Probiotics

Scientific Name(s): Lactobacillus spp., (eg, L. acidophilus , L. casei , L. rhamnosus , L. bulgaricus , L. plantarum , L. helveticus ), Bifidobacterium spp. (eg, B. bifidum , B. longum , B. breve , B. infantis ), Sacchromyces boulardii , Streptococcus salvarius , Enterococcus faecium

Common Name(s): Probiotics , yogurt , sour milk , VSL-3 , Indian yogurt , various commercial preparations

Uses

Sufficient clinical trials have been conducted to enable meta-analyses to be conducted for several clinical conditions. Evidence exists to support the use of probiotics in bacterial vaginosis, diarrhea (acute infectious, antibiotic-associated, and persistent), irritable bowel syndrome (IBS), necrotizing enterocolitis in neonates, and ventilator-associated pneumonia. Meta-analyses have shown no effect of probiotics in Crohn disease, eczema, pancreatitis, ulcerative colitis, or in patients in intensive care.

Dosing

Daily intake of oral probiotic preparations is usual practice, although some trials have used twice-weekly dosing. Preparation strength is commonly measured as colony-forming units per capsule.

Contraindications

The use of probiotics is not advised in patients at risk of opportunistic infections and in those with badly damaged GI tracts.

Pregnancy/Lactation

Information regarding safety and efficacy of specific preparations in pregnancy and lactation is lacking. Trials investigating probiotics have been conducted in pregnant women without obvious problems.

Interactions

None well documented.

Adverse Reactions

Probiotics are considered relatively safe. There are isolated reports linking probiotics to adverse reactions.

Toxicology

No data are available.

History

The use of probiotic preparations is evident throughout history. Abraham's longevity, as described in the Bible's Old Testament, may have been the result of drinking sour milk. Roman history (76 BC) describes fermented milk as a remedy for gastroenteritis. In 1916, experiments were conducted to implant Escherichia coli as a means of fighting pathogenic intestinal flora.

In 1965, the term probiotic was first used when describing “substances secreted by one microorganism which stimulates the growth of another.” 1 Revised versions of the definition have appeared in literature to accommodate mechanisms of action and components other than bacteria. An all-encompassing version has been proposed as follows: “A preparation of or a product containing viable, defined microorganisms in sufficient numbers, which alter the microflora (by implantation or colonization) in a compartment of the host, and by that exert beneficial health effects in this host.” 1 Related concepts of prebiotics and synbiotics also have been discussed. 1 , 2

Uses and Pharmacology

The potential mechanisms by which probiotics may exert their action 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.

Each agent or preparation may have unique actions, with some strains more or less effective than others. Trials included in meta-analyses are heterogeneous, especially with respect to the strain of probiotic used. 2 , 3 , 4 , 5 , 6

Animal data

Widespread usage of probiotics, together with a largely safe adverse event profile, makes data from animal experimentation largely redundant. Sufficient clinical trials have been conducted to enable meta-analyses to be conducted for certain clinical conditions.

Bacterial vaginosis
Clinical data

A meta-analysis of clinical trials conducted through December 2007 has found evidence of effect for short-course therapy (5 days) of Lactobacillus versus metronidazole in the treatment of bacterial vaginosis. 7 Long-term administration (6 months of once-weekly vaginal applications) of Lactobacillus rhamnosus has been compared with a single course of metronidazole (7-day course), and an impact on the restoration of normal vaginal flora was found even at 12 months. 8

Candidiasis, vaginal
Clinical data

Long-term trials investigating the effect of oral hydrogen peroxide–producing Lactobacillus acidophilus in preventing candidiasis have shown mixed results following long-term use (6 months), but were limited due to the high loss to follow-up of trial participants. 2 , 9 A large, randomized, placebo-controlled, double-blind trial of oral or vaginal L. rhamnosus and Bifidobacterium longum over 10 days showed no effect in treating post-antibiotic candidiasis compared with placebo. 10 In another placebo-controlled, double-blind trial, daily oral intake of L. rhamnosus and Lactobacillus fermentum modified the vaginal flora and decreased the amount of yeast and coliforms. 11

Crohn disease
Clinical data

Meta-analyses have consistently shown no effect of probiotics on clinical response in Crohn disease and a failure to have an impact on maintaining remission or on recurrent episodes. 12 , 13 , 14 , 15 One meta-analysis found a slightly increased risk of relapse for Lactobacillus versus placebo (relative risk [RR] clinical relapse, 1.15 [95% confidence interval [CI], 0.9 to 1.48]). 13

Diarrhea, acute infectious

Alongside rehydration, probiotics appear to have a role in acute infectious diarrhea. Trials are generally heterogeneous in nature, and further studies might provide more information about the efficacy of specific strains and appropriate regimens. 4

Clinical data

Trials conducted through 2010 evaluating the effect of probiotics on acute infectious diarrhea have been included in a Cochrane meta-analysis. Probiotics were found to be safe and to shorten both the mean duration of diarrhea (mean difference, 24.76 hours [95% CI, 15.9 to 33.6 hours]) and the likelihood of ongoing diarrhea after 4 days (RR, 0.41 [95% CI, 0.32 to 0.53]). 4

Results of trials investigating the effect of probiotics on Clostridium difficile infection are conflicting. Some trials suggest a positive effect (using S. boulardii or L. acidophilus with Bifidobacterium bifidum ), 2 , 16 and others show no effect (with L. acidophilus and Bifidobacterium lactis ) 17 or a trend toward an effect (with L. rhamnosus ). 2

Diarrhea, antibiotic-associated

Meta-analyses of clinical trials evaluating the effect of antibiotic-associated diarrhea provide equivocal data. As the condition is generally self-limiting, the use of probiotics should be reserved for those patients in whom diarrhea would be a clinically important adverse effect of antibiotic use, and then an adequate dosage should be used. 3

Clinical data

A meta-analysis of 6 clinical trials conducted in children (N = 766) found a reduction in the incidence of diarrhea when probiotics were used compared with placebo (RR, 0.44 [95% CI, 0.25 to 0.77]), and the number needed to treat (NNT) to prevent 1 incidence of diarrhea was determined to be 7. Effect on duration of diarrhea was not fully reported in the studies. Strength of effect was determined to be greatest with S. boulardii . 3

Similarly, a further meta-analysis found strong evidence (RR, 0.36 [95% CI, 0.25 to 0.53]) for a reduction in the incidence in diarrhea when doses of greater than 5 billion units of single strain probiotics were used. Analysis of all included trials, including lower dosages, found no difference when intent-to-treat analysis was used. 18

For Lactobacillus trials only, a meta-analysis of trials conducted among children (4 trials) found no effect, whereas the adult trials (6 trials) found a positive effect for Lactobacillus probiotic use in the prevention of antibiotic-associated diarrhea. 19

Diarrhea, persistent

Persistent (lasting more than 14 days) diarrhea is an important issue in undernourished children or other children at risk.

Clinical data

A Cochrane meta-analysis of 4 trials (N = 464) found a decrease in the duration of diarrhea (mean difference, 4.02 days [95% CI, 4.61 to 3.43]) and a decrease in stool frequency. The reviewers noted the limited availability of quality trials for analysis. 20

Eczema/Allergic dermatitis
Clinical data

A Cochrane review of clinical trials conducted in children with eczema found no effect of probiotics on symptom severity or participant/parent preference for treatment option. Important heterogeneity exists among the 12 included trials, except for 3 trials using the same probiotic strain ( L. rhamnosus GG), which were consistently negative. Subgroup analysis did not reveal any populations that might benefit from use of probiotics. 21 , 22

The use of probiotics for the prevention of eczema or atopic dermatitis remains unclear. 22

Helicobacter pylori eradication
Clinical data

Clinical trials to date have not shown probiotics to be effective in eradicating H. pylori , with only a trend toward increased eradication when used in conjunction with antibiotic therapy. Lactobacillus casei and B. lactis have shown in vitro activity against H. pylori . However, evidence for activity of L. acidophilus is conflicting. 23 , 24 , 25

A reduction in the incidence of adverse reactions (diarrhea, bleeding, taste disturbances) from triple and quadruple H. pylori treatment regimens, and consequently improved compliance, has been demonstrated with preparations containing Bifidobacterium and L. casei . 26 , 27 , 28

Intensive care patients, adults
Clinical data

A meta-analysis of clinical trials evaluating the effect of probiotics added to enteral feeds in critically ill patients found no changes in length of intensive care unit stay, incidence of nosocomial infections or pneumonia, or mortality. 29 , 30

Irritable bowel syndrome
Clinical data

Meta-analysis have been conducted in clinical trials through 2007 31 and May 2008. 32 Probiotics perform better than placebo in reducing symptoms of IBS (RR, 0.71 [95% CI, 0.57 to 0.88]). A reduction in overall symptoms, abdominal pain, and flatulence can be demonstrated, 31 , 32 and the NNT to prevent 1 occurrence of overall symptoms has been calculated to be 4. 32

Necrotizing enterocolitis, neonates

The role of probiotics in treating necrotizing enterocolitis is now well established. Further clinical trials are now required to establish efficacy of different strains and dosage regimens. Placebo-controlled trials are unnecessary. 33 , 34 Mechanisms of action are suggested to include colonization of the gut by beneficial organisms and the prevention of colonization by pathogens, improved maturity of the mucosal barrier, and modulation of relevant enzyme systems. 33 , 34

Clinical data

A meta-analysis of 11 clinical trials conducted through March 2009 of the effect of probiotics in preterm very low birth weight neonates (N = 2,176) found a reduced risk of all-cause mortality (RR, 0.42 [95% CI, 0.29 to 0.62]) and an NNT to prevent 1 death (all cause) of 20. 33 A Cochrane meta-analysis of 9 trials conducted through December 2006 (N = 1,425) found a significant decrease in the incidence of severe (stage II or more) necrotizing enterocolitis (RR, 0.32 [95% CI, 0.17 to 0.6]) and a significant decrease in mortality (RR, 0.43 [95% CI, 0.25 to 0.75]). No effect was found on the incidence of nosocomial sepsis or on total days of total parenteral nutrition. No adverse effects of probiotic use were found. 34

Pancreatitis
Clinical data

Meta-analyses, including clinical studies conducted through March 2010, have studied the effect of probiotics in acute pancreatitis. No reduction of clinical outcomes, including complications from infections, multiple organ failure, length of antibiotic therapy, surgical interventions, or mortality, has been found for probiotic use. 35 , 36 , 37

Pneumonia, ventilator-associated
Clinical data

A meta-analysis including trials conducted through April 2009 found a lower incidence of ventilator-associated pneumonia (odds ratio [OR], 0.61 [95% CI, 0.41 to 0.91]) and a lower incidence of colonization with Pseudomonas aeruginosa (OR, 0.35 [95% CI, 0.13 to 0.93]) for probiotics. No effect was found on all-cause mortality. 38

Respiratory tract infections/otitis media
Clinical data

Studies among healthy adults and children using the oral probiotics Lactobacillus reuteri , L. casei , and L. rhamnosus have shown a reduction in missed work/school days because of respiratory illness. The need for antibiotic intervention was also reduced. 39 , 40 , 41 , 42 , 43 Probiotics ingested for 3 weeks reduced nasal colonization with pathogenic bacteria and demonstrated efficacy in treating acute otitis media. 44 , 45

Ulcerative colitis
Clinical data

A meta-analysis of 13 clinical trials conducted through August 2009 found no additional benefit for probiotics in inducing remission. A more favorable profile than placebo was suggested in maintaining remission. 46 With regard to preventing pouchitis (a nonspecific inflammation of the ileal reservoir), evidence from meta-analyses suggest a potential role for probiotics in preventing relapse following anastomosis in chronic ulcerative colitis (OR, = 0.039 [95% CI, 0.011 to 0.142]). 47 , 48 Based on limited clinical data, VSL#3 ( Lactobacillus , Bifidobacterium , and Streptococcus ) may be more effective than single strain Lactobacillus . 48

Urinary tract infections
Clinical data

Few quality trials on the effect of probiotics in preventing recurrent or chronic urinary tract infections exist. A phase I study of Lactobacillus crispatus vaginal suppositories found positive results for the prevention of urinary tract infections in women versus placebo 49 ; whereas other trials have produced equivocal results. 2

Other uses
Cancer

Despite positive in vitro studies showing decreased carcinogenic aflatoxins and beta-glucuronidase, efficacy studies in humans are lacking. 50 , 51 The combination of L. acidophilus and lactulose appears beneficial in the therapy of radiotherapy-related intestinal adverse reactions. 52

Cystic fibrosis

Six months of Lactobacillus supplementation (6 billion units daily) reduced pulmonary exacerbations and hospital admissions in children with cystic fibrosis versus placebo. 53

General GI conditions

Probiotics increased fecal Bifidobacterium counts, reduced fecal blood and pH ( Bifidobacterium , L. acidophilus , and Enterococcus ), and decreased the incidence of fecal Clostridium ( Bacillus subtilis and E. faecium ) in patients with liver cirrhosis. 54 L. acidophilus reduced the length of hospital stay and the need for surgery in patients with partial adhesive small bowel obstruction 55 ; however, no effect was found for probiotics in patients undergoing elective abdominal surgery. 56 Postprandial gas-related intestinal symptoms were demonstrated to be reduced with probiotic use in a clinical trial. 57

Immunity

Dietary consumption of probiotics ( B. lactis and L. rhamnosus ) has enhanced some aspects of cellular immunity in elderly and stressed patients. 58 , 59 , 60 , 61 , 62

Infantile colic

Limited studies suggest more rapid gastric emptying times and decreased symptoms of colic with probiotic use in infants. No difference in weight gain, stool frequency, incidence of constipation, or regurgitations was found. 63 , 64

Insulin

A study conducted among patients with type 2 diabetes found a positive effect of L. acidophilus in maintaining insulin sensitivity versus placebo. 65

Lipid profile

It has been suggested that appropriately selected probiotics may be useful adjuncts in controlling hypercholesterolemia because of the bacteria's ability to assimilate cholesterol and grow well in the presence of bile. 66 However, evidence of effect remains equivocal. 67 , 68 , 69 , 70 , 71 , 72 , 73

Mastitis

Trials have evaluated the effect of probiotics as an alternative to antibiotic therapy in infectious mastitis. Greater reductions in bacterial count and pain score have been found for L. fermentum , Lactobacillus salvarius , and Lactobacillus gasseri in 1 large (n = 352) and 1 smaller study (n = 20). 74 , 75

Nutrition/Lactose intolerance

Milk and yogurts containing L. acidophilus have been studied in patients with lactose intolerance, but controversy regarding its efficacy in aiding lactose digestion remains. 76 , 77 The need for adequate, live bacteria, which may account for the variation of results in other studies, has been demonstrated in lactose-intolerant adults. 78

Oral health

Studies in some, but not all, populations have reported decreases in yeast counts and incidence of hyposalivation, suggesting a potential role in the prevention of oral candidiasis among elderly patients. 79 , 80 In orthodontic adolescents, probiotics decreased the count of salivary Streptococcus mutans , 81 while a review found a generally positive effect for probiotics on oral health, especially with regard to cariogenic and periodontal pathogens. 80

Reproductive hormones

Studies have investigated the effect of L. acidophilus and B. longum on plasma phytoestrogens, but no association has been found in pre- or postmenopausal women. 82 , 83 , 84

Rheumatoid arthritis

A small trial found improvements in patient pain assessment scores and pain scales for Bacillus coagulans versus placebo. 85

Dosage

Daily intake of oral probiotic preparations is usually recommended, but some trials have used twice-weekly dosing. Preparation strength is usually described as million/billion colony-forming units per capsule.

Necrotizing enterocolitis, neonates

Dosages used in clinical trials for necrotizing enterocolitis in neonates include the use of Bifidobacterium breve 0.5 billion to 1.6 billion units daily and L. casei GG and L. acidophilus 6 billion units daily; however, specific trials are required for definite recommendations. 33

Irritable bowel syndrome

Up to 5 billion units daily taken for 4 to 6 weeks has been used in clinical trials. 31

Pregnancy/Lactation

Information regarding safety and efficacy of the different strains of probiotics in pregnancy and lactation is lacking, despite studies being conducted in pregnant women for the prevention of atopic eczema in children and for the treatment of bacterial vaginosis.

A meta-analysis has been conducted regarding the safety of Lactobacillus and Bifidobacterium species used in pregnancy. 86 Of the 11 included trials (conducted through September 2007), no evidence of miscarriage or malformations was found. No effect on the incidence of caesarian section, birth weight, or gestational age was found either. 86

Interactions

None well documented. One study evaluated the effect of 2 weeks consumption of probiotics on vitamin B levels in healthy women. Vitamin B 1 (thiamine) and B 2 (riboflavin) levels were enhanced; however, no effect was observed on vitamin B 6 . 87

Adverse Reactions

Probiotics are considered relatively safe for use, even with low birth weight infants and neonates, but caution is advised for patients at risk of opportunistic infections and in those with badly damaged GI tracts. 2 , 34 There are isolated case reports linking probiotics to adverse reactions. 88 , 89 , 90

Toxicology

Research reveals little or no information regarding toxicology. No adverse reactions were found in a study examining the safety of B. longum in healthy adults. 91

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