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R E V I E W Open Access
Immune-modulatory effects of dietary Yeast
Beta-1,3/1,6-D-glucan
Heike Stier
1*
, Veronika Ebbeskotte
2
and Joerg Gruenwald
1
Abstract
Beta-glucans are a heterogeneous group of natural polysaccharides mostly investigated for their immunological
effects. Due to the low systemic availability of oral preparations, it has been thought that only parenterally applied
beta-glucans can modulate the immune system. However, several in vivo and in vitro investigations have revealed
that orally applied beta-glucans also exert such effects. Various receptor interactions, explaining possible mode of
actions, have been detected. The effects mainly depend on the source and structure of the beta-glucans. In the
meantime, several human clinical trials with dietary insoluble yeast beta-glucans have been performed. The results
confirm the previous findings of in vivo studies. The results of all studies taken together clearly indicate that oral
intake of insoluble yeast beta-glucans is safe and has an immune strengthening effect.
Keywords: Insoluble yeast β-glucans, Immune system, Clinical trial
Introduction
A well-functioning immune system is crucial for staying
healthy. Therefore, the potential of natural substances to
strengthen the immune system has long been the subject
of investigation. There are many synthetic and natural
preparations claiming to be immunomodulators. Prob-
ably the best known herbal preparations that exhibit ef-
fects on the immune system are preparations made from
Echinacea, Viscum (mistletoe), and Pelargonium. There
is, however, another very interesting and, by now, properly
investigated class of immunomodulators - the β-glucans.
Long before the substance class of β-glucans them-
selves were identified as immunomodulators, the benefi-
cial effects of β-glucan-containing mushrooms such as
Shiitake (Lentinus edodes) in Japan or Lingzhi (Gano-
derma lucidum) in China were utilized in the traditional
Oriental medicine for the strengthening of the body’s
immune system.
The research on β-glucans started in the middle of the
last century, when the immune-modulating effect of a
yeast insoluble fraction was first shown [1]. Later it was
demonstrated that the immunological activity of this
preparation derives from the β-(1,3)-D-glucans [2].
Most of our current knowledge on the health benefits
of β-glucans, the underlying mode of action, and its rela-
tionship to the structure of β-glucans was discovered
within the last 20 years (for review see [3,4]).
Meanwhile, more than 6000 publications investigating
the immune-modulating effects of β-glucans, such as
anti-inflammatory or antimicrobial abilities, have been
published [5]. Health effects were found not only in
humans but also in invertebrates, rodents, fishes as well
as farm animals such as cows or pigs (for review see [4]).
Further, numerous studies reported other health benefits
of β-glucans, including hepatoprotective, wound healing,
weight loss, antidiabetic and cholesterol lowering func-
tions (for review see [6,7]).
β-glucans are a heterogeneous group of natural poly-
saccharides, consisting of D-glucose monomers linked
by a β-glycosidic bond. They are important structural
elements of the cell wall or serve as energy storage in
bacteria, fungi including yeast, algae, and plants, while
they are absent in vertebrate and invertebrate tissue.
The individual glucose subunits are primarily linked ei-
ther by (1,3)-β,(1,4)-β,or(1,6)-βglycosidic bonds. In most
cases, β-glucans exhibit a uniformly constructed backbone
of various lengths with side-chains of D-glucose attached
by (1,4)-β,or(1,6)-βbindings.
However, not all β-glucans are able to modulate im-
mune functions. These properties mainly depend on the
* Correspondence: hstier@analyze-realize.com
1
analyze & realize GmbH, Waldseeweg 6, 13467 Berlin, Germany
Full list of author information is available at the end of the article
© 2014 Stier et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Stier et al. Nutrition Journal 2014, 13:38
http://www.nutritionj.com/content/13/1/38
primary chemical structure of the β-glucans. Cellulose for
example, a (1,4)-β-linked glucan, does not exhibit immune-
modulatory effects. In contrast, β-glucans derived from
fungi and yeast, which consist of a (1,3)-β-linked backbone
with small numbers of (1,6)-β-linked side chains, are essen-
tially known for their immune-modulating effects [8].
Apart from differences in the type of linkage and
branching, β-glucans can also vary in solubility, molecu-
lar mass, tertiary structure, degree of branching, polymer
charge and solution conformation (triple or single helix
or random coil). All these characteristics may influence
their immune modulating effects [9]. On the other hand,
the manufacturing process and, hence, the isolation
method impacts the structure of β-glucans and conse-
quentially their effects on the immune system. Indeed,
the immune-modulating activity of different β-glucans
from the same source might differ considerably in level
of purity, solubility, molecular mass, tertiary structure,
degree of branching, polymer charge and solution con-
formation [5].
Although there are numerous in vitro and in vivo in-
vestigations, human clinical trials confirming the pre-
clinical findings are rather scarce. Due to different
natural sources of the β-glucans, differences in application
(intraperitoneal, intravenous or subcutaneous injections,
or oral), differences in preparation and thus structural dif-
ferences, the results obtained in the resulting clinical stud-
ies are non-homogeneous and often contradictory [4].
Due to this heterogeneity, we focused our review
on the immune-modulating effects of insoluble yeast-
derived dietary β-glucans.
The main focus will be on the food product Yestimun® -
an insoluble, highly purified, well-characterized and in-
tensively studied β-glucan from Spent Brewers’Yeast.
The in vivo data obtained from this preparation, to-
gether with the efficacy results obtained during clinical
trials, will be presented and compared to the other dietary,
insoluble yeast β-glucan preparations available on the
market. Only randomized, controlled trials were consid-
ered for the purpose of this review. Possible mechanisms
of action will be presented, based on the current know-
ledge about structure-function relationships of β-glucans.
Studies investigating other aspects than the immune sys-
tem or studies with soluble β-glucans were excluded.
Characteristics of the proprietary yeast β-glucan
preparation (Yestimun®)
Yestimun® is an insoluble (1,3)-(1,6)-β-glucan made from
Spent Brewers’Yeast (Saccharomyces cerevisiae). The
brewers’yeast used in Yestimun® is grown exclusively on
malt and clean spring water with no other nutrients
added. It is a natural by-product of the fermentation
process used for beer production. Following gentle au-
tolysis with the yeast’s own enzymes, high-performance
centrifuges are used to separate the yeast autolysate into
the soluble yeast extract and the insoluble yeast cell wall.
Yeast cell walls contain typically about 30% of β-glucans
of dry weight. During several separation processes, the
β-glucans are further purified without the use of strong
alkaline in the hydrolysis process, and soluble com-
pounds are removed. Furthermore, the process does not
involve an acidic hydrolysis, leaving the acid-sensitive β-
1,6-glucan side chains mainly intact. This results in an
average of 22% relative linkage percentage from β-1,6
glucan (H-NMR analysis according to FCC VII, 3rd
suppl.; reference-glucan at 14%), with a minimum of
purity of 85% (dry mass).
Growth conditions of the yeast might result in some
heterogeneity of β-glucans within the cell wall [4].
Therefore, it can be speculated that β-glucans from cell
walls of S. cerevisiae grown during brewery have a differ-
ent β-glucan pattern than those from bakers’yeast,
which might also influence the immuno-modulating
abilities of the product.
Mode of action/structure function relationship
As humans cannot metabolize the β-glycosidic bonds
from β-glucans, it has long been suspected that the bac-
terial fermentation process taking place within the intes-
tinal system is involved in the health promoting effect of
β-glucans.
Meanwhile, different possible mechanisms have been
identified on how oral β-glucans modulate the immune
system (for review see [10,11]).
In general, humans cannot synthesize β-glucans. There-
fore, the immune system recognizes these compounds as
foreign. The innate immune system responds to invading
pathogens through pattern recognition receptors (PRR),
which are typically expressed by immune cells but also by
other cells. PRRs recognize conserved microbial struc-
tures, the so-called microbe-associated molecular patterns
(MAMPs) [12], formally called PAMPs [13,14]. β-glucans
are considered as one of the major MAMPs for the PRR-
mediated sensing of fungal infection. So far, the most im-
portant PRRs for β-glucans are the dectin-1 receptor, the
complement receptor 3 (CR3) and toll-like-receptors
(TLR), which are found on various immune cells such as
monocytes, macrophages, dendritic cells, neutrophils, eo-
sinophils, and natural killer cells, but also on intestinal
epithelial cells [10,15-17]. Binding of β-glucans to dectin-1
induced a cascade of innate and adaptive immune re-
sponse such as phagocytosis, oxidative burst, and the pro-
duction of cytokines and chemokines in dentritic cells and
macrophages [15]. Kankkunen et al. showed that particu-
late yeast β-glucan triggered interleukin-1β(IL-1β)medi-
ated cellular response in human primary macrophages via
dectin-1 signaling [18]. Earlier in vitro studies showed that
yeast β-glucan is a strong stimulant of macrophages [19]
Stier et al. Nutrition Journal 2014, 13:38 Page 2 of 9
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and induced mitogenic activity in rat thymocytes, indicat-
ing immunostimulatory effects [20].
The exact mechanism on how β-glucans affect im-
mune function depends in part on the route of admin-
istration. Strong effects were already observed in
studies in the early 1990s using intravenously injected
yeast β-glucans [21-23], when the biological efficacy of
orally administered β-glucans was critically discussed.
In terms of oral administration, the impact on immune
function is assumed to be primarily explained by the
interaction of β-glucans with pinocytic microfold (M)-
cells located in the small intestine [24]. It has been sug-
gested that M-cells take up β-glucans and transport
them from the intestinal lumen to the immune cells lo-
cated within the Peyer’s patches [11].
Uptake of β-glucans has been shown in mice with sol-
uble and particulate yeast (1,3)-(1,6)-glucans labeled with
fluorescein. Both types of yeast β-1,3-glucans were taken
up by gastrointestinal macrophages, and then processed
forms were transported to the lymph nodes, spleen and
bone marrow [25]. Also, in vitro experiments have shown
that β-glucans were degraded inside macrophages and re-
leased into the culture medium [25], which makes them
eventually available for the circulating system and a sys-
temic distribution.
Orally administered β-glucans induced phagocytic activ-
ity, oxidative bursts, and IL-1 production of peritoneal
macrophages in mice [26]. A higher phagocytic activity
and oxidative metabolism of neutrophils and monocytes,
indicating an immune restoring activity of yeast β-glucan
has also been shown in rats [27]. However, not only the
cellular but also the humoral acute phase immune reac-
tion is affected by yeast β-glucan feeding as shown by in-
creased lysozyme and ceruloplasmin activitiy [28].
Moreover, oral delivery of β-glucans impact mucosal
immunity, as shown by an increase of intraepithelial
lymphocytes in the intestine of mice [29]. In rats, the ab-
sorption of soluble β-glucans translocated from the
gastrointestinal tract into the systemic circulation leads
to an increased immune response and resistance against
infectious challenge [16]. The effect of an insoluble β-
glucan against anthrax infection in mice showed that the
treated animals survived the anthrax infection, while
50% of the control animals died, indicating an improved
immune function in animals fed with β-glucan [30].
Another important aspect to be considered is the solu-
bility of β-glucans, as soluble and particulate (insoluble)
β-glucans isolated from yeast may stimulate the immune
system via different pathways [31]. In vivo and in vitro
studies revealed that particulate (insoluble) β-glucan was
phagocytosed by dendritic cells and macrophages via
dectin-1 receptor pathway. Although particulate β-glucans
can also be taken up by dendritic cells through a dectin-1
receptor independent mechanism, the dectin-1 receptor
pathway is essential for the activation of dendritic cells,
which in turn induces T-cell response and cytokine release
[31]. However, not all insoluble particulate β-glucans are
able to bind to and activate the dectin-1 receptor. Studies
with synthetically produced β-glucans revealed that bind-
ing to dectin-1 receptor is specific for β-glucans with a
(1,3)-beta backbone. Backbones with mixed (1,3)/(1,4)-β-
bindings (e.g. barley derived β-glucans) are not recognized
by this receptor. Also, a backbone length of at least seven
glucose units is required for binding, in addition to one
(1,6)-β-side-chain branch (e.g. insoluble yeast β-glucans).
Furthermore, the binding activity increases with increas-
ing molecular weight of the polymer [32]. However, bind-
ing to the dectin-1 receptor alone does not activate the
signal cascade induced by this receptor. Indeed, dectin-
1 signaling and the concomitant immune responses are
only activated by particulate β-glucans but not by sol-
uble β-glucans [33]. Insoluble, particulate β-glucans in-
duced the process of phagocytosis, resulting in the
elimination of invading microbes by binding to the
dectin-1 receptor [31]. Further, particulate β-glucans pro-
motes T-cell differentiation into Th1-cells and enhances
cytotoxic T lymphocyte priming by the dectin-1 pathway.
Even though soluble β-glucans are also recognized by the
dectin-1 receptors, they cannot activate immune response
via this pathway. Soluble β-glucans are, however, able to
bind to the CR3 receptor. The activation of the CR3 leads
to complement system mediated immune process, sup-
ported by specific antibodies [31].
These results show that different β-glucan particles in-
fluence the immune system via different pathways. Insol-
uble β-glucans are able to activate both the innate and the
adaptive immune responses, whereas soluble β-glucans
are most effective via the complement system, which
needs specific antibodies.
Studies performed with the proprietary yeast
β-glucan preparation (Yestimun®)
In vivo studies with Yestimun®
Feeding experiments with Yestimun® (previously called
Biolex-Beta HP) in rats [34] showed that β-glucans in-
creased the phagocytic activity of granulocytes and mono-
cytes and the percentage of phagocytic cells. β-glucan
feeding tended to have positive effects on the oxidative
metabolism of these cell types. After stimulating mono-
cytes with E. coli, the oxidative metabolism was signifi-
cantly higher in the β-glucan group. Comparable effects
were observed after phorbol myristate acetate (PMA)
stimulation, a strong respiratory-burst stimulus [34].
Application of the same orally applied insoluble β-glucan
resulted in an increase in non-specific humoral immune
parameters in rats as shown by higher lysozyme and ceru-
loplasmin activities and serum γ-globulin levels [28]. This
indicates that β-glucans may affect the synthesis of acute
Stier et al. Nutrition Journal 2014, 13:38 Page 3 of 9
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phase proteins. When the blood phagocytic cells were ana-
lyzed for their respiratory burst activity and their potential
killing activity, the cells derived from the β-glucan fed
group showed higher activity. Also, the proliferation
rate of blood lymphocytes, when stimulated by Conca-
navalin A (ConA) or lipopolysaccharide (LPS), was higher
in the β-glucan group, also indicating effects of β-glucans
on cellular immunity [28].
These results were confirmed in another in vivo investi-
gation in rats with cyclophosphamide suppressed immune
systems [27]. Under these conditions, feeding β-glucans
led to an increased phagocytic activity of monocytes and
granulocytes. Also, the respiratory-burst activity and
the oxidative metabolism of granulocytes and monocytes
stimulated with formyl-Methionyl-Leucyl-Phenylalanine
(fMLP), PMA and E. coli was increased [27].
In a very recent investigation, the same β-glucan
preparation from Spent Brewers’Yeast was, for 42 days,
fed to dogs suffering from Inflammatory Bowel Disease
(IBD) [35]. Within this time, the animals treated with
β-glucan showed a significant improvement, measured
by the Canine Inflammatory Bowel Disease Acitivity
Index (CIBDAI). They further showed a decreased level
of the pro-inflammatory IL-6 and an increase of the
anti-inflammatory IL-10, as compared to untreated
control animals [35].
From these experiments (see Table 1), it may be con-
cluded that orally applied insoluble yeast β-glucans are
able to strengthen a weakened immune system.
Clinical trials performed with the proprietary yeast β-glucan
Susceptibility to common cold is related to a weak im-
mune status or a weak defense system. In the early
1990s, Cohen and colleagues demonstrated that the im-
mune status of people with a high susceptibility to com-
mon colds is affected by lifestyle factors such as stress,
emotional imbalance, mood, specific vitamin deficien-
cies, or exposure to wet conditions and low tempera-
tures, and that the susceptibility is correlated to the
occurrence of cold infections [36,37]. In contrast, a
lower susceptibility to cold episodes reflects an improved
defense against infections and, hence, a properly func-
tioning immune system. Therefore, common cold is
widely used as a proper model to investigate potential
immune-modulating properties of natural substances,
including β-glucans.
Two independent randomized, double-blind, placebo-
controlled clinical trials showed that daily oral adminis-
tration of the proprietary insoluble (1,3)-(1,6)-β-glucan,
derived from brewers’yeast, reduced the incidence of
common cold episodes during the cold season in other-
wise healthy subjects [38,39] (see Table 2).
In the trial conducted by Graubaum et al. [39], 100
subjects received either the yeast-derived β-glucan
preparation (900 mg/day) or a placebo over a period of
26 weeks. Results showed that, compared to placebo,
more subjects in the intervention group did not have a
common cold infection at all. The β-glucan group had
significantly more subjects without a common cold epi-
sode than the placebo group. During the most intense in-
fection season, the β-glucan group had significantly less
infections compared to placebo. Ingestion of β-glucans
significantly reduced the typical cold symptoms [39].
The second trial with 162 participants confirmed these
results, as the number of cold episodes was reduced by
25% in the β-glucan group, compared to the placebo
group (p = 0.041) [38]. Moreover, the authors reported a
milder progression of severe common cold episodes in
subjects supplemented with β-glucans. Also, sleeping diffi-
culties, regarded as a side effect of a cold infection, were
improved by the supplementation of β-glucan (p = 0.028).
The results of the common cold studies in healthy
adults showed the immune-stimulating effects of the
same brewers’yeast β-glucan preparation. As an immu-
nomodulator, however, β-glucans are also able to induce
anti-inflammatory abilities. Kohl et al. [40] showed an
anti-inflammatory action of the same β-glucan prepar-
ation in overweight and obese subjects. Obesity is often
associated with inflammatory conditions that lead to an
activation of the innate immune system. Long-term acti-
vation of the immune system may cause several other
health related problems, including insulin resistance [40]
(see Table 2). Indeed, yeast β-glucan consumption had
an impact on immune function, as shown by an increase
of both circulating levels and adipose tissue messenger
RNA (mRNA) expression of the anti-inflammatory cyto-
kine IL-10. Insulin sensitivity as well as circulating levels
and mRNA expression of pro-inflammatory cytokines
were, however, unaffected. The results indicate that
intake of particulated yeast β-glucans also has anti-
inflammatory properties.
These studies provide evidence on the potential
immunmodulatory effects of yeast β-glucans: On one
hand, the substances elicit/amplify (activate) the immune
reaction as shown in the prevention of infections; on the
other hand, they are capable of reducing the inflamma-
tory reaction by inducing anti-inflammatory processes.
The clinical findings confirmed the previous results of
the in vivo investigations performed with Yestimun® in-
vestigating the immunomodulatory effect (see Table 1).
Altogether, these in vivo studies, together with the hu-
man clinical trials, provide evidence on the substantial
biological relevance of the β-glucan preparation Yesti-
mun® on the immune system.
Clinical trials with other dietary yeast β-glucans
A search for other placebo-controlled human trials per-
formed with β-glucans derived from yeast (Saccharomyces)
Stier et al. Nutrition Journal 2014, 13:38 Page 4 of 9
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in the field of respiratory tract infection or common cold
was performed in PubMed database. The main search
terms were “controlled clinical trial”AND, “common cold
OR respiratory tract infection”in combination with “β-glu-
can AND yeast”. Apart from the clinical trials performed
with Yestimun®, we found nine other studies that fit our
search criteria [22,41-48]. The publications by Babineau
et al. [21] and Dellinger et al. [41] will not be discussed fur-
ther, since the β-glucans were applied intravenously and
not orally, to a group of high-risk surgical patients.
The following human studies were all performed with
the same insoluble bakers’yeast β-glucan preparation
Wellmun WGP® (relative% of 1,6 linkage: 10%-18%; H-
NMR analysis according to FCC VII, 3rd suppl.; purity:
minimum of 75% of dry matter). In one intervention,
healthy community-dwelling subjects (n = 40) received
either an insoluble β-glucan preparation (500 mg/day) or
placebo. Intake of β-glucans did not result in any signifi-
cant difference in incidences of respiratory infections.
Even though the number of infections was not different,
none of the subjects supplemented with β-glucans
missed school or work due to colds as opposed to pla-
cebo [42].
Similar results were obtained when healthy individuals
(n = 79) received either 250 mg/day β-glucans or placebo
over a period of 90 days during the peak upper respira-
tory tract infection (URTI) season. Even though there
was no statistically significant difference in the total
Table 1 In vivo studies performed with the proprietary yeast β-glucan preparation Yestimun
®
Title/reference Study design/duration/dosage Main results
Effect of β-1,3/1,6-D-glucan on the phagocytic
activity and oxidative metabolism of peripheral
blood granulocytes and monocytes in rats [34]
20 adult rats were fed for 14 days with either
12–19 mg/rat/day β-1,3/1,6-D-glucan
(Biolex-Beta HP*) or control diet
Arterial blood was analyzed for phagocytic activity
and oxidative metabolism in blood granulocytes
and monocytes:
•significant higher phagocytic activity and a
significant higher percentage of phagocytic cells
in granulocytes and monocytes of β-glucan fed
animal
•positive effects on the oxidative metabolism of
these cell types
•monocytes stimulated by E. coli showed
significantly higher oxidative metabolism in
the β-glucan group
Effect of Biolex β-HP on selected parameters
of specific and non-specific humoral and
cellular immunity in rats [28]
20 adult rats were fed for 14 days with
either 12–19 mg/rat/day β-1,3/1,6-D-glucan
(Biolex-Beta HP*) or control diet
Orally applied insoluble β-glucans are able to
increase non-specific humoral immune
parameters in rats:
•lysozyme and ceruloplasmin activities and serum
gamma-globulin levels were significant higher
•significant higher respiratory burst activity and
potential killing activity of blood phagocytic cells
•significant higher proliferation rate of blood
lymphocytes when stimulated by ConA or LPS
Effect of Biolex Beta-HP on phagocytic activity
and oxidative metabolism of peripheral blood
granulocytes and monocytes in rats intoxicated
by cyclophosphamide [27]
10 adult rats (control) and 10 rats treated with
cyclophosphamide were fed for 14 days with
β-(1,3)-(1,6)-D-glucan (Biolex-Beta HP*) at a dose
of 50 mg/kg body weight/day or control diet
Under the condition of an experimentally
suppressed immune system (treatment with
cyclophosphamide), feeding with β-glucan led to:
•increase of percentage of phagocytic monocytes
and granulocytes
•improvement of phagocytic activity of
monocytes and granulocytes
•a high level of oxidative metabolism of
granulocytes and monocytes stimulated with
fMLP, PMA and E. coli
The effectiveness of natural and synthetic
immunomodulators in the treatment of
inflammatory bowel disease in dogs [35]
28 dogs with IBD were treated for 42 days with Feeding with β-glucan led to:
I) β-(1,3)-(1,6)-D-glucan (Biolex-Beta HP*) at a
dose of 7 mg/kg body weight/day
•decrease of the IBD symptoms measured by IBD
Activity Index
II) β-hydroxy- β-metyl butyrate 30 mg/kg
bw/day
•decrease of the pro-inflammatory interleukin IL-6
III) levamisol 2 mg/kg bw/day •increase of the anti-inflammatory interleukin IL-10
IV) control, without supplementation
*Yestimun® was previously called Biolex-Beta HP.
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number of days with reported URTIs (β-glucans
198 days in 4.6%, versus 241 days in 5.5% in the control
group, p = 0.06), the symptoms tended to be lesser in
the β-glucan group. Of all assessed symptoms, only the
item “ability to breathe easily”was significantly better
in the β-glucan group than in the placebo group [47].
The ability to minimize post-exercise-induced immune
suppression was measured in physically active subjects
(n = 60), who consumed either 250 mg insoluble β-glucans
or placebo (rice flour; cross-over design) for 10 days (pre-
exercise supplementation period) before a bout of cycling.
Blood analysis showed that ingestion of β-glucans signifi-
cantly increases the total number of monocytes as well as
of pro-inflammatory monocytes (p < 0.05). Further ex vivo
LPS stimulation significantly increased plasma cytokine
production of IL-2, Il-4, IL-5, and interferon-gamma [46].
These ex vivo results confirmed the results obtained
from marathon runners (n = 75), who randomly received
either 250 or 500 mg/day β-glucan or a placebo over
four weeks post-marathon [43]. Particulate β-glucans
significantly reduced URTI symptoms compared to pla-
cebo (p < 0.05). The number of URTI after four weeks
post-marathon in both β-glucan groups was reported to
be only 8% compared to 24% in the placebo group (not
significant).
Long-term stress is another factor known to weaken
the immune system. When stressed women (n = 77) took
insoluble bakers’yeast β-glucan before breakfast for
12 weeks, they reported fewer upper respiratory tract
symptoms compared to placebo (p < 0.05) and a better
overall well-being (p < 0.05) [48]. Similar results have been
obtained in moderate to highly stressed subjects (n = 150;
placebo n = 50; 250 mg β-glucan/day n = 50; 500 mg
β-glucan/day n = 50) [44] as well as healthy stressed
subjects (screened for moderate level of psychological
stress n = 122) [45]. Once again, the subjects reported sig-
nificantly fewer URTI symptoms and improved well-being
(p < 0.05).
Although most of the trials mentioned above were
underpowered and the differences in number of infections
were not always significant compared to placebo, all are in
support of the positive effects of insoluble β-glucans on
the human immune system. The differences in the studies
conducted with different β-glucan preparations may be
explained by varying study conditions, sample size, study
populations, applied dosages, and the different sources or
Table 2 In vivo studies performed with the proprietary yeast β-glucan preparation Yestimun
®
Title/reference Study design/duration/dosage Main results
Increased interleukin-10 but unchanged
insulin sensitivity after 4 weeks of
(1, 3)(1, 6)-beta-glucan consumption
in overweight humans [40]
Randomized, double-blind, placebo-controlled,
crossover study;
In overweight or obese subject the orally applied
β-glucan leads to the following results:
12 healthy overweight and obese subjects
3 × 0.5 g of (1,3)(1,6)-D-glucan (Biolex-Beta
HP*) or placebo per day 2 × 4 weeks
•significant increase of both circulating levels and
adipose tissue messenger RNA (mRNA) expression
of the anti-inflammatory cytokine IL-10
•insulin sensitivity was unaffected
•no increase in non specific proinflammatory
markers CRP, IL-6 and MCP-1/CCL-2
•circulating levels and mRNA expression of
proinflammatory cytokines were unaffected
A double-blind, randomized, placebo-controlled
nutritional study using an insoluble yeast
beta-glucan to improve the immune defense
system [39]
Randomized, double-blind, placebo-controlled
clinical trial;
Supplementation with 1,3/1,6-D-glucan led
compared to placebo to:
100 healthy adults with recurring common
colds received 1,3/1,6-D-glucan (Yestimun®)
900 mg/day or a placebo for 26 weeks
•significant more subjects without incidences of
common cold
•significant less infections during the most intense
infection season
•significant reduction of the typical cold symptoms:
“sore throat and/or difficulty swallowing”,
“hoarseness and/or cough”and “runny nose”
Yeast (1,3)-(1,6)-beta-glucan helps to maintain
the body’s defense against pathogens: a
double-blind, randomized, placebo-controlled,
multicentric study in healthy subjects [38]
Randomized, double-blind, placebo-controlled
clinical trial;
Supplementation with 1,3/1,6-D-glucan led
compared to placebo to:
162 healthy adults with recurring common
colds received 1,3/1,6-D-glucan (Yestimun®)
900 mg/day or a placebo for 16 weeks
•a significant reduced number (by 25%) of
common cold infections in the per protocol
population
•a 15% lowered mean symptom score
•significant reduced sleep difficulties usually
caused by common cold episodes
*Yestimun® was previously called Biolex-Beta HP.
Stier et al. Nutrition Journal 2014, 13:38 Page 6 of 9
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isolation methods of β-glucan from brewers’yeast or
bakers’yeast.
These clinical trials were all performed with insoluble
yeast β-glucans. Only one human clinical trial investigat-
ing the immune effect of dietary soluble yeast β-glucans
has been found [49]. In that pilot trial, dietary intake of
soluble β-glucans leads to an increase in salvia IgA
concentration. Based on this pilot trial it is not pos-
sible to come to a final conclusion that also soluble
yeast β-glucans, when applied orally, are able to
strengthen the immune system the way it was shown
for the insoluble yeast β-glucan fraction.
Even though many of the clinical trials performed with
insoluble β-glucan preparations showed positive effects
on the immune system, none of them were so far able to
convince the European Food Safety Authority (EFSA) to
accept a health claim application in the area immune
system. EFSA rejected all generic claim applications
(13.1 claims) regarding beta-glucan and immune func-
tion. Also, the two product-specific 13.5 health claims
submitted for the product Yestimun® were rejected
[50,51]. The Panel concluded that a cause and effect re-
lationship has not been established. The major reasons
for rejection in those cases were the use of a non-
validated questionnaire on common cold as well as limi-
tations of the statistical analysis. However, EFSA has not
granted any of the applications for product-specific 13.5
health claims on immune function. Only generic 13.1
claims for vitamins and minerals have been accepted
[52,53]. These numerous rejections indicate the very
high benchmark demanded by EFSA for claim substanti-
ation on immune function.
Safety
Brewers’and bakers’yeast (S. cerevisiae) has a long his-
tory of safe consumption. It has been used for over a
thousand of years in the production of bread, wine, and
beer. Although allergies to S. cerevisiae from food con-
sumption might occur [54], they are rare. In general,
yeast products are very well tolerated. However, no stud-
ies addressing the beneficial as well as adverse effects
due to long-term intake of β-glucans are available as
yet. In a scientific opinion, the EFSA Panel on Dietetic
Products, Nutrition and Allergies (NDA) considered
“that the allergenic risk of the ‘yeast β-glucans’is not
higher than the risk from other products containing
bakers’yeast. β-glucans from other sources have already
been evaluated for safety by EFSA”[55]. The result of
the EFSA evaluation is, among others, based on the sig-
nificant history of safe use of yeast and on data from
human and animal studies.
In the above-presented human studies with orally ap-
plied yeast β-glucans, no signs of toxicity were reported.
In all these clinical trials, insoluble yeast β-glucans were
very well tolerated. When adverse events occurred, they
were either not associated with the intake of the study
products, or they were comparable to the intake of
placebo.
Single-dose acute and sub-chronic toxicity studies in
rats did not result in toxic effects of insoluble bakers’
yeast (S. cerevisiae) preparations. Single dosages of
2000 mg/kg did not lead to death or clinical abnormal-
ities in any of the tested rats. Also, oral application over
91 days of up to 100 mg/kg body weight did not lead to
adverse or toxic effects in rats [56].
In some publications, insoluble β-glucans are stated to
exhibit undesirable toxicological effects such as hepatos-
plenomegaly and granuloma formation. However, these
adverse reactions were only associated with intravenous
application [57,58]. Such adverse events never have been
reported after oral application.
The safety of β-glucans can also be deduced from the
mode of action. β-glucans do not directly attack the in-
fected cells or the infection causing agents, but instead
modulate the host’s defense mechanism. For example,
macrophages were activated, but only reacted if foreign
cells (bacteria, viruses, parasites) invade the system.
Conclusion
Many investigations on the immunomodulatory effects
of β-glucans were performed using parenteral applica-
tions. In the meantime, those effects have also been
shown for orally applied β-glucans. Therefore immune
stimulating effects may be achieved by dietary intake
of yeast β-glucans. Despite those positive effects the
European Food Safety Authority did not accept health
claim applications of β-glucans in the area immune sys-
tem. Based on several weaknesses regarding study design
and statistical evaluations the panel concluded that a
cause and effect relationship has not been established.
β-glucans from yeast are recognized by immune cells
within the intestinal mucosa, amongst others by the
dectin-1 receptor. Dectin-1 receptor activation induces
several immune-stimulating effects important in the
defense against invading pathogens. Furthermore, follow-
ing uptake of β-glucans via dectin-1-stimulated phagocyt-
osis, degradation processes within macrophages may make
β-glucans systemically available.
However, not all β-glucan preparations have the po-
tential to stimulate these reactions. In order to be able
to activate the dectin-1 receptor cascade, β-glucans must
comply with specific structural properties. It seems that
insoluble, particulate (1,3)-β-glucans with 1,6-β-branches
are able to activate this cascade, while soluble ones acti-
vate the antibody-mediated complement system via the
CR3 receptor.
Clinical trials performed with dietary insoluble par-
ticulate β-glucans have demonstrated positive effects on
Stier et al. Nutrition Journal 2014, 13:38 Page 7 of 9
http://www.nutritionj.com/content/13/1/38
the immune system. Therapeutic efficacy results for or-
ally applied soluble yeast β-glucans are not yet avail-
able. Whether or not the soluble fraction of the yeast
β-glucan, when orally applied, is equally active when in-
fluencing the human immune system needs to be
proven in confirmative clinical trials. So far, this has
only been shown for the insoluble fraction.
All the performed human clinical trials demonstrated
that intake of β-glucans isolated from brewers’yeast is
very well tolerated. Based on the clinical trials presented
in this review, an increased intake of dietary β-glucans
might help to improve immune functions.
Competing interests
This work has been funded by Leiber GmbH (Bramsche, Germany), the
manufacturer of the yeast β-glucan preparation Yestimun®. VE is an
employee of Leiber GmbH; HS and JG are employees of the contract
research organization (CRO) analyze & realize GmbH, and where previously
involved in the publication of two clinical trials with Yestimun®.
Authors’contributions
HS has drafted and written the manuscript. VE and JG have been involved in
drafting the manuscript and revising it critically for important intellectual
content. All authors read and approved the final manuscript.
Authors’information
HS is working as a Scientific Consultant for the CRO analyze & realize GmbH
(Germany); JG is the founder of the CRO analyze & realize GmbH (Germany).
VE is working as a scientist in the technical service of the animal nutrition
department of Leiber GmbH (Bramsche, Germany).
Acknowledgements
We thank I. Wohlfahrt for correction of the manuscript and editing of the
English language.
Author details
1
analyze & realize GmbH, Waldseeweg 6, 13467 Berlin, Germany.
2
Leiber
GmbH, Hafenstraße 24, 49565 Bramsche, Germany.
Received: 11 November 2013 Accepted: 15 April 2014
Published: 28 April 2014
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doi:10.1186/1475-2891-13-38
Cite this article as: Stier et al.:Immune-modulatory effects of dietary
Yeast Beta-1,3/1,6-D-glucan. Nutrition Journal 2014 13:38.
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