Probiotics: 'Living Drugs'

Abstract and Introduction

Abstract

The uses, mechanisms of action, and safety of probiotics are discussed.

Probiotics are live microorganisms or microbial mixtures administered to improve the patient's microbial balance, particularly the environment of the gastrointestinal tract and the vagina. The yeast Saccharomyces boulardii and the bacterium Lactobacillus rhamnosus, strain GG, have shown efficacy in clinical trials for the prevention of antimicrobial-associated diarrhea. Other probiotics that have demonstrated at least some promise as prophylaxis for this type of diarrhea are Lactobacillus acidophilus, Bifidobacterium longum, and Enterococcus faecium. The use of S. boulardii as an adjunctive treatment to therapy with metronidazole or vancomycin has been found in controlled studies to decrease further recurrences of Clostridium difficile-associated disease. Other gastrointestinal disorders for which probiotics have been studied include traveler's diarrhea, acute infantile diarrhea, and acute diarrhea in adults. Several Lactobacillus species given in yogurt or in tablet or suppository form have shown clinical efficacy as a treatment for vaginal infections. Lactobacillus strains have also been examined as a treatment for urinary-tract infections. Putative mechanisms of action of probiotics include production of pathogen-inhibitory substances, inhibition of pathogen attachment, inhibition of the action of microbial toxins, stimulation of immunoglobulin A, and trophic effects on intestinal mucosa. The available probiotics are considered nonpathogenic, but even benign microorganisms can be infective when a patient is severely debilitated or immunosuppressed.

Probiotics have demonstrated an ability to prevent and treat some infections. Effective use of probiotics could decrease patients' exposure to antimicrobials. Additional controlled studies are needed to clearly define the safety and efficacy of these agents.

Introduction

The concept of orally taking mixtures of microorganisms for improved health is not new. Yogurt has long been thought to have health benefits. As early as 1908, Metchnikoff, ^[1] a Nobel laureate, put a scientific spin on the ingestion of microbes in stating that "ingested lactobacilli can displace toxin-producing bacteria, promoting health and prolonging life." Until recently, however, this idea has not received serious attention in the United States and Canada. This lack of medical acceptance has probably been due to the ready availability of antimicrobials but also to a previous lack of sound evidence. Another consideration has been the uneven quality of products on the market.^[2]

Continued overuse of antimicrobials is leading to serious problems with antimicrobial resistance. Consequently, there is a need for innovative measures to prevent and treat infectious diseases. The therapeutic use of microorganisms antagonistic to pathogens would have the potential to decrease antimicrobial use. Another impetus for a reevaluation of therapeutic microorganisms has been the favorable results of recent randomized, controlled clinical trials testing newer products.

There is some confusion about the terms applied to microbial preparations used therapeutically. The name used most commonly, including on commercial labels, is "probiotics." A probiotic is generally defined as a live microorganism or microbial mixture administered to "beneficially affect the host animal by improving its microbial balance."^[3] These products are taken orally, although there is also interest in intravaginal use to treat vaginal infections. Probiotic doses are usually standardized in terms of the amount of living bacteria per unit of volume. The reader may be most familiar with the many commercial lactobacillus-based probiotic products used orally for diarrhea. "Biotherapeutic agent" has been used to describe a microbe having specific therapeutic activity against a specific disease.^[4,5] An example of effective use of a biotherapeutic agent is the oral administration of Saccharomyces boulardii to treat recurrent Clostridium difficile-associated disease.^[6] Another name used is "prebiotic"; this refers to the use of chemicals or nutrients that modify the environment of the gastrointestinal tract to favor proliferation of the beneficial components of the intestinal microflora.^[7,8] The prebiotic approach, while promising, has not been thoroughly tested.

This article discusses the uses, mechanisms of action, safety, and selection of probiotics.

Cite this: Probiotics: 'Living Drugs' - Medscape - Jun 15, 2001.

Table 1. Placebo-Controlled Trials of Oral Probiotics for Prevention of Antimicrobial-Associated Diarrhea
a	Significantly different from corresponding value for control group (p < 0.05).

Table 2. Placebo-Controlled Trials of Oral Probiotics for Treatment of Acute Diarrhea
Probiotic	Ref(s).	No. Subjects	Days of Treatment	Duration and Frequency of Diarrhea ^[a]
Probiotic	Ref(s).	No. Subjects	Days of Treatment	Treatment Group	Control Group
L. rhamnosus GG	52	71 children	5	1.4 days ^[b]	2.4 days
	53	40 children	2	31% (at day 2)^[b]	75% (at day 2)
	54	26 children	2	1.9 days ^[b,c]	3.3 days
	55	123 children	5	2.7 days ^[b,d]	3.7 days
	56	287 children	Until diarrhea stopped	2.4 days ^[b]	3.0 days
L. reuteri	57	66 children	5	1.5 days ^[b,e]	2.5 days
	58	40 children	5	26% (at day 2)^[b]	81% (at day 2)
S. boulardii	59	130 children	4	15% (at day 2)^[b]	60% (at day 2)
	60	98 adults	7	4.9% (at day 3)^[b]	23.9% (at day 3)
	61	35 adults with HIV	7	44%^[b]	94%
E. faecium SF68	30	78 adults	7	0.6%b	8.7%
	62	114 adults with vibriorelated cholera	3	3.3 days	3.3 days
	62	41 adults with enterotoxigenic E. coli	3	2 days	2 days
a	Mean number of days of diarrhea during treatment interval or frequency of diarrhea at end of treatment or period indicated.
b	Significantly different from corresponding value for control group (p < 0.05).
c	Benefit seen only in children with nonbloody diarrhea.
d	Benefit seen only in children with rotavirus-associated diarrhea.
e	Effect seen at highest dose (1 x 10 10 organisms).

a	Mean number of days of diarrhea during treatment interval or frequency of diarrhea at end of treatment or period indicated.
b	Significantly different from corresponding value for control group (p < 0.05).
c	Benefit seen only in children with nonbloody diarrhea.
d	Benefit seen only in children with rotavirus-associated diarrhea.
e	Effect seen at highest dose (1 x 10 10 organisms).

Table 3. Potential Mechanisms of Action of Probiotics
Mechanism	Probiotic Microorganism	Observation	Ref(s).
Production of pathogen-inhibitory substances	L. reuteri	In vitro	85
Production of pathogen-inhibitory substances	L. rhamnosus GG	In vitro	86
Inhibition of pathogen attachment	S. boulardii	Human erythrocytes in vitro	87
Inhibition of pathogen attachment	L. acidophilus	Piglet mucus in vitro	88
Inhibition of action of microbial toxins	S. boulardii	Rat ileal loops	89-91
Stimulation of immunoglobulin A	S. boulardii	Rat intestine	92
Stimulation of immunoglobulin A	L. rhamnosus GG	Human serum	93
Trophic effects on intestinal mucosa	S. boulardii	Rat intestine	94,95

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Probiotics: 'Living Drugs'

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