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Protection from gastrointestinal diseases with the use ofprobiotics1–3
Philippe R Marteau, Michael de Vrese, Christophe J Cellier, and Jürgen Schrezenmeir
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
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
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
) the use of S. boulardii
to prevent further recurrence of
shown: digestion of lactose in the gut lumen by the lactase con-
associated diarrhea, and 4
) the use of fer-
tained in the yogurt bacteria (the yogurt bacteria deliver lactase
mented milks containing Lactobacillus rhamnosus
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
infections, inflammatory bowel disease, and
ie, a yeast that contains the enzyme sucrase (9). This is yet another
Am J Clin Nutr
example of a direct effect of a probiotic; however, its relevance inthe treatment of sucrase deficient subjects is not established.
Probiotics, bifidobacteria, lactobacilli,
nal infections, antibiotic-associated diarrhea, gastroenteritis,
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
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
Randomized controlled trials showing a significant therapeutic effect of probiotics in the prevention of antibiotic-associated intestinal symptoms (mainly diarrhea)
Lactobacillus acidophilus + Lactobacillus bulgaricus
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
shown in Table 1
; the effects of probiotics on C. difficile
[≥ 109 colony-forming units (CFU)/250 mL] or placebo. The dura-
are shown in the next section. Three randomized, dou-
tion of diarrhea was 58 ± 28 h in the L
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
reduced by L
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
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
(ie, effects against the population levels of C. difficile
GG was as effective as living L
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
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
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-
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
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
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
Randomized controlled trials showing a significant therapeutic effect of probiotics to shorten the duration of acute gastroenteritis
and Streptococcus thermophilus
G Boudraa, unpublished observations, 1996.
and S. thermophilus.
During follow-up, diarrhea
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-
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
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
these studies suggested a therapeutic effect, especially because
, 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
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
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
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
colonization but was ineffective (58).
probiotic compared with 7.4% in those not treated (P
Randomized controlled trials of probiotics to prevent traveler’s diarrhea
Lactobacillus acidophilus + Lactobacillus bulgaricus
Lactobacilli + bifidobacteria + streptococci
28.7% compared with 39.1% (P
41.0% compared with 46.5% (P
3.9%/d compared with 7.4%/d (P
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
(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
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/
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
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-
NDCO 1748 during pelvic irradiation. Previous open
fective (84). Administration of Lactobacillus reuteri
trials suggested the efficacy of freeze-dried lactic acid bacteria
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
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
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or a placebo for 7 wk in addition to the standard
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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