Protection from gastrointestinal diseases with the use ofprobiotics1–3 Philippe R Marteau, Michael de Vrese, Christophe J Cellier, and Jürgen Schrezenmeir ABSTRACT
Probiotics are nonpathogenic microorganisms IMPROVED LACTOSE DIGESTION AND OTHER
that, when ingested, exert a positive influence on the health or DIRECT ENZYMATIC EFFECTS
physiology of the host. They can influence intestinal physiology Lactose maldigestion occurs frequently, especially in adults (pri- either directly or indirectly through modulation of the endoge- mary lactose maldigestion) and in persons with bowel resection or nous ecosystem or immune system. The results that have been enteritis (secondary lactose maldigestion). It is well established that shown with a sufficient level of proof to enable probiotics to be persons with lactose maldigestion experience better digestion and used as treatments for gastrointestinal disturbances are 1) the tolerance of the lactose contained in yogurt than of that contained in good tolerance of yogurt compared with milk in subjects with milk (3). The mechanisms involved have been extensively investi- primary or secondary lactose maldigestion, 2) the use of Sac- gated. The importance of the viability of lactic acid bacteria was charomyces boulardii and Enterococcus faecium SF 68 to pre- speculated as pasteurization reduced the observed digestibility. At vent or shorten the duration of antibiotic-associated diarrhea, least 2 mechanisms, which do not exclude each other, have been 3) the use of S. boulardii to prevent further recurrence of shown: digestion of lactose in the gut lumen by the lactase con- Clostridium difficile–associated diarrhea, and 4) the use of fer- tained in the yogurt bacteria (the yogurt bacteria deliver lactase mented milks containing Lactobacillus rhamnosus GG to when lyzed by bile acids) and slower intestinal delivery or transit shorten the duration of diarrhea in infants with rotavirus enteri- time of yogurt compared with milk (3–6). In clinical practice, the tis (and probably also in gastroenteritis of other causes). Effects replacement of milk with yogurt or fermented dairy products allows that are otherwise suggested for diverse probiotics include alle- for better digestion and decreases diarrhea and other symptoms of viation of diarrhea of miscellaneous causes; prophylaxis of gas- intolerance in subjects with lactose intolerance, in children with trointestinal infections, which includes traveler’s diarrhea; and diarrhea, and in subjects with short-bowel syndrome (3, 4, 7, 8). An immunomodulation. Trials of gastrointestinal diseases that enhanced digestion of a sucrose load was shown in infants with involve the ecosystem are currently being performed, eg, Heli- sucrase deficiency when they consumed Saccharomyces cerevisiae, cobacter pylori infections, inflammatory bowel disease, and ie, a yeast that contains the enzyme sucrase (9). This is yet another Am J Clin Nutr 2001;73(suppl):430S–6S.
example of a direct effect of a probiotic; however, its relevance inthe treatment of sucrase deficient subjects is not established.
Probiotics, bifidobacteria, lactobacilli, intesti- nal infections, antibiotic-associated diarrhea, gastroenteritis, ANTIBIOTIC-ASSOCIATED DIARRHEA
traveler’s diarrhea, intestinal flora, inflammatory bowel disease, Diarrhea occurs in ≤ 20% of patients who receive antibiotics.
Antibiotic-associated diarrhea (AAD) results from a microbialimbalance that leads to a decrease in the endogenous flora that isusually responsible for colonization resistance and to a decrease INTRODUCTION
in the fermentation capacity of the colon. Clostridium difficile Probiotics can be defined as nonpathogenic microorganisms and Klebsiella oxytoca contribute to the occurrence of AAD in that, when ingested, exert a positive influence on the health or some cases and play a role in the pathogenesis of colonic lesions.
physiology of the host (1). They consist of either yeast or bacte- Several attempts have been made to determine whether the admin- ria, especially lactic acid bacteria. Their fate in the gastrointesti- istration of probiotics would prevent antibiotic-associated nal tract and their effects differ among strains (2). The effects ofprobiotics can be direct or indirect through modulation of the endogenous flora or of the immune system (2). Many health From the Gastroenterology Department, Hôpital Europèen Georges Lompidou, Assistance Publique des Hôpitaux de Paris and Paris V University, claims have been made concerning probiotics, especially con- Paris, and the Institute of Physiology and Biochemistry of Nutrition, Federal cerning their potential to prevent or help cure intestinal distur- Dairy Research Center, Kiel, Germany.
bances; however, only a few probiotic strains were shown to be 2 Presented at the symposium Probiotics and Prebiotics, held in Kiel, Ger- efficacious in randomized placebo-controlled clinical trials. In this article, we summarize the present knowledge on the thera- 3 Address correspondence to P Marteau, Service de Gastro-entérologie, Hôpi- peutic effects of probiotics in human gastrointestinal diseases.
tal Europèen Georges Lompidou, Lorue Leblanc, 75908 Paris Cedex 15, France.
Am J Clin Nutr 2001;73(suppl):430S–6S. Printed in USA. 2001 American Society for Clinical Nutrition TABLE 1
Randomized controlled trials showing a significant therapeutic effect of probiotics in the prevention of antibiotic-associated intestinal symptoms (mainly diarrhea)
Lactobacillus acidophilus + Lactobacillus bulgaricus 1 Percentage of subjects with antibiotic-associated intestinal symptoms in the probiotic and control groups, respectively.
2 The authors reported a positive effect of the probiotic but did not provide the percentage of subjects with antibiotic-associated adverse effects in the 2 groups.
intestinal symptoms (mainly AAD). Randomized controlled tri- they received oral rehydration solution formulated according als that showed a significant therapeutic effect of probiotics are to usual recommendations in addition to L. rhamnosus GG shown in Table 1; the effects of probiotics on C. difficile and
[≥ 109 colony-forming units (CFU)/250 mL] or placebo. The dura- K. oxytoca are shown in the next section. Three randomized, dou- tion of diarrhea was 58 ± 28 h in the L. rhamnosus GG group and ble-blind, placebo-controlled studies showed that oral adminis- 72 ± 36 h in the placebo group (NS); diarrhea was significantly tration of Saccharomyces boulardii (Ultralevure, Biocodex, reduced by L. rhamnosus GG in children with rotavirus infection France) can decrease the risk of AAD (Table 1). Another study (56 ± 17 h compared with 77 ± 42 h; P < 0.05) but not in the showed that S. boulardii significantly shortened the duration of 186 children who were rotavirus negative (59 ± 33 h compared AAD (22). The mechanism involved is unclear because multiple with 69 ± 22 h). Administration of L. rhamnosus GG also short- biological effects of the yeast in the gastrointestinal tract have ened the duration of the hospital stay and the course of weight been shown, which may contribute to the clinical efficacy of gain (38). The results of one study suggested that heat-inactivated S. boulardii (ie, effects against the population levels of C. difficile, L. rhamnosus GG was as effective as living L. rhamnosus GG toxins, and intestinal secretion) (23, 24). The therapeutic efficacy in reducing the duration of diarrhea; however, the effect of the of other probiotics is not as well established. It is possible that living probiotic was more pronounced on rotavirus specific differences in probiotic preparation may explain why a mixture of immunoglobulin A response (45). Enterococcus faecium SF 68 freeze-dried lactobacilli significantly prevented diarrhea in 1 study (Bioflorin, Giuliani, Switzerland) was shown to significantly but not in 2 other studies (10, 11, 25; Table 1). Whether yogurt shorten the duration of diarrhea in 4 randomized controlled trials, may help to prevent or cure AAD was suggested in open trials but 2 in infants and 2 in adults (Table 2). Other probiotics are proba- has not been studied in controlled experiments (2).
bly also effective (Table 2). Boudraa et al performed a random-ized study of yogurt compared with a milk formula in 112 youngAlgerian children with acute diarrhea (data not published). Both GASTROENTERITIS
formulas were comparable in terms of lactose content, pH, flavor, Gastroenteritis is the main cause of acute diarrhea and is a fre- and texture. The mean duration of diarrhea was significantly quent disorder that usually heals spontaneously within a few reduced from 65 ± 5 h in the milk group to 44 ± 5 h in the yogurt days. Gastroenteritis can be due to several viral or bacterial group. At 48 h, 35% of children in the milk group were cured of pathogens or to parasites, but the most frequent cause in children their diarrhea, compared with 64% in the yogurt group. The dif- is rotavirus infection. The use of oral rehydration solutions is the ference was even more pronounced when only the 72 infants main treatment, but it does not shorten the duration of diarrhea.
with rotavirus were considered: 27% were cured with milk, com-pared with 68% with yogurt (G Boudraa, unpublished observa- Curative treatment
tions, 1996). Note that a significant shortening of gastroenteritis Several controlled randomized trials showed a beneficial effect was reported in adults treated with heat-killed lactobacilli of probiotics and fermented dairy products in infantile or, less (Lacteol fort, Lactéol du Dr Boucard, France) (46).
often, adult gastroenteritis; however, this is not a general propertyof all probiotics (26–28). Lactobacillus rhamnosus GG (L. GG, Prevention
Valio, Finland) has been shown to be effective in the treatment of Several nonrandomized trials suggest a preventive effect of infant rotavirus diarrhea (Table 2). L. rhamnosus GG repeatedly
some fermented products on the risk of diarrhea in children (2, 47).
reduced the duration of diarrhea by about half in randomized con- Saavedra et al (44) showed that feeding Bifidobacterium bifidum trolled trials (Table 2). It also proved effective in the treatment of and Streptococcus thermophilus to infants admitted to the hospital acute diarrhea in children in Asia (34, 35). Guandalini et al (38) significantly reduced the risk of diarrhea and the shedding of recently reported the results of a double-blind multicenter Euro- rotavirus (Table 2). In a double-blind placebo-controlled trial, pean trial in children with acute diarrhea. Two-hundred eighty- 55 children admitted to a chronic medical care unit were randomly seven children aged 1–36 mo with acute diarrhea were enrolled; assigned to receive a standard formula or a standard formula with TABLE 2
Randomized controlled trials showing a significant therapeutic effect of probiotics to shorten the duration of acute gastroenteritis
Lactobacillus casei strain Shirota Bifidobacterium bifidum and Streptococcus thermophilus 1 G Boudraa, unpublished observations, 1996.
B. bifidum and S. thermophilus. During follow-up, diarrhea Helicobacter pylori would be a good target for an efficient occurred in 7% of the children receiving the probiotic and in 31% probiotic therapy. Colonization of the gastric mucosa is of the control subjects (P = 0.035), and shedding rotavirus occurred strongly associated with gastritis, duodenal and gastric ulcers, in 10% of children compared with 39% (P = 0.025), respectively.
and some malignancies. Antagonistic actions of some Lacto-bacillus strains against H. pylori in vitro were reported (59).
Attempts to eradicate H. pylori in vivo with a probiotic have INTESTINAL INFECTIONS AND COLONIZATION BY
failed until now (60). However, a significant reduction of ure- PATHOGENIC BACTERIA
ase activity was reported in patients treated with a supernatant The protective effects of probiotics against intestinal infections of Lactobacillus johnsonii LA1 (Nestlé, Switzerland Lausanne) were shown in animal models (23, 24, 47). Mechanisms that may be implicated include the production of acids, hydrogen peroxide,or antimicrobial substances; competition for nutrients or adhesionreceptors; antitoxin actions; and stimulation of the immune system.
Open trials suggested that some probiotics may help to eradi- Acute diarrhea occurs in about half of travelers who visit high- cate pathogens in chronic carriers of salmonella and campy- risk areas. Although most cases are mild and self-limiting, there is lobacter (48, 49). Several reports related to patients experiencing a considerable morbidity. Antibiotics are effective prophylaxis but a recurrence of C. difficile infections. This serious clinical prob- are not recommended for widespread use (62, 63) and there is thus lem occured in Ϸ20% of the subjects treated for a first episode a need for cost-effective alternative treatments. Several studies of infection with this microorganism and in > 40% of subjects were performed with the use of probiotics (Table 3). Some studies
who experienced several episodes. Several open studies per- that used lactobacilli had negative results, whereas 4 studies that formed in a limited number of subjects suggest a beneficial role used diverse probiotics reported positive results (Table 3). Black et of L. rhamnosus GG, S. boulardii, and Lactobacillus plantarum al (67) treated 94 Danish tourists participating in a 2-wk trip to LP299v during C. difficile–related infections (50–56). Although Egypt with a mixture of Lactobacillus acidophilus, Lactobacillus these studies suggested a therapeutic effect, especially because bulgaricus, bifidobacteria, and S. thermophilus or a placebo in a they pertained to subjects with recurrent infection, they did not randomized study. The frequency of traveler’s diarrhea was have the proof level of randomized controlled trials.
reduced from 71% (very high) to 43% (P < 0.001). In a double- McFarland et al (57) performed a study that included 124 patients blind randomized study, Oksanen et al (69) reported a reduction of who were randomly asigned to receive a standard antibiotic diarrhea by L. rhamnosus GG administration to subjects traveling treatment combined with either S. boulardii (1 g/d for 28 d) or a to Turkey; however, the effect was significant for only one destina- placebo. The risk of clinical recurrence for the subjects who had tion in Turkey. Another study used the same strain in 400 American experienced several episodes of C. difficile infection was signifi- travelers who were randomly assigned to receive L. rhamnosus GG cantly reduced in the S. boulardii group: 34.6% compared with or a placebo (70). One hundred fifty-five travelers were excluded, 64.7% in the placebo group (P = 0.04). The administration of mainly because they did not take the medication. When only the L. rhamnosus GG to preterm infants hospitalized in a neonatal subjects who took the capsules were considered, the risk of having intensive care unit was attempted to decrease the risk of K. oxy- diarrhea on any given day was 3.9% for patients treated with the toca colonization but was ineffective (58).
probiotic compared with 7.4% in those not treated (P = 0.05).
Randomized controlled trials of probiotics to prevent traveler’s diarrhea
Lactobacillus acidophilus + Lactobacillus bulgaricus Lactobacillus fermentum strain KLD L. acidophilus (unspecified strain) Lactobacilli + bifidobacteria + streptococci 28.7% compared with 39.1% (P < 0.05) 41.0% compared with 46.5% (P = 0.065) 3.9%/d compared with 7.4%/d (P = 0.05) 1 Percentage of subjects with traveler’s diarrhea in the probiotic and control groups, respectively.
Kollaritsch et al (68) used S. boulardii in a double-blind placebo- or without mild gastrointestinal symptoms, and the often- controlled trial in which only 1016 of 3000 Austrian travelers were claimed improvement of well-being by probiotics has not been compliant. The protection against the occurrence of diarrhea was mild but significant and was dose-dependent (68; Table 3).
In a recent controlled, randomized, double-blind study (de Vrese and Schrezenmeir, unpublished observations, 1998), 66 healthy,lactose-tolerant adults in 3 groups—after a 3-wk preperiod with- IRRITABLE BOWEL SYNDROME AND VARIOUS
out fermented food—consumed 125 g/d of a chemically acidi- CONDITIONS WITH DIARRHEA
fied milk product without bacteria (control) or with 2 strains of Some probiotics, including acidophilus or bifidus milk, were probiotic Lactobacillus (1010 CFU/d). Gastrointestinal symp- reported to relieve constipation in a short series of patients (2); how- toms and well-being were recorded by validated questionnaires ever, these studies were not controlled. In a randomized placebo- and expressed as a sum score of 5 characteristics concerning controlled study including only 34 patients, Maupas et al (71) intestinal function and pain. Within 1 wk, both probiotics, but observed that S. boulardii decreased functional diarrhea but did not not the artificially acidified milk product without bacteria, influence other symptoms of irritable bowel syndrome. Halpern et al improved well-being and decreased gastrointestinal symptoms, (72) suggested in a randomized, double-blind, crossover trial that from 6 to 4 points (on a scale of 0–30 points). These differences administration of heat-killed lactobacilli for 6 wk was more efficient were significant (P < 0.05) with respect to both the control sub- than was placebo in relieving symptoms of irritable bowel syn- jects and the preperiod without probiotics. This was the first time drome. However, only 18 of 29 randomly assigned subjects were that such an effect was observed in healthy persons.
studied and this poor compliance was a weakness of that study.
Hentschel et al (73) assessed the efficacy of 2 probiotic preparationscontaining lactobacilli and Escherichia coli (Hylac and Hylac N INFLAMMATORY BOWEL DISEASE
forte, Merckle, Blaubeuren, Germany) in 126 subjects suffering Inflammatory bowel disease refers to disorders of unknown from nonulcer dyspepsia and did not observe any amelioration.
cause that are characterized by chronic or recurrent intestinal S. boulardii decreased the duration of diarrhea induced by tube inflammation. Such disorders include ulcerative colitis, Crohn feeding in 3 trials (74–76). The most recent study was double- disease, and pouchitis. The mechanisms responsible for initiation blind and compared the administration of 2 g S. boulardii/d with and perpetuation of the inflammatory process remains unknown, placebo in 128 critically ill tube-fed patients (76). Treatment with but the main theory is that inflammatory bowel disease may result the probiotic reduced the percentage of days patients experienced from abnormal host responses to some members of the intestinal diarrhea from 18.9% to 14.2% (P = 0.007). Two open studies pro- flora or from a defective mucosal barrier (82, 83). Treatment may posed that lactobacilli might have some efficacy against small be difficult and there is a need for new treatments to decrease the intestinal bacterial overgrowth (77, 78), but S. boulardii was inef- occurrence of symptoms and to prevent recurrence.
fective in the only randomized placebo-controlled study (79).
Several studies showed interesting effects of probiotics on Diarrhea is a nearly constant adverse effect of irradiation of the inflammatory bowel disease in animals. Intracolonic administration pelvis. A randomized controlled study by Salminen et al (80) of L. reuteri R2LC to rats with acetic acid-induced colitis signifi- showed a significant decrease in diarrhea in patients receiving cantly decreased the disease, whereas Lactobacillus HLC was inef- L. acidophilus NDCO 1748 during pelvic irradiation. Previous open fective (84). Administration of Lactobacillus reuteri R2LC and trials suggested the efficacy of freeze-dried lactic acid bacteria Lactobacillus plantarum DSM 9843 to rats with methotrexate- cultures for the same indications (80). Such potentially interesting induced enterocolitis was associated with low intestinal permeabil- therapeutic effects should be studied more thoroughly. Elmer et al ity, bacterial translocation, and plasma endotoxin concentrations (81) reported that high doses of S. boulardii might be effective in compared with rats with enterocolitis and no treatment (85). A few some subjects with HIV-related chronic diarrhea; however, further studies were also performed in patients. In an open study, a 10-d evaluation is warranted before firm conclusions can be drawn.
administration of L. rhamnosus GG to 14 children with active orinactive Crohn disease resulted in an increase in immunoglobulinA–secreting cells to ␤-lactoglobulin and casein, which indicates an WELL-BEING
interaction between the probiotic and the local immune system Compared with the numerous studies in patients, there have (86). The lactobacilli did not influence the disease activity, how- been only a few investigations of otherwise healthy people with ever, because the study group was too small and the study was too short to assess accurately a clinical effect (86). Plein and Hotz (87) 4. Marteau P, Flourié B, Pochart P, Chastang C, Desjeux JF, Rambaud performed a pilot, double-blind, controlled study of the efficacy of JC. Effect of the microbial lactase activity in yogurt on the intesti- S. boulardii on symptoms of Crohn disease. Twenty patients with nal absorption of lactose: an in vivo study in lactase-deficient active, moderate Crohn disease were randomly assigned to receive 5. Mahé S, Marteau P, Huneau JF, Thuilier F, Tomé D. Intestinal nitro- either S. boulardii or a placebo for 7 wk in addition to the standard gen and electrolyte movements following fermented milk ingestion treatment. A significant reduction in the frequency of bowel move- in human. Br J Nutr 1994;71:169–80.
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Two studies (88, 89) compared the efficacy of an oral E. coli 7. Arrigoni E, Marteau P, Briet F, Pochart P, Rambaud JC, Messing B.
preparation [E. coli strain Nissle (Mutaflor, Ardeypharm GmbH, Tolerance and absorption of lactose from milk and yogurt during Herdecke, Germany)] and mesalazine (ie, the standard treatment) short-bowel syndrome in humans. Am J Clin Nutr 1994;60:926–9.
in maintaining remission of ulcerative colitis. The first study 8. Marteau P, Messing B, Arrigoni E, et al. Do patients with short bowel syndrome need a lactose free diet? Nutrition 1997;13:13–6.
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9. Harms HK, Bertele-Harms RM, Bruer-Kleis D. Enzyme substitu- After 12 wk, 11.3% of the subjects treated with mesalazine had tion therapy with the yeast Saccharomyces cerevisiae in congenital relapsed, compared with 16% of those treated with the probiotic.
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The second study included 116 patients and also showed that the 10. Gotz V, Romankiewicz JA, Moss J, Murray HW. Prophylaxis probiotic preparation was as effective as mesalazine in inducing against ampicillin-associated diarrhea with a lactobacillus prepara- remission and preventing relapse (89). Several studies are cur- tion. Am J Hosp Pharm 1979;36:754–7.
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the modulation of carcinogenesis. Both may be influenced by 13. Borgia M, Sepe N, Brancato V, et al. A controlled clinical study on probiotics and this has led to trials investigating the role of pro- Streptococcus faecium preparation for the prevention of side reac- biotics in preventing or curing tumors in animals (91). Several tions during long-term antibiotic treatments. Curr Ther Res 1982; authors showed that some probiotics may decrease the fecal con- centrations of enzymes, mutagens, and secondary bile salts that 14. Wunderlich PF, Braun L, Fumagalli I, et al. Double-blind report on the efficacy of lactic acid-producing Enterococcus SF68 in the pre- may be involved in colon carcinogenesis (91). Some but not all vention of antibiotic-associated diarrhoea and in the treatment of epidemiologic studies also suggest that consumption of fer- acute diarrhoea. J Int Med Res 1989;17:333–8.
mented dairy products may have some protective effect against 15. Colombel JF, Cortot A, Neut C, Romond C. Yoghurt with Bifi- large colon adenomas or cancer (92). It is thus impossible to dobacterium longum reduces erythromcyin-induced gastrointestinal draw any conclusion at this time. Clinical studies are currently ongoing in Europe to study the effects of probiotics and prebi- 16. Siitonen S, Vapaatalo H, Salminen S, et al. Effect of Lactobacillus otics in subjects with colonic adenomas.
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17. Young RJ, Vanderhoof JA. Successful probiotic therapy of chronic CONCLUSIONS
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Inbox: fw: microbial drug resistance (133 of 1172)

Thu, 14 Aug 2008 15:00:32 +0200 [08/14/08 08:00PM ICT] To: Subject: Fw: Microbial Drug Resistance Priority: 1 Part(s): Headers: Dear Dung, could you please reply to my email and answer the questions of reviewer n°2 mentioned in his/her minor comments: Materials and methods 1) Bacterial strains: Please give information on how representative the sample is for all the E. ictaluri is


Journal of Medical Microbiology (2012), 61, 984–989Outbreak of pulmonary infection caused byKlebsiella pneumoniae isolates harbouring blaIMP-4and blaDHA-1 in a neonatal intensive care unit inChinaFangyou Yu,1 Qunhua Ying,2 Chun Chen,3 Tingjian Li,3 Baixing Ding,4Ying Liu,3 Yuanyuan Lu,3 Zhiqiang Qin,5 Chris Parsons,5Cassandra Salgado,5 Di Qu,6 Jingye Pan4 and Liangxing Wang31Department of Lab

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