Академический Документы
Профессиональный Документы
Культура Документы
ORIGINAL CONTRIBUTIONS
Accumulating data have strongly linked gut microbes to human health. Accordingly, manipulating intestinal
microbiota holds promise as a potential treatment for restoring health. Although antibiotics have been the primary
clinical choice for achieving this objective, supplementing the gastrointestinal microbiota with probioticsor
encouraging their growth with prebioticsis now widely used as an alternative approach. Among gastrointestinal
disorders, data of varying quality support the use of probiotics in preventing and treating diarrhea, inflammatory bowel
disease (particularly pouchitis), irritable bowel syndrome, and liver disease. Although some data are indeed promising,
the profusion of probiotic products and the fact that species, strain, and formulation all clearly influence efficacy have
led to significant confusion regarding the best choice for different indications. Although sufficient evidence is not
currently available to provide a clear guidance on the best probiotic for a particular clinical indication, key scientific
concepts are now emerging. Building on these concepts, this review will provide practical information on the use of
these products in clinical practice.
Am J Gastroenterol Suppl 2012; 1:3440; doi:10.1038/ajgsup.2012.7
INTRODUCTION
As reviewed in detail in this supplement, the intestinal microbiota
and the human host have an intimate, bidirectional interaction
that can have both positive and negative influences on human
health. Interactions between the gut microbiota and the host
have been shown to influence intestinal and systemic immunity,
defense against pathogens, intestinal motility, sensation, secretion
and barrier functions, liver metabolism, detoxification of xenobiotics, energy harvest, growth and development, and behavior.
Moreover, the gut microbiota have been implicated in triggering or exacerbating numerous disease states, includingbut not
limited toinflammatory bowel disease (IBD) and irritable bowel
syndrome (IBS). As illustrated throughout this supplement, data
from animal studies have shown that the intestinal microbiota
have a direct effect on the host through modulation of gene expression, immunological, physiological, and psychological functions.
In turn, the host is able to influence the composition and activity
of its gut microbiota.
As the recognition of the importance of intestinal microbiota
and their interaction with the host grew, so did the interest in targeting the intestinal microbiota as a mean to maintain and promote health. The possibility that manipulating the gastrointestinal
microbiota could achieve a preventative and therapeutic effect is
attractive. Indeed, more than a century ago, the Nobel laureate Elie
Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; 2Alimentary
Pharmabiotic Center, Department of Medicine, University College Cork, Cork, Ireland; 3Section of Gastroenterology, New Mexico VA Health Care System and University of New
Mexico, Albuquerque, New Mexico, USA. Correspondence: Yehuda Ringel, MD, FACG, Division of Gastroenterology and Hepatology, Department of Medicine, University of
North Carolina School of Medicine, 4107 BioInformatics Building, 130 Mason Farm Road, Chapel Hill, North Carolina 27599-7080, USA. E-mail: ringel@med.unc.edu
This article was published as part of a supplement sponsored by the Gi Health Foundation, a nonprofit 501(c)(3) educational organization dedicated to increasing
awareness of the effect of gastrointestinal disorders in the United States. The foundations goal is to provide health professionals with the most current education
and information on gastrointestinal health.
The American Journal of GASTROENTEROLOGY Supplements
Prebiotics
Synbiotics
35
36
Ringel et al.
Table 2. Selected probiotic strains and products available in the US and Europe
Straina
Commercial availabilityb
Sold by
L. acidophilus NCFM
B. lactis Bi-07
B. lactis HN019 (DR10)
L. rhamnosus HN001 (DR20)
Sold as ingredient
Florastor
B. infantis 35264
Align
L. rhamnosus R0011
L. acidophilus R0052
Sold as ingredient
B. lactis Bb-12
L. acidophilus LA5
L. paracasei CRL 431
L. fermentum VRI003 (PCC)
L. reuteri RC-14
L. rhamnosus GR-1
L. paracasei F19
Sold as ingredient
L. casei Shirota
B. breve strain Yakult
Yakult
L. rhamnosus GG (LGG)
Culturelle
L. rhamnosus LB21
Lactococcus lactis L1A
Sold as ingredient
L. salivarius UCC118
B. longum BB536
L. acidophilus LB
Sold as ingredient
This table does not constitute an endorsement of any of these products, nor does it include all strains/mixtures currently available. Table developed by Sanders and used
with permission.
a
Parenthetic entries indicate alternative strain designations; B. lactis is a shorthand designation for Bifidobacterium animalis subsp lactis.
b
Strains sold as ingredients are available in numerous consumer products; contact responsible company for product list. Products listed are examples and do not reflect a
comprehensive list of available products containing the indicated strain.
potentially through Toll-like receptor signaling (17,20). In general, it seems that the anti-inflammatory effects of probiotics
often observed in in vitro and animal studies may not always
translate to clinical beneficial effects of probiotics. This may relate
to the complex immunomodulatory effects of probiotics, with the
net effect not only difficult to predict but often highly specific to disease and health states and the individual probiotic strain (19,21).
Probiotics have also been shown to have a number of functional
effects on the gastrointestinal tract. For example, Lactobacillus
paracasei NCC2461 has been shown to attenuate postinfectious
intestinal dysmotility in a mouse model (22). Additional animal
studies have found that administration of probiotics appears to
alleviate visceral hypersensitivity (2325), an effect potentially
VOLUME 1 | ISSUE 1 | JULY 2012 www.amjgastro.com
37
38
Ringel et al.
favor of the treatment group (P < 0.0001), suggesting that probiotics can provide considerable benefit in this patient population (39).
Five small studies, each of which evaluated a different probiotic, have evaluated the efficacy of probiotics in inducing and/or
maintaining remission in patients with ulcerative colitis (40); of
these, four showed significant results in favor of probiotics. A sixth
study compared the efficacy of 5-aminosalicylic acid, with or without S. boulardii, as maintenance treatment in Crohns disease in
32 patients (41). This study is notable in that clinical relapses were
observed in 37.5% of patients who received mesalamine alone,
compared with only 6.25% of patients who received the combination. Overall, probiotics may be beneficial in mild to moderate
ulcerative colitis as adjuvant therapy. In contrast to ulcerative colitis, the evidence supporting the benefits of probiotics in patients
with Crohns disease is much weaker. Indeed, a recent review of
five studies in adults and a single study in children conclude that
currently the data do not support the use of probiotics in adult or
children with Crohns disease (40).
Recommendations. The efficacy of probiotics in IBD is discussed
extensively elsewhere in this supplement. The best evidence exists
for VSL#3 (a probiotic mixture ), at a dosage of 4.51011 CFU twice
daily, for the maintenance of remission in patients with pouchitis
(42). In ulcerative colitis, E. coli Nissle 1917 (at a dosage of 200 mg
once daily) has been shown to be as effective as mesalamine 500 mg
three times daily in a well-designed, double-blind, double-dummy
trial (43). However, there is insufficient evidence at this time on
the efficacy of other probiotic preparations and more studies are
clearly needed before probiotics can be recommended as routine
therapy in this patient population. As noted above, little evidence
suggests that probiotics have any effect in Crohns disease.
Irritable bowel syndrome. A meta-analysis of clinical trials of
probiotics in the treatment of IBS was conducted by Moayyedi
et al. (44). In this analysis, 18 randomized, controlled clinical
trials, enrolling 1,650 patients with IBS, were identified examining products including Lactobacillus (6 studies), Bifidobacterium
(3 studies), Streptococcus (1 study), and various combination products (9 studies) (note that 1 trial reported on both Lactobacillus
and Bifidobacterium). Of these, 10 (n = 918) provided outcomes as
a dichotomous variable; in these studies, probiotics significantly
reduced IBS symptoms (relative risk of symptoms persisting in the
treatment group, 0.71; 95% CI 0.570.88), with a number needed
to treat of 4. Fifteen trials reported outcomes as a continuous variable; when grouped for meta-analysis, these trials also found that
probiotics had a statistically significant effect in improving IBS
symptoms compared with placebo. This meta-analysis has shown
little difference among different types of probiotics, with Lactobacillus (3 trials enrolling 140 patients), Bifidobacterium (2 trials
enrolling 422 patients), Streptococcus (1 trial enrolling 54 patients),
and various combination products (4 trials enrolling 302 patients)
all showing a trend towards benefit (44). In terms of individual symptoms, probiotics had a statistically significant effect on
improving pain scores and flatulence, as well as a trend toward
improvement of bloating.
The American Journal of GASTROENTEROLOGY Supplements
Recommendations. Patients with IBS, arguably, represent the largest target patient population for probiotic use, and this is reflected
by the number of articles and small clinical trials assessing the
efficacy of these products in IBS. A critical evaluation of the published data on this issue, including the meta-analysis of Moayyedi
et al. (44) (summarized above) and other published meta-analyses
and critical reviews (45), have concluded that some probiotics are
beneficial in improving symptoms and reducing the risk of persistent symptoms in some patients with IBS, although the overall
effect is modest. There is little evidence for harm associated with
probioticsin fact, in the meta-analysis of Moayyedi et al. (44),
there was no significant difference in adverse events between probiotics and placebo (relative risk for an adverse event on probiotic,
0.93; 95% CI 0.641.36), suggesting that the potential benefit may
outweigh any risks associated with these products (44).
Little formal information is available to guide the use of probiotics in IBS. The American Gastroenterological Society, as part of
its systematic review on the management of IBS, provides limited
guidance. According to these guidelines, which are based on a systematic review of the evidence, lactobacilli do not appear to be
effective in the management of IBS but some efficacy is reported
with bifidobacteria and certain probiotic combinations (46). Additional data have accumulated since these guidelines were published in 2009, demonstrating some efficacy with several groups
of probiotics and combinations of probiotics in IBS, although the
preferred probiotic strains, products, and regimen of use are not
clear (45,47).
Current guidelines for the use of probiotics
probiotics market is at this point largely unregulated, due caution is recommended when selecting patients and products for
therapeutic use, as host immunocompetency and quality, composition, and formulation among products should be expected
to vary widely.
It is important to emphasize that currently all probiotic products
marketed in the United States are either dietary supplements or
foods, and only one product (VSL#3) is sold as a medical food.
By definition, these products are targeted to the generally healthy
population in contrast to drugs, which can be targeted toward
people with disease conditions.
Good Manufacturing Practices were developed by the FDA so
that dietary supplements (including probiotics) are processed in
a consistent manner and meet quality standards (http://www.fda.
gov/Food/DietarySupplements/GuidanceComplianceRegulatoryInformation/RegulationsLaws/ucm110858.htm) and the current
US law requires that all products be labeled in a truthful and not
misleading manner (http://www.fda.gov/Food/LabelingNutrition/
LabelClaims/StructureFunctionClaims/default.htm).However,there
is a need for better adherence, and possibly reinforcement, of these
standards and regulations as there still appears to be probiotic products that do not conform to these regulations. In Europe, for example,
the European Food Safety Authority (EFSA) has adopted a more
pharma-like approach to the assessment of all food-related health
claims (49). Furthermore, several recent articles proposed standardized guidelines for the performance of clinical trials (50,51) and
assessment of safety in relation to pre- and probiotics (52).
We believe that greater adherence to standardization and regulation and better data from high-quality clinical trials assessing
efficacy and safety will help direct health-care providers in making educated decisions on the proper use of probiotics in specific
clinical conditions.
Clinical Implications and Conclusions
CONFLICT OF INTEREST
39
40
Ringel et al.
34. DSouza AL, Rajkumar C, Cooke J et al. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002;324:1361.
35. McFarland LV. Meta-analysis of probiotics for the prevention of travelers
diarrhea. Travel Med Infect Dis 2007;5:97105.
36. Thomas DW, Greer FR. Probiotics and prebiotics in pediatrics. Pediatrics
2010;126:121731.
37. Gosselink MP, Schouten WR, van Lieshout LM et al. Eradication of
pathogenic bacteria and restoration of normal pouch flora: comparison of
metronidazole and ciprofloxacin in the treatment of pouchitis. Dis Colon
Rectum 2004;47:151925.
38. Mimura T, Rizzello F, Helwig U et al. Once daily high dose probiotic
therapy (VSL#3) for maintaining remission in recurrent or refractory
pouchitis. Gut 2004;53:10814.
39. Elahi B, Nikfar S, Derakhshani S et al. On the benefit of probiotics in
the management of pouchitis in patients underwent ileal pouch anal
anastomosis: a meta-analysis of controlled clinical trials. Dig Dis Sci
2008;53:127884.
40. Guandalini S. Update on the role of probiotics in the therapy of pediatric
inflammatory bowel disease. Expert Rev Clin Immunol 2010;6:4754.
41. Guslandi M, Mezzi G, Sorghi M et al. Saccharomyces boulardii in
maintenance treatment of Crohns disease. Dig Dis Sci 2000;45:14624.
42. Gionchetti P, Rizzello F, Helwig U et al. Prophylaxis of pouchitis onset
with probiotic therapy: a double-blind, placebo-controlled trial.
Gastroenterology 2003;124:12029.
43. Kruis W, Fric P, Pokrotnieks J et al. Maintaining remission of ulcerative
colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with
standard mesalazine. Gut 2004;53:161723.
44. Moayyedi P, Ford AC, Talley NJ et al. The efficacy of probiotics in the
treatment of irritable bowel syndrome: a systematic review. Gut
2010;59:32532.
45. Ringel Y, Ringel-Kulka T. The rationale and clinical effectiveness of
probiotics in irritable bowel syndrome. J Clin Gastroenterol 2011;45:
(Suppl): S145S148.
46. Brandt LJ, Chey WD, Foxx-Orenstein AE et al. An evidence-based
position statement on the management of irritable bowel syndrome.
Am J Gastroenterol 2009;104 (Suppl 1): S135.
47. Whelan K. Probiotics and prebiotics in the management of irritable bowel
syndrome: a review of recent clinical trials and systematic reviews. Curr
Opin Clin Nutr Metab Care 2011;14:5817.
48. Floch MH, Walker WA, Madsen K et al. Recommendations for probiotic
use-2011 update. J Clin Gastroenterol 2011;45:Suppl: S168S171.
49. Guarner F, Sanders ME, Gibson G et al. Probiotic and prebiotic claims in
Europe: seeking a clear roadmap. Br J Nutr 2011;106:17657.
50. Shane AL, Cabana MD, Vidry S et al. Guide to designing, conducting, publishing and communicating results of clinical studies involving probiotic
applications in human participants. Gut Microbes 2010;1:24353.
51. Sanders ME, Heimbach JT, Pot B et al. Health claims substantiation for
probiotic and prebiotic products. Gut Microbes 2011;2:12733.
52. Sanders ME, Akkermans LM, Haller D et al. Safety assessment of probiotics
for human use. Gut Microbes 2010;1:16485.