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Review Article

Yogurt and gut function1,2

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) includeLactobacillusandStreptococcusspecies. The bene-

fits of yogurt and LAB on gastrointestinal health have been inves-

tigatedin animalmodels and, occasionally,in human subjects.Some

studies using yogurt, individual LAB species, or both showedprom-

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 with any of theseconditionscould possibly benefit

from theconsumptionof yogurt. Thebenefitsof yogurtconsumption

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 consumptionon gastrointestinalhealth, thereis 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 Nutr2004;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

colonization of pathogenic bacteriain the intestine, which has 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 from thefermentation of

lactic acid in milk by Lactobacillus bulgaricusand 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 gastrointestinalenvironment, 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

in amounts108organisms/g at 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 from the1990son thepossiblehealth 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 new perspectives 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 suggestingthat 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 From theJeanMayerUSDAHumanNutritionResearch Centeron Aging

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: [email protected].

Received October 3, 2003.Accepted for publication February 12, 2004.

245Am J Clin Nutr2004;80:24556. Printed in USA. 2004 American Society for Clinical Nutrition

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biohydrogenated derivative of linoleic acid, than does themilk from

which the yogurt was processed (24). A fermented dairy product

from India, referred to as dahi, has also been shown to have higher

CLA content 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 CLA in both human adipose tissue (26) and human milk (27). It

was hypothesizedthatbiohydrogenation alsooccursduring fermen-tationof milk andresultsinhigherconcentrationsof CLAin thefinal

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

propertiesofCLAmaybeduetotheabilityofsomeCLAisomers

to inhibit the expression of cyclins and thus halt the progression

of thecellcycle from G1 to S phase.In addition,CLA induced the

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.

Oneof the major functionsof calcium istherole itplaysin 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 thepostmenopausalyears

(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, calcium retention 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 D dependent 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,with2.5 g (100IU) 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 POTENTIALBENEFITS 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

Lactobacilliare 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, theymust adapt to the host intestinal environment and be capable of

prolonged survival in the intestinal tract (40 43). 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 ofBifidobacterium(B. infantis, B. bifidum, B.

adolescentis, and B. longum) were compared,B. longum was the

most resistant to the effects of gastric acid (44).Bifidobacterium

animaliswas reported to have a high survival rate during intes-

tinal transit in human subjects (45).

The effect of feeding yogurt fermented withS. thermophilus,

L. bulgaricus, andLactobacillus casei on the fecal microflora of

healthy infants aged 10 18 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, butS. ther-

mophilusandL. bulgaricuswere not recovered (43).Bifidobac-

teriumsp 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 gastrointestinaltract 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 ofLactobacillusfor 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 andL. bulgaricus, are of interest because they relate

to yogurt. It was found, in both in vitro and in vivo models using

BALB/c mice, thatL. bulgaricusdid not associate with Peyers

patches or with the lymphoid villous intestinal tissues. L. aci-

dophilushad 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 ofLactobacillus

tested showed high rates of survival when Lactobacillus was

administered orally.

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Theability of LAB to decrease thegastrointestinal invasion of

pathogenic bacteria has also been described (39, 49). Bernet et al

(39) reported a dose-dependentL. acidophilusmediated inhibi-

tion of the adherence of enteropathogenic Escherichia coliand

Salmonella typhimurium to the enterocyte cell-line Caco-2. In

addition,L. acidophilusinhibited the entry ofE. coli,S. typhi-

murium, and Yersinia pseudotuberculosisinto Caco-2 cells. In

another report (49), the sameauthorsdescribed similarinhibitory

effects when 2 different strains ofBifidobacteria (B. breve andB.infantis) were used. Inaddition, long-termfeedingof yogurtdoes

not result in a significant change in the 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 LAB to 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 LAB to the

epithelium (51, 52).

Gut-associated immune response

The mucosal lymphoid tissue of the gastrointestinaltract playsan important role as a first line of defense against ingested patho-

gens. The interactions of LAB with 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.

Themainsiteof themucosalimmunesystemin thegut 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, sIgA inhibits 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

production of intestinal sIgArequiresthe presenceof 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 how the 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. caseiand the feeding of yogurt increased

both IgA production and the number of cells secreting IgA in 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. Thisreport suggeststhat the IgAsecretedby thechallenged

intestinal B cells 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

from micefed 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. typhimuriumwas 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-

dophilusor 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 withL. 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 mainlyproduced by macrophages, T lymphocytes are thesource of most

cytokines investigated in those reports. T cells are frequently

classified into2 categoriestype 1 (Th1)and type 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

LAB by themselves modulates the production of several cytokines,

such as IL-1, IL-6, IL-10, IL-12, IFN-, and TNF- (60 63).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 liveL. bulgaricus

andS. thermophiluswasalso reported to augment 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, althoughfeasiblewith theuse of biopsysamples

from the intestines of healthy subjects (65), are difficult to carry

out, and good animal models currently do not exist.

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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 theeffect of yogurt or its components on chemokine modulation in

the gastrointestinal tract. The effects of different strains ofLac-

tobacilluson chemokine production by the intestinal epithelial

cell-line, HT-29, were investigated by Wallace et al (68). All 3

LAB species investigatedL. acidophilus, Lactobacillus rham-

nosus,and Lactobacillus delbrueckii had 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 ropymilk, an

L. bulgaricus and S. thermophilusfermented milk product

indigenous to Sweden, than for unfermented milk. Another study

showed thatmilk fermented withL. bulgaricusand S. thermophi-

lus reduced intestinal transit time in human subjectswith habitual

constipation (G Wilhelm, unpublished observations, 1993). Inthe 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. acidophiluswas

consumed,the number of defecations increasedfurther to 15/wk.

Studies were conductedof theeffects of a commerciallyavail-

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 18 45 y (72). Likewise, in a group of elderly

subjects experiencing lengthy orofecal gut transit time but oth-

erwise free of any gastrointestinal pathology,B. animalisintake

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

population is lactose intolerant.In developmentalterms,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 thisprocess 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

bacteriaproducesmethane, hydrogen,and carbon dioxide.Thesegases 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 to100%. Lactose intolerance varies greatly between European

countries, from 2% prevalence in Scandinavian adults to

70% among Southern Italian adults (74).

Lactose maldigestionmay develop secondary to inflammation

oras a resultof functional loss ofthe smallintestinalmucosa(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 yogurtthanin 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 yogurtorganisms (13, 15, 75). Kolarset 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

thecurvefor breathhydrogenwas smaller after yogurtconsump-

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

indicatedthat lactose in yogurtwas bettertolerated than thesame

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

to environmental factors.Forexample,it wasshownthat thelactase

activity ofyogurtwas preservedand even increasedwhen theyogurt

was subjected to an environment that simulated the temperature

and low pH values of the gut(15). As suggested by the authors, this

study supports the notion that lactose in yogurt is autohydrolyzedonce it is in the jejunal environment. Other studies reported that

lactase activity is less stable in response to acidic environment.

Pochartet al(76)reported that lactase activityin yogurtdecreased by

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. In addition,the bacterial lactaseactivity corresponds withthe survivaltime 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).

A study 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 agroup of lactose maldigesters.

Although the organisms that make up the live cultures in

yogurt are recognized as having functional lactase activityand 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

Diarrheais a common problemamong childrenworldwide and

has been reported to contribute substantially to pediatric physi-

cian visits and hospitalizations in the United States (81). Since

the early 20thcentury,it has beenhypothesized thatlive 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 usingLactobacillus strains

offered a safe and effective means of treating acute infectious

diarrheain children. Boththe durationand frequencyof diarrheal

episodes were reduced when compared with those in control

subjects. The benefit ofLactobacillus therapywas seenin diarrheal

diseases caused by various pathogens. The effect of supplementing

formula withB. bifidum andS. thermophiluson preventingthe onset

of acute viral diarrhea in infants was examined in a double-blind,

placebo-controlledtrial(83).The infants receiving bacterial therapy

developed diarrhea and shed rotavirus less than did the infants fed

the control formula. Evidence of the beneficial effect of LABon the

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 effectsof probiotic bacteriaon

diarrhea associated with the use of antibiotics. The most likely

cause of diarrhea associated with antibiotic use is the negativeinfluence 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 difficilethat 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 ofLactobacilli and

Bifidobacteria(9194). Of those 4 studies, 2 showed a signifi-

cant benefit of probioticuse 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 LAB to reestablish the intestinal microflora,to increase

the intestinal barrier by competing with pathogenic bacteria for

adhesion to the enterocytes, or to increase mucosal IgA response

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.

Theroleof diet in theetiology of cancerhas been given greater

attention in recent years. Although the relation between colon

cancer and certain food constituents, such as fiber and fat, gen-

erated the mostinterest, the possibility thatfermented dairy prod-

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

effectof various strains of LAB on colon carcinogenesis showed

inconsistent results.

Wollowski et al (100) investigatedtheprotective effectof 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 whenS. thermophiluswas administered. The au-

thors did not ascertain the mechanisms of protection byL. bulgari-

cus, buttheyspeculatedthatthiol-containingbreakdownproducts of

proteins that resultfromtheproteolyticactivityofL. bulgaricusmay

have produced the effect.

In a previousstudy using a similar DMH-induced colon cancer

model in rats, Shackelford et al (99) showed that milk fermentedwithL. 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 eitherB. longum orL. casei

(101). Those authors did, however, observe a protective effect of

L. acidophilusand 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 increasedrisk of colon cancer (103, 104). The

activity of these enzymes can be altered by diet or antibiotic

intake (10, 105). L. acidophilus(106) andL. 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

ofLactobacilli feeding. Likewise, Guerin-Danan et al (46) re-

ported that 10 18-mo-old infants fed yogurt fermented withS.

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

thatmay be involved includeenhancement ofthehosts gutimmune

response, suppression of harmful intestinal bacteria, sequestration

of potential mutagens, production of antimutagenic compounds,

reduction of pH concentrations in the colon, and alteration of other

physiologicconditions(107). Furthermore,it wasshownby Pedrosa

et al (43) that the feeding of yogurt or Lactobacillusreduced 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 thathave comparable symptomsbut thataffect

the digestive tract in very different ways (66). Ulcerative colitis

involves inflammationof thecolon andrectum andnot that of the

uppergastrointestinal tract, whereas Crohn disease can affect the

upperintestinaldigestive tract and thuscan leadto malabsorption

of both macronutrients and micronutrients. The etiologies of

these diseasesare unknown,but studies suggest thatthe 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 Crohndisease 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 hasbeen suggestedthat theproportions of different

intestinal microflora are altered in patients with IBD. For exam-

ple, colonic biopsy specimens have shown lower concentrations

ofLactobacillus and lower fecal concentrations of both Lacto-

bacillus andBifidobacterium species in patients with Crohn dis-

ease than in healthy subjects (110). This disturbance in intestinalflora 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 from luminal bacteria. It has been reported that patients with

IBDhavediminished mucosal protectionas a resultof changesin the

composition andthicknessof themucosallayerandalterationsin the

glycosylationstatusof mucosal glycoproteins(111). Thesechanges

in theintestinalmucosa arealso associatedwith decreasedintestinal

IgA activity and increased IgG activity, which coincides with re-

duced state of protection and a proinflammatory condition. With

weakened mucosalbarrier and thereby increased adherence of bac-

terial pathogens to the mucosa, sustained inflammation results, andthat leads to further damage to the gut mucosa. In recent years,

immunosuppressive and immunomodulating therapies, such as the

steroids usedsincethe1960s,havebecome 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 roleof 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-10 defi-

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 now well 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 engineeredLactococcus lactishas

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 ofLactobacillus in the gastrointestinal lumen

were restored by rectal delivery ofLactobacillus 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 from the same laboratory (116), oral

administration ofL. 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 LAB on Crohn disease and ulcerative colitis, the exact

mechanism through which LAB species antagonize the progres-

sion of these diseases is poorlyunderstood. The exact etiology of

IBD is also unknown, but it is likely that, in susceptible persons,

IBD results from an ongoing inflammatoryresponse, 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

modestclinical benefits andare safe foruse 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. pylorito survive by

neutralizing the acidic gastric environment (118).H. pyloripro-

duces catalase, which may play a role in protecting the bacteria

from free radicals that are released by activated leukocytes. H.

pyloriinfection is associated with a massive infiltration of neu-

trophils into the gastric wall and local production of IFN-,

proinflammatory cytokines eg,TNF-, IL-1, and IL-6and

the chemokine IL-8.

Infection withH. pyloriis 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. pyloriis also well doc-

umented:H. pyloriinfection 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. pyloriinfection 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 ofH. pylori and less adhesion of the bacteria to human

intestinal mucosal cells after treatment with variousLactobacil-

lusstrains (120). In series of in vitro assays, Midolo et al (121)

showed that the growth ofH. pyloriwas inhibited by lactic acid

in a pH-independent manner. They also found that 6 strains ofL.

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 ofH. pyloriin vitro, independent of lactic acid concen-

trations. In addition, the adhesion ofH. 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 byLactoc. lactis

were shown to have the greatest anti-Helicobacteractivity when

used against several strains ofH. pylori(123).

Studies that indicate promising inhibitory effects of LAB onH.

pylori survival andfunction in vitro were extended to in vivo studies

using human patients. Armuzzi et al (124) reported that, when 120

asymptomatic subjects who were positive for H. pyloriinfection

received anL. caseistrain GG supplement over a 14-d period in

addition to a standard 1-wk antibiotic therapy regimen, the eradica-

tion ofH. pyloriwas faster than that in control subjects.

Although promising results have been reported, the effects of

LAB on H. pyloriinfection in humans remain ambiguous. Forexample, L. acidophilus and L. gasseri were both shown to

decreaseH. pyloriinfection, as indicated by reduced [13C] urea

breath testvalues(125, 126), and therapy withL. acidophiluswas

shown to reduce gastric mucosal inflammation (125). However,

gastric biopsies did not show eradication ofH. pylori. Similarly,

Cats et al (127) reported that viable L. casei was required to

inhibit the growth ofH. pyloriin vitro, but only a slight nonsig-

nificant trend was observed toward an in vivo suppressive effect

of anL. casei-supplemented milk drink.

Allergic reactions

The effects of yogurt and LAB on allergic reactions in thegastrointestinal tract have received some interest (128, 129). It

was reported that a delay in the development ofBifidobacterium

andLactobacillusin 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

viableL. rhamnosusGG on infants with atopic eczema and cow

milk allergy. Milk formula supplemented with viable but not

heat-inactivatedL. rhamnosusGG significantlyimproved atopic

eczema andsubjectivesymptoms 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

mucosathat is induced by food allergensmay impairthe function

of the intestinal barrier. It is possible that LAB may prevent

allergic reactions by having a protective effect on the function of

theintestinal barrier, although themechanism of such an effectispoorly understood. A more direct link between the function of

GALT andallergic responsesis also possible. Oneof theprimary

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-4 mediated 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, theways in which LAB or other components of yogurt

influence the production of these immunoregulatorycytokines in

thegut remainto be elucidated, as do thepossiblemechanisms 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 LAB with clinical infections

(53, 136) because benignmicroorganisms 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 and23 hadreceived 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

withL. 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 originof theLactobacillus is most likely thehost.

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,Lactobacilliisolated 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 hasnot 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 reduction by 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 possiblebeneficial effectsin increasing the eradication rateof

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 to 1) substantiate or extend these findingsby using animal

models and clinical trials;2) ascertain whether these effects areage-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 from these 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-

provinggut health. In the absence of a universally accepted

definition or any definition ofgut 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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