than the placebo group (15.6% vs 2.0%; p = 0.019). During the most intense
infection season (first 13 weeks of the study), the beta-glucan group had significantly less infections compared to pla-
cebo (p = 0.02). Beta-glucan significantly reduced the typical cold symptoms (“sore throat and/or difficulty swallow-
ing”, “hoarseness and/or cough” and “runny nose”) as opposed to placebo. Conclusion: The present study demonstrates
a prophylactic effect of yeast beta-glucan on the occurrence of common colds as opposed to placebo. In addition, when
these episodes occurred, they were from the beginning less pronounced and subsided faster.
Keywords: Randomized Placebo-Controlled Study; Insoluble Yeast Beta-Glucan; Common Cold; Immune System
1. Introduction
Beta-glucans are natural polysaccharides containing D-
glucose subunits, linked by beta-glycosidic bindings.
They are found in cell walls of bacteria, yeast, fungi,
algae, but also in the walls of grain and other plants.
Initial studies investigating the inmunomodulatory ac-
tivity of beta-glucan were performed in 1956. In that
study, a chitin/beta-glucan preparation led to an unspe-
cific stimulation of the immune system, leading to an
increased anti-bacterial and anti-viral activity after ap-
plication of the substance to rabbits and guinea pigs [1].
Since these early studies, numerous publications and
patents on the effects and mode of actions of beta-glu-
cans have been published.
Beta-glucan is neither synthesized by the human or-
ganism nor is it a component of the human body, there-
fore it is identified by the immune system as foreign,
leading to activation of both the innate as well as the
adaptive immune response [2]. Even though the mode of
action is not fully understood, several effects of beta-
glucan on various parts of the immune system have been
demonstrated. It has been found that Dectin-1 and toll-
like receptors (TLR), expressed on macrophages, neu-
trophils and dendritic cells are responsible at least par-
tially for the innate immune response, leading to acti-
vated immune cells and the release of various cytokines.
Via binding to the activated complement receptor 3
(CR3), cell lysis or monoclonal antibody reaction might
be potentiated by beta-glucans [2,3].
Many of these effects found in in vitro investigations
have been confirmed in vivo. Studies on breeding cattle
demonstrated a positive effect of beta-glucans on their
ability to activate their immune system. Fleischer et al.
(2001) investigated the effect of (1,3)-(1,6)-
on the immune system of chicks and breeding sows [4].
During this study, the regular animal feed was mixed
with yeast beta-glucan. Several immune parameters (such
as number of monocytes, activation status of macro-
phages and monocytes by the indicator neopterin, im-
Copyright © 2012 SciRes. FNS
A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble
Yeast Beta-Glucan to Improve the Immune Defense System
munoglobulin A etc.) were measured to determine the
immune status under various conditions (under physical
exertion, growth phases, pregnancy, birth and lactation).
As a result, they found that yeast beta-glucan, when
mixed with the regular feed, led to increased resistance
against Escherichia coli in the growing chick, the breed-
ing sows as well as in their offspring.
In another study, (1,3)-(1,6)-
-D-glucan was given to
piglets and the immunological effects were investigated
in vivo as well as in vitro. In vivo (1,3)-(1,6)-
led to a reduced production of IL-6 and TNF
, and a
simultaneous increase of IL-10. The reduction of IL-6
und TNF
had also been observed in vitro [5].
All these studies demonstrate that beta-glucan streng-
thens the immune function in general. It has been shown
that beta-glucan is able to improve the resistance against
various invading pathogens. Animal studies showed pos-
itive effects on the defense against infection by Staphy-
lococcus aureus, Escherichia coli, Candida albicans,
Pneumocystis carinii, Listeria monocytogenes, Leishma-
nia donovani, and influenza virus but also against an-
thrax challenge (for review see [6]).
Beta-glucans are not a unique class, but occur in dif-
ferent molecular weight and structures. Depending on the
origin and structure of the molecule, they differ in their
biological specificity as well as in their efficacy. For the
biological activity, the molecular weight as well as the
branching structure seems to be important [6]. It seems
that the more complex the structure, the more potent are
the immunmodulatory effects [7]. Highly polymer beta-
glucans with a molecular weight of 100,000 Da - 200,000
Da expressed the highest immune stimulating activity,
whereas fractions of very short beta-glucans between
5000 Da - 10,000 Da, extracted from the same organism,
exhibited no activity [8]. Further investigations showed
that particles with
-(1,6) branching together with
branching are more effective than
-(1,3) branching
alone [9]. It seems that at least for common cold preven-
tion, soluble (1,3)-(1,4)-
-glucan prepared from oat is
not effective [10]. Therefore it is very important to
clearly differentiate between results obtained from vari-
ous molecules.
In this study, the insoluble (1,3)-(1,6)-
-glucan made
from brewers’ yeast (Saccharomyces cerevisiae: Yes-
timun®, previously called Biolex Beta-HP), was used.
The positive effects of this specific preparation on the
immune system have been confirmed in various in vitro
studies [11-13]. Herein the common cold was used as a
model system to show that the insoluble beta-glucan
preparation activates the human defense system against
various pathogens. The common cold is a well-known
and, in most cases, harmless infection, typically affecting
adults 2 - 5 times per year [14]. The aim of this study
was to show that intake of a functional food composed of
beta-glucan led to less infections of reduced intensity in
the general population. The results of this human trial
with this product are presented here.
2. Methods
2.1. Study Design
This nutrition study was conducted as a prospective,
multi-centric, randomized, double-blind, placebo-controlled
study in healthy outpatient subjects, with recurring com-
mon colds, in Berlin (Germany) between November
2006 and September 2007. It was conducted in the prac-
tices of five physicians. The effect of an insoluble yeast
beta-glucan preparation on the incidences of common
colds was compared to placebo. The study was per-
formed according to the declaration of Helsinki/Hong
Kong 1989/Somerset 1996 as well as the ICH-GCP
guidelines (CPMP/ICH/135/95).
2.2. Study Population
One hundred healthy subjects with recurring common
colds were included in this nutritional study. They had to
meet the inclusion criteria: age 18, written consent to
participate, and at least three infections within the last six
months. The exclusion criteria were as follows: allergic
rhinitis or asthma, known sensibility to one of the ingre-
dients of the study product, fever (39˚C), severe organ
or systemic disorders, stomach or intestinal diseases,
intake of preparations that can influence the study out-
come, such as immunosuppressives or common cold
therapeutics, bacterial tonsillitis, incidence of alcohol,
medication or drug abuse, cancer or being HIV positive,
pregnancy or nursing, participation in a clinical study
within the previous 30 days, or problems with compli-
ance or following the protocol due to language difficul-
All of the screened subjects met the inclusion criteria
and did not violate the exclusion criteria and were ran-
domized into this nutritional trial. They represent the
intention to treat (ITT) population (see Figure 1). In total,
six subjects withdrew from the study. One case was due
to insufficient efficacy (placebo group = PG), two were
without giving a reason (active group = AG), one was
due to a move (AG), one stated aversion to capsules
(AG), and one (AG) was due to loss of motivation.
Therefore, in total 94 subjects completed the entire study.
Of these 94 subjects who completed the entire study,
nine were excluded from the per protocol (PP) analysis
due to poor compliance (4 PG, 5 AG) resulting in n = 85
subjects (41 AG, 44 PG).
Of the 100 subjects taken into the study, 58 were
Copyright © 2012 SciRes. FNS
A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble
Yeast Beta-Glucan to Improve the Immune Defense System
Copyright © 2012 SciRes. FNS
Figure 1. Schematic representation of the study population. ITT: intention to treat; PP: per protocol.
Table 1. Characteristics of the participants at baseline.
women and 42 were men. All subjects reported that they
had experienced at least three cold episodes in the six
months prior to beginning the study. The mean height,
weight and body mass index (BMI) for the subjects are
provided in Table 1. All the study participants were clas-
sified as Caucasian. With respect to these baseline char-
acteristics, there were no statistically significant differ-
ences between the beta-glucan group and placebo group
(Table 1).
Study population
Beta-glucan (n = 50) Placebo (n = 50) p-value
Age (years) 45.6 ± 16.9 47.1 ± 16.4 0.629
Sex (m/f) 22/28 20/30 0.685
Height (cm) 173.5 ± 9.1 171.5 ± 9.1 0.394
Body weight (kg) 74.4 ± 13.8 74.6 ± 17.1 0.929
BMI kg/m2 24.7 ± 3.8 25.3 ± 5.2 0.672
2.3. Interventions
The study participants were instructed to take two times
daily one capsule of the active treatment (one capsule
contains 450 mg insoluble yeast beta-glucan; Yestimun®,
formerly called Biolex Beta-HP; Leiber, Germany) or
placebo (microcrystalline cellulose) over a period of 26
weeks (prophylactic treatment). The beta-glucan prepara-
tion is an insoluble (1,3)-(1,6)-
-glucan made from
brewers’ yeast (Saccharomyces cerevisiae), with a purity
of min. 85% on dry matter. (branching factor approxi-
mately: 1,3 (backbone):1,6 (side chain):1,3/1,6 (branch-
ing) = 10:1:0.6). During the study period, three regular
visits (V1 at baseline, V2 after 12 - 14 weeks, and V3
after 25 - 27 weeks) were performed in the practices of
one of the five investigators. In case of a beginning
common cold episode, the participant took for a period of
five days two times daily two capsules of the assigned
product (active treatment or placebo) and had to visit the
investigator for the first episode visit. After these five
days (day six), the participant had to consult once more
the investigator for the second episode visit. For each
occurring infection, the same procedure was performed.
Thus, the total number of visits per participant varies
depending on the number of infection episodes.
Participants with a common cold episode at the begin-
ning of the nutritional study (for no longer than 24 h),
started with the two capsules two times daily for five
days treatment, followed by the prophylactic phase
(regular intake two times daily one capsule).
All the subjects were encouraged to continue their
normal background diet during the duration of the study.
2.4. Outcome Measures
2.4.1. Primary Outcome
The primary objective of this double-blind, randomized,
placebo controlled nutritional study was to prove a sig-
nificant reduction of common cold episodes by the in-
soluble yeast beta-glucan preparation, as compared to
placebo, in subjects with an increased risk of common
cold infections, over a period of 26 weeks. All the com-
mon cold episodes had to be documented in a diary and
confirmed by an investigator.
2.4.2. Secondary Outcome
The secondary objective was to prove a significant re-
duction of common cold symptoms by the yeast insolu-
A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble
Yeast Beta-Glucan to Improve the Immune Defense System
ble beta-glucan as compared to placebo within the first
five days of each common cold episode. During the in-
fection episode, the participants had to rate six prede-
fined common cold symptoms (general malaise, head-
ache and/or pain in the limbs, “sore throat and/or diffi-
culty swallowing”, “hoarseness and/or cough”, “runny
nose”, insomnia due to common cold) on a rating scale (0
points = complaint free, 1 point = weak symptoms, 2
points = strong symptoms) and had to document them in
his/her dairy. By summation of the scores of the individ-
ual symptoms, a sum of scores (=total score) was calcu-
2.4.3. Concurrent Variable
As a concurrent variable, the efficacy of the investiga-
tional product was evaluated by the subjects and the in-
vestigator at the end of each common cold episode as
“very good” “good”, “moderate”, or “poor”.
2.4.4. Safety Assessment
The safety and tolerability of the product was evaluated
by the documentation of adverse events as well as by the
global evaluation of the tolerability by the investigator
and the subject at the end of the study.
2.5. Randomization/Blinding
The human study was conducted double-blind; neither
the participants nor the investigators knew which study
participants had the active or placebo treatment.
Group assignment to the two study groups was per-
formed during the first examination (baseline) randomly
and double-blind, if the inclusion and exclusion criteria
were met. The randomization was performed by block
randomization (block size 4) using the randomization
scheme EDGAR (Experimental Design Generator and
Randomizer). The issued containers comprising the ac-
tive treatment or the placebo product were pre-numbered
(externally) according to the randomization. The random
code remained blinded until the final closing of the data-
2.6. Statistical Methods/Sample Size Calculation
All the variables contained in the data collection were
presented descriptively using their statistical key data or
their frequency distribution and statistically analyzed in
view of the group specific differences ( 2
-value). Or-
dinal and metric data were evaluated using the U-test as
well as the Mann-Whitney U-test for independent sample
testing (pu-values), and the Wilcoxon-test for dependent
sample testing. The t-test was additionally used for met-
ric data (pt-values), whereby testing for equality of vari-
ances in comparison to independent or paired data was
performed by means of an F-test. All statistical analyses
were carried out on an intention-to-treat (ITT) and per
protocol (PP) basis with SPSS. Values of p < 0.05 were
considered significant. Means are given with standard
deviation (SD).
A sample size calculation was not performed, due to
missing preliminary data. The number of subjects was
adjusted to 50 subjects each group.
3. Results
3.1. Total Number of Infections
For the primary objective (total number of infections),
the ITT population consisted of only 94 subjects, due to
six drop-outs, which had a shorter study period and
therefore unavoidably less total infections (see Figure 1).
Within the ITT population, a total of 171 cold episodes
occurred in the prophylactic period of 26 weeks (Table
2). Of these, 76 affected 38 subjects of the active group
(AG; 44.4%) and 95 affected 48 subjects in the placebo
group (PG; 55.6%). Even though the AG showed 25%
less infection episodes than the PG, and a total of seven
subjects (15, 6%) of the AG compared to only one of the
PG (2%) had no common cold episode during the entire
study period ( 2
= 0.019), the difference in the fre-
quency distribution showed only a tendency towards sig-
nificance between the two treatment groups (ITT: 2
= 0.094; PP: 2
= 0.060), and no significant difference
in the total number of episodes (ITT: pu = 0.406; PP: pu =
0.614, respectively).
However, if the same data analysis was made for the
first half (13 weeks) of the prophylactic period, from
Table 2. Number of common cold episodes during the entire
study (26 weeks) in the intention to treat (ITT) and per
protocol (PP) population.
AG (ITT n = 45/PP n = 41) PG (ITT n = 49/PP n = 44)
Number of
episodes Number % Number %
0 7/7 15.6/17.1 1/1 2.0/2.3
1 11/10 24.4/24.4 18/18 36.7/40.9
2 19/17 42.2/41.5 18/16 36.7/36.4
3 5/4 11.1/9.8 10/8 20.4/18.2
4 3/3 6.7/7.3 1/0 2.0/0
7 0/0 0/0 1/1 2.0/2.3
Total 76/68 100/100.1 95/81 99.8/100.1
pu 0.406/0.614
pu: p-value for total number of episodes; 2
: p-value for distribution; AG:
active group; PG: placebo group.
Copyright © 2012 SciRes. FNS
A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble
Yeast Beta-Glucan to Improve the Immune Defense System
November to March, when most of the common cold
episodes occurred, the AG had significantly less infec-
tions as compared to PG (pu = 0.020; see Tables 3 and
3.2. Reduction of the Common Cold Symptoms
(Secondary Objective)
To evaluate the effect of beta-glucan on the common
cold episodes, each subject rated the six predefined
symptoms during each episode for five days. The symp-
tom “general malaise” was excluded from summation,
because it has been shown that this parameter was un-
specific and was without group difference in 95% of all
the episodes ( 2
= 0.818).
Table 5 summarizes the total score during the course
of the episodes. It is obvious that the total scores were
significantly lower in the AG than in the PG at all stages
of the episodes.
For the three typical cold symptoms “sore throat
Table 3. Number of common cold episodes during common
cold episode season (13 weeks) in the intention to treat (ITT)
and per protocol (PP) population.
AG (ITT n = 45/PP n= 41) PG (ITT n = 49/PP n=44)
Number of
episodes Number % Number %
0 13/13 28.9/31.7 6/6 12.2/13.6
1 20/18 44.4/43.9 20/20 40.8/45.5
2 9/7 20.0/17.1 18/15 36.7/34.1
3 3/3 6.7/7.3 4/2 8.2/4.5
4 0/0 0/0 1/1 2.0/2.3
total 47/41 100/100 72/60 99.9/100
pu 0.020/0.045
pu: p-value for total number of episodes; AG: active group; PG: placebo
Table 4. Mean common cold episodes after 13 and 26 weeks
(intention to treat population).
Common cold episodes
Time point Number of
Episodes AG PG pu-value
Total 47 72 0.020
13 weeks
Average ± SD 1.04 ± 0.88 1.47 ± 0.89 0.022
Total 76 95 0.406
26 weeks
Average ± SD 1.69 ± 1.08 1.94 ± 1.13 0.277
pu: p-value obtained by U-test; AG: active group; PG: placebo group; SD:
standard deviation.
and/or difficulty swallowing”, “hoarseness and/or cough”,
and “runny nose”, a significantly higher success (defined
as being complaint-free during the first five days of an
episode) was shown in the AG (p = 0.034, respectively <
0.0001, respectively 0.001). These three typical cold
symptoms and the total cold sum score were significantly
less pronounced at the beginning of the episodes in the
AG than in the PG ( 2
= 0.011 to 0.046, respectively
pu = 0.029).
The results of the secondary objectives clearly demon-
strate that the prophylactic intake of beta-glucan led to
milder common cold symptoms in case of an infection
3.3. Global Evaluation of the Efficacy during
Episodes (ITT)
Global evaluation of the efficacy after each episode was
judged as “very good” or “good” for 74.1% of partici-
pants of the active treatment and for 48.3% of partici-
pants of the placebo treatment, as assessed by physicians,
and for 76.6% (49.4%) of participants, as assessed by
participants. Both participants and physicians rated the
efficacy of the beta-glucan preparation significantly better
than the placebo ( 2
= 0.001, 2
= 0.002, respec-
tively; Table 6).
3.4. Safety Evaluation
All measured clinical parameters, body weight, tempera-
ture, heart rate and blood pressure remained almost con-
stant during the study, with no significant differences
between the two study populations.
The global assessment of tolerability for both treat-
ments was rated at the end of the study as “very good” by
approximately 2/3 of participants and physicians, or as
“good” by approximately 1/3 of participants and physi-
cians with no group differences ( 2
= 0.568, 2
0.395, respectively).
Adverse Events
A total of six adverse events occurred during this nutri-
tional study. Four of them occurred in the AG (gastro-
intestinal infection, hypertonic blood pressure, pain in
lumbar spine region during physical activity, pain/
swelling of the upper ankle joint after playing soccer)
and two in the PG (cut into finger, pain in the knee joint).
All of them were “not severe”, did not lead to termina-
tion of the study, and were judged as being “unlikely”
connected to the intake of the investigational product.
The two study groups did not differ in the proportion of
subjects with adverse events (AG: 8.0% vs PG: 4.0%;
= 0.4). None of the adverse events led to a preterm
rop-out. d
Copyright © 2012 SciRes. FNS
A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble
Yeast Beta-Glucan to Improve the Immune Defense System
Copyright © 2012 SciRes. FNS
Table 5. Total score values in the course of the common cold episodes.
Common cold score
Day 1 mean ± SD Day 2 mean ± SD Day 3 mean ± SD Day 4 mean ± SD Day 5 mean ± SD
Total 5.1 ± 2.3 5.3 ± 2.4 4.2 ± 2.4 2.9 ± 2.4 1.7 ± 2.0
AG 4.6 ± 2.1 4.8 ± 2.3 3.5 ± 2.1 2.4 ± 1.9 1.4 ± 1.6
PG 5.5 ± 2.6 5.7 ± 2.4 4.8 ± 2.5 3.4 ± 2.6 2.0 ± 2.3
pU-value 0.029 0.014 0.001 0.015 0.059
pt-value 0.018 0.009 0.001 0.005 0.034
pu or pt: p-value obtained by U-test or t-test; AG: active group; PG: placebo group; SD: standard deviation.
Table 6. Global evaluation of the efficacy by the investiga-
tors and participants.
Evaluation [%]
Very good Good Moderate Poor p-value
By investigators
AG 24.7 49.4 22.1 3.9
PG 20.2 28.1 31.5 20.2
By patients
AG 23.4 53.2 19.5 3.9
PG 20.2 29.2 31.5 19.1
: p-value for distribution; AG: active group; PG: placebo group.
4. Discussion
During this placebo-controlled, randomized, nutritional
study, the effect of an insoluble yeast beta-glucan on the
body’s resistance against invading pathogens was inves-
tigated. The common cold was used as a model system.
Over a period of 26 weeks, the number of common cold
infections was evaluated in subjects with recurring
common colds. The beta-glucan group had significantly
fewer subjects without infections (AG 15.6% vs PG
2.0%; p = 0.019), and 20% fewer infections compared to
placebo (AG n = 76 versus PG n = 95 infection), but both
groups did not differ statistically regarding the total
number of infections (p = 0.406).
However, if the data of the first half of the study (first
13 weeks—which was during the most intense infection
time) are analyzed, then the beta-glucan group has sig-
nificantly fewer infections than the PG group. During
this time of intense infection, 69.5% of the infections
occurred (119 of 171) from which only 47 occurred in
the beta-glucan group and 72 in the PG group (p = 0.02).
The low incidence of common colds during the second
half of the study, March till June, cannot be explained by
the efficacy of beta glucans on the subjects in the active
group, since the number of infections occurring in the
placebo group was equal to the number of infections in
the active group. This reduction of common cold epi-
sodes might be caused by higher temperatures and gen-
erally increased well-being of humans during spring and
summer time. Thus, the greatest effect of Yestimun® on
the primary outcome variable, which was the number of
common cold infections, was observed during the winter
One limitation of the study was the number of partici-
pants included into this nutritional being determined to
be 50 per group, due to missing previous product-specific
studies. Furthermore, the included subjects had to be
susceptible to common cold (at least three within the last
six months). However, the subjects of the PG had fewer
episodes than expected (mean number of infections in
PG: 1.94 within 26 weeks). The small number of partici-
pants, together with the lower rate of actual infection,
and the realization of the second study half during spring
and summer time were probably responsible for the fail-
ure to show statistical significance regarding the total
number of infections during the whole study duration.
Therefore, the effects observed in this study have to be
confirmed in a larger scale study exclusively during the
winter period with increased risk of common cold.
Several investigations using other beta-glucan prepa-
rations to prevent the risk of common cold infections
have already been published.
In one study, the effect of beta-glucan preparations has
been investigated on the respiratory tract of athletes [15].
Enhanced exercises seem to weaken the immune system
and may cause increased risk of upper respiratory tract
infections [16,17]. In the study by Talbott, marathon run-
ners were treated with either 250 or 500 mg of a β-1,3/
1,6-glucan preparation from Saccharomyces cerevisiae
(Wellmune WPG®) for four weeks post-marathon. Both
beta-glucan groups reported significantly fewer infec-
tions symptoms and better overall health, compared to
placebo. While only 8% of the subjects of both beta-
glucan groups reported infections at week four, 24% of
A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble
Yeast Beta-Glucan to Improve the Immune Defense System
the placebo group subjects reported infection symptoms.
Furthermore, the subjects reported better overall health
and a more positive mood state compared to placebo four
weeks after completing the marathon [15]. In another
study, the effect of a beta-glucan preparation made from
Pleurotus ostreatus together with vitamin C on the cellu-
lar immune response and upper respiratory tract infec-
tions (URTI) was investigated on athletes of different
sports disciplines [18]. Fifty athletes took either two cap-
sules containing 100 mg beta-glucan and 100 mg vitamin
C or 100 mg vitamin C alone for three months. In that
trial, the beta-glucan-treated athletes reported signifi-
cantly less URTI than the vitamin C group (65 versus
117 episodes) [18]. In one clinical trial lasting 12 weeks
[19], the effect of beta-glucan (500 mg/day) from Sac-
charomyces cerevisiae (Wellmune WPG®) was com-
pared to placebo in healthy subjects. In that study, the
investigators found no difference in the incidence of
common cold infections. Even though the number of
infections was not different, the symptoms strength was
reduced in the beta-glucan group since none of the sub-
jects missed school or work due to colds, while the pla-
cebo group did so on average for 1.38 days.
The results of these above cited studies cannot be di-
rectly compared to our study, since time courses, applied
dosages, subject populations or measured outcomes are
not comparable. However, subjects treated with the
above-described beta-glucan preparation had fewer in-
fections or reduced symptoms, like in the study presented
here. All these studies were made with insoluble be-
ta-glucan preparations.
It is known that various beta-glucan preparations have
different effects on the immune system, where not only
the size and the degree of branching are responsible but
also the solubility [7,9,20]. One explanation could be the
fact that for activation of the Dectin-1 receptor, whole
beta-glucans are necessary, as shown very recently.
Smaller size particles or soluble beta-glucans are inactive,
despite efficient binding to the receptor [21]. Based on
this result, Goodridge et al. [21] hypothesized “that a
larger molecule may be required to provide a greater de-
gree of receptor crosslinking to permit activation”.
Beta-glucan is thought to strengthen the immune sys-
tem by activation of innate and adaptive immune re-
sponse mechanisms [2]. Various other nutritional and
herbal agents have been investigated for their immune
system strengthening abilities. One of them is Echinacea,
commonly used for prevention of common cold infection
and known for its immune system stimulating abilities.
Its efficacy, however, is discussed controversially [22-
24]. Due to the fact that all of the intervention trials dif-
fer in study collectives, time courses and primary and
secondary outcomes it is not possible to directly compare
the effect of Echinaceae preparations to the preventive
effect of beta-glucan. In one trial, the effect of an Echi-
naceae preparation was also investigated on subjects
with recurring infections [25]. However, the treatment
duration was only 8 weeks. Within that period, 25.9% of
the placebo-treated subjects were free from infections
compared to 35.2% of the active group. Based on this
data, the effect size was calculated to be 9.3% (difference
Echinacea treatment versus placebo). Similar results
were also observed by Grimm and Müller [26]. During
their two months study, they observed 35% of Echina-
ceae treated subjects without infections and 26% of the
placebo treated subjects in a group of subjects with re-
curring infection (effect size 9%). This data can be com-
pared to our data of the first 15 weeks of the study, where
28.9% of the AG and 12.2% of the PG were free from
infection, which represents an effect size of 16.7%.
Based on these results, we conclude that beta-glucan
might be at least as effective as Echinaceae in the pre-
vention of common colds. This, however, has to be
shown in a comparative two-armed study where both
preparations are compared directly.
As another treatment to prevent common cold, high
dosages of vitamin C are frequently used. However, in
the Cochrane review [27], the author came to the conclu-
sion that high intakes of Vitamin C do not reduce the
incidence of episodes in the normal population. Only
people with high physical stress (athletes or soldiers)
might benefit.
Zinc is also important for the normal function of the
immune system. When taken within 24 hours of onset of
a cold episode, the severity of symptoms and the duration
of the common cold is reduced. Further, when zinc is
supplemented for at least 5 months, the rate of incidences
as well the prescription of antibiotics in children is re-
duced [28]. However, it will not prevent common cold
episodes in the normal, non-deficient population.
Both substances, vitamin C and zinc, are undeniably
important for the function of our immune system. How-
ever, it seems that only subpopulations with a deficiency
of these substances may profit from supplementation,
which then reduces the incidences of cold episodes.
The insoluble beta-glucan preparation made of brew-
ers’ yeast used in this study was well tolerated when
taken for 26 weeks. Neither placebo nor beta-glucan
showed any difference in the number of observed ad-
verse events (p = 0.4), from which none was judged to be
treatment related. All the measured clinical parameters
(body weight, temperature, heart rate and blood pressure)
remained almost constant in both groups during the study.
Approximately 2/3 of the subjects evaluated the safety in
agreement with the investigators, without a group differ-
ence, as “very good” and about 1/3 as “good”. Consider-
Copyright © 2012 SciRes. FNS
A Double-Blind, Randomized, Placebo-Controlled Nutritional Study Using an Insoluble
Yeast Beta-Glucan to Improve the Immune Defense System
ing the six terminations and nine study plan violations,
compliance (intake of the capsules, adherence to the
study period) of the subjects was assessed as good for
this six months nutritional study. The overall good com-
pliance demonstrates the consumers’ acceptance of the
study product.
In conclusion, the present study demonstrates a pro-
phylactic effect of an insoluble yeast beta-glucan prepa-
ration on the occurrence of common colds as opposed to
placebo during seasons with increased common cold in-
cidences. When episodes occurred, they were from the
beginning less pronounced and subsided faster. This re-
sult, however, has to be confirmed by further investiga-
tions with an appropriate sample size.
5. Acknowledgements
The study was funded by Leiber GmbH (Bramsche,
Germany). The authors declare no conflict of interest.
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... can be used as mixtures or in their isolated and concentrated form (Zhu et al. 2016) and their biological activity results from the non-synthetization of these molecules in the human body in any configuration (Brown and Gordon 2005). This characteristic made them immunostimulators (Bach et al. 2017) and potentialize their activity due to the non-existence of β-glucanases enzymes, which are responsible for the β-glucans hydrolyses in the vertebral organisms (Graubaum et al. 2012). Therefore, these molecules remain in the body for a long time, inducing both natural and adaptive immune responses (Graubaum et al. 2012), which are subsequently degraded by slow oxidative processes (Novak and Vetvicka 2009;Del Buono et al. 2016). ...
... This characteristic made them immunostimulators (Bach et al. 2017) and potentialize their activity due to the non-existence of β-glucanases enzymes, which are responsible for the β-glucans hydrolyses in the vertebral organisms (Graubaum et al. 2012). Therefore, these molecules remain in the body for a long time, inducing both natural and adaptive immune responses (Graubaum et al. 2012), which are subsequently degraded by slow oxidative processes (Novak and Vetvicka 2009;Del Buono et al. 2016). ...
Full-text available
Among the most important sources of β-glucans are edible and medicinal mushrooms. These molecules are components of the cellular wall of basidiomycete fungi (mushrooms) and can be extracted even from the basidiocarp as the mycelium and its cultivation extracts or biomasses. Mushroom β-glucans are recognized by their potential effects as immunostimulants and immunosuppressants. They are highlighted as anticholesterolemic, anti-inflammatory, adjuvant in diabetes mellitus, mycotherapy for cancer treatment, as well as adjuvants for COVID-19 vaccines. Due to their relevance, several techniques of β-glucans extraction, purification, and analysis have already been described. Despite the previous knowledge of β-glucans’ benefits for human nutrition and health, the main information about this topic refers to the molecular identification, properties, and benefits, as well as their synthesis and action on cells. Studies on biotechnology industry applications (product development) and the registered products of β-glucans from mushrooms are still limited and more common for feed and healthcare. In this context, this paper reviews the biotechnological production of food products containing β-glucans from basidiomycete fungi, focusing on food enrichment, and presents a new perspective on fungi β-glucans’ use as potential immunotherapy agents. Key points • Mushrooms’ β-glucans for product development in the biotechnology industry • Biotechnological production of food products containing mushrooms’ β-glucans • Basidiomycete fungi β-glucans are used as potential immunotherapy agents Graphical Abstract
... When ingested, ßglucan serves as a mimetic of microbial surface structures that activate pattern recognition receptors (PRRs) present in immune cells, such as fungal ß-glucan that activates C-type-Lectin-like receptor (Dectin 1) [24], and subsequently results in enhanced immunity should these cells subsequently encounter with invading pathogens. This "priming" effect works well for individuals who are immune-compromised and/or those who are facing immune challenges, such as athletes who are going through high intensity training [25][26][27][28][29], people with repeated upper respiratory tract infections [30,31], surgical patients [32,33], and mentally stressed [34] and older [35] individuals. Nonetheless, assuming the infection has already taken place, immune cell stimulation by pathogens will preclude or decrease the mimicry effect of ß-glucan. ...
... Nevertheless, research surrounding the prophylactic use of these TUMHS is sparse. To the best of our knowledge, only a few clinical trials of this kind are available in the literature, including those on the use of β-glucan to forestall infections [25][26][27][28][29][30][31][32][33][34][35], GLP1R [118][119][120] and AMPK [121] inducers to decrease postprandial hyperglycemia, PPARα agonist (bezafibrate) to prevent type 2 diabetes [122], and Nrf2 inducers to protects against stresses such as chemotherapy [123], air pollution [124], and intense exercise [125] in relevant at-risk individuals. This is unfortunate since if one considers the fundamental mechanism that these drugs depend on, i.e., by eliciting an adaptive response that is ordinarily induced by a stress signal, these drugs would be less effective, or ineffective, in situations where the stress is already in place and has progressed to a disease stage. ...
Homeostasis was initially conceptualized by Bernard and Cannon around a century ago as a steady state of physiological parameters that vary within a certain range, such as blood pH, body temperature, and heart rate1,2. The underlying mechanisms that maintain homeostasis are explained by negative feedbacks that are executed by the neuronal, endocrine, and immune systems. At the cellular level, homeostasis, such as that of redox and energy steady state, also exists and is regulated by various cell signaling pathways. The induction of homeostatic mechanism is critical for human to adapt to various disruptive insults (stressors); while on the other hand, adaptation occurs at the expense of other physiological processes and thus runs the risk of collateral damages, particularly under conditions of chronic stress. Conceivably, anti-stress protection can be achieved by stressor-mimicking medicinals that elicit adaptive responses prior to an insult and thereby serve as health risk countermeasures; and in situations where maladaptation may occur, downregulating medicinals could be used to suppress the responses and prevent subsequent pathogenesis. Both strategies are preemptive interventions particularly suited for individuals who carry certain lifestyle, environmental, or genetic risk factors. In this article, we will define and characterize a new modality of prophylactic intervention that forestalls diseases via modulating homeostatic signaling. Moreover, we will provide evidence from the literature that support this concept and distinguish it from other homeostasis-related interventions such as adaptogen, hormesis, and xenohormesis.
... Fungal β-glucans are known as immunostimulant and immunosuppressive molecules [71], presenting an effect of inducing innate and adaptive immune responses in the human body [72]. In addition to immunomodulatory activity [26], these molecules present bioactive properties, such as antioxidant, neuroprotective [70], hepatoprotective, antimicrobial, antiallergic, anti-inflammatory [73], anti-atherogenic, anti-diabetic, cardiovascular, radioprotective [27], anti-cancer [71] activities. ...
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Purpose This paper aims to assess the potential of basidiomycete fungi to mycoremediate brewery wastewater and generate a bioactive molecule (β-glucan) for industrial applications. Methods Six basidiomycete fungi, Ganoderma applanatum, Ganoderma lipsiense, Pleurotus ostreatus, Pycnoporus sanguineus, Lentinula edodes, and Oudemansiela canarii were grown in submerged fermentation using brewery wastewater (BW). β-glucan production, biomass concentration, reducing sugar content, and pH were evaluated and the fungus with the highest β-glucan production was subjected to a kinetic study of β-glucan production. Results Results showed that BW has important nutrients for fungi growth and all species had high biomass production. The highest production of β-glucans was for G. lipsiense (23.87%) and its kinetic study showed the highest production of β-glucans at 14 days and the greatest increase in biomass at 21 days. There was a correlation between the production of β-glucans and the consumption of BW substrate and a decrease in chemical oxygen demand (81% at 21 days), nitrate (<3.00 mg L⁻¹), total phosphorus (66.326 mg L⁻¹), and total dissolved solids (634.1 mg L⁻¹). Conclusion This study highlighted a sustainable use of BW for its remediation besides fungal biomass production as a source of a high-value product for the biotechnology industry, opening prospects in the circular bioeconomy.
... Fungal β-glucans are well-known immunomodulatory compounds that elicit a proinflammatory response from cells of the innate immune system. Therefore, fungal β-glucans have been suggested to be used as adjuvants in cancer treatments or vaccines, and as treatment against infections (dos Santos et al., 2019;Graubaum et al., 2012;Vetvicka et al., 2020). Their typical structural features are described as (1➔3)-β-Dglucans, with branches of β-(1➔6)-linked glucan residues at O-6 to varying extents. ...
Full-text available
Fungal β-glucans have received a lot of interest due to their proinflammatory activity towards cells of the innate immune system. Although commonly described as (1➔3)-β-glucans with varying degree of (1➔6)-branching, the fungal β-glucans constitute a diverse polysaccharide class. In this study, the alkali-soluble β-glucans from the edible mushroom Pleurotus eryngii were extracted and characterized by GC, GC–MS and 2D NMR analyses. The extracts contain several structurally different polysaccharides, including a (1➔3)-β-d-glucan with single glucose units attached at O-6, and a (1➔6)-β-d-glucan, possibly branched at O-3. The immunomodulatory activities of the P. eryngii extracts were assessed by investigating their ability to bind to the receptor dectin-1, and their ability to induce production of the proinflammatory cytokines TNF-α, IL-6 and IL-1β in LPS-differentiated THP-1 cells. Although the samples were able to bind to the dectin-1a receptor, they did not induce production of significant levels of cytokines in the THP-1 cells. Positive controls of yeast-derived (1➔3)-β-d-glucans with branches at O-6 induced cytokine production in the cells. Thus, it appears that the P. eryngii β-glucans are unable to induce production of proinflammatory cytokines in LPS-differentiated THP-1 cells, despite being able to activate the human dectin-1a receptor.
... 34,35 For this reason, β-glucans are not recognized by the immune system as safe molecules and, consequently, induce innate and adaptive immune responses. 36 These molecules present bioactive properties, such as immunomodulatory activity, 4 and can act against cancer. 33 Also, β-glucans show antioxidant, neuroprotective, 17 glycemic levels for diabetic individuals does not work in the same way as for healthy individuals, in who the body itself tends to normalize glycemic levels when it is elevated. ...
This study aims to analyze the peach palm by-product (shells) bioconversion by culinary-medicinal mushroom Lentinula edodes to obtain a food ingredient for dietary supplementation containing high contents of dietary fiber, protein, and β-glucans. The β-glucans production by L. edodes mycelium was optimized through a solid-state fermentation, checking the influence of the heart of palm shells and supplements (rice bran, manioc flour, and sorghum flour) through an experimental mixing plan. The cultivation treatment that presented the highest tendency for β-glucans production was analyzed by the centesimal composition and in vivo biological activity. Treatments 4 (with shells, rice bran, and manioc flour) and 6 (with shells, sorghum flour, and manioc flour) presented the highest β-glucans content. A flour was obtained with high dietary fiber and protein content, and low lipids and carbohydrates content, and low caloric value. The in vivo biological activity demonstrated high protein quality and promoted a lower elevation of the glycemic curve. Thus, technology for the transformation of peach palm shells into a food ingredient was made feasible. It could generate a gluten-free and lactose-free dietary supplement that is both nutritive and bioactive, enhancing human health and well-being as well as environmental sustainability.
... Yeast-based glucans have been applied in clinical studies of bacterial and viral infections. Two independent randomized, double-blind, placebocontrolled clinical trials showed that daily oral administration of the yeast b-glucans reduced the incidence of common cold episodes during the cold season (36,37). Another yeast-derived b-glucan was able to protect mice infected with a lethal titer of the A/Puerto Rico/8/34 (PR8; H1N1) strain of influenza virus (38). ...
Full-text available
Sepsis is a life-threatening condition caused by an abnormal immune response induced by infection with no approved or specific therapeutic options. We present our perspectives for the therapeutic management of sepsis through a four-way approach: (1) infection control through immune enhancement; (2) immune suppression during the initial hyper-inflammatory phase; (3) balanced immune-modulation to counter the later immune-paralysis phase; and (4) advantageous effects on metabolic and coagulation parameters throughout. COVID-19 is a virus-triggered, accelerated sepsis-like reaction that is associated with the rapid progress of an inflammatory cascade involving a cytokine storm and multiorgan failure. Here, we discuss the potential of the biological response modifiers, β-glucans (BRMGs), in the management of sepsis based on their beneficial effects on inflammatory-immune events in COVID-19 clinical studies. In COVID-19 patients, apart from metabolic regulation, BRMGs, derived from a black yeast, Aureobasidium pullulans strain AFO-202, have been reported to stimulate immune responses. BRMGs, produced by another strain (N-163) of A. pullulans, have been implicated in the beneficial regulation of inflammatory markers and immunity, namely IL-6, C-reactive protein (CRP), D-Dimer, ferritin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCR), leucocyte-to-C-reactive protein ratio (LeCR), and leukocyte-to-IL-6 ratio (LeIR). Agents such as these β-glucans, which are safe as they have been widely consumed by humans for decades, have potential as adjuncts for the prevention and management of sepsis as they exert their beneficial effects across the spectrum of processes and factors involved in sepsis pathology, including, but not limited to, metabolism, infection, inflammation, immune modulation, immune enhancement, and gut microbiota.
... Administration of β-glucan from brewer's yeast in two randomised, double-blind, placebo-controlled clinical trials reduced the incidence of common cold episodes in healthy subjects. Some studies have also demonstrated that β-glucan positively enhances the immune system after exercise [73,74]. When yeast β-glucan was provided prophylactically before cycling activity, it affected the production of cytokines in response to heat and exercise [75]. ...
Full-text available
β-glucans are a large class of complex polysaccharides with bioactive properties, including immune modulation. Natural sources of these compounds include yeast, oats, barley, mushrooms, and algae. Yeast is abundant in various processes, including fermentation, and they are often discarded as waste products. The production of biomolecules from waste resources is a growing trend worldwide with novel waste resources being constantly identified. Yeast-derived β-glucans may assist the host’s defence against infections by influencing neutrophil and macrophage inflammatory and antibacterial activities. β-glucans were long regarded as an essential anti-cancer therapy and were licensed in Japan as immune-adjuvant therapy for cancer in 1980 and new mechanisms of action of these molecules are constantly emerging. This paper outlines yeast β-glucans’ immune-modulatory and anti-cancer effects, production and extraction, and their availability in waste streams.
... is characterized by common cold or flu-like symptoms. In randomized, double-blind, placebocontrolled studies, oral dose of β -glucan was demonstrated to reduce common cold occurrences by one-fourth (Graubaum et al. 2012, Auingeretal. 2013 Thus, modulation of the cytokine storm through β-glucan-mediated controlled expression of proand anti-inflammatory cytokines could aid in withstanding COVID-19 pathogenesis (Hetland et al. 2020, Murphy et al. 2020. ...
Disease outbreaks have devastated mankind throughout history, altering the course of history and, in some cases, marking the end of entire civilizations. Those incidents have had a profound impact on human civilization’s economic, political, and social importance, with consequences that may last for centuries. Today, the 2019 novel coronavirus (SARS-CoV-2) (COVID-19) spreads rapidly across the world, causing a great threat to public health and global economies. By 2021, several vaccines were produced for the battle against the COVID-19 and simultaneously more vaccine candidates are in the process of development. Despite many advancements in science, there were several reports on complications and side effects after vaccination. Furthermore, continuous emergence of new variants through mutation, lack of well-designed in vivo tests, and randomized controlled clinical studies made COVID-19 vaccination processes less effective. However, many researchers believe that mushroom-based therapeutic approaches would greatly benefit for the COVID-19 patients. Medicinal mushrooms had been used since ancient times for longevity and better health. They are used in multiple therapeutic activities as well as dietary supplements to prevent and treat many diseases. Several epidemiological and clinical studies have shown that mushrooms and mushroom-derived supplements can boost the efficiency of our innate and adaptive immune responses to a range of pathogens including viruses. Some of the medicinal mushrooms have shown anti-microbial activity against viral agents in vitro and in vivo. Here, we review anti-viral and anti-inflammatory properties of selected medicinal mushrooms and their potential as a candidate to combat health issues against COVID-19.
... Several studies suggested that β-glucan supplementation improved mucosal innate immunity and reduced upper respiratory tract infection incidence and symptom severity in pediatric patients [196][197][198]. β-glucan supplementation may be also associated with defense against infection in adults and the elderly [199,200]. In particular, there is some evidence that adults suffering from allergies benefit from β-glucan supplementation to reduce symptom severity [201]. ...
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β-glucans are a diverse group of polysaccharides composed of β-1,3 or β-(1,3-1,4) linked glucose monomers. They are mainly synthesized by fungi, plants, seaweed and bacteria, where they carry out structural, protective and energy storage roles. Because of their unique physicochemical properties, they have important applications in several industrial, biomedical and biotechnological processes. β-glucans are also major bioactive molecules with marked immunomodulatory and metabolic properties. As such, they have been the focus of many studies attesting to their ability to, among other roles, fight cancer, reduce the risk of cardiovascular diseases and control diabetes. The physicochemical and functional profiles of β-glucans are deeply influenced by their molecular structure. This structure governs β-glucan interaction with multiple β-glucan binding proteins, triggering myriad biological responses. It is then imperative to understand the structural properties of β-glucans to fully reveal their biological roles and potential applications. The deconstruction of β-glucans is a result of β-glucanase activity. In addition to being invaluable tools for the study of β-glucans, these enzymes have applications in numerous biotechnological and industrial processes, both alone and in conjunction with their natural substrates. Here, we review potential applications for β-glucans and β-glucanases, and explore how their functionalities are dictated by their structure.
... Beta-glucans contribution in promoting stimulation against viral attack has been demonstrated in numerous human trials (192,193). Results of several studies have shown a reduction in cold and flu symptoms and upper respiratory infections when compared to placebo. The mechanism of action of beta-glucans against viruses other than COVID-19 might be promoting viral elimination or inhibition by priming innate immune function (194). ...
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SARS-CoV-2, a novel Corona virus strain, was first detected in Wuhan, China, in December 2019. As of December 16, 2021, almost 4,822,472 people had died and over 236,132,082 were infected with this lethal viral infection. It is believed that the human immune system is thought to play a critical role in the initial phase of infection when the viruses invade the host cells. Although some effective vaccines have already been on the market, researchers and many bio-pharmaceuticals are still working hard to develop a fully functional vaccine or more effective therapeutic agent against the COVID-19. Other efforts, in addition to functional vaccines, can help strengthen the immune system to defeat the corona virus infection. Herein, we have reviewed some of those proven measures, following which a more efficient immune system can be better prepared to fight viral infection. Among these, dietary supplements like- fresh vegetables and fruits offer a plentiful of vitamins and antioxidants, enabling to build of a healthy immune system. While the pharmacologically active components of medicinal plants directly aid in fighting against viral infection, supplementary supplements combined with a healthy diet will assist to regulate the immune system and will prevent viral infection. In addition, some personal habits, like- regular physical exercise, intermittent fasting, and adequate sleep, had also been proven to aid the immune system in becoming an efficient one. Maintaining each of these will strengthen the immune system, allowing innate immunity to become a more defensive and active antagonistic mechanism against corona-virus infection. However, because dietary treatments take longer to produce beneficial effects in adaptive maturation, personalized nutrition cannot be expected to have an immediate impact on the global outbreak.
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The experimental material comprised 20 adult Wistar rats aged 12 weeks, divided into two equal groups (control and experimental) including five males and five females each. From the first day of the experiment, the experimental group was fed Murigran feed supplemented with β-1,3/1,6-D-glucan (Biolex Beta-HP) at a dosage of 12-19 mg/rat/d, depending on body weight, while the control animals were administered the same feed without any additives. On days 1 and 14 of the experiment, arterial blood samples were collected and diluted with heparin, and then the following parameters were determined: total protein and γ-globulin contents, lysozyme and ceruloplasmin activities, the proliferative response of blood lymphocytes after stimulation with LPS or ConA, metabolic activity, and the potential killing activity of phagocytes. The results showed that Biolex-Beta HP modulated the selected parameters of specific and non-specific humoral and cellular immunity in rats.
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The experiment was performed on 20 adult Wistar rats aged 12 weeks, divided into two equal groups (control and experimental), each comprised of five males and five females. From the first day of the experiment, the experimental group rats were fed Murigran feed supplemented with β-1,3/1,6-D-glucan at a dosage of 12-19 mg/rat/d, subject to body weight, while the controlgroup was administered the same feed without any additives. At the beginning of the experiment and then after 14 days, arterial blood samples were collected from the rats and diluted with heparin to measure and compare the phagocytic activity and oxidative metabolism of peripheral blood granulocytes and monocytes by flow cytometry. Statistically higher levels of the activity were observed in the group of rats administered glucan than in controls, expressed in terms of the percentage of phagocytic cells as well as average fluorescence intensity. β-1,3/1,6-D-glucan also had a positive effect on the oxidative metabolism of both granulocytes and monocytes after stimulation with E. coli, and on the oxidative metabolism of granulocytes after stimulation with PMA.
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β-Glucans are well known for their immunomodulatory capacities in humans and mice. For this reason, together with the European ban on growth-promoting antibiotics, β-glucans are intensively used in pig feed. However, as shown in the present study, there is much variation in the stimulatory capacities of β-glucans from different sources. Since dendritic cells (DCs) are the first cells that are encountered after an antigen is taken up by the intestinal epithelial cell barrier, we decided to investigate the effect of two concentrations (5 and 10 μg/ml) of five commercial β-glucan preparations, differing in structure and source, on porcine monocyte-derived dendritic cells (MoDCs). Although all β-glucans gave rise to a significant reduction of the phagocytic activity of DCs, only Macrogard induced a significant phenotypic maturation. In addition to Macrogard, zymosan, another β-glucan derived from Saccharomyces cerevisiae, and curdlan also significantly improved the T-cell-stimulatory capacity of MoDCs. Most interesting, however, is the cytokine secretion profile of curdlan-stimulated MoDCs, since only curdlan induced significant higher expression levels of interleukin-1β (IL-1β), IL-6, IL-10, and IL-12/IL-23p40. Since the cytokine profile of DCs influences the outcome of the ensuing immune response and thus may prove valuable in intestinal immunity, a careful choice is necessary when β-glucans are used as dietary supplement.
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Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required.
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An ever-growing volume of peer-reviewed publications speaks to the recent and rapid growth in both scope and understanding of exercise immunology. Indeed, more than 95% of all peer-reviewed publications in exercise immunology (currently >2, 200 publications using search terms "exercise" and "immune") have been published since the formation of the International Society of Exercise and Immunology (ISEI) in 1989 (ISI Web of Knowledge). We recognise the epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition. Extreme physical activity of any type may have implications for the immune system. However, because of its emotive component, exercise is likely to have a larger effect, and to date the great majority of our knowledge on this subject comes from exercise studies. In this position statement, a panel of world-leading experts provides a consensus of current knowledge, briefly covering the background, explaining what we think we know with some degree of certainty, exploring continued controversies, and pointing to likely directions for future research. Part one of this position statement focuses on 'immune function and exercise' and part two on 'maintaining immune health'. Part one provides a brief introduction and history (Roy Shephard) followed by sections on: respiratory infections and exercise (Maree Gleeson); cellular innate immune function and exercise (Jeffrey Woods); acquired immunity and exercise (Nicolette Bishop); mucosal immunity and exercise (Michael Gleeson and Nicolette Bishop); immunological methods in exercise immunology (Monika Fleshner); anti-inflammatory effects of physical activity (Charlotte Green and Bente Pedersen); exercise and cancer (Laurie Hoffman-Goetz and Connie Rogers) and finally, "omics" in exercise (Hinnak Northoff, Asghar Abbasi and Perikles Simon). The focus on respiratory infections in exercise has been stimulated by the commonly held beliefs that the frequency of upper respiratory tract infections (URTI) is increased in elite endurance athletes after single bouts of ultra-endurance exercise and during periods of intensive training. The evidence to support these concepts is inconclusive, but supports the idea that exercised-induced immune suppression increases susceptibility to symptoms of infection, particularly around the time of competition, and that upper respiratory symptoms are associated with performance decrements. Conclusions from the debate on whether sore throats are actually caused by infections or are a reflection of other inflammatory stimuli associated with exercise remains unclear. It is widely accepted that acute and chronic exercise alter the number and function of circulating cells of the innate immune system (e.g. neutrophils, monocytes and natural killer (NK) cells). A limited number of animal studies has helped us determine the extent to which these changes alter susceptibility to herpes simplex and influenza virus infection. Unfortunately, we have only 'scratched the surface' regarding whether exercise-induced changes in innate immune function alter infectious disease susceptibility or outcome and whether the purported anti-inflammatory effect of regular exercise is mediated through exercise-induced effects on innate immune cells. We need to know whether exercise alters migration of innate cells and whether this alters disease susceptibility. Although studies in humans have shed light on monocytes, these cells are relatively immature and may not reflect the effects of exercise on fully differentiated tissue macrophages. Currently, there is very little information on the effects of exercise on dendritic cells, which is unfortunate given the powerful influence of these cells in the initiation of immune responses. It is agreed that a lymphocytosis is observed during and immediately after exercise, proportional to exercise intensity and duration, with numbers of cells (T cells and to a lesser extent B cells) falling below pre-exercise levels during the early stages of recovery, before returning to resting values normally within 24 h. Mobilization of T and B cell subsets in this way is largely influenced by the actions of catecholamines. Evidence indicates that acute exercise stimulates T cell subset activation in vivo and in response to mitogen- and antigen-stimulation. Although numerous studies report decreased mitogen- and antigen-stimulated T cell proliferation following acute exercise, the interpretation of these findings may be confounded by alterations in the relative proportion of cells (e.g. T, B and NK cells) in the circulation that can respond to stimulation. Longitudinal training studies in previously sedentary people have failed to show marked changes in T and B cell functions provided that blood samples were taken at least 24 h after the last exercise bout. In contrast, T and B cell functions appear to be sensitive to increases in training load in well-trained athletes, with decreases in circulating numbers of Type 1 T cells, reduced T cell proliferative responses and falls in stimulated B cell Ig synthesis. The cause of this apparent depression in acquired immunity appears to be related to elevated circulating stress hormones, and alterations in the pro/anti-inflammatory cytokine balance in response to exercise. The clinical significance of these changes in acquired immunity with acute exercise and training remains unknown. The production of secretory immunoglobulin A (SIgA) is the major effector function of the mucosal immune system providing the 'first line of defence' against pathogens. To date, the majority of exercise studies have assessed saliva SIgA as a marker of mucosal immunity, but more recently the importance of other antimicrobial proteins in saliva (e.g. alpha-amylase, lactoferrin and lysozyme) has gained greater recognition. Acute bouts of moderate exercise have little impact on mucosal immunity but prolonged exercise and intensified training can evoke decreases in saliva secretion of SIgA. Mechanisms underlying the alterations in mucosal immunity with acute exercise are probably largely related to the activation of the sympathetic nervous system and its associated effects on salivary protein exocytosis and IgA transcytosis. Depressed secretion of SIgA into saliva during periods of intensified training and chronic stress are likely linked to altered activity of the hypothalamic-pituitary-adrenal axis, with inhibitory effects on IgA synthesis and/or transcytosis. Consensus exists that reduced levels of saliva SIgA are associated with increased risk of URTI during heavy training. An important question for exercise immunologists remains: how does one measure immune function in a meaningful way? One approach to assessing immune function that extends beyond blood or salivary measures involves challenging study participants with antigenic stimuli and assessing relevant antigen-driven responses including antigen specific cell-mediated delayed type hypersensitivity responses, or circulating antibody responses. Investigators can inject novel antigens such as keyhole limpet haemocyanin (KLH) to assess development of a primary antibody response (albeit only once) or previously seen antigens such as influenza, where the subsequent antibody response reflects a somewhat more variable mixture of primary, secondary and tertiary responses. Using a novel antigen has the advantage that the investigator can identify the effects of exercise stress on the unique cellular events required for a primary response that using a previously seen antigen (e.g. influenza) does not permit. The results of exercise studies using these approaches indicate that an acute bout of intense exercise suppresses antibody production (e.g. anti-KLH Ig) whereas moderate exercise training can restore optimal antibody responses in the face of stressors and ageing. Because immune function is critical to host survival, the system has evolved a large safety net and redundancy such that it is difficult to determine how much immune function must be lost or gained to reveal changes in host disease susceptibility. There are numerous examples where exercise alters measures of immunity by 15-25%. Whether changes of this magnitude are sufficient to alter host defence, disease susceptibility or severity remains debatable. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. Evidence suggests that the prophylactic effect of exercise may, to some extent, be ascribed to the anti-inflammatory effect of regular exercise mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise (e.g. via increases in circulating anti-inflammatory cytokines including interleukin (IL)-1 receptor antagonist and IL-10). To understand the mechanism(s) of the protective, anti-inflammatory effect of exercise fully, we need to focus on the nature of exercise that is most efficient at allieviating the effects of chronic inflammation in disease. The beneficial effects of endurance exercise are well known; however, the antiinflammatory role of strength training exercises are poorly defined. In addition, the independent contribution of an exercise-induced reduction in visceral fat versus other exercise-induced anti-inflammatory mechanisms needs to be understood better. There is consensus that exercise training protects against some types of cancers. Training also enhances aspects of anti-tumour immunity and reduces inflammatory mediators. However, the evidence linking immunological and inflammatory mechanisms, physical activity, and cancer risk reduction remains tentative. (ABSTRACT TRUNCATED)
(1→3)-β-d-Glucans that have β-d-glucopyranosyl units attached by (1→6) linkages as single unit branches enhance the immune system systemically. This enhancement results in antitumor, antibacterial, antiviral, anticoagulatory and wound healing activities. The (1→3)-β-d-glucan backbone is essential. The most active polymers have degrees of branching (DB) between 0.20 and 0.33. Data suggest both that triple helical structures formed from high molecular weight polymers are possibly important for immunopotentiating activity and that activity is independent of any specific ordered structure. Other data indicate that it is the distribution of the branch units along the backbone chain that is responsible for activity. There are data that indicate both that β-d-glucopyranosyl units are required for immunopotentiating activity and that the specific nature of the substituent is unimportant. There are also data that indicate both that the more water-soluble polymers are more active (up to a certain degree of substitution (DS) or DB) and that some insoluble aggregates are more stimulatory than the soluble polymers. The best conclusion at this time is that the immunopotentiating activity of (1→3)-β-d-glucans depends on a helical conformation and on the presence of hydrophilic groups located on the outside surface of the helix. Immunopotentiation effected by binding of a (1→3)-β-glucan molecule or particle probably includes activation of cytotoxic macrophages, helper T cells, and NK cells, promotion of T cell differentiation, and activation of the alternative complement pathway.
The common cold is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Trials conducted since 1984 investigating the role of zinc for the common cold symptoms have had mixed results. Inadequate treatment masking and reduced bioavailability of zinc from some formulations have been cited as influencing results. To assess the effect of zinc on common cold symptoms. We searched CENTRAL (2010, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May week 3, 2010) and EMBASE (1974 to June 2010). Randomised, double-blind, placebo-controlled trials using zinc for at least five consecutive days to treat, or for at least five months to prevent the common cold. Two review authors independently extracted data and assessed trial quality. We included 13 therapeutic trials (966 participants) and two preventive trials (394 participants). Intake of zinc is associated with a significant reduction in the duration (standardized mean difference (SMD) -0.97; 95% confidence interval (CI) -1.56 to -0.38) (P = 0.001), and severity of common cold symptoms (SMD -0.39; 95% CI -0.77 to -0.02) (P = 0.04). There was a significant difference between the zinc and control group for the proportion of participants symptomatic after seven days of treatment (OR 0.45; 95% CI 0.2 to 1.00) (P = 0.05). The incidence rate ratio (IRR) of developing a cold (IRR 0.64; 95% CI 0.47 to 0.88) (P = 0.006), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06), bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) and nausea (OR 2.15; 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children. There is potential for zinc lozenges to produce side effects. In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used.
Prolonged and exhausting physical activity causes numerous changes in immunity and sometimes transient increases the risk of upper respiratory tract infections (URTIs). Nutritional supplements as countermeasures to exercise-induced changes have increasingly been studied in the last decade. One of the most promising nutritional supplements is β-glucan, a well-known immunomodulator with positive effects on the function of immunocompetent cells. In this double blind, placebo-controlled study, we investigated the effect of pleuran, an insoluble β-(1,3/1,6) glucan from mushroom Pleurotus ostreatus, on selected cellular immune responses and incidence of URTI symptoms in athletes. Fifty athletes were randomized to pleuran or placebo group, taking pleuran (commercial name Imunoglukan(®)) or placebo supplements during 3 months. Venous whole blood was collected before and after 3 months of supplementation and additionally 3 months after supplementation period was completed. Incidence of URTI symptoms together with characterization of changes in phagocytosis and natural killer (NK) cell count was monitored during the study. We found that pleuran significantly reduced the incidence of URTI symptoms and increased the number of circulating NK cells. In addition, the phagocytosis process remained stable in pleuran group during the study in contrast to placebo group where significant reduction of phagocytosis was observed. These findings indicate that pleuran may serve as an effective nutritional supplement for athletes under heavy physical training. Additional research is needed to determine the mechanisms of pleuran function.