Review Article

Yogurt and gut function

1,2
Oskar Adolfsson, Simin Nikbin Meydani, and Robert M Russell
ABSTRACT
In recent years, numerous studies have been published on the health
effects of yogurt and the bacterial cultures used in the production of
yogurt. In the United States, these lactic acidproducing bacteria
(LAB) include Lactobacillus and Streptococcus species. The bene-
fits of yogurt and LAB on gastrointestinal health have been inves-
tigated in animal models and, occasionally, in human subjects. Some
studies using yogurt, individual LABspecies, or both showed prom-
ising health benefits for certain gastrointestinal conditions, includ-
ing lactose intolerance, constipation, diarrheal diseases, colon can-
cer, inflammatory bowel disease, Helicobacter pylori infection, and
allergies. Patients withanyof these conditions couldpossiblybenefit
fromthe consumptionof yogurt. The benefits of yogurt consumption
to gastrointestinal function are most likely due to effects mediated
through the gut microflora, bowel transit, and enhancement of gas-
trointestinal innate and adaptive immune responses. Although sub-
stantial evidence currently exists to support a beneficial effect of
yogurt consumptionongastrointestinal health, there is inconsistency
in reported results, which may be due to differences in the strains of
LAB used, in routes of administration, or in investigational proce-
dures or to the lack of objective definition of gut health. Further
well-designed, controlled human studies of adequate duration are
needed to confirm or extend these findings. Am J Clin Nutr
2004;80:24556.
KEY WORDS Yogurt, gut function, gut immunity, gastroin-
testinal diseases, gut microflora
INTRODUCTION
Components of the human intestinal microflora and of the
foodenteringthe intestine mayhave harmful or beneficial effects
on human health. Abundant evidence implies that specific bac-
terial species used for the fermentation of dairy products such as
yogurt and selected from the healthy gut microflora have pow-
erful antipathogenic and antiinflammatory properties. These mi-
croorganisms are therefore involved with enhanced resistance to
colonizationof pathogenic bacteria inthe intestine, whichhas led
to the introduction of novel modes of therapeutic and prophy-
lactic interventions based on the consumption of monocultures
and mixed cultures of beneficial live microorganisms as probi-
otics. Probiotics are defined as living microorganisms, which
on ingestion in sufficient numbers, exert health benefits beyond
inherent basic nutrition (1).
Yogurt is one of the best-known of the foods that contain
probiotics. Yogurt is defined by the Codex Alimentarius of 1992
as a coagulated milk product that results fromthe fermentation of
lactic acid in milk by Lactobacillus bulgaricus and Streptococ-
cus thermophilus (2). Other lactic acid bacteria (LAB) species
are now frequently used to give the final product unique charac-
teristics. As starter cultures for yogurt production, LAB species
display symbiotic relations during their growth in milk medium
(3). Thus, a carefully selected mixture of LAB species is used to
complement each other and to achieve a remarkable efficiency in
acid production. Furthermore, to increase the number of LAB
that survive the low pH and high acidity of the gastrointestinal
environment, some LAB species that are indigenous to the hu-
man intestine have been used in yogurt production. To meet the
National Yogurt Associations criteria for live and active cul-
ture yogurt, the finished yogurt product must contain live LAB
inamounts 10
8
organisms/gat the time of manufacture (3), and
the cultures must remain active at the end of the stated shelf life,
as ascertained with the use of a specific activity test.
In many modern societies, fermented dairy products make up
a substantial proportion of the total daily food consumption.
Furthermore, it has long been believed that consuming yogurt
and other fermented milk products provides various health ben-
efits (4). Studies fromthe 1990s on the possible health properties
of yogurt added to this belief (1, 5).
Probiotic therapy is based on the notion that there is such a
thing as a normal healthy microflora, but normal healthy mi-
croflora has not been defined except perhaps as microflora with-
out a pathogenic bacterial overgrowth. The development of
novel means of characterizing and modifying the gut microflora
has opened up newperspectives on the role of the gut microflora
in health and disease. Numerous studies suggested beneficial
therapeutic effects of LAB on gut health. However, results have
been inconsistent, which may be due to differences in the strains
of LAB, routes of administration, and investigational procedures
used in these studies.
Several LAB species are currently used in the production of
yogurt. This review focuses on the current evidence suggesting
that yogurt and specific LAB species that are used for the fer-
mentation of milk may or may not have valuable health-
promoting properties or therapeutic effects on various gastroin-
testinal functions and diseases.
1
Fromthe JeanMayer USDAHumanNutritionResearchCenter onAging
at Tufts University, Boston.
2
Address reprint requests to SN Meydani, Nutritional Immunology Lab-
oratory, JM USDA-HNRCA at Tufts University, 711 Washington Street,
Boston, MA 02111. E-mail: simin.meydani@tufts.edu.
Received October 3, 2003.
Accepted for publication February 12, 2004.
245 Am J Clin Nutr 2004;80:24556. Printed in USA. 2004 American Society for Clinical Nutrition

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NUTRITIONAL VALUE OF YOGURT
The nutrient composition of yogurt is based on the nutrient
composition of the milk from which it is derived, which is af-
fected by many factors, such as genetic and individual mamma-
lian differences, feed, stage of lactation, age, and environmental
factors such as the season of the year. Other variables that play a
role during processing of milk, including temperature, duration
of heat exposure, exposure to light, and storage conditions, also
affect the nutritional value of the final product. In addition, the
changes in milk constituents that occur during lactic acid fer-
mentation influence the nutritional and physiologic value of the
finished yogurt product. The final nutritional composition of
yogurt is also affected by the species and strains of bacteria used
in the fermentation, the source and type of milk solids that may
be added before fermentation, and the temperature and duration
of the fermentation process.
B vitamins
Dairy products have generally been considered an excellent
source of high-quality protein, calcium, potassium, phosphorus,
magnesium, zinc, and the B vitamins riboflavin, niacin, vitamin
B-6, and vitamin B-12 (6). A much greater loss of vitamins than
of minerals may occur during the processing of yogurt because
vitamins are more sensitive to changes in environmental factors
than are minerals. Some of the factors that are important during
the processing of milk and that are known to have adverse effects
on the vitamin content of dairy products in general include heat
treatment and pasteurization, ultrafiltration, agitation, and oxi-
dative conditions. In addition, bacterial cultures used during the
fermentation process of yogurt can influence the vitamin content
of the final product (6).
LAB species do require B vitamins for growth, but some
cultures are capable of synthesizing B vitamins (6). An example
of a B vitamin that is utilized by LAB is vitamin B-12 (7, 8).
Vitamins required for the growth of LABcultures vary fromone
strain to another. Significant losses of vitamin B-12 can be cor-
rected by the careful use of supplementary LABcultures that are
capable of synthesizing vitamin B-12 (9).
Folate is the best example of a B vitamin that some LAB
species synthesize (10, 11). Depending on the bacterial strains
used, the folate content of yogurt can vary widely, ranging from
4 to 19 g/100 g (8). The major form of folate present in milk is
5-methyl-tetrahydrofolate (12). In a recent study, bacterial iso-
lates fromvarious species used for milk fermentation and yogurt
productionwere examinedfor their abilitytosynthesize or utilize
folate (11). S. thermophilus and Bifidobacteria were folate pro-
ducers, whereas Lactobacilli depleted folate from the milk me-
dia. Acombination of folate-producing cultures resulted in even
greater folate content of the final fermented product. Further
studies on the effect of changes in the vitamin B content of milk
on fermentation would be of great practical significance.
Lactose
Dairy products and foods prepared with the use of dairy ingredi-
ents are an exclusive source of the disaccharide lactose in human
diets. Before absorption, lactose is hydrolyzed by the intestinal
brush border -galactosidase (lactase) into glucose and galactose.
These monosaccharides are absorbed and used as energy sources.
Before fermentation, the lactose content of the yogurt mix gen-
erally is 6% (3). One example of a significant bacteria-induced
change that occurs duringthe fermentationprocess is the hydrolysis
of 2030% of the disaccharide lactose to its absorbable monosac-
charide components, glucose and galactose (2). In addition, a por-
tion of the glucose is converted to lactic acid. Depending on other
ingredients added, this hydrolysis results in lower lactose concen-
trations in yogurt than in milk, which in part explains why yogurt is
toleratedbetter thanmilkbypersons withlactose maldigestion(13
15). However, other factors also seem to play a role. For example,
lactose-intolerant subjects exhibitedbetter tolerance for yogurt with
arelativelyhighamount of lactosethanfor milkcontainingasimilar
amount of lactose (13, 15). In another example, bacteria present in
yogurt, such as L. bulgaricus and S. thermophilus, expressed func-
tional lactase, the enzyme that breaks down lactose (16). This ex-
pression may also contribute to better tolerance of lactose in yogurt
than of lactose in milk by persons with lactose maldigestion (15).
Protein
The protein content of commercial yogurt is generally higher
thanthat of milkbecause of the additionof nonfat drymilkduring
processing and concentration, which increases the protein con-
tent of the final product. It has been argued that protein from
yogurt is more easily digested than is protein from milk, as
bacterial predigestion of milk proteins in yogurt may occur (8,
17). This argument is supported by evidence of a higher content
of free aminoacids, especiallyproline andglycine, inyogurt than
in milk. The activity of proteolytic enzymes and peptidases is
preserved throughout the shelf life of the yogurt. Thus, the con-
centration of free amino groups increases up to twofold during
the first 24 h and then doubles again during the next 21 d of
storage at 7 C(18). Some bacterial cultures have been shown to
have more proteolytic activity than do others. For example, L.
bulgaricus was shown to have a much higher proteolytic activity
during milk fermentation and storage than does S. thermophilus,
as indicated by elevated concentrations of peptides and free
amino acids after milk fermentation (19).
During fermentation, both heat treatment and acid production
result in finer coagulation of casein, which may also contribute to
the greater protein digestibility of yogurt than of milk. Proteins in
yogurt are of excellent biological quality, as are those in milk,
because the nutritional value of milk proteins is well preserved
during the fermentation process (20). Both the caseins and the
whey proteins in yogurt are rich sources of all the essential amino
acids, and the intestinal availability of nitrogen has been reported
as being high (93%; 21, 22). Labeling of milk proteins with the
stable isotope
15
N has made it possible to discriminate between
exogenous and endogenous nitrogen fractions in serum after
ingestion of
15
N-labeled milk or
15
N-labeled yogurt proteins. In
a study of human subjects, Gaudichon et al (23) found that pro-
teins from both milk and yogurt were rapidly hydrolyzed after
ingestion, but the gastroduodenal transfer of dietarynitrogenwas
slower when yogurt was fed than when milk was fed.
Lipids
Milk fat also goes through biochemical changes during the
fermentation process. Minor amounts of free fatty acids are re-
leasedas a result of lipase activity(3). Because most of the yogurt
sold in the United States is of the low-fat and nonfat varieties,
hydrolysis of lipids contributes little to the attributes of most
yogurt products. However, yogurt has been shown to have a higher
concentration of conjugated linoleic acid (CLA), a long-chain
246 ADOLFSSON ET AL

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biohydrogenatedderivative of linoleic acid, thandoes the milkfrom
which the yogurt was processed (24). A fermented dairy product
from India, referred to as dahi, has also been shown to have higher
CLAcontent than does nonfermented dahi (25). The major sources
of CLA in our diets are animal products from ruminants, in which
CLA is synthesized by rumen bacteria. Increased consumption of
dairy fat was shown to be associated with increased concentrations
of CLAin both human adipose tissue (26) and human milk (27). It
was hypothesizedthat biohydrogenationalsooccurs duringfermen-
tationof milkandresultsinhigher concentrationsof CLAinthefinal
product (28).
CLA was reported to have immunostimulatory and anticarci-
nogenic properties (29). In a recent study of breast and colon
cancer cells, Kemp et al (30) showed that the anticarcinogenic
properties of CLAmaybe due tothe abilityof some CLAisomers
to inhibit the expression of cyclins and thus halt the progression
of the cell cycle fromG1toSphase. Inaddition, CLAinducedthe
expression of the tumor suppressor p53.
Minerals
In addition to being a good source of protein, yogurt is an
excellent source of calcium and phosphorus. In fact, dairy prod-
ucts such as milk, yogurt, and cheese provide most of the highly
bioavailable calcium in the typical Western diet. Because of the
lower pH of yogurt compared with that of milk, calcium and
magnesium are present in yogurt mostly in their ionic forms.
One of the major functions of calciumis the role it plays in bone
formation and mineralization. The calcium requirements during
growth, pregnancy, and lactation are increased. However, the aver-
age calcium intake of women of childbearing age is consistently
less than is recommended (31). In addition, calcium intake of
women tends to fall even lower during the postmenopausal years
(32). This is especially important for postmenopausal women,
who are at increased risk of bone loss and osteoporosis. Dietary
fiber has an adverse effect on calcium absorption, whereas lac-
tose may enhance the absorption of calcium (33). In the rat
model, calciumretention was greater with consumption of a diet
in which lactose made up half the total carbohydrates ingested
than with consumption of the control diet (34). Schaafsma et al
(35), investigating the effect of dairy products on mineral ab-
sorption by using rat models, reported that lactose enhances the
absorption of calcium, magnesium, and zinc. Because yogurt has
a lactose content lower than that of milk, the bioavailability of
these minerals may be negatively affected, although the effect is
likely to be small.
The acidic pH of yogurt ionizes calcium and thus facilitates
intestinal calcium uptake (36). The low pH of yogurt also may
reduce the inhibitory effect of dietary phytic acid on calcium
bioavailability. Vitamin D plays a major regulatory role in in-
testinal calcium absorption. The active, saturable, transcellular
route of calcium absorption in the duodenum and proximal jeju-
num requires calbindin-D, a vitamin Ddependent calcium-
binding protein (37). In the United States, milk and infant for-
mula are fortified with vitamin D, and hence they serve as good
dietary sources, with 2.5g (100 IU) vitamin D/237-mLserving.
However, other dairy products, such as yogurt, typically are not
fortified with vitamin D.
Few studies have investigated the effect of yogurt-derived
calcium on bone mineralization in animals (34, 38). Kaup et al
(34) reported that yogurt-fed rats showed greater bone mineral-
ization than did rats fed a diet containing calcium carbonate.
These studies may suggest that the bioavailability of calcium in
yogurt is greater and yogurt may increase bone mineralization
more than do nonfermented milk products. However, there are
currently no published studies that show a superior effect of
yogurt on bone mineralization in human subjects.
MECHANISTIC RATIONALE FOR POTENTIAL
BENEFITS OF YOGURT ON GUT FUNCTION AND
HEALTH
It has been suggested that yogurt and LAB contribute to sev-
eral facets of gastrointestinal health: the makeup of the gastro-
intestinal flora, the immune response, and laxation.
Gut microflora
Lactobacilli are among the components of microbial flora in
both the small and large intestines. The ability of nonpathogenic
intestinal microflora, such as LAB, to associate with and bind to
the intestinal brush border tissue is thought to be an important
attribute that prevents harmful pathogens from accessing the
gastrointestinal mucosa (39). For LAB to have an effect, they
must adapt to the host intestinal environment and be capable of
prolonged survival in the intestinal tract (4043). LAB survival
is influenced by gastric pH as well as by exposure to digestive
enzymes and bile salts (42), and LAB species differ in their
ability to survive in the gastrointestinal environment (43).
When 4 strains of Bifidobacterium (B. infantis, B. bifidum, B.
adolescentis, and B. longum) were compared, B. longumwas the
most resistant to the effects of gastric acid (44). Bifidobacterium
animalis was reported to have a high survival rate during intes-
tinal transit in human subjects (45).
The effect of feeding yogurt fermented with S. thermophilus,
L. bulgaricus, and Lactobacillus casei on the fecal microflora of
healthy infants aged 1018 mo was investigated by Guerin-
Danan et al (46). Whereas the number of infants with fecal
Lactobacillus increased after the feeding, the total numbers of
anaerobes, Bifidobacteria, bacteroides, and enterobacteria were
not affected by yogurt intake. In a group of elderly patients with
atrophic gastritis and hypochlorhydria, Lactobacillus gasseri
survived passage through the gastrointestinal tract, but S. ther-
mophilus and L. bulgaricus were not recovered (43). Bifidobac-
terium sp has also been shown to survive passage through the
gastrointestinal tract: fecal concentrations were detectable for
8 d after the cessation of intake (47).
Another important factor that limits the survival of lactobacilli
within the upper gastrointestinal tract is the inherent ability of the
organisms to adhere to intestinal epithelial cells (42). With the
use of scanning electron microscopy, Plant and Conway (48)
screened 16 strains of Lactobacillus for their capacity to associ-
ate with Peyers patches and the lymphoid villous intestinal tis-
sues in mice. Two of the 16 strains investigated, Lactobacillus
acidophilus and L. bulgaricus, are of interest because they relate
to yogurt. It was found, in both in vitro and in vivo models using
BALB/c mice, that L. bulgaricus did not associate with Peyers
patches or with the lymphoid villous intestinal tissues. L. aci-
dophilus had a low degree of association with Peyers patches
and no association to the lymphoid villous intestinal tissue. Nev-
ertheless, the authors stated that the strains of Lactobacillus
tested showed high rates of survival when Lactobacillus was
administered orally.
YOGURT AND GUT FUNCTION 247

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The ability of LABto decrease the gastrointestinal invasion of
pathogenic bacteria has also been described (39, 49). Bernet et al
(39) reported a dose-dependent L. acidophilusmediated inhibi-
tion of the adherence of enteropathogenic Escherichia coli and
Salmonella typhimurium to the enterocyte cell-line Caco-2. In
addition, L. acidophilus inhibited the entry of E. coli, S. typhi-
murium, and Yersinia pseudotuberculosis into Caco-2 cells. In
another report (49), the same authors describedsimilar inhibitory
effects when 2 different strains of Bifidobacteria (B. breve and B.
infantis) were used. Inaddition, long-termfeedingof yogurt does
not result ina significant change inthe results of breath-hydrogen
tests, which indicates the absence of a significant change in the
intestinal survival of the yogurt organisms (50). Furthermore, it
is possible that the ability of LABto compete with pathogens for
adhesion to the intestinal wall is influenced by their membrane
fluidity. This possibility was suggested by studies indicating that
the type and quantities of polyunsaturated fatty acids in the ex-
tracellular milieu influence the adhesive properties of LABto the
epithelium (51, 52).
Gut-associated immune response
The mucosal lymphoid tissue of the gastrointestinal tract plays
an important role as a first line of defense against ingested patho-
gens. The interactions of LABwith the mucosal epithelial lining
of the gastrointestinal tract, as well as with the lymphoid cells
residing in the gut, have been suggested as the most important
mechanism by which LAB enhances gut immune function. Sev-
eral factors have been identified as contributing to the immuno-
modulating and antimicrobial activities of LAB, including the
production of low pH, organic acids, carbon dioxide, hydrogen
peroxide, bacteriocins, ethanol, and diacetyl; the depletion of
nutrients; and competition for available living space (1, 5, 53).
The gastrointestinal tract is a complex immune system tissue.
The mainsite of the mucosal immune systeminthe gut is referred
to as gut-associated lymphoid tissue (GALT), which can be di-
vided into inductive and effector sites. In the small intestine, the
inductive sites are in the Peyers patches, which consist of large
lymphoid follicles in the terminal small intestine. The best-
defined effector component of the mucosal adaptive immune
system is secretory immunoglobulin A (sIgA). sIgA is the main
immunoglobulin of the humoral immune response, which to-
gether with the innate mucosal defenses provides protection
against microbial antigens at the intestinal mucosal surface (54).
In a healthy person, sIgAinhibits the colonization of pathogenic
bacteria in the gut, as well as the mucosal penetration of patho-
genic antigens. At least 80% of all the bodys plasma cells, the
source of sIgA, are located in the intestinal lamina propria
throughout the length of the small intestine. IgA is the most
abundantly produced immunoglobulin in the human body. The
productionof intestinal sIgArequires the presence of commensal
microflora (55), which indicates that the production of intestinal
sIgA is induced in response to antigenic stimulation. It is not yet
clear, however, how lamina propria B cells are activated to be-
come IgA-secreting plasma cells or howthe intestinal microflora
influence this process. Most studies on the effect of fermented
milk or specific LAB on gut immune function have centered on
their immune adjuvant effects in the gut.
The ability of LAB to modulate IgA concentrations in the gut
has also been the subject of several studies. Orally administered
L. acidophilus and L. casei and the feeding of yogurt increased
both IgAproduction and the number of cells secreting IgAin the
small intestine of mice in a dose-dependent manner (5). Simi-
larly, a report by Puri et al (56) indicated that S. typhimurium-
induced serum IgA concentrations were significantly higher in
mice fed yogurt over a period of 4 wk than in milk-fed control
mice. This report suggests that the IgAsecretedbythe challenged
intestinal Bcells enters the circulation and increases the concen-
trations of IgA in the serum. Thus the IgA-enhancing effect of
yogurt intake may have both an effect on the gut and a systemic
effect. The same study also showed that intestinal lymphocytes
frommice fed yogurt had a higher mitogen-induced proliferative
response after a challenge with S. typhimurium than did those
from control-fed mice.
In a study using human subjects, Link-Amster et al (57)
showed that the specific anti-IgA titer to S. typhimurium was 4
times greater in subjects fed fermented milk containing L. aci-
dophilus than in control subjects fed diets without fermented
milk. Total sIgA concentrations also increased in subjects fed
fermented milk.
Macrophages play an important role as a part of the innate
immune response in the gut, and they represent one of the first
lines of nonspecific defense against bacterial invasion. The ef-
fects of feeding milk fermented with either L. casei or L. aci-
dophilus or both on the specific and nonspecific host defense
mechanisms in Swiss mice were investigated by Perdigon et al
(58). They showed that feeding milk fermented with L. casei, L.
acidophilus, or both for 8 d increased the in vitro and in vivo
phagocytic activity of peritoneal macrophages and the produc-
tion of antibodies to sheep red blood cells. The activation of the
immune system began on day 3, peaked on day 5, and decreased
somewhat on day 8 of feeding. Phagocytic activity was further
boosted in mice given a single dose of fermented milk on day 11
of feeding.
Modulation of cytokine production by yogurt and LAB has
also been the focus of several studies. In addition to interleukin
(IL)-1 and tumor necrosis factor (TNF) , which are mainly
produced by macrophages, Tlymphocytes are the source of most
cytokines investigated in those reports. T cells are frequently
classifiedinto2categoriestype 1(Th1) andtype 2(Th2) helper
T cells. On activation, these cells produce 2 diverse patterns of
cytokines (59). Th1 cells are the main producers of interferon-
(IFN-) and IL-2, and Th2 cells produce IL-4, IL-5, IL-6, and
IL-10. The Th1 cytokines boost cell-mediated immunity, and the
Th2 cytokines augment humoral immunity. IFN- plays a criti-
cal role in the induction of other cytokines and in mediation of
macrophage and natural killer cell activation.
Several reports indicated that consumption of yogurt or intake of
LABby themselves modulates the production of several cytokines,
such as IL-1, IL-6, IL-10, IL-12, IFN-, and TNF- (6063).
Moreover, the production of IFN- in an in vitro culture system
using human lymphocytes was reported to be greater with cultures
in the presence of LAB (L. bulgaricus and S. thermophilus) than
with those without LAB(64). Yogurt containing live L. bulgaricus
andS. thermophilus was alsoreportedtoaugment IFN-production
by purified T cells from young adults after 4 mo feeding (62).
Effects of yogurt consumption on the modulation of cytokine
production in the human gastrointestinal tract, whether by cells
of the GALT or by others, have not been investigated. These
types of studies, although feasible with the use of biopsy samples
from the intestines of healthy subjects (65), are difficult to carry
out, and good animal models currently do not exist.
248 ADOLFSSON ET AL

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Even though cytokines play diverse roles in regulating
immune functions, some cytokines, eg, IL-1, IL-6, and TNF-,
have been given more attention than others because they have
traditionally been classified as proinflammatory and as such are
known to be associated with inflammatory conditions such as
Crohn disease and ulcerative colitis (66). Another diverse family
of immune modulators that play important roles in the health of
the gastrointestinal tract consists of chemokines and their recep-
tors (67). Currently, only limited data have been published on the
effect of yogurt or its components on chemokine modulation in
the gastrointestinal tract. The effects of different strains of Lac-
tobacillus on chemokine production by the intestinal epithelial
cell-line, HT-29, were investigated by Wallace et al (68). All 3
LABspecies investigatedL. acidophilus, Lactobacillus rham-
nosus, and Lactobacillus delbrueckiihad suppressive effects
on the production of 2 chemokines, RANTES (a member of the
IL-8 superfamily of cytokines) and IL-8, by activated HT-29
cells. As is the case with proinflammatory cytokines, these che-
mokines are necessary for normal immune function. However, a
high production of these chemokines during an inflammatory
condition is believed to exacerbate the inflammatory response.
Laxation
Few reports have discussed the effects of yogurt and LAB on
laxation. In the studies published, however, both significant ef-
fects (G Wilhelm, unpublished observations, 1993; 69) and no
effects (70) of yogurt or LAB on laxation and gastrointestinal
transit time were described.
Strandhagen et al (69) reported that the transit time for 50%
(t50) of gastric content was significantly greater for ropy milk, an
L. bulgaricus and S. thermophilusfermented milk product
indigenous to Sweden, than for unfermented milk. Another study
showedthat milkfermentedwithL. bulgaricus andS. thermophi-
lus reducedintestinal transit time inhumansubjects withhabitual
constipation (G Wilhelm, unpublished observations, 1993). In
the same study, subjects consuming fermented milk also had
improved bowel function. The number of defecations increased
from 3/wk during a control period to 7/wk when fermented milk
was consumed. When milk fermented with L. acidophilus was
consumed, the number of defecations increased further to 15/wk.
Studies were conducted of the effects of a commercially avail-
able yogurt fermented with B. animalis on orofecal gut transit
time (71, 72). In a double-blind, randomized, crossover design,
B. animalis reduced the colonic transit time in a group of healthy
women aged 1845 y (72). Likewise, in a group of elderly
subjects experiencing lengthy orofecal gut transit time but oth-
erwise free of any gastrointestinal pathology, B. animalis intake
provided led to a significant reduction in transit time (71). Thus,
the effect of LAB ingestion on orofecal gut transit time appears
to be dependent on the bacterial strain used and the population
being studied.
YOGURT AND DISEASES OF THE
GASTROINTESTINAL TRACT
Lactase deficiency and lactose maldigestion
Lactase deficiency among adults is the most common of all
known enzyme deficiencies. More than half of the worlds adult
populationis lactose intolerant. Indevelopmental terms, this may
not necessarily be considered abnormal, because humans are the
only known mammal in whom lactase activity in the small
intestine is sustained after weaning. In the case of lactose mal-
digestion, undigested lactose remains in the intestinal lumen,
and, as it reaches the colon, it is fermented by colonic bacteria.
Byproducts of this process include short-chain fatty acids such as
lactate, butyrate, acetate, and propionate. These fatty acids as-
sociate with electrolytes and lead to an osmotic load that can
induce diarrhea. Furthermore, fermentation of lactose by colonic
bacteria produces methane, hydrogen, andcarbondioxide. These
gases may stay in the lumen and eventually will both be excreted
as flatus, diffusing into the circulation, and be exhaled via the
lungs. Exhaled hydrogen after a lactose load has been used as an
indirect but measurable indicator of lactose maldigestion. In
addition to lactose, some sources of dietary fiber and other un-
absorbed carbohydrates can serve as substrates for colonic fer-
mentation that results in increased hydrogen production.
Inability to digest lactose varies widely among ethnic and
geographic populations (73, 74). In the United States, the prev-
alence of primary lactose intolerance in adults is 53% among
Mexican Americans, 75% among African Americans, and 15%
among whites. The prevalence among adults in South America
and Africa is 50% and that in some Asian countries is close to
100%. Lactose intolerance varies greatly between European
countries, from 2% prevalence in Scandinavian adults to
70% among Southern Italian adults (74).
Lactose maldigestionmaydevelopsecondarytoinflammation
or as a result of functional loss of the small intestinal mucosa (14),
which can result from conditions such as Crohn disease, celiac
sprue, short bowel syndrome, or bacterial and parasitic infec-
tions. In addition, lactose maldigestion may develop as a conse-
quence of severe protein calorie malnutrition. The disorder is
clinically expressed by symptoms of abdominal cramps, diar-
rhea, and flatulence after milk ingestion. However, most persons
who have symptoms of lactose intolerance can endure small
amounts (210 g) of lactose in a meal without becoming symp-
tomatic (14).
It is well known that, for many lactose-intolerant people, fer-
mented milk products are better accepted than are unfermented
milk products. There may be more than one reason for this.
During fermentation of milk, lactose is partially hydrolyzed,
which results in a lower lactose content in yogurt than in milk (2).
However, this reduction in lactose may not be significant, be-
cause milk solids are usually added during processing. The
greater tolerance of lactose from yogurt than of that from milk
among lactose-intolerant subjects may be due to the endogenous
lactase activity of yogurt organisms (13, 15, 75). Kolars et al (15)
used a series of breath hydrogen tests as well as a subjective
assessment to ascertain whether subjects who were identified as
lactose-intolerant digested and absorbed lactose in yogurt better
than they digested and absorbed lactose in milk. The area under
the curve for breath hydrogen was smaller after yogurt consump-
tion than after consumption of milk or lactose in water, which
indicates better digestion and absorption of lactose from yogurt
than of that from either milk or lactose in water. Subjective
assessment by the subjects in the study of Kolars et al also
indicated that lactose in yogurt was better tolerated than the same
amount of lactose from milk or in water. Using breath hydrogen
measurement, Savaiano et al (75) investigated the effects of 3
varieties of cultured milk products on the digestion of lactose by
9 lactase-deficient human subjects. When yogurt, cultured milk
(buttermilk), and sweet acidophilus milk were compared, yogurt
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had the most beneficial effect on lactose digestion in these sub-
jects. Lactase activity and the number of surviving LAB were
significantly reduced when the yogurt was pasteurized.
The enzyme activity of lactase is generally stable in response
toenvironmental factors. For example, it was shownthat thelactase
activityof yogurt was preservedandevenincreasedwhentheyogurt
was subjected to an environment that simulated the temperature
and lowpHvalues of the gut (15). As suggested by the authors, this
study supports the notion that lactose in yogurt is autohydrolyzed
once it is in the jejunal environment. Other studies reported that
lactase activity is less stable in response to acidic environment.
Pochart et al (76) reportedthat lactaseactivityinyogurt decreasedby
80% at a pH of 5.0 in an in vitro model.
However, heating yogurt does significantly decrease lactase
activity, which indicates that yogurt that has been heat treated is
not as beneficial for lactose-intolerant persons is yogurt contain-
ing live and active cultures. Thus, there is a growing body of
evidence that yogurt containing live and active cultures is better
tolerated by lactose malabsorbers than are heat-treated fer-
mented milks (50). During the fermentation process, the amount
of lactose present in yogurt is reduced. The lactose content also
varies withthe durationof storage after fermentation. Inaddition,
the bacterial lactase activitycorresponds withthe survival time of
lactobacilli after ingestion. The enhanced digestion of lactose is
explained partly by the improved lactase activity after yogurt
ingestion and partly by other enzymatic functions, such as the
activity of the lactose transport system (permease) that allows
lactose to enter the probiotic cell (77, 78). Furthermore, animal
studies have suggested that LAB may induce lactase activity of
the gut intestinal endothelial cells (79).
Astudy by Martini et al (80) supports the microbial mediation
of lactase activity in the gastrointestinal tract. Those authors
showed that lactase activity in yogurt was stable at pH 4.0, but
that microbial cell disruption resulted in 80% loss of lactase
activity and a twofold increase in lactose malabsorption in a
group of lactose maldigesters.
Although the organisms that make up the live cultures in
yogurt are recognized as having functional lactase activity and as
contributing to the digestion of lactose, their survival in the
gastrointestinal tract is short. On average, significant numbers
survive for 1 h after ingestion (15, 50). Regardless of this
somewhat limited survival time, the beneficial effect of LAB on
lactose digestion in those suffering from lactose intolerance is
now widely accepted.
Diarrheal diseases
Diarrhea is a commonproblemamongchildrenworldwide and
has been reported to contribute substantially to pediatric physi-
cian visits and hospitalizations in the United States (81). Since
the early 20th century, it has been hypothesized that live bacterial
cultures, such as those used for the fermentation of dairy prod-
ucts, may offer benefits in preventing and treating diarrhea (4).
A recent meta-analysis of randomized, controlled studies by
Van Neil et al (82) found that therapy using Lactobacillus strains
offered a safe and effective means of treating acute infectious
diarrhea in children. Both the duration and frequency of diarrheal
episodes were reduced when compared with those in control
subjects. The benefit of Lactobacillus therapy was seen in diarrheal
diseases caused by various pathogens. The effect of supplementing
formulawithB. bifidumandS. thermophilus onpreventingtheonset
of acute viral diarrhea in infants was examined in a double-blind,
placebo-controlledtrial (83). Theinfants receivingbacterial therapy
developed diarrhea and shed rotavirus less than did the infants fed
the control formula. Evidence of the beneficial effect of LABonthe
occurrence of diarrhea of bacterial origin is more contradictory be-
cause both benefits (84, 85) and no effects (86, 87) of feeding LAB
were reported.
Several studies investigatedthe effects of probiotic bacteria on
diarrhea associated with the use of antibiotics. The most likely
cause of diarrhea associated with antibiotic use is the negative
influence of antibiotics on the bacterial steady state of the intes-
tines (88). Most cases of antibiotic-associated diarrhea are mild,
and they end shortly after antibiotic therapy is discontinued. A
less common but more serious type of antibiotic-associated di-
arrhea is due to antibiotic-mediated overgrowth of pathogenic
bacterial species such as Clostridium difficile that is associated
with pseudomembranous colitis (89).
A recent meta-analysis evaluated the ability of several differ-
ent probiotic LAB species to prevent antibiotic-associated diar-
rhea (90). Of the 9 studies that were included in the analysis, 4
used Lactobacilli strains or a combination of Lactobacilli and
Bifidobacteria (9194). Of those 4 studies, 2 showed a signifi-
cant benefit of probiotic use in comparison with placebo (93, 94).
The authors concluded that probiotic bacteria supplied in cap-
sules or as yogurt-based products may be useful in preventing
antibiotic-associated diarrhea. However, none of these studies
provide evidence for a role of probiotic bacteria in the treatment
of such diarrhea.
The mechanisms by which LAB may provide a beneficial
effect against some forms of diarrheal disease are unknown. It
has been suggested that the beneficial effect may stem from the
ability of LABto reestablish the intestinal microflora, to increase
the intestinal barrier by competing with pathogenic bacteria for
adhesion to the enterocytes, or to increase mucosal IgAresponse
to pathogens.
Colon cancer
According to the National Cancer Institute, cancer of the colon
is the second leading cancer diagnosis among both women and
men in the United States (95). Colon cancer is also the second
most common cause of cancer death. Risk factors for colorectal
cancer include both genetic and environmental factors, and sev-
eral reports have suggested that interactions between dietary
factors, colonic epithelium, and intestinal flora are central to the
development of colon cancer.
The role of diet in the etiology of cancer has been given greater
attention in recent years. Although the relation between colon
cancer and certain food constituents, such as fiber and fat, gen-
eratedthe most interest, the possibilitythat fermenteddairyprod-
ucts may protect against tumor formation in the colon was also
investigated. Epidemiologic evidence suggests a negative corre-
lation between the incidence of certain cancers, including colon
cancer, and the intake of fermented dairy products (96). More-
over, fermented dairy products or the bacteria used for milk
fermentation were shown to have an effect on colon cancer and
certain other tumors in murine models of carcinogenesis (97
100). However, a number of animal studies investigating the
effect of various strains of LABon colon carcinogenesis showed
inconsistent results.
Wollowski et al (100) investigatedthe protective effect of several
strains of LAB, traditionally used for milk fermentation, against
1,2-dimethylhydrazine (DMH)induced colon carcinogenesis in
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rats. Oral treatment with L. bulgaricus for 4 d protected against
DMH-induced DNAdamage in the colon. In contrast, there was no
protective effect when S. thermophilus was administered. The au-
thors did not ascertain the mechanisms of protection by L. bulgari-
cus, but theyspeculatedthat thiol-containingbreakdownproductsof
proteins that result fromtheproteolyticactivityof L. bulgaricus may
have produced the effect.
Ina previous studyusinga similar DMH-inducedcoloncancer
model in rats, Shackelford et al (99) showed that milk fermented
with L. bulgaricus resulted in greater survival than did nonfer-
mented milk. However, in contrast to the findings of Wollowski
et al (100), L. bulgaricus-fermented milk did not reduce the
number of rats that developed colon tumors, whereas S.
thermophilus-fermented milk did do so (99). In a study using
azoxymethane to induce aberrant crypt foci in the colon of rats,
no significant effects were seen with either B. longumor L. casei
(101). Those authors did, however, observe a protective effect of
L. acidophilus and inulin, but only when the total fat content of
the diet was increased.
Using a colon carcinoma cell culture system, Ganjam et al
(102) isolated a yogurt fraction that decreased cell proliferation,
as ascertained with the use of thymidine incorporation. Cell pro-
liferation was not inhibited in response to a similarly isolated
milk fraction or to lactic acid.
Elevated activity of several bacterial fecal enzymes, some of
which are involved in the metabolism of genotoxic nitrates, was
associated with an increased risk of colon cancer (103, 104). The
activity of these enzymes can be altered by diet or antibiotic
intake (10, 105). L. acidophilus (106) and L. gasseri (43) were
shown to reduce the fecal enzyme activity of nitroreductase,
azoreductase, and -glucuronidase in humans, with a reduction
by 50%or 75%in the activities of these enzymes during a period
of Lactobacilli feeding. Likewise, Guerin-Danan et al (46) re-
ported that 1018-mo-old infants fed yogurt fermented with S.
thermophilus, L. bulgaricus, and L. casei had lower fecal
-glucuronidase activity than did a similar group of infants fed
milk or yogurt not fermented with L. casei.
The mechanism by which LAB may have an effect on colon
carcinogenesis is currently unknown. Some of the mechanisms
that maybeinvolvedincludeenhancement of thehosts gut immune
response, suppression of harmful intestinal bacteria, sequestration
of potential mutagens, production of antimutagenic compounds,
reduction of pHconcentrations in the colon, and alteration of other
physiologicconditions(107). Furthermore, it wasshownbyPedrosa
et al (43) that the feeding of yogurt or Lactobacillus reduced fecal
enzymes, which convert procarcinogens to carcinogens, such as
azoreductase and nitroreductase.
Inflammatory bowel disease
Inflammatory bowel disease (IBD) is a term used for certain
chronic immunemediated conditions of the intestinal tract.
These chronic diseases include Crohn disease and ulcerative
colitis, conditions that have comparable symptoms but that affect
the digestive tract in very different ways (66). Ulcerative colitis
involves inflammation of the colon and rectumand not that of the
upper gastrointestinal tract, whereas Crohn disease can affect the
upper intestinal digestive tract andthus canleadtomalabsorption
of both macronutrients and micronutrients. The etiologies of
these diseases are unknown, but studies suggest that the intestinal
microflora play a crucial pathogenic role (108). This notion is
supported by animal models of Crohn disease, in which the
presence of intestinal microflora is absolutely required for the
development of disease.
Proinflammatory cytokines, particularly TNF-, have also
been recognized as playing a central role in the pathogenesis of
Crohn disease. However, despite earlier hopes, the results from
studies using TNF- antagonists were disappointing, and there
were some reports of severe complications (109). Nevertheless,
reducing the production or effect of TNF- (or both) in Crohn
disease patients is belived to be beneficial. Bourrel et al (63)
reported that, when inflamed intestinal mucosa from a group of
Crohns disease patients was cocultured in the presence of L.
casei or L. bulgaricus, expression and release of TNF- by
intraepithelial lymphocytes were reduced.
Normally, a healthy mucosal barrier provides a first defense
mechanism against both the intestinal microflora and invading
pathogens. It has been suggested that the proportions of different
intestinal microflora are altered in patients with IBD. For exam-
ple, colonic biopsy specimens have shown lower concentrations
of Lactobacillus and lower fecal concentrations of both Lacto-
bacillus and Bifidobacteriumspecies in patients with Crohn dis-
ease than in healthy subjects (110). This disturbance in intestinal
flora may increase the opportunity for colonization of pathogens
and bring about a subsequent proinflammatory response.
In the case of IBD, a defective mucosal barrier allows for in-
creased uptake of antigens and proinflammatory mediators origi-
nating fromluminal bacteria. It has been reported that patients with
IBDhavediminishedmucosal protectionasaresult of changesinthe
compositionandthicknessof themucosal layer andalterationsinthe
glycosylationstatus of mucosal glycoproteins (111). These changes
inthe intestinal mucosa are alsoassociatedwithdecreasedintestinal
IgA activity and increased IgG activity, which coincides with re-
duced state of protection and a proinflammatory condition. With
weakened mucosal barrier and thereby increased adherence of bac-
terial pathogens to the mucosa, sustained inflammation results, and
that leads to further damage to the gut mucosa. In recent years,
immunosuppressive and immunomodulating therapies, such as the
steroids usedsince the 1960s, have become more andmore frequent
in the treatment of these conditions. Although efficacious, these
types of drugs can increase the prevalence of opportunistic infec-
tions as well as the severity of any underlying infection that may be
present (112). Other side effects of these treatments may include
hepatotoxicity, fibrosis, lymphoma, and pathologic suppression of
bone marrow function.
The role of beneficial intestinal microflora in the prevention of
intestinal inflammation was investigated by using gene-targeted
IL-10 knockout (IL-10
/
) mice (113, 114). These IL-10defi-
cient mice spontaneously develop ileocolitis with many similar-
ities to Crohn disease in humans. Furthermore, affected mice
respond favorably to immunosuppression or immunomodula-
tory drugs that are similar to those used to treat human IBD. The
immunoregulatory activity of IL-10 has been studied exten-
sively. It is nowwell established that IL-10 plays a role in down-
regulating both the synthesis of inflammatory cytokines and
the presentation of antigens. Thus, IL-10 has been suggested for
use as an immunomodulator for the treatment of Crohn disease.
Targeted in vivo delivery of IL-10 to the affected intestinal ep-
ithelium by using genetically engineered Lactococcus lactis has
shown great promise in 2 mouse models of IBD (114).
Madsen et al (113) found that IL-10
/
mice had increased
adherence of luminal bacteria to the mucosal layer in the colon
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that preceded the development of colitis. This occurred in par-
allel to decreased numbers of luminal Lactobacillus. When the
concentrations of Lactobacillus in the gastrointestinal lumen
were restored by rectal delivery of Lactobacillus reuteri or by
oral lactulose therapy, colitis was attenuated. The concentrations
of adherent and translocated bacteria in the mucosal wall also
were reduced.
Another benefit of LAB in Crohn disease may be due to the
stimulation of the IgA response. A report by Malin et al (115)
suggests that oral bacteriotherapy using L. casei can restore
antigen-specific IgA immune response in persons with Crohn
disease. In a previous study fromthe same laboratory (116), oral
administration of L. casei to patients with viral gastroenteritis
promoted antigen-specific IgA responses and shortened the pa-
tient diarrhea.
Although experimental evidence exists indicating beneficial
effects of LABon Crohn disease and ulcerative colitis, the exact
mechanismthrough which LABspecies antagonize the progres-
sion of these diseases is poorly understood. The exact etiology of
IBD is also unknown, but it is likely that, in susceptible persons,
IBDresults froman ongoing inflammatory response, which may
be due to a defect in both the regulation of the mucosal proin-
flammatory response and the function of the intestinal epithe-
lium. Currently, evidence suggests that yogurt and LAB have
modest clinical benefits and are safe for use in patients with these
conditions. Further studies are required to ascertain whether yo-
gurt is beneficial as a prophylactic or a therapeutic regimen for
IBD (or both) and to establish exactly which mechanisms are
involved.
Helicobacter pylori
It has only been 20 y since Helicobacter pylori, a gram-
negative, spiral-shaped bacterium that is found in the gastric
mucous layer or adherent to the epithelial lining of the stomach,
was discovered (117). H. pylori relies on the ammonia-
producing surface protein urease for adherence and colonization
to the gastric epithelium. Urease allows H. pylori to survive by
neutralizing the acidic gastric environment (118). H. pylori pro-
duces catalase, which may play a role in protecting the bacteria
from free radicals that are released by activated leukocytes. H.
pylori infection is associated with a massive infiltration of neu-
trophils into the gastric wall and local production of IFN-,
proinflammatory cytokineseg, TNF-, IL-1, and IL-6and
the chemokine IL-8.
Infection with H. pylori is now known to play a role in peptic
ulcer disease, chronic gastritis, gastric adenocarcinoma, and
mucosa-associated lymphoid tissue lymphoma. The association
between duodenal ulcer disease and H. pylori is also well doc-
umented: H. pylori infection is reported in 90% of duodenal
ulcer patients (119). Treatment of this infection involves the use
of proton pump inhibitors, often in combination with antibiotics.
However, the use of antibiotics to treat H. pylori infection has
been associated with adverse effects and frequently leads to
resistance to antibiotic therapy.
Several in vitro and animal studies have shown reduced via-
bility of H. pylori and less adhesion of the bacteria to human
intestinal mucosal cells after treatment with various Lactobacil-
lus strains (120). In series of in vitro assays, Midolo et al (121)
showed that the growth of H. pylori was inhibited by lactic acid
in a pH-independent manner. They also found that 6 strains of L.
acidophilus and L. casei inhibited the growth of H. pylori,
whereas B. bifidus and L. bulgaricus did not. The inhibitory
effect correlated with the concentrations of lactic acid produced
by the LAB examined. In another study, Coconnier et al (122)
reported that conditioned media fromL. acidophilus reduced the
viability of H. pylori in vitro, independent of lactic acid concen-
trations. In addition, the adhesion of H. pylori to human mucose-
creting HT-29 cells decreased. Several in vitro studies were con-
ducted to ascertain whether the effects of LAB on H. pylori
survival and function are due to lactic acid or to other antibac-
terial products generated by LAB, such as bacteriocins. Of the
several bacteriocins tested, lacticins produced by Lactoc. lactis
were shown to have the greatest anti-Helicobacter activity when
used against several strains of H. pylori (123).
Studies that indicate promising inhibitory effects of LAB on H.
pylori survival andfunctioninvitrowere extendedtoinvivostudies
using human patients. Armuzzi et al (124) reported that, when 120
asymptomatic subjects who were positive for H. pylori infection
received an L. casei strain GG supplement over a 14-d period in
addition to a standard 1-wk antibiotic therapy regimen, the eradica-
tion of H. pylori was faster than that in control subjects.
Although promising results have been reported, the effects of
LAB on H. pylori infection in humans remain ambiguous. For
example, L. acidophilus and L. gasseri were both shown to
decrease H. pylori infection, as indicated by reduced [
13
C] urea
breathtest values (125, 126), andtherapywithL. acidophilus was
shown to reduce gastric mucosal inflammation (125). However,
gastric biopsies did not showeradication of H. pylori. Similarly,
Cats et al (127) reported that viable L. casei was required to
inhibit the growth of H. pylori in vitro, but only a slight nonsig-
nificant trend was observed toward an in vivo suppressive effect
of an L. casei-supplemented milk drink.
Allergic reactions
The effects of yogurt and LAB on allergic reactions in the
gastrointestinal tract have received some interest (128, 129). It
was reported that a delay in the development of Bifidobacterium
and Lactobacillus in the gastrointestinal microflora is a general
finding in children with allergic reactions (128). Isolauri (130)
reported data suggesting that Lactobacillus GG can be used to
prevent food allergies.
Heat treatment was suggested as a way of reducing the ability
of milk proteins to cause allergic reactions, which would make
milk a more suitable source of protein for persons with an im-
munologic sensitization to cow milk protein (131). However,
Kirjavainen et al (129) used a randomized double-blind design to
investigate in a recent study the effects of heat-inactivated and
viable L. rhamnosus GG on infants with atopic eczema and cow
milk allergy. Milk formula supplemented with viable but not
heat-inactivated L. rhamnosus GGsignificantly improved atopic
eczema and subjective symptoms of cowmilk allergy in subjects
in comparison with the control group. These results suggest that,
in persons with cow milk allergy, the presence of viable LAB
may provide benefits that outweigh the possible detrimental
effects that undenatured milk proteins may have on milk al-
lergy. Furthermore, the immunologic response to native milk
proteins may differ from that to heat-denatured milk proteins. A
recent study using a rat model showed that heat-denaturated
-lactoglobulin induced a local mucosal inflammatory response,
whereas native -lactoglobulin induced an IgE-mediated
systemic response (132). Heat denaturation is likely to result in
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conformational changes that expose or hide (or both) epitopes
and lead to the activation of different subpopulations of immune
cells and thus to different end results.
The mechanisms of the protective effects of LAB on allergic
reactions are not known. A proinflammatory response in the gut
mucosa that is induced by food allergens may impair the function
of the intestinal barrier. It is possible that LAB may prevent
allergic reactions by having a protective effect on the function of
the intestinal barrier, although the mechanismof such an effect is
poorly understood. A more direct link between the function of
GALTand allergic responses is also possible. One of the primary
mechanisms of active cellular suppression of proinflammatory
events in the gut after antigen-specific triggering is the secretion
of suppressive cytokines, such as transforming growth factor
and IL-10. Transforming growth factor is produced by both
CD4

and CD8

GALT-derived T cells and is an important

mediator of the active suppression component of oral tolerance.
Furthermore, IL-4mediated isotype switching of immunoglob-
ulin from IgM to IgE and IgE-dependent degranulation of mast
cells has been shown to be involved in the pathogenesis of food
allergyrelated enteropathy (133).
Yogurts LAB are known to enhance the production of IFN-
(62, 134), which acts to inhibit isotype switching to IgE. IgE-
mediated hypersensitivity reaction, also known as type 1 allergy,
is triggered by the cross-linking of antigens with IgE antibodies
that are bound to Fc receptors on mast cells. It was reported that
L. casei inhibited antigen-induced IgE production by mouse
splenocytes (135). In addition, production of the immunosup-
pressive cytokine IL-10 is induced by LAB (60).
A combination of enhancing and suppressive effects is the
most likely mechanism by which LAB may have their effects.
However, the ways in which LABor other components of yogurt
influence the productionof these immunoregulatorycytokines in
the gut remain to be elucidated, as do the possible mechanisms of
LAB-mediated protection.
SAFETY
Although the safe use of nonsporing anaerobic LAB in fer-
mented foods is widespread and has a long history, there have
been occasional reports associating LABwith clinical infections
(53, 136) because benign microorganisms have been shown to be
infective when a patient is severely debilitated or immunosup-
pressed (137, 138). Some of the diseases that have been associ-
ated with LAB infection include septicemia, infective endocar-
ditis, and dental caries.
Very rarely, cases of lactobacillemia have been reported in
patients with severe underlying illness, many of whom received
a prior antibiotic therapy that may have selected-out for the
organism (139, 140). Moreover, Husni et al (141) reviewed the
cases of 45 patients with clinically significant lactobacillemia
and reported that 11 of the patients were receiving immunosup-
pressive therapy and 23 had received antibiotics. In none of these
reports was a definitive link made between the consumption of
fermented milk products and infection.
In addition, rare cases of endocarditis have been associated
with L. rhamnosus, a LAB indigenous to the human gastrointes-
tinal tract (142144). However, as with lactobacillemia, no re-
ports to date have been able to identify a connection between
LAB from fermented milk and infection in humans. In most of
these cases, the origin of the Lactobacillus is most likely the host.
There is also a hypothetical risk of the transfer of antimicrobial
resistance from LAB to other microorganisms with which LAB
might come in contact, but this has not yet been described in the
literature.
In the past, Lactobacilli isolated from infections were habit-
ually dismissed as contaminants or secondary invaders. However,
recent evidence suggests that they might function as opportunistic
pathogens in a small number of severely immunosuppressed
persons. Even in these patients, this is a very rare event, and it has
not yet been reported in a large group of immunosuppressed
persons, such as the elderly or persons with AIDS. LAB have a
long history of safe use in foods and also in products that have
been tested in clinical trials. However, as with any new food
ingredient, the safety of a new strain of LAB must be clearly
established before it is introduced into fermented dairy products.
CONCLUDING REMARKS AND RECOMMENDATIONS
FOR FUTURE STUDIES
It has long been believed that the consumption of yogurt and
other fermented milk products provides various health benefits.
Recent studies of the possible health benefits of yogurt in gut-
associated diseases substantiate some of these beliefs. Of partic-
ular interest are the reductionby yogurt, yogurt bacteria, or
bothin the duration of diarrheal diseases in children, the pre-
ventive or therapeutic (or both) effects on IBD and colon cancer
as suggested by epidemiologic evidence and animal studies, and
the possible beneficial effects inincreasingthe eradicationrate of
H. pylori as indicated by in vitro and preliminary human studies.
In addition, there is ever-increasing evidence of the beneficial
effect of yogurt containing live and active cultures on the diges-
tion of lactose in persons with lactose intolerance.
These findings are interesting and should encourage future
studies to1) substantiate or extendthese findings byusinganimal
models and clinical trials; 2) ascertain whether these effects are
age-specific or can be observed across all age groups: eg, ascer-
tain whether yogurt would have effects similar to those observed
in children on attenuation of the incidence or duration of diar-
rheal diseases in elderly people, a group that has high morbidity
and mortality fromthese infections; and 3) investigate the mech-
anisms through which yogurt exerts its effects and ascertain the
critical components of yogurt involved in its mechanisms of
action. Finally, in recent years, yogurt has been touted as im-
proving gut health. In the absence of a universally accepted
definition or any definition of gut health, it is difficult to sub-
stantiate these claims. Studies focused on determining the char-
acteristics of a healthy gut would be extremely helpful in eval-
uating the effect of yogurt on gut health.
All 3 authors participated in the literature review and the development of
the manuscript outline, and SNM and RMR determined the areas to be
discussed. OA conducted the literature search and organized and wrote the
manuscript. SNM provided corrections. RMR revised the manuscript.
This review was prepared in response to a request from the National
Yogurt Association for a critical and objective review, for which the authors
received an honorarium.
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