Article

Immunologic effect of yogurt

Abstract

Many investigators have studied the therapeutic and preventive effects of yogurt and lactic acid bacteria, which are commonly used in yogurt production, on diseases such as cancer, infection, gastrointestinal disorders, and asthma. Because the immune system is an important contributor to all of these diseases, an immunostimulatory effect of yogurt has been proposed and investigated by using mainly animal models and, occasionally, human subjects. Although the results of these studies, in general, support the notion that yogurt has immunostimulatory effects, problems with study design, lack of appropriate controls, inappropriate route of administration, sole use of in vitro indicators of the immune response, and short duration of most of the studies limit the interpretation of the results and the conclusions drawn from them. Nevertheless, these studies in toto provide a strong rationale for the hypothesis that increased yogurt consumption, particularly in immunocompromised populations such as the elderly, may enhance the immune response, which would in turn increase resistance to immune-related diseases. This hypothesis, however, needs to be substantiated by well-designed randomized, double-blind, placebo-controlled human studies of an adequate duration in which several in vivo and in vitro indexes of peripheral and gut-associated immune response are tested.
ABSTRACT Many investigators have studied the therapeu-
tic and preventive effects of yogurt and lactic acid bacteria,
which are commonly used in yogurt production, on diseases such
as cancer, infection, gastrointestinal disorders, and asthma.
Because the immune system is an important contributor to all of
these diseases, an immunostimulatory effect of yogurt has been
proposed and investigated by using mainly animal models and,
occasionally, human subjects. Although the results of these stud-
ies, in general, support the notion that yogurt has immunostimu-
latory effects, problems with study design, lack of appropriate
controls, inappropriate route of administration, sole use of in
vitro indicators of the immune response, and short duration of
most of the studies limit the interpretation of the results and the
conclusions drawn from them. Nevertheless, these studies in toto
provide a strong rationale for the hypothesis that increased
yogurt consumption, particularly in immunocompromised popu-
lations such as the elderly, may enhance the immune response,
which would in turn increase resistance to immune-related dis-
eases. This hypothesis, however, needs to be substantiated by
well-designed randomized, double-blind, placebo-controlled
human studies of an adequate duration in which several in vivo
and in vitro indexes of peripheral and gut-associated immune
response are tested. Am J Clin Nutr 2000;71:861–72.
KEY WORDS Yogurt, lactic acid bacteria, Lactobacillus,
Bifidobacterium,Enterococcus,Streptococcus,Salmonella,
immunostimulatory effects, immune system, cancer, infection,
gastrointestinal disorders, asthma, review
INTRODUCTION
Yogurt is defined by the Codex Alimentarius of 1992 as a
coagulated milk product that results from fermentation of lactic
acid in milk by Lactobacillus bulgaricus and Streptococcus ther-
mophilus (1). Other lactic acid bacteria (LAB) species can be
combined with L. bulgaricus and S. thermophilus. In the finished
product, the LAB must be alive and in substantial amounts. LAB
have been used for thousands of years to produce fermented food
and milk products. Fermented products contain a variety of fer-
menting microorganisms belonging to various genera and
species, all of which produce lactic acid.
With few exceptions, milk and yogurt have similar vitamin and
mineral compositions. During fermentation, vitamins B-12 and C
are consumed and folic acid is produced. The differences in other
vitamins between milk and yogurt are small and depend on the
strain of bacteria used for fermentation. Although milk and yogurt
have similar mineral compositions, some minerals, eg, calcium,
are more bioavailable from yogurt than from milk. In general,
yogurt also has less lactose and more lactic acid, galactose, pep-
tides, free amino acids, and free fatty acid than does milk (2, 3).
After Metchnikoff (4) postulated that L. bulgaricus suppresses
toxins produced by putrefactive bacteria in human intestines,
many investigators studied the therapeutic effects of LAB. How-
ever, results were inconsistent. Varying reports of the therapeutic
efficacy of LAB may be due to differences in the strains of LAB
and experimental procedures used in the various studies.
Although results obtained from studies in which LAB were
administered parenterally might not be a good predictor of
results of oral consumption of yogurt, both oral and parenteral
administration of LAB, in general, were shown to strengthen
nonspecific immune response or to act as adjuvants in antigen-
specific immune response (5–8).
Most studies indicated that the potential therapeutic effects of
LAB and yogurt, including their immunostimulatory effect, are
due primarily to yogurt-induced changes in the gastrointestinal
(GI) microecology. Increased amounts of LAB in the intestines
can suppress the growth of pathogenic bacteria (9–12), which
contributes in turn to reduced infection (13–15) and heightened
anticarcinogenic effects (5, 16).
The immunostimulatory effect of LAB also depends on the
degree of contact with lymphoid tissues while the bacteria are
transiently colonizing the intestinal lumen (17, 18). Thus, the
ability of LAB to survive in the GI tract can influence the bacte-
ria’s immunogenicity (19–25). The survival rate of LAB in the
GI tract varies with gastric pH (26). Within the Lactobacillus
genus, L. acidophilus is more resistant to gastric juice than is
conventional lactic culture, L. bulgaricus, and is more resistant
Am J Clin Nutr 2000;71:861–72. Printed in USA. © 2000 American Society for Clinical Nutrition
Immunologic effects of yogurt1–4
Simin Nikbin Meydaniand Woel-Kyu Ha
861
1From the Jean Mayer US Department of Agriculture Human Nutrition
Research Center on Aging and the Department of Pathology, Sackler Graduate
School of Biomedical Sciences, Tufts University, Boston, and the Research
and Development Laboratory, Maeil Dairy Industry Co, Ltd, Seoul, Korea.
2Any opinions, findings, conclusions, or recommendations expressed in
this article are those of the authors and do not necessarily reflect the views of
the US Department of Agriculture.
3Supported by the US Department of Agriculture agreement 58-1950-9-001.
4Address reprint requests to SN Meydani, Nutritional Immunology Lab-
oratory, Jean Mayer USDA Human Nutrition Research Center on Aging at
Tufts University, 711 Washington Street, Boston, MA 02111. E-mail:
s_meydani_ im@hnrc.tufts.edu.
Received May 18, 1999.
Accepted for publication December 8, 1999.
Review Article
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than S. thermophilus (20). Of the 4 Bifidobacterium species studied
(B. infantis, B. bifidum, B. adolescentis, and B. longum), B. longum
was the most resistant to gastric acid (27). The LAB that survive the
GI process adhere to epithelial cells in the wall of the GI tract
(28–30) and can bind to the luminal surface of M cells (31). Animal
studies showed that gut-associated lymphoid tissue is stimulated by
these surviving LAB, resulting in enhanced production of cytokine
and antibody [secretory immunoglobulin (sIg) A] and increased
mitogenic activity of Peyer’s patch (PP) cells and splenocytes.
In human studies, cytokine production (6, 32–36), phagocytic
activity (37, 38), antibody production (39), T cell function (36,
40), and natural killer (NK) cell activity (32, 41) were shown to
increase with yogurt consumption or when cells were exposed to
LAB in vitro. There is some evidence that yogurt-induced
immune enhancement is associated with a lowered incidence of
conditions such as cancer, GI disorders, and allergic symptoms.
IMMUNE SYSTEM FUNCTIONS
The main functions of the immune system are to eliminate
invading viruses and foreign microorganisms, to rid the body of
damaged tissue, and to destroy neoplasms in the body. Healthy
humans have 2 immune mechanisms: acquired (specific) immunity,
which responds to specific stimuli (antigens) and is enhanced by
repeated exposure; and innate (nonspecific) immunity, which does
not require stimulation and is not enhanced by repeated exposure.
Innate immune mechanisms consist of physical barriers, such as
mucous membranes, and the phagocytic and cytotoxic function of
neutrophils, monocytes, macrophages, and lymphatic cells (NK
cells). Acquired immunity can be classified into 2 types on the
basis of the components of the immune system that mediate the
response, ie, humoral immunity and cell-mediated immunity.
Humoral immunity is mediated by immunoglobulins produced by
bone marrow–derived lymphocytes (B lymphocytes) and is respon-
sible for specific recognition and elimination of extracellular anti-
gens. Cell-mediated immunity is mediated by cells of the immune
system, particularly thymus-derived lymphocytes (T lymphocytes).
Cell-mediated immunity is responsible for delayed-type hypersen-
sitivity (DTH) reactions, foreign graft rejection, resistance to many
pathogenic microorganisms, and tumor immunosurveillance. In
addition to their involvement in nonspecific immunity, macro-
phages are important in cell-mediated immunity as antigen-pre-
senting cells and through the production of regulatory mediators
such as cytokines and eicosanoids. Several in vitro and in vivo tests
were developed to assess the function of immune cells. Although
the study of immune response in animals and humans is based on
similar principles, the methods used to separate cells, the types of
stimuli used in vitro, and the antigen used for in vivo challenge
vary. In addition, the type of antibody used to measure different
mediators or to determine cell-surface proteins is species specific.
IN VITRO INDEXES OF IMMUNE FUNCTION
To study immune function in vitro, immune cells are first sep-
arated from whole blood, lymphoid tissues, and gut-associated
immune cells. The cells are then maintained and cultured with
and without various immune cell stimuli. To measure the activ-
ity of isolated phagocytes, the cells are incubated with bacteria
or other engulfable materials with or without opsonin for a
limited time and then stained for uptake of foreign bodies. Lym-
phocytes are usually stimulated for varying lengths of time by a
variety of stimuli (mitogens, antigens, and other stimulator or
target cells) for measurement of their proliferative or cytotoxic
activity or release of immunologically active molecules such as
antibodies, cytokines, and eicosanoids.
Phagocytic activity
The ability to perform phagocytosis and kill microbes, including
bacterial pathogens, is a major effector function of macrophages.
These properties of macrophages are particularly important for
host defense against facultative intracellular organisms, which can
replicate within macrophages. The pathogenesis of facultative
intracellular bacteria is determined by their ability to survive within
macrophages. Several organisms were used previously as targets to
determine macrophage killing. These include Staphylococcus
aureus,Escherichia coli, Pseudomonas aeruginosa, Salmonella
typhimurium, Listeria monocytogenes, and Candida albicans.
Bacteria bind to complement components and the bacterium-
complement complexes bind complement receptors on the sur-
face of macrophages. Phagocytosis may also be mediated by
specific antibodies that function as opsonins, which bind to
particles, rendering them susceptible to phagocytosis. The bac-
terium-antibody complex then binds the macrophages via the
Fc receptor and phagocytosis begins.
Measurement of phagocytic activity of macrophages was
among the earliest techniques for evaluating the immunologic
effects of LAB. This assay measures the ability of macrophages
to bind, internalize, and phagocytose bacteria. Monocytes or
macrophages isolated from human peripheral blood mononu-
clear cells (PBMCs) or from the peritoneal cavity of animals are
mixed with bacteria in suspension and incubated at 378C. Extra-
cellular bacteria are then removed through washing and centrifu-
gation or through washing only over sucrose. The degree of
phagocytosis is determined by examining stained cells under oil-
immersion microscopy and quantifying the number of internal-
ized bacteria in each cell. This method takes into account not
only the percentage of phagocytic cells but also the strength of
the phagocytic ability of these cells, ie, how many bacteria are
internalized by each cell (42).
Lymphocyte proliferation assay
Measurement of the proliferative response of lymphocytes is
the most commonly used technique for evaluating cell-mediated
immune response. Quantitative analysis of proliferative response
involves measuring the number of cells in culture in the presence
and absence of a stimulatory agent such as an antigen or a mito-
gen. The most common polyclonal mitogens used to test the
proliferation of lymphocytes are concanavalin A (ConA), phyto-
hemagglutinin, lipopolysaccharide (LPS), and pokeweed mitogen.
T and B lymphocytes are stimulated by different polyclonal mito-
gens. ConA and phytohemagglutinin stimulate T cells, LPS stim-
ulates B cells, and pokeweed mitogen stimulates both T and
B cells. When mitogens are used, prior exposure of the host to the
mitogens is not necessary. However, to measure antigen-specific
proliferation, the host should be exposed to the antigen before the
cells are stimulated with that antigen in vitro. Lymphocytes nor-
mally exist as resting cells in the G0phase of the cell cycle.
When stimulated with polyclonal mitogens, lymphocytes
rapidly enter the G1phase and progress through the cell cycle.
Measuring incorporation of [3H]thymidine into DNA is the most
commonly used method for estimating changes in the number of
cells. The proliferative assay is used to assess the overall
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immunologic competence of lymphocytes, as manifested by the
ability of lymphocytes to respond to proliferation signals.
Decreased proliferation, observed in chronic diseases such as
cancer and HIV infection and in the aging process, may indicate
impaired cell-mediated immune function.
Cytokine production
Cytokines, which are protein mediators produced by immune
cells, are involved in the regulation of cell activation, growth and
differentiation, inflammation, and immunity. Measurement of
cytokine production, as determined by techniques such as bio-
assay, radioimmunoassay, and enzyme-linked immunosorbent
assay, has been used to examine various immune functions.
Details of cytokine measurement were published previously (42).
Interleukin 2 (IL-2) is a T cell growth factor produced by
T helper (TH) 1 and NK cells. As an autocrine and paracrine
growth factor, IL-2 induces proliferation and differentiation of
T and B cells. IL-2 is responsible for the progress of T lympho-
cytes from the G1to the S phase in the cell cycle and also for
stimulation of B cells for antibody synthesis. IL-2 stimulates the
growth of NK cells and enhances the cytolytic function of these
cells, producing lymphokine-activated killer (LAK) cells. IL-2
can also induce interferon (IFN)-gsecretion by NK cells. IFN-g
is an important macrophage-activating lymphokine. IL-2 secreted
in culture media or biological fluids can be measured by
immunoassay or bioassay, the most common of which uses the
IL-2-dependent cytotoxic T lymphocyte line. Proliferation of
cytotoxic T lymphocyte line cells reflects IL-2 activity. IL-2
activity in samples can be calculated according to a standard
curve generated by adding varying concentrations of recombinant
IL-2. Enzyme-linked immunosorbent assay is also used to meas-
ure IL-2. Although this assay is more specific than is the cytotoxic
T lymphocyte line in measuring IL-2 protein concentrations, it
does not differentiate between biologically active and nonactive
proteins. Under most conditions, changes in IL-2 production are
associated with the change in lymphocyte proliferation, although
sometimes these changes do not correlate with one another.
IFN-gis involved in the induction of other cytokines, particu-
larly TH2 cytokines, such as IL-4, IL-5, and IL-10. Because of its
role in mediating macrophages and NK cell activation, IFN-gis
important in host defense against intracellular pathogens (such as
Mycobacterium tuberculosis and L. monocytogenes) and viruses
and against tumors. It was suggested that mice and humans con-
tinuously produce small amounts of IFN (43, 44), which may pro-
duce a state of alertness against tumor cells, pathogenic bacteria,
and viruses (45, 46). Because of the short half-life of IFN-g,
plasma concentrations of IFN-gare low and difficult to measure
(47), potentially making treatment-induced changes in plasma
IFN-gconcentrations difficult to detect (48). IFN-gproduced by
PBMCs or purified T cells has been shown to be more sensitive to
yogurt-induced changes than is plasma IFN-g(6, 32, 35, 36, 49).
In addition to ex vivo production of IFN-g,29-59A synthetase
activity was used as an index of the biological responsiveness of
cells to IFN-g. 29-59A synthetase is an IFN-g-inducible enzyme.
The amount of 29-59A synthetase in different organs of mice
increases severalfold after treatment of mice with IFN or IFN
inducers, such as viral and synthetic double-stranded RNAs.
Cytotoxicity assay
The activity of both cytotoxic T lymphocytes and NK cells can
be assessed by cytotoxicity assay. Cytotoxic T lymphocytes kill tar-
get cells via cell-surface-antigen recognition. NK and LAK cells
directly lyse tumor cells and virus-infected cells. In the cytotoxic
T lymphocyte activity assay, target cells can be lymphoblasts, tis-
sue culture cells, or tumor cells that are labeled with 51Cr and then
incubated with effector cells (stimulated effector cells in cytotoxic
T lymphocyte assay or IL-2-stimulated effector cells in LAK
assay) at different ratios. The percentage of 51Cr released represents
the lysis of target cells, which reflects the cytotoxic activity of
effector cells. Cytotoxic T lymphocytes, NK cells, and LAK cells
are important in the host response to tumors and viral infections.
Flow cytometric analysis
Immune cells bear specific markers (antigens) on their surface
that are used to identify various types of cells (eg, lymphocytes
and macrophages) and cell subpopulations (eg, B and T lympho-
cytes). A population of cells can be classified into subsets
according to the surface markers of the cells. Cell subsets play
various roles in regulating immune response. For example,
T cells can be classified as CD4+or CD8+cells, which are
defined, according to their function, as THcells and suppressor
cells, respectively. Properly identifying cells with different sur-
face markers may be a step toward understanding the cellular
basis of immune response. For flow cytometry, a fluorescence-
activated cell-sorter technology has been used widely to charac-
terize and quantify viable subpopulations of immune cells. Flow
cytometric analysis consists of 3 steps: 1) prepared cells are
incubated with a specific antibody against a particular cell
surface marker and labeled with fluorescent reagents, such as
fluorescein isothiocyanate; 2) the stained cells are processed
(identified and separated) by flow cytometry and appropriate
data are collected; and 3) the collected data are analyzed to
obtain quantitative information on cell subpopulations. Details
of flow cytometry methods were published previously (42).
IN VIVO INDEXES OF IMMUNE FUNCTION
Although immune function is measured predominantly through
in vitro methods, a limited number of in vivo methods are also
available. In vivo methods may include factors not found under in
vitro conditions and thus provide more accurate measurements.
Assessment of phagocytosis
In vivo activation of macrophages is important in suppressing
tumor growth. The method depends mainly on measurement of the
clearance from the circulation of intravenously injected materials
(eg, colloids, bacteria, macromolecules, and opsonized red cells).
Blood samples are collected at designated intervals after the intra-
venous inoculation of a colloidal carbon-particle suspension. After
dissolution of the erythrocytes in blood samples, the contents of
injected materials in blood are measured by optical density.
Studies on the clearance of injected materials from the circu-
lation provide information on the functional state of the macro-
phages in the liver (Kupffer cells), lung, and spleen. However,
blood clearance of particulate matter is affected by factors such
as the blood flow rate, the presence or absence of opsonized fac-
tors, the adhesiveness of particles to vessel walls, and changes in
phagocytic cells in the liver.
Delayed-type hypersensitivity reaction
DTH reaction is used extensively as an in vivo assay to deter-
mine cell-mediated immune function and to assess immuno-
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competence. Several investigators showed that a decrease in DTH
is associated with increased mortality (50–53). DTH is based on
an antigen-specific, T cell-dependent recall response manifested as
an inflammatory reaction that reaches peak intensity <24–48 h
after antigenic challenge. In the DTH skin test, a small amount of
soluble antigen is injected into the epidermis and superficial dermal
tissue. Circulating T cells sensitized to the antigen from prior con-
tact react with the antigen in the skin and induce a specific immune
response, which includes mitosis (blastogenesis) and the release of
soluble mediators. The reaction process involves antigen presenta-
tion by macrophages, release of IL-1 and tumor necrosis factor
(TNF) from activated macrophages, release of IL-2 and IFN-g
from activated T cells, and interaction between these mediators. In
humans and guinea pigs, the intensity of DTH is evaluated by
measuring the redness and induration of an area of shaved skin
exposed to the antigen (54). In humans, DTH to several recall anti-
gens can be measured with multitest cell-mediated immunity (55),
but this method does not work well in mice. An alternative method
was developed in which antigens are injected subcutaneously into
the footpad of a primed mouse (56). After 24 h, footpad swelling
is measured with a caliper.
Antibody production
Immunization with appropriate antigens (viral or bacterial)
can elicit serum antibodies. Particular antigens can produce an
immune response at the mucosal level. Antibody production as a
response to antigen challenge involves several cellular events,
such as antigen processing and presentation, recognition of the
presented antigen by TH1 cells, and TH1 cell activation and pro-
duction of cytokines that augment the response of memory
B cells. Therefore, the qualitative and quantitative assays for
antibodies provide information about B cell responsiveness and
T cell cooperation. Antibody response to a particular antigen,
including vaccines and innocuous bacteria such as LAB, has been
used as an index in evaluating the host resistance to infections.
YOGURT COMPONENTS WITH POTENTIAL
IMMUNOSTIMULATORY EFFECTS
Although yogurt has long been known to bolster host-defense
mechanisms against invading pathogens, the components respon-
sible for these effects have not been fully defined (57, 58). The
immunostimulatory effects of yogurt are believed to be due to
yogurt’s bacterial components. However, the mechanism or
mechanisms responsible for these effects have not been fully
determined (57, 59). After entering the intestine, live or biologi-
cally active LAB particles may activate specific and nonspecific
immune responses of gut-associated lymphoid tissue and the
systemic immune response. The immunogenicity of intestinal
bacteria depends on the degree of contact with lymphoid tissue
in the intestinal lumen (17, 18). Therefore, dead bacteria are gen-
erally less efficient as antigens than are live bacteria because
dead bacteria are rapidly dislodged from the mucosa (31, 60).
Some studies, however, showed no difference in immunogenic-
ity between viable and nonviable bacteria (61).
LAB are gram-positive bacteria with cell wall components
such as peptidoglycan, polysaccharide, and teichoic acid, all of
which have been shown to have immunostimulatory properties
(62). In addition to cell wall components, immunostimulatory
effects were observed with antigens originated from the cyto-
plasms of some strains of LAB.
Nonbacterial milk components and components produced
from milk fermentation also may contribute to the immunostim-
ulatory activity of yogurt. Peptides and free fatty acids generated
by fermentation have been shown to enhance the immune
response. Milk components such as whey protein, calcium, and
certain vitamin and trace elements also can influence the
immune system (62).
Bacterial components
The LAB most commonly used to ferment milk are L. bulgar-
icus and S. thermophilus. To increase LAB’s survival rate and
resistance to low pH and bile acid in the GI tract, LAB indige-
nous to the human intestine, including L. acidophilus, Lacto-
bacillus casei, and Bifidobacterium species, are now being used
in yogurt production.
Yogurt consumption and oral administration of LAB were
shown to stimulate the host immune system. It is believed that
LAB are essential for yogurt to exert immunostimulatory effects
and that the LAB cell walls contain the main immunomodulatory
component (63). The LAB cell wall is composed mainly of pep-
tidoglycan (30–70% of the total cell wall), polysaccharide, and
teichoic acid. Peptidoglycans are glycopeptides released from
the bacterial cell wall by bacteriolytic enzymes, such as
lysozyme. Lysozyme, which is secreted into the intestine from
paneth cells (64), can release peptidoglycan and muramyl dipep-
tide (MDP), a lower-molecular-weight product of peptidoglycan.
Peptidoglycans are known to have adjuvant effects on immune
response (65–67). Binding sites for peptidoglycans were identi-
fied on lymphocytes and macrophages (68). LAB, which are
very sensitive to lysozyme digestion, may liberate peptidoglycan
in the intestine and induce adjuvant activity at the mucosal sur-
face (39). Bogdanov et al (69) reported that the immunostimula-
tory activity in the host by cultured dairy products is mediated by
glycopeptides in the bacterial cell wall.
MDP is a main constituent of peptidoglycan in the cell wall of
pathogenic and nonpathogenic bacteria such as LAB. MDP stim-
ulates macrophages to release IL-1, which is needed for activa-
tion of T lymphocytes (70–72) and induces IFN-gproduction by
lymphocytes (73). Tufano et al (73) showed that MDP stimulates
the production of IL-1, IL-6, and TNF-aby monocytes as well
as that of IL-4 and IFN-gby lymphocytes. Aattouri and Lemon-
nier (36) showed that MDP in vitro increased IFN-gproduction,
an effect that was diminished in the presence of anti-CD4 (which
depletes CD4+T cells) or when monocytes were depleted. This
indicates that MDP might stimulate PBMCs to produce IFN-g
through a CD4–T cell antigen receptor–human leukocyte antigen
complex and that MDP might be a component of the bacterial
cell wall, which is recognized by monocytes and presented to
CD4+lymphocytes in the context of human leukocyte antigen.
Also, enzymatic digestion of the LAB cell wall was shown to
increase nonspecific host immunity to L. monocytogenes in mice
(74), to Klebsiella infection (75), and to tumor cells (76) and to
increase cytokine production by human PBMCs (36, 77), PP
lymphocyte proliferative activity (62), and DTH and antibody
titer to hepatitis B in guinea pigs (78). Sato et al (79) reported
that the enhancement of host-defense activity by L. casei against
L. monocytogenes infection in mice may be attributed to the cell
wall components of L. casei, one of which is peptidoglycan.
Other cell-wall components contribute to the immunostimulatory
activity of LAB. Teichoic acids stimulate the production of IL-1,
TNF-a, and IL-6 by monocytes in vitro (73, 80–83).
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The cytoplasmic component of LAB was also shown to
increase the proliferative response of PP cells in a strain-depen-
dent manner. Rangavajhyala et al (84) reported that the non-
lipopolysaccharide (enterotoxin) component of L. acidophilus
(strain DDS-1, La1) stimulates the production of IL-1aand
TNF-aby mouse macrophages in vitro. Cell-free water-soluble
extract of L. acidophilus and B. longum was found to stimulate
phagocytic activity in an in vitro murine macrophage system
(61). Thus, although many studies showed that peptidoglycan in
the cell wall stimulates macrophages, antibody formation, and
T lymphocyte activity, other bacterial components may exert
some immunoenhancing effects.
The immunogenicity of LAB differs depending on the prop-
erties of a particular strain rather than on the common charac-
teristics of the species (85). LAB’s exact structural attributes,
however, have not been fully determined. The immunogenicity
of LAB depends on the bacteria’s survival in the GI tract, resis-
tance to gastric acid and bile acid, and ability to adhere to the
mucosal surface (37).
Nonbacterial components
Although yogurt, like milk, is a rich source of protein,
riboflavin, folic acid, and calcium, compositional changes occur as
milk is converted into yogurt. These changes include a decrease in
lactose and vitamins B-6 and B-12 and an increase in peptide, free
amino acid, free fatty acid, folic acid, and choline contents. Yogurt
contains calcium lactate whereas milk contains calcium caseinate.
In addition to changes in nutrient and nonnutrient contents, other
functional components are generated during fermentation.
Because proteases from microorganisms hydrolyze milk pro-
teins more randomly than do intestinal proteases, bacterial pro-
teases are not substrate specific. During fermentation of milk
by LAB, the physicochemical state of milk proteins changes,
causing significant amounts of free amino acids and peptides to
be produced.
Proteolysis was shown to affect the phagocytic capabilities of
macrophages (86). A more proteolytically hydrolyzed milk
resulted in increased stimulation of phagocytosis from the pul-
monary alveolar macrophages in mice (86). Therefore, peptides
produced from the fermentation of milk may also contribute to
the immunoenhancing effect of yogurt. Parker et al (87) identi-
fied a hexapeptide, isolated from casein after enzymatic diges-
tion, which, when intravenously injected into mice (5-wk-old
females), improved resistance to K. pneumonia. In vitro, this
hexapeptide stimulated the phagocytosis of sheep red blood cells
by peritoneal macrophages of mice (87). In addition, these
bioactive peptides might stimulate the proliferation and matura-
tion of T cells and NK cells for the defense of the host against a
wide range of bacteria, particularly enteric bacteria (88).
Denatured and native whey protein, both of which have
remarkably higher cysteine contents than do other common edi-
ble proteins, may contribute to the immunostimulatory effects of
yogurt. Cysteine is a rate-limiting component in the biosynthesis
of glutathione (89). Glutathione is important for detoxification
of endogenous and exogenous carcinogen and free radicals and
in regulation of immune function. Depletion of cellular glu-
tathione was reported to suppress mitogenic response of lym-
phocytes (90–93), to prevent lymphocytes from entering the
S phase in the cell cycle (94), and to decrease antibody-depen-
dent cellular cytotoxicity and spontaneous cell-mediated cyto-
toxicity (95, 96) and IL-2 induced LAK activity (97).
McIntosh et al (98) showed that rats fed whey protein had
higher liver glutathione concentrations than did rats fed a control
diet. Bounous et al (99) showed that feeding whey protein con-
centrate to 3 HIV-positive persons for 3 mo significantly
increased PBMC glutathione concentrations and body weights.
Wong and Watson (100) showed that bovine whey protein
increased antibody response to ovalbumin and DTH and prolif-
erative response of splenocytes to T cell mitogen ConA in young
BALB/c mice. Several studies showed that whey protein
decreased the incidence of infections (101) and neoplastic dis-
eases (98, 102) and increased longevity (103).
Biochemical changes in milk fat may also occur during milk fer-
mentation. Milk contains conjugated linoleic acid (CLA), a fatty
acid with immunostimulatory and anticarcinogenic properties.
CLA was discovered in meat products from ruminant animals, eg,
cows and sheep, and in dairy products. Rumen bacteria can convert
linoleic acid to CLA through biohydrogenation. It was speculated
that biohydrogenation may occur during the fermentation of milk
and that some new free fatty acids are formed after fermentation,
depending on the origin of the milk and the bacterial strain (2, 104).
Rao and Reddy (105) reported an increase in concentrations of free
stearic and oleic acid after the fermentation of cow milk by L. bul-
garicus or S. thermophilus, which they attributed mostly to partial
saturation of the linoleic acid. Shantha et al (106) reported that
yogurt had a higher CLA content than did the milk from which it
was processed. Fermented dahi (the Indian equivalent of yogurt)
has a higher CLA content than does nonfermented dahi (107).
Milk fermentation results in a complete solubilization of cal-
cium, magnesium, and phosphorus and a partial solubilization of
trace minerals (108). Therefore, milk fermentation may exert
some effect on mineral bioavailability. Calcium and phosphorus
were shown to be more bioavailable in yogurt than in milk (109).
Long-term yogurt consumption was shown to be associated with
a significant increase in serum ionized calcium (35). Calcium
was shown to enhance immune function, including lectin bind-
ing by lymphocytes (110), IL-2 production (111), and lympho-
cyte tumor cytotoxicity (112).
Ayebo et al (113) reported that the dialysate and the anion
exchange fraction of yogurt showed significant inhibitory action
against tumors in a mouse assay in vivo and suggested that
increased antitumor or anticarcinogenic activity might be due to
the enhancement of nonspecific immunity in the host. Biffi et al
(114) suggested that soluble compounds produced by LAB dur-
ing milk fermentation can be used to prevent GI disorders and
cancer. Perdigon et al (115) reported that the supernate of fer-
mented milk cultured with L. casei and L. acidophilus increased
the immune response independent of the presence of lactobacilli.
De Simone et al (32) reported that filtered yogurt, which is free
of microorganisms, increased IFN-gproduction and NK activity
of human peripheral blood lymphocytes.
These studies strengthen the notion that components of yogurt
other than bacteria also may contribute to yogurt’s immunostim-
ulatory effect. In addition, yogurt is a nutrient-dense food con-
taining high-quality protein; vitamins, especially folic acid; and
trace elements, all of which are necessary for maintaining opti-
mal immune response.
YOGURT AND IMMUNE FUNCTION
Fermented milk containing viable LAB is known to be
beneficial to health, acting as prophylaxis against intestinal
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infections (13, 15) and as an anticarcinogen (69, 116–120). In
light of this, many investigators have evaluated the effect of
yogurt on the immune responses of animals and humans.
Animal studies
Macrophages represent one of the first lines of nonspecific
defense against bacterial invasion and tumors. Macrophages kill
bacteria and tumor cells through several effector mechanisms,
including the production of soluble factors such as nitric oxide,
hydrogen peroxide, and superoxide (121–123). Macrophages can
also use receptor-mediated attachments to kill tumor cells
through direct cell-to-cell contact. The Fcgreceptor of immuno-
globulin on macrophages enables these cells to attach to
opsonized (IgG coated) tumor cells, thereby mediating tumor
cell cytotoxicity (124). During activation, macrophages acquire
the capacity to bind unopsonized tumor cells as well (125).
Macrophage responses to bacteria and bacterial products are
processed by a mechanism similar to that of tumoricidal activity
(126). It was suggested that the antitumor effect of LAB is due
to enhancement of macrophage activity (115, 120, 127, 128).
A limited number of animal studies were conducted on the
effect of yogurt on macrophages. Goulet et al (129) found that
phagocytic activity of alveolar macrophages was significantly
(P < 0.05) higher in mice fed milk fermented with B. longum,
L. acidophilus, L. casei rhamnosus, or Lactobacillus helveticus
than in control mice fed ultrahigh-temperature-treated milk. How-
ever, no significant stimulation of phagocytic activity was
observed with streptococci-fermented milk (129). Perdigon et al
(130) showed that feeding milk (100 mg protein/d) fermented with
L. casei, L. acidophilus, or both for 8 d increased the in vitro and
in vivo phagocytic activity of peritoneal macrophages and anti-
body production against sheep red blood cells in Swiss mice. The
activation of the immune system began on the third day, peaked on
the fifth day, and decreased on the eighth day of feeding. However,
a further increase in immune response was observed in mice given
a dose of fermented milk (100 mg) on the 11th day of feeding.
Other studies in which reconstituted lyophilized LAB were
administered orally or intraperitoneally showed enhancement of
macrophage activation by LAB (74, 115, 120, 131). Kitazawa et al
(132) reported that L. acidophilus induced production of IFN-a
and IFN-bin murine peritoneal macrophage cell culture.
If an antigen overcomes the nonspecific host-defense system,
both the humoral and the cell-mediated immune responses are
activated. Orally administered LAB may pass through the GI
lumen to reach the local lymphatic organs in the gut. Subse-
quently, translocation of LAB can lead to the activation of the
local immune system in the gut, which results, in turn, in
mucosal antibody production, especially of sIgA from PP cells
(39, 133, 134). Generally, sIgA is induced very poorly after
intramuscular or subcutaneous immunization but can be induced
vigorously by oral immunization (135). SIgA inhibits coloniza-
tion of pathogenic microorganisms (enteric infection) and pene-
tration of dangerous luminal antigens.
Perdigon et al (134) reported that orally administered LAB
(L. acidophilus and L. casei) and yogurt feeding increased sIgA
production and the number of sIgA-producing cells in the small
intestine of mice in a dose-dependent manner. Puri et al (58)
reported that serum IgA concentrations in yogurt-fed mice were
significantly higher than concentrations in milk-fed mice after
salmonella challenge. These investigators proposed that the IgA
secreted by the intestinal B cell enters the circulation and raises
the serum IgA concentration. Takahashi et al (62) reported signi-
ficantly (P < 0.01) greater specific IgG and IgA to LAB cyto-
plasm (B. longum) and cell wall (L. acidophilus) in mice fed
LAB than in mice not fed LAB.
As with yogurt, orally fed L. casei was shown to increase sIgA
secretion into the intestinal lumen. Perdigon et al (133) proposed
that the increase in sIgA concentration is due to the stimulation of
PP cells by LAB and a change in the ratios of CD4+T lympho-
cytes (helper cells) to CD8+T lymphocytes (suppressor cells).
De Simone et al (136) reported that mice fed live LAB (L. bul-
garicus and S. thermophilus)-containing yogurt for 7 and 14 d
had a higher percentage of B lymphocytes (P < 0.01) in the PP
cells than did mice fed a control diet supplemented with cow
milk. In addition, blastogenic response to phytohemagglutinin
and LPS of PP cells from animals fed live LAB (L. bulgaricus
and S. thermophilus)-containing yogurt for 14 or 21 d was signi-
ficantly higher than that of the control group. In a similar exper-
iment, Puri et al (58) showed that intestinal lymphocytes from
mice fed live LAB-containing yogurt had a higher proliferative
response to ConA and LPS than did mice fed milk after a chal-
lenge with S. typhimurium.
De Simone et al (137) studied the influence of a yogurt-sup-
plemented diet on the immunocompetence and survival of ani-
mals subsequently infected with S. typhimurium. Their results
suggested that feeding a diet supplemented with yogurt contain-
ing live LAB for 4 wk increases the rate of survival of young
mice against S. typhimurium infection. These authors attributed
the effect to the ability of live LAB to enhance local and sys-
temic immune response. Interestingly, yogurt supplemented with
heat-killed bacteria was not effective (137). Puri et al (59) stud-
ied the proliferative response of splenic lymphocytes to 3 mito-
gens (ConA, phytohemagglutinin, and LPS). These researchers
reported that the mitogenic response to ConA and phytohemag-
glutinin was significantly higher in mice fed a yogurt diet than in
mice fed a milk diet but that no significant difference was
observed in response to LPS (59).
Muscettola et al (31) showed that in vitro production of IFN-g
from spleen cells of young (aged 7 wk) and old (aged 19 mo) mice
fed live LAB (L. bulgaricus and S. thermophilus) was higher than
that of control mice. They reported that a diet supplemented with
lactobacilli for 7 and 15 d significantly (P < 0.001) increased
IFN-aand IFN-gproduction in young mice and reduced the
cytokine levels in aged mice to less than those in the young mice.
It was suggested that the immunostimulatory function seen
with oral administration of LAB is partially mediated by
increased secretion of IFN-gfrom PP cells in gut-associated
lymphoid tissue. IFN-gwas shown to enhance expression of the
secretory component, thus playing an important role in increas-
ing external transport of dimeric IgA (49). Solis-Pereyra et al
(49) showed that L. bulgaricus and S. thermophilus induced
plasma IFN-aand IFN-bproduction in mice.
Human studies
Human studies examining the immunostimulatory effects of
LAB focused primarily on the effect of yogurt consumption on ex
vivo indicators of immune response, such as PBMC cytokine pro-
duction (6, 32–36, 48, 138, 139), phagocytic activity (37, 38),
specific humoral immune response (39, 140, 141), T lymphocyte
(CD4+and CD8+) function (36, 40), and NK cell activity (32, 41).
It was shown that phagocytic leukocyte activity of human
blood cells, particularly granulocytes, was enhanced by the
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ingestion of fermented milk supplemented with L. acidophilus
La1 and B. bifidum Bb12 for 3 wk (37, 38). Consumption by
healthy humans of fermented milk containing L. bulgaricus and
S. thermophilus was reported to stimulate cytokine production of
PBMCs. De Simone et al (32) reported that lymphocytes cul-
tured with L. bulgaricus and S. thermophilus produced more
IFN-gwhen stimulated with ConA than did control cultures.
L. bulgaricus was more effective than was S. thermophilus in
enhancing IFN-gproduction. Increased production of IFN-gby
isolated T lymphocytes in young adults (aged 20–40 y) consum-
ing yogurt containing live L. bulgaricus and S. thermophilus
(450 g/d for 4 mo) was reported (35). Long-term consumption of
yogurt containing viable LAB was shown to increase IL-1b,
IL-6, IL-10, IFN-g, and TNF-aproduction (6, 34–36, 49).
Contrary to the results of in vitro studies on cytokine release,
yogurt consumption does not appear to affect plasma concen-
trations of IFN-g. Trapp et al (48) reported that consuming 200 g
yogurt/d for 1 y had no effect on plasma IFN-gconcentrations.
IFN-ghas a very short half-life in plasma and is secreted
locally in low amounts (47). Thus, using plasma IFN-gcon-
centrations to detect the effect of yogurt on IFN-gproduction
may not be appropriate. Solis-Pereyra and Lemonnier (33)
suggested that 29-59A synthetase (an IFN-g-inducible protein)
be assayed instead of assaying for IFN-gitself and showed
that subjects consuming yogurt had higher plasma concentra-
tions of 29-59A synthetase than did subjects consuming milk.
These authors also reported a transient increase in plasma
IFN-gconcentrations. Link-Amster et al (39) showed that the
S. typhimurium-specific anti-IgA titer was 4 times higher in
subjects fed fermented milk containing L. acidophilus than in
subjects fed diets without fermented milk (P < 0.04).
In summary, the results of animal and human studies indicate
that yogurt consumption can stimulate certain in vitro indexes
of immune response, such as cytokine production, macrophage
activity, and lymphocyte mitogenic response. However, very
few studies have investigated the effects of yogurt consumption
on in vivo indexes of immune response. Furthermore, most of the
studies lacked appropriate control groups and used short-term
feeding protocols, which might induce a transient adjuvant effect
rather than long-term stimulation of the immune response.
YOGURT AND IMMUNE-RELATED DISEASE
The health benefits of yogurt are due primarily to the ability
of LAB to survive in the human GI tract. LAB commonly used
for yogurt production were shown to survive in the stomach and
were found in the feces (19, 20, 142), although survival rates are
not known for all strains of LAB. Some strains of LAB show a
survival rate of 0.001–2.0% (21–25, 143). Live LAB were shown
to have several prophylactic effects (5, 84).
Cancer
Yogurt containing LAB can inhibit the growth of trans-
plantable and chemically induced tumors in animals. However,
results from epidemiologic studies on the relation between
consumption of fermented milk products and the incidence of
cancer are not consistent. Although high consumption of fer-
mented milk products (yogurt, buttermilk, and Gouda cheese)
may protect against breast cancer (144–146), yogurt consump-
tion was shown to be correlated with a higher incidence of
ovarian cancer (147).
Animal studies showed that LAB exerts anticarcinogenic
effects (13, 148–152). Diet-induced microfloral alteration may
retard the development of colon cancer (148). Some indigenous
LAB, such as L. acidophilus (153, 154), B. longum (155), Lac-
tobacillus GG (156), and components of LAB (eg, insoluble
fraction of sonicated cells of L. bulgaricus) (117), were shown to
exert tumor-suppressing effects.
Although the mechanisms by which LAB exert antitumor and
anticarcinogenic effects are not fully understood, preliminary
findings suggest that the potential mechanisms can be classified
into 3 categories. One potential mechanism involves the changes
in fecal enzymes thought to be involved in colon carcinogenesis.
Nitrate was shown to be metabolized by nitrate reductase, an
intestinal bacterial enzyme, to nitrite and may be metabolized
further to nitrogen or ammonia. Nitrite may also be an important
intermediary in the formation of N-nitroso compounds, which
have been found to be highly carcinogenic in animals. Yogurt
bacteria were shown to have nitrate reductase activity (157).
Thus, these yogurt bacteria can reduce nitrite concentrations,
thereby eliminating the substrate for the formation of carcino-
genic compounds and nitrosamines (119, 153, 157).
A second possible mechanism involves LAB cellular uptake
of mutagenic compounds, such as nitrite, in the gastrointestinal
tract, thereby reducing the compounds’ potential conversion to
carcinogenic compounds, nitrosamines (13). The third potential
mechanism involves suppression of tumors by enhancement of
immune response, as discussed previously (15, 154). Although
animal studies showed that LAB may inhibit tumorigenesis, no
evidence in this regard is available for humans. L. acidophilus,
however, was shown to reduce fecal enzyme activity of b-glu-
curonidase, nitroreductase, and azoreductase (119).
Gastrointestinal disorders
Yogurt’s microorganisms may prevent infections of the GI
tract by influencing its microbial ecosystem. However, LAB that
are colonized in the human intestine, L. acidophilus and Bifi-
dobacterium species, are more resistant to gastric acid than are
LAB conventionally used for yogurt fermentation (L. bulgaricus
and S. thermophilus).
The inhibitory mechanisms of LAB against disease-causing
bacteria are due primarily to 2 metabolites of lactic acid fermen-
tation—organic acid (158, 159) and bacteriocin (160). It was also
shown that prevention of and recovery from infection with path-
ogenic bacteria or viral infection in children with acute rotavirus-
associated diarrhea can be enhanced through augmentation of the
local immune defense, particularly by increasing the number of
immunoglobulin-secreting cells (140, 141). In addition, oral
microbial therapy with LAB can be effective in preventing anti-
biotic-induced GI disorders and in recovery from diarrhea.
Colombel et al (161) reported that the simultaneous intake of
B. longum–containing yogurt with erythromycin reduced the fre-
quency of GI disorders in human subjects who were taking ery-
thromycin and a yogurt placebo. Thus, consumption of yogurt with
LAB can reduce antibiotic-induced alterations of the intestinal
microflora. Several animal studies also showed beneficial effects of
yogurt consumption in building resistance to GI pathogens.
Immunolobulin E–mediated hypersensitivity
LAB in yogurt are known to enhance concentrations of IFN-g,
which is produced mainly from TH1 cells. IgE-mediated hyper-
sensitivity (type 1 allergy) is triggered by antigens cross-linking
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with preformed IgE antibodies that are bound to antibody recep-
tors (FceR1) on mast cell surfaces. The TH2 cytokine, IL-4,
upregulates isotype switching of IgM to IgE but IFN-gproduced
by TH1 cells inhibits isotope switching.
In human studies, it was shown that long-term consumption of
large quantities of yogurt (450 g/d) can increase production of
IFN-gby lymphocytes (32), isolated T cells (35), and PBMCs
(36). Shida et al (162) reported that L. casei added in vitro to
splenocytes from ovalbumin-primed BALB/c mice induced IFN-g
production but inhibited IL-4 and IL-5 secretion and markedly
suppressed total and antigen-specific IgE secretion by ovalbu-
min-stimulated lymphocytes. Treatment of L. casei with pepsin
at low pH for 3 h had no effect on the ability of L. casei to reduce
IgE. This implies that oral consumption of L. casei might also be
effective in reducing IgE production. These results showed that
yogurt might be effective in reducing IgE-mediated pathologies,
such as asthma. Human studies, however, produced inconsistent
results. Trapp et al (48) reported that consumption of yogurt
(200 g/d) with live active cultures reduced allergic symptoms in
young subjects but had no effect on IFN-g, total IgE, or specific
IgE concentrations. Older subjects who consumed yogurt con-
taining live bacteria, however, had lower IgE concentrations than
did a control group. Wheeler et al (138) found no effect of yogurt
consumption on asthma-related symptoms and pulmonary func-
tion in a group of patients with asthma.
SUMMARY
Many investigators have studied the therapeutic effects of
yogurt and LAB commonly used in yogurt production on dis-
eases such as cancer, infection, GI disorders, and asthma.
Because the immune system is an important contributor to all of
these diseases, the immunostimulatory effects of yogurt were
studied by several investigators. Most of these studies used ani-
mal models; few human studies on the immunostimulatory
effects of yogurt have been conducted.
Although the results of these studies mostly support the notion
that yogurt has immunostimulatory effects, poor study design, lack
of appropriate controls, and short duration of most of the studies
limit the value of the conclusions that can be drawn from them.
Most early animal and human studies included too few animals or
subjects in each group and most did not include statistical analysis.
Although more recent studies addressed these points, none pro-
vided the statistical basis for the selected number of subjects; that
is, it seems that no power calculations were performed.
Most studies used short-term feeding protocols, which might
induce a transient adjuvant effect rather than a long-term stimu-
lation of the immune response. This was shown by several stud-
ies in which a maximum effect was seen with 2–5 d of yogurt
consumption, after which the stimulatory effect of yogurt or
yogurt bacteria diminished significantly. Furthermore, most
studies investigated the effect of intravenous or intraperitoneal
administration or in vitro application of yogurt bacteria on dif-
ferent variables of the immune response. Because yogurt is usu-
ally consumed orally and because bacterial and nonbacterial
components of yogurt may be altered in the GI tract, the results
of these studies may not reflect those that would be found if the
yogurt had been consumed orally. Also, many studies lacked a
placebo group or did not use a randomized, blinded design.
Most animal and human studies investigated the effects of
yogurt on in vitro indexes of the immune response, whereas very
few examined variables of the immune system in vivo. Because a
quantitative correlation between in vitro tests of the immune sys-
tem and resistance to diseases is not yet available, care should be
taken in using the in vitro results as supporting evidence for health
benefits of yogurt. Further, although most past studies focused on
the peripheral immune response, the gut-associated immune sys-
tem is increasingly being recognized as playing an important role
in host defense. This aspect of the immune response is particularly
relevant to determining the beneficial effects of yogurt because the
systemic effects of yogurt may depend on the interaction of
yogurt’s bacterial components with the immune cells of the gut.
Despite the design problems of previous studies, these studies
provide a strong rationale for the hypothesis that increased
yogurt consumption, particularly in immunocompromised
populations such as the elderly, may enhance immunity. This
hypothesis, however, needs to be substantiated by well-designed
randomized, double-blind, placebo-controlled human studies of
adequate duration in which several in vitro and in vivo indexes
of the immune response are tested. In particular, clinically rele-
vant indexes such as response to vaccine and DTH should be
included, as should a systematic evaluation of the gut-associated
immune response. Future studies should use recent technical
advances in fluorescent tagging of yogurt bacteria to enable an
understanding of yogurt’s immunostimulatory effects. Informa-
tion on the mechanisms by which yogurt protects is essential
before the scientific community accepts claims regarding the
health benefits of yogurt.
Although yogurt has long been believed to be beneficial for
host-defense mechanisms, the components responsible for these
effects or the way in which these components exert their
immunologic modifications are not completely understood. The
presence of LAB is thought to be essential for yogurt to exert
immunostimulatory effects but components of nonbacterial
yogurt, such as whey protein, short peptides, and CLA, are
believed to contribute to yogurt’s beneficial effects as well. It is
proposed that the LAB that survive through the GI tract, whether
intact or modified, can bind to the luminal surface of M cells.
LAB-bound M cells reaching to the dome region of PP cells
stimulate local immune response, resulting in production of IFN-g
by gd T cells. This may increase the M cell population with sub-
sequent rapid amplification of bacterial translocation, which can
further activate the local immune system, resulting in stimulation
of the local and the systemic immune response. As mentioned
previously, further studies are needed to substantiate this.
Finally, once the efficacy of yogurt in improving the immune
response has been shown in humans, the benefits of these
effects will need to be shown in large clinical trials in which
the main outcomes are the incidence and severity of infectious
disease. Infectious disease rather than other immune-related
diseases are suggested because such studies can be conducted
in a relatively short (eg, 1 y) time compared with studies of dis-
eases such as cancer.
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... 1,2) Some LAB strains have been reported to have potent health benefits with regard to immune modulation and lifestyle-related diseases. [3][4][5][6][7][8][9][10] LAB strains are roughly classified into two groups based on their isolation sources. One group consists of strains isolated from dairy products and intestines, and the other includes isolates from plant sources, such as vegetables, fruits, flowers, and medicinal herbs. ...
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A lactic acid bacterial strain, Lactobacillus plantarum SN35N, which has been isolated from the pear, secretes negatively charged acidic exopolysaccharide (EPS) to outside cells. We have previously found that the SN35N-derived acidic EPS inhibits the catalytic activity of hyaluronidase (EC 3.2.1.35) promoting inflammation. The aim of this study is to find other health benefits of EPS. EPS has been found to exhibit an inhibitory effect against the influenza virus (Alphainfluenzavirus Influenza A virus) and feline calicivirus (Vesivirus Feline calicivirus), which is recognized as a model of norovirus. Although more studies on the structure–function relationship of EPSs are needed, SN35N-derived EPS is a promising lead for developing not only anti-inflammatory agents, but also antiviral substances. Fullsize Image
Article
Background: Probiotics are live micro-organisms that may give a beneficial physiological effect when administered in adequate amounts. Some trials show that probiotic strains can prevent respiratory infections. Even though our previously published review showed the benefits of probiotics for acute upper respiratory tract infections (URTIs), several new studies have been published. This is an update of a review first published in 2011 and updated in 2015. Objectives: To assess the effectiveness and safety of probiotics (any specified strain or dose), compared with placebo or no treatment, in the prevention of acute URTIs in people of all ages, at risk of acute URTIs. Search methods: We searched CENTRAL (2022, Issue 6), MEDLINE (1950 to May week 2, 2022), Embase (1974 to 10 May 2022), Web of Science (1900 to 10 May 2022), the Chinese Biomedical Literature Database, which includes the China Biological Medicine Database (from 1978 to 10 May 2022), the Chinese Medicine Popular Science Literature Database (from 2000 to 10 May 2022), and the Master's Degree Dissertation of Beijing Union Medical College Database (from 1981 to 10 May 2022). We searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov for completed and ongoing trials on 10 May 2022. Selection criteria: We included individual randomised controlled trials (RCTs) and cluster-RCTs comparing probiotics with placebo or no treatment to prevent acute URTIs. The participants were children, adults, or the elderly in the community, care facilities, schools, or hospitals. Our main outcomes were the number of participants diagnosed with URTIs (at least one event and at least three events), the incidence rate (number of cases/person year) of acute URTIs, and the mean duration of an episode of URTIs. Our secondary outcomes were the number of participants who were absent from childcare centre, school, or work due to acute URTIs; the number of participants who used prescribed antibiotics for acute URTIs; and the number of participants who experienced at least one adverse event from probiotics. We excluded studies if they did not specify acute respiratory infections as 'upper'; studies with more than 50% of participants vaccinated against influenza or other acute URTIs within the last 12 months; and studies with significantly different proportions of vaccinated participants between the probiotics arm and the placebo or no treatment arm. Data collection and analysis: Two review authors independently assessed the eligibility of trials and extracted data using standard Cochrane methodological procedures. We analysed both intention-to-treat and per-protocol data and used a random-effects model. We expressed results as risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, both with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach. Main results: We included 23 individual RCTs and one cluster-RCT. As one of the individual RCTs did not report outcomes in a usable way, we could only meta-analyse data from 23 trials, involving a total of 6950 participants including children (aged from one month to 11 years old), adults (mean age 37.3), and older people (mean age 84.6 years). One trial reported 22.5% flu-vaccine participants within the last 12 months, and 25.4% flu-vaccine participants during the intervention. Probiotics were more likely to be given with milk-based food in children; administered in powder form in adults; and given with milk-based food or in capsules in the elderly. Most of the studies used one or two strains (e.g. Lactobacillus plantarum HEAL9, Lactobacillus paracasei (8700:2 or N1115)) and 109 or 1011 colony-forming units (CFU)/day of probiotics for more than three months. We found that probiotics may reduce the number of participants diagnosed with URTIs (at least one event) (RR 0.76, 95% CI 0.67 to 0.87; P < 0.001; 16 studies, 4798 participants; low-certainty evidence); likely reduce the number of participants diagnosed with URTIs (at least three events) (RR 0.59, 95% CI 0.38 to 0.91; P = 0.02; 4 studies, 763 participants; moderate-certainty evidence); may reduce the incidence rate (number of cases/person year) of URTIs (rate ratio 0.82, 95% CI 0.73 to 0.92, P = 0.001; 12 studies, 4364 participants; low-certainty evidence); may reduce the mean duration of an episode of acute URTIs (MD -1.22 days, 95% CI -2.12 to -0.33; P = 0.007; 6 studies, 2406 participants; low-certainty evidence); likely reduce the number of participants who used prescribed antibiotics for acute URTIs (RR 0.58, 95% CI 0.42 to 0.81; P = 0.001; 6 studies, 1548 participants; moderate-certainty evidence); and may not increase the number of participants who experienced at least one adverse event (RR 1.02, 95% CI 0.90 to 1.15; P = 0.79; 8 studies, 2456 participants; low-certainty evidence). Evidence showing a decrease in the number of people absent from childcare centre, school, or work due to acute URTIs with probiotics is very uncertain (RR 0.14, 95% CI 0.03 to 0.59; 1 study, 80 participants; very low-certainty evidence). Adverse events from probiotics were minor, and most commonly gastrointestinal symptoms, such as vomiting, flatulence, diarrhoea, and bowel pain. AUTHORS' CONCLUSIONS: Overall, we found that probiotics were better than placebo or no treatment in preventing acute URTIs.
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