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Fri Mar 21, 2003 3:22 pm

Probiotics in Human Disease

 

 

 

 

American Journal of Clinical Nutrition, Vol. 73, No. 6, 1142S-1146S,

June 2001

© 2001 American Society for Clinical Nutrition

 

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Supplements

 

Probiotics in human disease1,2,3

Erika Isolauri

1 From the Department of Pediatrics, University of Turku, Finland.

 

2 Presented at a symposium held at Experimental Biology 2000, in San

Diego, April 2000.

 

3 Address reprint requests to E Isolauri, Department of Pediatrics,

University of Turku, 20520 Turku, Finland. E-mail:

erika.isolauri.

 

 

Western civilization is facing a progressive increase in immune-

mediated, gut-related health problems, such as allergies and

autoimmune and inflammatory diseases, and genetic factors are an

unlikely explanation for these rapid increases in disease incidence.

Two environmental factors that relate to the modern lifestyle in

Western societies are hygiene and nutrition. There has been a

decline in the incidence of micro-bial stimulation by infectious

diseases as a result of improved hygiene, vaccination, and

antimicrobial medication. In the past, methods of food preservation

involved either the natural fermen-tation or drying of foods; thus,

the human diet once contained several thousand times more bacteria

than it does today. The development of probiotic, functional foods

aims to " kill two birds with one stone, " which is accomplished by

providing a microbial stimulus to the host immune system by means of

ben-eficial live microorganism cultures that are characteristic of

the healthy, human gut microflora, ie, probiotics. Probiotic

bacteria were shown to reinforce the different lines of gut defense,

which are immune exclusion, immune elimination, and immune regula-

tion. They were also shown to stimulate nonspecific host resistance

to microbial pathogens, thereby aiding in pathogen eradication.

Consequently, the best documented clinical application of probi-

otics is in the treatment of acute diarrhea. In humans, docu-mented

effects were reported for the alleviation of intestinal

inflammation, normalization of gut mucosal dysfunction, and down-

regulation of hypersensitivity reactions. These data show that

probiotics promote endogenous host defense mechanisms. Thus,

modification of gut microflora by probiotic therapy may offer a

therapeutic potential in clinical conditions associated with gut-

barrier dysfunction and inflammatory response.

 

 

Key Words: Atopy • diarrhea • food allergy • gastrointestinal

tract • infant • inflammation • probiotics

 

 

HEALTH BURDEN OF MODERN SOCIETY: FROM ALLERGIES TO INFLAMMATORY

DISEASES

 

 

At the beginning of the third millenium, allergic diseases, atopic

eczema, allergic rhinitis and asthma, together with chronic

inflammatory bowel disease, Crohn disease, ulcerative colitis,

diabetes, and arthritis, represent chronic diseases of rising

importance in industrialized countries worldwide. Notwithstanding

intensive research, the causes of these devastating inflammatory

conditions remain unknown. In general, such outbreaks are thought to

require genetic predisposition, immunologic disturbance, and the

influence of intraluminal triggering agents, eg, allergens and

antigens, bacteria, or viruses. Moreover, these diseases are

associated with impairment of gut-barrier function (1, 2). These

findings considered together would strongly suggest that the host

defense mechanisms in the gut, primed to assimilate potentially

harmful challenges, have decreased in Western societies during the

past decades.

 

Given that significant immunologic and even inflammatory activation

constantly prevails in the gut, deprivation of the stimuli priming

for protective mechanisms directs the milieu in the gut toward a

propensity to inflammatory disease (3). The earliest and most

substantial driving forces for the development of the defense

mechanisms in the gut are derived from dietary and microbial

antigens. Specific strains of the healthy, normal gut microflora,

ie, probiotics, promote gut-barrier functions, give maturational

signals for the gut-associated lymphoid tissues, and balance the

generation of pro- and antiinflammatory cytokines, thereby creating

healthy interactions between the host and microbes in the gut that

are needed to keep inflammatory responses regulated but

concomitantly readily primed (4).

 

As a result, the diet and composition of the gut microflora may have

an effect on the risk of inflammatory diseases (Figure 1).

Conversely, these represent an exciting opportunity for the

development of preventive and therapeutic dietary intervention

strategies directed against the rising trend of inflammatory

diseases in the modern world.

 

 

 

 

 

FIGURE 1. Gut microflora in inflammation. Inflammation is

accompanied by an imbalance of the intestinal microflora, and a

strong inflammatory response may be mounted to microfloral bacteria,

leading to perpetuation of the inflammation and gut-barrier

dysfunction. Ig, immunoglobulin.

 

 

 

 

 

GUT-BARRIER FUNCTIONS: A TARGET OF PROBIOTIC THERAPY

 

 

 

The gastrointestinal tract provides a protective interface between

the internal environment and the constant challenge from food-

derived antigens and from microorganisms in the external environment

(2). This first line of host defense is directed toward the

exclusion of antigens, the elimination of foreign antigens that have

penetrated the mucosa, and the regulation of ensuing antigen-

specific immune responses (5). As a result, the gastrointestinal

barrier controls antigen transport and the generation of immunologic

phenomena in the gut. Even in physiologic conditions, a

quantitatively insignificant but immunologically important fraction

of antigens bypass the defense barrier. Antigens are absorbed across

the epithelial layer by transcytosis along the following 2

functional pathways: a degradative pathway that entails lysosomal

processing of protein to smaller peptide fragments, thus reducing

the immunogenicity of the protein and aiding host defense by

diminishing the antigen load (>90% of internalized protein are

absorbed this way), and a minor pathway that allows for the

transport of intact proteins, which results in antigen-specific

immune responses (6).

The regulatory events constituting the intestinal immune response

take place in organized lymphoepithelial tissue and secretory sites.

The organized lymphoid tissues are composed of Peyer's patches,

which play an essential role in intestinal immune function, and

lymphocytes and plasma cells that are distributed throughout the

lamina propria. Intraepithelial lymphocytes are located above the

basal lamina in the intestinal epithelium. These aggregations of

lymphoid follicles are covered by a unique epithelium composed of

cuboidal epithelial cells, very few goblet cells, and specialized

antigen sampling cells, ie, M cells. Although blood-borne and tissue

immunity has a predominance of immunoglobulin (Ig) G antibodies

compared with IgA and IgM, IgA antibody production is abundant at

mucosal surfaces and secretory IgA is present in dimeric or

polymeric form (5). These secretory IgA antibodies in the gut form

part of the common mucosal immune system, including the respiratory

tract and lacrimal, salivary, and mammary glands. Consequently, an

immune response initiated in the gut-associated lymphoid tissue can

affect immune response at other mucosal surfaces.

 

Intestinal permeability is a reflection of the gut-barrier function

(1). An immature gut barrier may lead to increased intestinal

permeability and aberrant antigen transfer and immune responses,

thus explaining vulnerability to infection, inflammation, and

hypersensitivity at an early age. Intestinal permeability can be

increased secondarily due to mucosal dysfunction that is induced by

viruses, bacteria, or dietary antigens (7, 8). A great amount of

antigens could thus traverse the mucosal barrier and the routes of

transport could be altered.

 

Environmental factors, particularly those associated with intestinal

inflammation, may flaw the normal immune regulation in the gut to

the point of local and systemic inflammatory responsiveness (9).

However, even in the absence of inflammatory stimuli from the

environment, the healthy and mature intestine is in a

proinflammatory state, provoking many differentiated and activated

lymphocytes that generate proinflammatory cytokines, a state called

controlled inflammation (10). The existence of active

counterregulating processes primed to mount antiinflammatory

responses may be mandatory for healthy interactions across the

barrier.

 

 

NORMAL MICROFLORA AND GUT-BARRIER FUNCTIONS

 

REFERENCES

Intestinal colonization is accompanied by an increase in the numbers

of intestinal lymphocytes and maturation of mucosal immune function

(11, 12). Intraluminal bacterial antigens elicit specific responses

in gut-associated lymphoid tissue. It was shown in experimental

animal models that the capacity to generate IgA-producing cells is

initiated with the establishment of the gut microflora and with the

onset of a specific IgA response to the number of translocating

bacteria drops, reflecting maturation of the intestine's immunologic

defense mechanisms (13). Moreover, there is a reduction in the

number of lamina propria lymphocytes and the concentrations of serum

immunoglobulin. It has been shown that the secondary lymphoid

organs, ie, the spleen and lymph nodes, are poorly developed in

germfree animals because of the lack of antigenic stimulation (11).

 

The role of the intestinal microflora in oral tolerance induction

(ie, the unresponsiveness to nonpathogenic antigens encountered at

the mucosal surface) to the IgE response was investigated in

germfree mice (14). In contrast with control mice, germfree animals

maintained their tendency to systemic immune response, eg, the

production of IgE antibodies, after oral administration of

ovalbumin. Abrogation of oral tolerance was due to a lack of

intestinal flora. The aberrant IgE response in germfree mice could

be corrected by reconstitution of the microflora at the neonatal

stage but not later. These results suggest that the gut microflora

direct the regulation of systemic and local immune responsiveness by

affecting the development of gut-associated lymphoid tissue at an

early age.

 

Parallel results were obtained in humans. Recent studies after

microfloral development in vaginally born infants and in infants

born by cesarean delivery showed major differences in culturable

microflora (15). Colonization was associated with the maturation of

humoral immune mechanisms, particularly of circulating IgA- and IgM-

secreting cells (16).

 

The regulatory role of specific strains of the gut microflora was

shown previously by a suppressive effect of immune responses to

dietary antigens in allergic individuals (17), partly attributable

to enhanced production of antiinflammatory cytokines, eg,

interleukin 10 (18) and transforming growth factor ß (19), whereas

the capacity to stimulate nonspecific immune responses was retained

(20, 21). Thus, as mucosal tolerance and immunization represent a

continuum of immunologic competence in health (22), this pattern of

immune response is not altered by the consumption of single and

mixed cultures of probiotic microorganisms (23).

 

 

HEALTHY GUT MICROFLORA—THE SOURCE OF PROBIOTICS

 

 

 

Microbial colonization begins after birth, and initially,

facultative anaerobic strains dominate. Thereafter, lactic acid

bacteria and coliforms become the predominant microorganisms of the

gut microflora (11). After weaning, the type of diet determines the

relative distribution of bacterial species. Breast-feeding

encourages the growth of bifidobacteria in the gut, whereas formula-

fed infants have a more complex microflora that contains

bifidobacteria, bacteroides, clostridia, and streptococci. After

weaning, the composition of the microflora resembles that of the

adult flora (23). In the ileum, bacterial concentrations gradually

increased to 1014 total bacterial cells of different culturable

species. Several reports have indicated that 5 genera account for

most of the viable forms of anaerobic bacteria: Bacteroides,

Eubacterium, Bifidobacterium, Peptostreptococcus, and Fusobacterium

(11, 23). Various facultative and aerobic organisms are also present

in the colon. Most of these bacteria are hitherto uncharacterized

because of the presence of nonculturable bacteria and the inaccuracy

and insufficiency of the identification procedures available.

 

The complex ecosystem of the adult intestinal microflora is

estimated to harbor 500 different bacterial species. Some of these

species are considered potentially harmful because of their

abilities of toxin production, mucosal invasion, or activation of

carcinogens and inflammatory responses (23). The strains with health-

promoting properties principally include bifidobacteria and

lactobacilli. In infectious and inflammatory conditions the balance

of the gut microecology is altered in such a way that the number of

potentially pathogenic bacteria grows and the healthy interaction

between the host and microbe is disturbed such that an immune

response may be induced by resident bacteria.

 

Probiotics are beneficial bacteria that exist in the healthy gut

microflora. The classification of a strain as probiotic requires

that its beneficial physiologic effects be proven scientifically,

that the strain be of human origin, be safe for human use, be stable

in acid and bile, and that it adhere to the intestinal mucosa (23).

The most frequently used genera fulfilling these criteria are

Lactobacillus and Bifidobacterium.

 

 

PROBIOTIC FUNCTIONAL FOODS—AN OLD RECIPE FOR MODERN COOKING

 

ABSTRACT

HEALTH BURDEN OF MODERN...

 

 

 

The role of diet in health and well-being has changed as the science

of nutrition has evolved. The principal role of the diet clearly

lies in the provision of energy to meet the requirements of

metabolism and growth. Currently, research is being directed toward

improving our understanding of specific physiologic effects of the

diet beyond its nutritional effect (24). The science of functional

food evaluates the potential of the diet to promote health and well-

being and to reduce the risk of diseases. A food can be defined as

functional if it is shown to beneficially affect one or more target

functions in the body beyond adequate nutritional effects in a way

that is relevant to either the state of well-being and health, or to

a reduction in disease incidence (23).

 

The Westernized diet includes few fresh nutritional components and

among the nonnutritional components there are few microbes (25). It

is characteristic of the diet in economically developed countries to

include processed and sterile foods containing artificial

sweeteners, preservatives, and in some extreme cases, even

antibiotics. Such a diet may deprive the immune system of important

tolerogenic signals from the environment. These include

antiinflammatory processes promoted by specific microbes (17, 26,

27) and external antioxidants provided by fresh fruit and vegetables

(28).

 

Inflammation is accompanied by an imbalance in the intestinal

microflora (29–31; PV Kirjavainen, E Apostolou, T Arvola, SJ

Salminen, GR Gibson, E Isolauri, unpublished observations, 2001),

and a strong inflammatory response may be mounted to microfloral

bacteria, leading to perpetuation of the inflammation (Figure 1).

Oral introduction of probiotics may halt the vicious circle in

normalizing the increased intestinal permeability and altered gut

microecology, thus improving the intestine's immunologic barrier and

alleviating the intestinal inflammatory response. The targets for

probiotic therapy are thus identified as clinical conditions with

impaired mucosal barrier function, particularly infectious and

inflammatory diseases (4).

 

 

PROBIOTICS IN THE PREVENTION AND TREATMENT OF HUMAN DISEASE

 

 

 

 

Probiotic functional foods can improve specific physiologic

functions in the human gastrointestinal tract, eg, the host immune

defense, thereby reducing the risk of contracting illnesses. This

conclusion is based on more recent in vitro and in vivo studies (4,

23).

 

Specific probiotic bacteria were shown to promote nonspecific host

resistance to microbial pathogens (23). Several probiotic strains

were shown to induce in vitro the release of proinflammatory

cytokines, tumor necrosis factor , and interlukin 6, which reflects

the stimulation of nonspecific immunity (32). Enhanced phagocytosis

was substantiated in humans by Lactobacillus acidophilus strain La1

(33) and Lactobacillus rhamnosus strain GG (20). These effects could

be crucial in the exclusion and eradication of pathogens. The

stimulation of the host's nonspecific and specific humoral immune

responses to potentially harmful antigens has been documented for,

among others, Bifidobacterium bifidum, Bifidobacterium breve, and L.

rhamnosus GG (21, 34, 35). The specific IgA response could

contribute to the preventive potential of probiotics. This was

clinically documented in a reduction of diarrheal episodes in

infants who were administered Lactobacillus helveticus– and

Streptococcus thermophilus–fermented formula (36), L. acidophilus–

and Lactobacillus casei–fermented milk (37), or a formula

supplemented with B. bifidum and S. thermophilus (38).

 

The principal effect of probiotics is characterized by stabilization

of the gut microflora (23). The clinical benefit of probiotics was

shown when used to treat conditions in which the gut microecology is

disturbed by changes in the environment (traveler's diarrhea) or by

oral antimicrobial therapy (antibiotic-associated diarrhea). The

value of probiotic preparations in prophylaxis for traveler's

diarrhea has been assessed and more recent double-blind, placebo-

controlled studies would indicate that some strains of lactic acid

bacteria may protect against traveler's diarrhea (39). Similarly,

evidence from recent well-controlled studies indicates that

probiotics may be of value in the prevention of antibiotic-

associated diarrhea (40). In balancing the gut microecology, the

incidence of slower gastric emptying and partial hydrolysis of

lactose during fermentation may be associated with the documented

alleviation associated with symptoms of secondary lactose

intolerance in adults (39).

 

The best-documented clinical application of probiotics is in the

treatment of acute diarrhea and as adjunct therapy in gut-related

inflammatory conditions (40). The beneficial, clinical effect of

probiotics was explained by stabilization of the indigenous

microflora (29), a reduction in the duration of rotavirus shedding

(38), and a reduction in increased gut permeability caused by

rotavirus infection (41) together with a significant increase in IgA-

secreting cells to rotavirus (21, 35). The multicenter study of the

European Society of Pediatric Gastroenterology, Hepatology and

Nutrition (42) extended this observation to preventing the evolution

of rotavirus diarrhea toward a protracted course and thus confirmed

the clinical benefit of probiotics in the treatment of rotavirus

diarrhea in infants.

 

There is an increasing appreciation of the role of cytokines in

regulating inflammatory responses at a local and systemic level. The

ingestion of probiotic bacteria can potentially stabilize the

immunologic barrier in the gut mucosa by reducing the generation of

local proinflammatory cytokines (43, 44). Alteration of the

properties of the indigenous microflora by probiotic therapy was

shown to reverse some immunologic disturbances characteristic of

Crohn disease (45), food allergy (44), and atopic eczema (19).

 

Recently, probiotics were shown to modulate the host's immune

responses to foreign antigens with a potential to dampen

hypersensitivity reactions (24). Unheated and heat-treated

homogenates were prepared from probiotic strains, including L.

rhamnosus strain GG, Bifidobacterium lactis, L. acidophilus,

Lactobacillus delbrückii subsp. bulgaricus, and S. thermophilus

(26). The phytohemagglutinin-induced proliferation of mononuclear

cells was suppressed in these homogenates compared with controls

with no homogenate, indicating that probiotic bacteria possess heat-

stable, antiproliferative components, which could be therapeutically

exploited in inflammatory conditions. Moreover, qualitative and

quantitative differences between probiotic homogenates in these

antiinflammatory properties were documented in vitro, even when

adjusted for their protein concentrations or enzymatic activity (26,

27).

 

The intestinal microflora contribute to the processing of food

antigens in the gut. To characterize the immunomodulatory effect of

probiotics in allergic inflammation, a study was conducted to

determine cytokine production by anti-CD3–induced peripheral blood

mononuclear cells in atopic infants with cow milk allergy (46).

Unhydrolyzed casein increased the production of interleukin 4,

whereas L. rhamnosus strain GG-hydrolyzed casein reduced it. This

indicates that probiotics modify the structure of potentially

harmful antigens and reduce their immunogenicity. The clinical

correlate of this effect is seen as a significant improvement in the

clinical course of atopic dermatitis (eczema) in infants who were

administered a probiotic-supplemented elimination diet, and in

parallel, markers of intestinal (44) and systemic (19) allergic

inflammation decreased significantly. Similar results were obtained

in a study of milk-hypersensitive adults in whom a milk challenge in

conjunction with a probiotic strain prevented the immunoinflammatory

response characteristic of the challenge without probiotics (20). On

the basis of these more recent studies of allergic inflammation, a

novel target of probiotic therapy may be to control the excess

formation of IgE and the development of T helper subset 2 cell–

skewed immune responsiveness, both of which are key features of

atopy. The T helper cells are divided on the basis of their cytokine

profiles and IgE responses are under the control of cytokines that

are produced by competing signals from the T helper cells. Patients

with atopic disease manifest a high production of interleukin 4 (T

helper subset 2 cells). Thus, the objective of the intervention is

to redirect the immunologic memory away from the T helper subset 2

cell phenotype before such immune responsiveness to environmental

antigens is consolidated.

 

 

 

 

 

Probiotic therapy is based on the concept of a healthy microflora.

Probiotics can help stabilize the gut microbial environment and the

intestine's permeability barrier and enhance systemic and mucosal

IgA responses, thereby promoting the immunologic barrier of gut

mucosa. The probiotic approach, ie, therapeutically consuming

beneficial microorganism cultures of the healthy human microflora,

holds great promise for the prevention and treatment of clinical

conditions associated with impaired gut mucosal barrier functions

and sustained inflammatory responses.

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