Probiotics as related to Obesity & Human Disease

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Probiotics as related to Obesity & Human Disease

Apr 04, 2003 10:46 PST

 

American Journal of Clinical Nutrition,

Vol. 73, No. 6 June 2001

 

© 2001 American Society for Clinical Nutrition

--

 

Probiotics and disease

Address reprint requests to E Isolauri,Department of Pediatrics,

University of Turku, 20520 Turku, Finland.

E-mail: erika.i-.

ABSTRACT

 

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 regulation.

 

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

 

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.

 

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.

 

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.

 

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

an effect on the risk of inflammatory diseases.

 

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.

 

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

..

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.

 

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 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.

 

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

 

.. 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 .

 

 

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

 

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.

 

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.

 

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

Intestinal colonization is accompanied by an increase in the numbers

of intestinal lymphocytes and maturation of mucosal immune function

 

.. 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.

 

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.

 

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.

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 invaginally born

infants and in infants born by cesarean delivery

showed major differences in culturable microflora.

 

Colonization was associated with the maturation of humoral immune

mechanisms, particularly of circulating IgA- and IgM-secreting

cells.

 

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, partly attributable

to enhanced production of antiinflammatory cytokines, eg,

interleukin 10 and transforming growth factor ß, whereas

the capacity to stimulate nonspecific immune responses was

retained .

 

Thus, as mucosal tolerance and immunization represent a

continuum of immunologic competence in health, this pattern of

immune response is not altered by the consumption of single and

mixed cultures of probiotic microorganisms .

 

 

 

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.

 

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

 

.. 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

..

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.

 

 

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.

 

The most frequently used genera fulfilling these criteria are

Lactobacillus and Bifidobacterium.

 

 

PROBIOTIC FUNCTIONAL FOODS—AN OLD RECIPE FOR MODERN COOKING

 

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).

 

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.

 

The Westernized diet includes few fresh nutritional components and

among the nonnutritional components there are few microbes.

 

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 and external antioxidants provided by fresh fruit and

vegetables

..

 

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.

 

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

 

.. 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.

 

Specific probiotic bacteria were shown to promote nonspecific host

resistance to microbial pathogens.

 

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 .

 

Enhanced phagocytosis

was substantiated in humans by Lactobacillus acidophilus strain La1

and Lactobacillus rhamnosus strain GG. 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.

 

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, L. acidophilus–

and Lactobacillus casei–fermented milk, or a formula

supplemented with B. bifidum and S. thermophilus.

 

The principal effect of probiotics is characterized by stabilization

of the gut microflora.

 

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.

 

Similarly, evidence from recent well-controlled studies indicates

that

probiotics may be of value in the prevention of antibiotic-

associated diarrhea.

 

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.

 

The best-documented clinical application of probiotics is in the

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

inflammatory conditions.

 

The beneficial, clinical effect of probiotics was explained by

stabilization of the indigenous microflora , a reduction in the

duration of rotavirus shedding , and a reduction in increased gut

permeability caused by

rotavirus infection together with a significant increase in IgA-

secreting cells to rotavirus .

 

The multicenter study of the European Society of Pediatric

Gastroenterology, Hepatology and

Nutrition 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.

 

Alteration of the properties of the indigenous microflora by

probiotic therapy was

shown to reverse some immunologic disturbances characteristic of

Crohn disease, food allergy , 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.

 

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 .

 

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.

 

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.

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 and systemic 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.

 

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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