Probiotics in human dia 1–3
Erika Isolauri
by guest on January 13, 2017
ajcn.nutrition Downloaded from
important fraction of antigens bypass the defen barrier. Anti-gens 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 frag-ments,thus reducing the immunogenicity of the protein and aid-ing host defen 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 respons (6).
The regulatory events constituting the intestinal immune
respon take place in organized lymphoepithelial tissue and cretory sites. The organized lymphoid tissues are compod of Peyer’s patches,which play an esntial role in intestinal immune function,and lymphocytes and plasma cells that are dis-tributed throughout the lamina propria. Intraepithelial lymphocytes are located above the basal lamina in the intestinal epithelium.The aggregations of lymphoid follicles are covered by a unique epithelium compod 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 (I g) G antibodies compared with
I gA and I gM,I gA antibody production is abundant at mucosal surfaces and cretory IgA is prent in dimeric or polymeric form (5).The cretory IgA antibodies in the gut form part of the com-mon mucosal immune system,including the respiratory tract and lacrimal,salivary,and mammary glands. Conquently,an immune respon initiated in the gut-associated lymphoid tissue can affect immune respon at other mucosal surfaces.
Intestinal permeability is a reflection of the gut-barrier func-tion (1). An immature gut barrier may lead to incread intesti-nal permeability and aberrant antigen transfer and immune respons,thus explaining vulnerability to infection,inflamma-tion,and hypernsitivity at an early age. Intestinal permeability can be incread condarily due to mucosal dysfunction that is induced by virus,bacteria,or dietary antigens (7,8). A great amount of antigens could thus traver the mucosal barrier and the routes of transport could be altered.
Environmental factors,particularly tho 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 abnce of inflamma-tory stimuli from the environment,the healthy and mature intes-tine is in a proinflammatory state,provoking many differentiated and activat
ed lymphocytes that generate proinflammatory cyto-kines,a state called controlled inflammation (10). The existence of active counterregulating process primed to mount antiin-flammatory respons may be mandatory for healthy interactions across the barrier.
NORMAL MICROFLORA AND GUT-BARRIER FUNCTIONS
I ntestinal colonization is accompanied by an increa in the numbers of intestinal lymphocytes and maturation of mucosal immune function (11,12). Intraluminal bacterial antigens elicit specific respons in gut-associated lymphoid tissue. I t was shown in experimental animal models that the capacity to gener-ate IgA-producing cells is initiated with the establishment of the gut microflora and with the ont of a specific IgA respon to the number of translocating bacteria drops,reflecting maturation of the intestine’s immunologic defen mechanisms (13). More-over,there is a reduction in the number of lamina propria lym-phocytes and the concentrations of rum immunoglobulin. I t has been shown that the condary lymphoid organs,ie,the spleen and lymph nodes,are poorly developed in germfree ani-mals becau of the lack of antigenic stimulation (11).
The role of the intestinal microflora in oral tolerance induc-tion (ie,the unresponsiveness to nonpathogenic antigens encoun-tered at the mucosal surface) to the IgE respon was investigated
in germfree mice (14). In contrast with control mice,germfree animals maintained their tendency to systemic immune respon,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 I gE respon in germfree mice could be corrected by reconstitution of the microflora at the neonatal stage but not later. The 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.
月季花几月份开花
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-creting cells (16).
The regulatory role of specific strains of the gut microflora was shown previously by a suppressive effect of immune respons to dietary antigens in allergic individuals (17),partly attributable to enhanced production of antiinflammatory cytokines,eg,inter-leukin 10 (18) and transforming growth factor (19),whereas the capacity to stimulate nonspecific immune respons was retained (20,21). Thus,as mucosal tolerance and immunization reprent a continuum of immunologic competence in
health (22),this pat-tern of immune respon is not altered by the consumption of sin-gle and mixed cultures of probiotic microorganisms (23).HEALTHY GUT MICROFLORA—THE SOURCE OF PROBIOTICS
Microbial colonization begins after birth,and initially,facul-tative anaerobic strains dominate. Thereafter,lactic acid bacteria
PROBIOTICS IN HUMAN DISEASE 1143S
FIGURE 1.Gut microflora in inflammation. nflammation is accompanied by an imbalance of the intestinal microflora,and a strong inflammatory respon may be mounted to microfloral bacteria,lead-ing to perpetuation of the inflammation and gut-barrier dysfunction.Ig,immunoglobulin.
by guest on January 13, 2017
ajcn.nutrition Downloaded from
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 for-mula-fed infants have a more complex microflora that
contains bifidobacteria,bacteroides,clostridia,and streptococci. After weaning,the composition of the microflora rembles that of the adult flora (23). I n the ileum,bacterial concentrations gradu-ally incread to ≤1014total bacterial cells of different cultur-able 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 prent in the colon. Most of the bacteria are hitherto uncharacterized becau of the prence of noncul-turable bacteria and the inaccuracy and insufficiency of the iden-tification procedures available.
口才艺术The complex ecosystem of the adult intestinal microflora is estimated to harbor Ϸ500 different bacterial species. Some of the species are considered potentially harmful becau of their abilities of toxin production,mucosal invasion,or activation of carcinogens and inflammatory respons (23). The strains with health-promoting properties principally include bifidobacteria and lactobacilli. I n 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 respon 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 u,be sta-ble in acid and bile,and that it adhere to the intestinal mucosa (23). The most frequently ud genera fulfilling the 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,rearch 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 dias. A food can be defined as functional if it is shown to beneficially affect one or more target functions in the body beyond adequate nutri-tional effects in a way that is relevant to either the state of well-being and health,or to a reduction in dia incidence (23).The Westernized diet includes few fresh nutritional compo-nents and among the nonnutritional components there are few microbes (25). I t is characteristic of the diet in economically developed countries to include procesd and sterile foods con-taining artificial sweeteners,prervatives,and in some extreme cas,even antibioti
cs. Such a diet may deprive the immune sys-tem of important tolerogenic signals from the environment.The include antiinflammatory process promoted by specific microbes (17,26,27) and external antioxidants provided by fresh fruit and vegetables (28).
nflammation is accompanied by an imbalance in the intestinal microflora (29–31; PV Kirjavainen,E Apostolou,T Arvola,SJ Salminen,GR Gibson,E Isolauri,unpublished obr-vations,2001),and a strong inflammatory respon 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 incread intestinal per-meability and altered gut microecology,thus improving the intestine’s immunologic barrier and alleviating the intestinal inflammatory respon. The targets for probiotic therapy are thus identified as clinical conditions with impaired mucosal barrier function,particularly infectious and inflammatory dias (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 defen,thereby reducing the risk of contracting illness. This con-clusion is bad 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 sho
wn to induce in vitro the relea of proinflam-matory cytokines,tumor necrosis factor ␣,and interlukin 6,which reflects the stimulation of nonspecific immunity (32).Enhanced phagocytosis was substantiated in humans by Lacto-bacillus acidophilus strain La1 (33) and Lactobacillus rhamnosus strain GG (20). The effects could be crucial in the exclusion and eradication of pathogens. The stimulation of the host’s non-specific and specific humoral immune respons to potentially harmful antigens has been documented for,among others,Bifi-dobacterium bifidum ,Bifidobacterium breve,and L. rhamnosus GG (21,34,35). The specific IgA respon could contribute to the preventive potential of probiotics. This was clinically docu-mented in a reduction of diarrheal episodes in infants who were administered Lactobacillus helveticus – and Streptococcus ther-mophilus –fermented formula (36),L. acidophilus – and Lacto-bacillus cai –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 ud 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 assd 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 bal-ancing the gut microecology,the incidence of slower gastric empty-ing and partial hydrolysis of lacto during fermentation may be associated with the documented alleviation associated with symp-toms of condary lacto 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 indige-nous microflora (29),a reduction in the duration of rotavirus shedding (38),and a reduction in incread gut permeability caud by rotavirus infection (41) together with a significant
1144S ISOLAURI
by guest on January 13, 2017
ajcn.nutrition
Downloaded from
increa in IgA-creting cells to rotavirus (21,35). The multi-center study of the European Society of Pediatric Gastroenterol-ogy,Hepatology and Nutrition (42) extended this obrvation to preventing the evolution of rotavirus diarrhea toward a pro-tracted cour and thus confirmed the clinical benefit of probi-otics in the treatment of rotavirus diarrhea in infants.
There is an increasing appreciation of the role of cytokines in regulating inflammatory respons at a local and systemic level.The ingestion of probiotic bacteria can potentially stabilize the immunologic barrier in the gut mucosa by reducing the genera-tion of local proinflammatory cytokines (43,44). Alteration of the properties of the indigenous microflora by probiotic therapy was shown to rever some immunologic disturbances charac-teristic of Crohn dia (45),food allergy (44),and atopic eczema (19).
Recently,probiotics were shown to modulate the host’s immune respons to foreign antigens with a potential to dampen hypernsitivity reactions (24). Unheated and heat-treated homogenates were prepared from probiotic strains,including L. rhamnos us strain GG ,Bifidobacterium lactis ,L.acidophilus ,Lactobacillus delbrückii subsp . bulgaricus,and S.thermophilus (26). The phytohemag
glutinin-induced prolifera-tion of mononuclear cells was suppresd in the homogenates compared with controls with no homogenate,indicating that probiotic bacteria posss heat-stable,antiproliferative compo-nents,which could be therapeutically exploited in inflammatory conditions. Moreover,qualitative and quantitative differences between probiotic homogenates in the antiinflammatory prop-erties 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 con-ducted to determine cytokine production by anti-CD3–induced peripheral blood mononuclear cells in atopic infants with cow milk allergy (46). Unhydrolyzed cain incread the produc-tion of interleukin 4,whereas L. rhamnos us strain GG-hydrolyzed cain reduced it. This indicates that probiotics modify the structure of potentially harmful antigens and reduce their immunogenicity. The clinical correlate of this effect is en as a significant improvement in the clinical cour of atopic der-matitis (eczema) in infants who were administered a probiotic-supplemented elimination diet,and in parallel,markers of intestinal (44) and systemic (19) allergic inflammation decread significantly. Similar results were obtained in a study of milk-hypernsitive adults in whom a milk challenge in conjunction with a probi
otic strain prevented the immunoinflammatory respon characteristic of the challenge without probiotics (20).On the basis of the more recent studies of allergic inflamma-tion,a novel target of probiotic therapy may be to control the excess formation of IgE and the development of T helper subt 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 respons are under the control of cytokines that are produced by competing signals from the T helper cells. Patients with atopic dia manifest a high production of interleukin 4 (T helper subt 2 cells). Thus,the objective of the intervention is to redirect the immunologic memory away from the T helper subt 2 cell phenotype before such immune responsiveness to environmental antigens is consolidated.
CONCLUSION
Probiotic therapy is bad on the concept of a healthy microflora. Probiotics can help stabilize the gut microbial envi-ronment and the intestine’s permeability barrier and enhance systemic and mucosal I gA respons,thereby promoting the immunologic barrier of gut mucosa. The probiotic approach,ie,therapeutically consuming beneficial microorganism cultures of the healthy human microflora,holds great promi for the pre-vention and treatment of clinical conditions associated with
impaired gut mucosal barrier functions and sustained inflamma-tory respons.REFERENCES
1.Editorial. Intestinal permeability. Lancet 1985;1:256–8.
2.Sanderson IR,Walker WA. Uptake and transport of macromolecules by the intestine:
possible role in clinical disorders (an update). Gas-troenterology 1993;104:622–39.
3.Carol M,Lambrechts A,Van Gossum A,Libin M,Goldman M,Mascart-Lemone F. Spontaneous cretion of interferon-␥and interleukin 4 by human intraepithelial and lamina propria gut lym-phocytes. Gut 1998;42:643–9.
4.Isolauri E,Sütas Y ,Kankaanpää P,Arvilommi H,Salminen S. Probi-otics:effects on immunity. Am J Clin Nutr 2001;73(suppl):444S–50S.
5.Brandtzaeg P. Molecular and cellular aspects of the cretory immunoglobulin system. APMIS 1995;103:1–19.
6.Ducroc R,Heyman M,Beaufrere B,Morgat JL,Desjeux JF. Hor-radish peroxida transport across rabbit jejunum and Peyer’s patches in vitro. Am J Physiol 1983;245:G54–8.
7.Isolauri E,Juntunen M,Wiren S,Vuorinen P,Koivula T. Intestinal permeability changes in acute gastroenteritis:effects of clinical fea-tures and nutritional management. J Pediatr Gastroenterol Nutr 1989;4:466–73.
8.Majamaa H,Isolauri E. Evaluation of gut mucosal barrier:evidence for incread antigen transfer in children with atopic eczema.J Allergy Clin Immunol 1996;97:985–90.
9.Fargeas MJ,Theodorou V,More J,Wal JM,Fioramonti J,Bueno L.Boosted systemic immune and local responsiveness after intestinal inflammation in orally nsitized guinea pigs. Gastroenterology 1995;109:53–62.
10.O’Farrelly C. Just how inflamed is the normal gut? Gut 1998;42:
603–6.
11.Berg RD. The indigenous gastrointestinal microflora. Trends Micro-biol 1996;4:430–5.
书名号的作用12.Cebra JJ. I nfluences of microbiota on intestinal immune system
development. Am J Clin Nutr 1999;69(suppl):1046S–51S.
13.Shroff KE,Meslin K,Cebra JJ. Commensal enteric bacteria engen-der a lf-limiting humoral mucosal immune respon while perma-nently colonizing the gut. Infect Immun 1995;63:3904–13.
14.Sudo N,Sawamura S,Tanaka K,Aiba Y,Kubo C,Koga Y. The
requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction.J Immunol 1997;159:1739–45.
15.Grönlund MM,Lehtonen OP,Eerola E,Kero P. Fecal microflora in
healthy infants born by different methods of delivery:permanent changes in intestinal flora after cesarean delivery. J Pediatr Gas-troenterol Nutr 1999;28:19–25.
16.Grönlund MM,Arvilommi H,Kero P,Lehtonen OP,I solauri E.
Importance of intestinal colonisation in the maturation of humoral immunity in early infancy:a prospective follow up study of healthy infants aged 0–6 months. Arch Dis Child 2000;83:F186–92.
17.Sütas Y,Soppi E,Korhonen H,et al. Suppression of lymphocyte
proliferation in vitro by bovine cains hydrolyd with Lactobacil-lus GG-derived enzymes. J Allergy Clin Immunol 1996;98:216–24.18.Pessi T,Sütas Y,Hurme M,Isolauri E. Interleukin-10 generation in
atopic children following oral Lactobacillus rhamnos us GG. Clin Exp Allergy 2000;30:1804–8.
PROBIOTICS IN HUMAN DISEASE
1145S
by guest on January 13, 2017
ajcn.nutrition Downloaded from
19.I solauri E,Arvola T,Sütas Y,Salminen S. Probiotics in the man-agement of atopic eczema. Clin Exp Allergy 2000;30:1605–10.20.Pelto L,Isolauri E,Lilius EM,Nuutila J,Salminen S. Probiotic bac-teria downregulate the milk-induced inflammatory respon in milk-hypernsitive subjects but have an immunostimulatory effect in healthy subjects. Clin Exp Allergy 1998;28:1474–9.
21.Kaila M,I solauri E,Soppi E,Virtanen E,Laine S,Arvilommi H.
Enhancement of the circulating antibody creting cell respon in human diarrhea by a human Lactobacillus strain. Pediatr Res 1992;32:141–4.
自律作文800字22.Weiner HL,van Rees EP. Mucosal tolerance. Immunol Lett 1999;
69:3–4.
23.Salminen S,Bouley C,Boutron-Ruault MC,et al. Functional food
science and gastrointestinal physiology and function. Br J Nutr 1998;80(suppl):S147–71.
24.Isolauri E,Salminen SJ,Mattila-Sandholm T. New functional foods
in the treatment of food allergy. Ann Med 1999;31:299–302.
25.Bengmark S. Ecological control of the gastrointestinal tract. The
role of probiotic flora. Gut 1998;42:2–7.
26.Pessi T,Sütas Y,Saxelin M,Kallioinen H,Isolauri E. Antiprolifera-tive effects of homogenates derived from five strains of candidate probiotic bacteria. Appl Environ Microbiol 1999;65:4725–8.
27.Kankaanpää P,Sütas Y,Salminen S,solauri E. Homegenates
derived from probiotic bacteria provide downregulatory signals for peripheral blood mononuclear cells. Clin Exp Immunol (in press).28.Soutar A,Seaton A,Brown K. Bronchial reactivity and dietary
antioxidants. Thorax 1997;52:166–70.
29.Isolauri E,Kaila M,Mykkänen H,Ling WH,Salminen S. Oral bac-teriotherapy for viral gastroenteritis. Dig Dis Sci 1994;39:2595–600.30.Malin M,Verronen P,Mykkänen H,Salminen S,solauri E.
ncread bacterial urea activity in faeces in juvenile chronic arthritis:evidence of altered intestinal microflora? Br J Rheumatol 1996;35:689–94.
31.Duchmann R,Kair I,Hermann E,Mayet W,Ewe K,Meyer zum
Büschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel dia (IBD). Clin Exp Immunol 1995;102:448–55.科研工作
32.Miettinen M,Vuopio-Varkila J,Varkila K. Production of human
tumor necrosis factor alpha,interleukin-6,and interleukin-10 is induced by lactic acid bacteria. Infect Immun 1996;64:5403–5.33.Schiffrin EJ,Rochat F,Link-Amster H,Aeschlimann JM,Donnet-Hughes A. Immunomodulation of human blood cells following the ingestion of lactic acid bacteria. J Dairy Sci 1994;78:491–7.
34.Yasui H,Nagaoka N,Mike A,Hayakawa K,Ohwaki M. Detection
of Bifidobacterium strains that induce large quantities of I gA.Microb Ecol Health Dis 1992;5:155–62.
35.Majamaa H,Isolauri E,Saxelin M,Vesikari T. Lactic acid bacteria
早餐粥in the treatment of acute rotavirus gastroenteritis. J Pediatr Gas-troenterol Nutr 1995;20:333–9.
36.Brunr O,Araya M,Espinoza J,Guesry PR,Secretin MC,Pacheco I.
Effect of an acidified milk on diarrhoea and the carrier state in infants of low socio-economic stratum. Acta Paediatr Scand 1989;78:259–64.
37.Gonzalez S,Albarracin G,Locascio de Ruiz Pesce M,et al. Preven-tion of infantile diarrhoea by fermented milk. Microbiologie Ali-ments Nutr 1990;8:349–54.
38.Saavedra JM,Bauman NA,Oung I,Perman JA,Yolken RH. Feed-ing of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994;344:1046–9.
39.Salminen S,Deighton MA,Benno Y,Gorbach SL. Lactic acid bac-teria in health and dia. In:Salminen S,von Wright A,eds. Lac-tic acid bacteria. New York:Marcel Dekker Inc,1998:211–53.
40.Saavedra JM. Clinical application of probiotic agents. Am J Clin
Nutr 2000;73(suppl):1147S–51S.
41.Isolauri E,Kaila M,Arvola T,et al. Diet during rotavirus enteritis
affects jejunal permeability to macromolecules in suckling rats.Pediatr Res 1993;33:548–53.
42.Guandalini S,Pensabene L,Zikri MA,et al. Lactobacillus GG
administered in oral rehydration solution to children with acute diarrhoea:a multicenter European trial. J Pediatr Gastroenterol Nutr 2000;30:54–60.
43.Isolauri E,Majamaa H,Arvola T,Rantala I,Virtanen E,Arvilommi
学习炸鸡腿
H. Lactobacillus cai strain GG revers incread intestinal per-meability induced by cow milk in suckling rats. Gastroenterology 1993;105:1643–50.
44.Majamaa H,Isolauri E. Probiotics:a novel approach in the manage-ment of food allergy. J Allergy Clin Immunol 1997;99:179–86.45.Malin M,Suomalainen H,Saxelin M,Isolauri E. Promotion of IgA
immune respon in patients with Crohn’s dia by oral bacte-riotherapy with Lactobacillus GG. Ann Nutr Metab 1996;40:137–45.
46.Sütas Y,Hurme M,Isolauri E. Downregulation of antiCD3 antibody-induced IL-4 production by bovine cains hydrolyd with Lacto-bacillus GG-derived enzymes. Scand J Immunol 1996;43:687–9.
1146S ISOLAURI
by guest on January 13, 2017怎么冲咖啡
ajcn.nutrition
Downloaded from
