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Many trials on p robiotics are now published that use

established methods t o demonstrate their c linical efficacy.C onvincing p rogress has been made in the field of inflammatory

bowel disease and allergy prevention in infants. Experimental

studies show clear differences (and even sometimes oppos ite

effects) betw een apparently closely related p robiotics and

suggest new mechanisms for the observed effects, such as

immunostimulation by bac terial D NA and interaction w ith Toll-

like receptors and d endritic cells in the g astrointestinal tract.

AddressesGastroenterology Department, European Hospital Georges Pompidou,Assistance Publique des Hpitaux de Paris & Paris V University, France*e-mail: [email protected]

Current Opinion in Biotechnology 2002, 13 :486489

095 8-1669/ 02/$ see front matter 2 002 Elsevie r S c ien ce Ltd. Al l r ights reserve d .

AbbreviationsIL-10 interleukin 1 0ISS-DNA immunostimulatory DNA sequenceRCT randomized controlled trial

IntroductionProbiotics have been defined as non-pathogenic micro-

organisms that, when ingested, exert a positive influence

on host health or physiology [1]. Many physicians havelong been sceptical about their efficacy, as evidence for

their efficacy was low and information on the stability of

the strains in the products and their survival in the

gastrointestinal tract was often lacking. However, a phar-

macological approach has now been used to assess the

effects and pharmacokinetics [2], and both scientists and

health providers are showing renewed interest. Before

1990, 22 articles on probiotics were quoted in the Medline

library, whereas more than 1000 have been published in

the past ten years, including more than 200 in the first six

months of this year. We now know that the pharmacokinetics

of probiotics varies between strains and that many are

indeed effective, as shown by positive double-blindrandomized controlled trials (RCTs). Probably the most

interesting and unexpected data were produced in the past

few years in the field of immunomodulation with probiotics:

treatment of allergic diseases or inflammatory bowel

diseases. We summarize here recent data and ideas.

Probiotics and immunomodulationThe microorganisms present in the gastrointestinal tract,

including the endogenous flora, interact with the mucosal

cells including epithelial cells [3] and immune cells.

Progress has been made in our understanding of the mech-

anism of this interaction. Considerable interest has focused

on dendritic cells. Dendritic cells belong to the group of

antigen-presenting cells that initiate the local immune

response in the intestinal mucosa and play a pivotal

immunoregulatory role in the balance of T helper cellsTh1, Th2 and Th3. Christensen et al. [4] showed that different

species of lactobacilli exert very different activation

patterns on the dendritic cells. Furthermore, Lactobacillus

reuteri DSM12246 inhibited the activities of the other

species. Clearly, not all probiotics share the same

immunomodulating properties and can even have opposite

effects on some parameters. Moreover, in this model the

dose of probiotics also strongly influenced the nature of the

immune response [4], which leaves us with new questions.

It has been recently discovered that bacterial DNA contains

immunostimulatory sequences (ISS-DNA), especially

non-methylated CpG motifs, which interact with Toll-like

receptor-9 of epithelial cells; these sequences are potent

activators of the innate immunity and exhibit anti-apoptotic

properties in the mucosa [5]. Rachmilewitz et al. [5]

showed that the administration of ISS-DNA was beneficial

for the colonic mucosa in mice with chemically induced

colitis. They then showed that the beneficial effect of the

probiotic mixture VSL#3 (which contains three strains of

bifidobacter, four strains of lactobacilli and a Streptococcus

thermophilus) on this colitis model was derived from its

DNA, as VSL genomic unmethylated DNA was effective

whereas VSL methylated DNA and calf thymus DNA

were ineffective [6]. These interesting and original resultsopen avenues for the discovery of new treatments of

inflammatory bowel disease and also demonstrate

unsuspected mechanisms for some of the effects of

probiotics. Madsen et al. [7] recently showed that bacterial

VSL#3 DNA downregulated proinflammatory cytokine

secretion by attenuation of the NF-B pathway in intestinalepithelial cells.

Probiotics and intestinal inflammationBacteria in the gastrointestinal tract strongly influence

intestinal inflammation and the majority of inflammatory

bowel diseases, both in humans and animals, are more

severe in the presence of the endogenous flora. Animalstudies have demonstrated that some probiotics may

significantly prevent or help cure inflammatory bowel

diseases. Several RCTs have now confirmed a beneficial

effect in humans with pouchitis, ulcerative colitis or

Crohns disease. Gionchetti et al. [8] performed a double-

blind RCT comparing the effects of the probiotic VSL#3

and a placebo in preventing the recurrence of chronic

relapsing pouchitis (an inflammatory bowel disease occurring

after surgical resection of the colon). A total of 40 patients

were treated for nine months; a relapse occurred in 15% of

those in the VSL#3 group versus 100% in the placebo

group (p [the statistical probability]


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Probiotics and health: new facts and ideas Marteau, Seksik and Jian 48 7

patients versus 94% in the placebo-treated patients [9].

Interestingly, VSL#3 increased the tissue levels of inter-

leukin 10 (IL-10) in these patients [10]. The same authors

studied the effects of VSL#3 in the prevention of pouchitis

[11]. Forty patients who had colectomy and ileo-pouch

anal anastomosis for ulcerative colitis were randomized toreceive either VSL#3 or placebo immediately after surgery

and for one year. Pouchitis occurred in 10% of the patients

in the VSL#3 group versus 40% in the placebo group

(p


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488 Food biotechnology

modified the genome of a Lactococcus lactis strain to make

it produce high levels of IL-10. Intragastric administration

of this IL-10-secreting probiotic caused a 50% reduction in

mice with colitis induced with dextran sodium sulfate and

prevented the onset of colitis in IL-10 knockout mice (two

models of inflammatory bowel disease). Thus, the probioticvector could provide a way to deliver the active ingredient

(IL-10) at the site of inflammation. Other probiotics carrrying

different immunomodulating molecules are currently

being tested (e.g. superoxide dismutase, trefoil peptides).

As Crohns disease mainly affects the distal ileum and

colon in humans, a probiotic vector with good pharmaco-

kinetics to this target should be selected for future trials.

ConclusionsThere is now real evidence that probiotics significantly

influence health; however, they are not a panacea.

Negative trials have also been published and should beencouraged, as one might learn from them and because no

information should be hidden. New molecular tools, espe-

cially DNA microarray techniques, will allow us to further

our understanding of how commensal or exogenous

microorganisms modulate the expression of genes involved

in several important intestinal functions including immunity.

References and recommended readingPapers of particular interest, published within the annual period of review,have been highlighted as:

of special interest of outstanding interest

1. Dunne C, Murphy L, Flynn S, OMahony L, OHalloran S, Feeney M,Morrissey D, Thornton G, Fitzgerald G, Daly C et al.: Probiotics: frommyth to reality. Demonstration of functionality in animal models ofdisease and in human clinical trials. Antonie Van Leeuwenhoek1999 , 76 :279-292.

2. Marteau PR, Vrese MD, Cell ier CJ, Schrezenmeir J: Protection fromgastrointestinal diseases with the use of probiotics. Am J ClinNutr2001, 73 :430S-436S.

3. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI: Molecular analysis of commensal host-microbial relationships in

the intestine. Science2001, 29 1 :881-884.This paper shows that c ommensal bacteria modulate the expression of someof the host genes involved in several important intestinal functions, includingmucosal barrier fortification. These findings provide perspectives about theinteractions betw een resident or ingested microorganisms and their hosts.

4. Chris tensen HR, Frok iaer H, Pestka JJ: Lactobacilli differentially

modulate expression of cytokines and maturation surfacemarkers in murine dendritic cells. J Immunol2002, 1 6 8 :171-178.

5. Rachmilewitz D, Karmeli F, Takabayashi K, Hayashi T, Leider-Trejo L, Lee J, Leoni LM, Raz E: Imm unostimulatory DNA ameliorates

experimental and spontaneous m urine colitis. Gastroenterology2002, 122 :1428-1441.

Immunostimulatory DNA sequences (ISS-DNA) from bacteria were shownfor the first time to decrease inflammation in several models of inflammatorybow el disease in rodents (dextran sodium sulfate-induced colitis and hapten-induced colitis in Balb c mice, and spontaneous colitis occurring in IL-10knockout mice). The ISS-DNA inhibited the induction of colonic proinflam-matory cytokines and chemokines and suppressed the induction of c olonicmatrix metalloproteinases. As the gastrointestinal tract, especially the ileumand the c olon, is exposed to bacterial DN A, these findings suggest a physi-ological, anti-inflammatory role for immunostimulatory DNA from endogenousbacteria in the gastrointestinal tract.

6. Rachmilewitz D, Karmeli F, Takabayashi K, Hayashi T, Raz E:Amelioration of experimental colitis by probiotics is due to theimmunostimulatory effect of its DNA. Gastroenterology2002,122 :abstract T10 04 .

7. Madsen K, Ji jon H, Yeung H, McKaigney C, De Simone C: DNA fromprobiotic bacteria exerts anti-inflammatory actions on epithelialcells by inhibition of N FB. Gastroenterology2002,122 :abst ract 546.

8. G ionchetti P, Rizzello F, Venturi A, Brigidi P, Matteuzzi D, Bazzocchi G, Poggioli G, M iglioli M, Camp ieri M: Oral bacteriotherapy as

maintenance treatment in patients with chronic pouchitis:a double-blind, placebo-controlled trial. Gastroenterology2000,11 9 :305-309.

A well-designed double-blind placebo-controlled study showing that aprobiotic preparation is very effective in the treatment of chronic relapsingpouchitis (an inflammatory bowel disease that occurs in humans afterileoanal anastomosis and in w hich the endog enous flora is thought to havea role).

9. Mimura T, Rizzello F, Schreiber S, Talbot IC, Nicholls R, Gionchetti P,Campieri M, Kamm M: Once daily high dose probiotic therapymaintains remission and improved quality of life in patients withrecurrent or refractory pouchitis: a randomized, placebo-controlled double-blind trial. Gastroenterology2002,122 :abstract 667.

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12 . Kruis W, Schutz E, Fric P, Fixa B, Judmaier G, Stolte M: Double-blindcomparison of an oral Escherichia colipreparation andmesalazine in maintaining remission of ulcerative colitis. AlimentPharmacol Ther1997, 1 :853-858.

13 . Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT:Non-pathogenic Escherichia coliversus mesa lazine for thetreatment of ulcerative colitis: a randomised trial. Lancet1999 ,3 5 4 :635-639.

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Escherichia coliNissle 1917 and with standard mesalamine.Gastroenterology2001, 120 :A139.

15 . Isolauri E, Arvola T, Sutas Y, Moilanen E, Salminen S: Probiotics inthe management of atopic eczema. Clin Exp Allergy2000,3 0 :1604-1610.

16 . Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E: Probiotics in primary prevention of atopic disease: a randomised

placebo-controlled trial. Lancet2001, 3 57 :1076-1079.This double-blind randomized placebo-controlled study show s that prob ioticadministration in mothers before birth, during lactation and in infants signifi-cantly decreases the risk of developing atopic eczema in the first two yearsof life. This result is in keeping with the theory that an excessive hygiene (ora too low bacterial priming of the immune system) in infancy is associatedwith an increased risk of allergy.

17. Rautava S, Kalliomaki M, Isolauri E: Probiotics during pregnancy andbreast-feeding might confer immunom odulatory protection

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18 . Kirjavainen PV, Apostolou E, Arvola T, Salminen SJ, Gibson G R,Isolauri E: Characterizing the composition of intestinal microfloraas a prospective treatment target in infant allergic disease. FEMSImmunol Med Microbiol2001, 32 :1-7.

19 . Apostolou E, Pelto L, Kirjavainen PV, Isolauri E, Salminen SJ,G i bs on GR: Differences in the gut bacterial flora of healthy andmilk-hypersensitive adults, as measured by fluorescence in situhybridization. FEMS Immunol Med Microbiol2001, 3 0 :217-221.

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on birch-pollen allergy: a placebo-controlled double-blind study.Allergy2002, 57 :243-246.

This paper shows that L. rhamnosus GG is not effective in every case ofallergy, as no effect was o bserved in adults or teenagers w ith birch pollen

and apple allergy.21. Coconnier MH, Lievin V, Hemery E, Servin AL: Antagonistic activity

against Helicobacter infection in vitroan d in vivoby the hum an


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Probiotics and health: new facts and ideas Marteau, Seksik and Jian 48 9

Lactobacillus acidophilusstrain LB. Appl Environ Microbiol1998 ,6 4 :4573-4580.

22 . Cremonini F, Canducci F, Di Caro S, Santarelli L, Armuzzi A,Gasbarrini G, G asbarrini A: Helicobacter p yloritreatment: a role forprobiotics? Dig Dis2001, 1 9 :144-147.

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25 . Mukai T, Asasaka T, Sato E, Mori K, Matsumoto M, Ohori H: Inhibitionof binding of Helicobacter p ylorito the glycolipid receptors byprobiotic Lactobacillus reuteri. FEMS Immunol Med Microbiol2002, 32 :105-110.

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This paper shows that bacteria that are lysed by bile in the upper smallintestine may be used to transport enzymes and cure disease. L. lactis thatwas genetically modified to contain high levels of lipase helped lipid

digestion in a pig model with pancreatic insufficiency. Clinical applicationscan be expected, especially in patients with cystic fibrosis and insufficientresponse to classical pancreatic enzyme supplementation. Geneticallymodified probiotics could constitute new treatment strategies.

28. Sidhu H, All ison MJ, Chow JM, Clark A, Peck AB: Rapid reversal ofhyperoxaluria in a rat model after probiotic administration ofOxalobacter formigenes. J Urol2001, 1 6 6 :1487-1491.

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