Probiotics: Clinical Use

2010

It is generally agreed that a probiotic must be capable of colonising the intestinal tract to influence human health. Currently, one of the most extensively studied probiotics is Lactobacillus GG. Probiotic supplements are usually standardised in terms of the amount of living organisms per unit of volume and dosages range from 1 billion colonies to as high as 450 billion daily.

DIARRHOEA

Infectious diarrhea A Cochrane review analysed results from 23 RCTs that compared a specified probiotic agent with placebo or no probiotic in people with acute diarrhea proven or presumed to be caused by an infectious agent. Overall, 1917 volunteers were involved, of whom 1449 were infants or children (age <18 years). The review concluded that probiotics reduced the risk of diarrhea at 3 days and the mean duration of diarrhea by 30.5 hours and supplementation was a useful adjunct to rehydration therapy in treating acute, infectious diarrhea in adults and children. Several different probiotics were tested: all were lactic acid bacilli, except in two studies that tested the yeast Saccharomyces boulardii. With the exception of a trial of live Streptococcus thermophilus and Lactobacillus bulgaricus, a beneficial effect in the probiotic group compared to controls was observed in all trials. Due to the variation in treatment regimens, further investigation is required to clarify which particular one is best in specific patient groups.

Travellers’ diarrhea

Travellers’ diarrhea is the most common health problem in those visiting developing countries, affecting 20% to more than 50% of tourists. Although it is usually benign, travellers’ diarrhea represents a considerable socioeconomic burden for both the traveller and the host country. The most common enteropathogen is Escherichia coli.

Some clinical studies have found various probiotics somewhat effective against travellers’ diarrhea; however no probiotic has been able to demonstrate clinically relevant protection worldwide.

A large, randomised, placebo-controlled double-blind study of the efficacy of Lactobaallus GG in preventing travellers’ diarrhea involved 820 people on holiday to Turkey to two destinations. The group was randomly assigned either L. GG or placebo in identical sachets. On the return flight each participant completed a questionnaire indicating the incidence of diarrhea and related symptoms during the trip. Of the original group, 756 (92%) subjects completed the study. The overall incidence of diarrhea was 43.8% (331 cases) and the total incidence of diarrhea in the L. GG group was 41.0% compared with 46.5% in the placebo group, indicating an overall protection of 11.8%. Protection rates varied between two different destinations, with the maximum protection rate reported as 39.5% and no side-effects reported.

In another placebo-controlled double-blind study, two doses (250 mg and 1000 mg) of Saccharomyces boulardii were administered prophylactically to 3000 Austrian travellers. A significant reduction in the incidence of diarrhea was observed, with success depending directly on the rigorous use of the preparation. A tendency was noted for S. boulardii to have a regional effect, which was particularly marked in North Africa and in Turkey. The effect was dose-dependent, with participants taking the higher dose of probiotics experiencing the lowest incidence of travellers’ diarrhea (29%) and little difference observed between low-dose S. boulardii supplementation (34%) and placebo (39%). Treatment was considered very safe.

AIDS-related diarrhea Two studies have found probiotics beneficial in the treatment of AIDS-related diarrhea. In patients given S. boulardii (3 g/day of the yeast) for 1 week, 10 of 18 improved compared with 1 of 11 patients given placebo. In another study, a similar protocol improved the condition of 7 of 11 patients.

Antibiotic-induced diarrhea According to a 2002 meta-analysis, Lactobacillus spp. and Saccharomyces boulardii are superior to placebo in preventing antibiotic-associated diarrhea. Of nine randomised, double-blind placebo-controlled trials of probiotics, two of which involved children, four used the yeast S. boulardii, four used lactobacilli, one used a strain of Enterococcus-producing lactic acid, and three used a combination of probiotics.

In all nine trials, probiotics were given in combination with antibiotics, whereas the control groups received placebo with the antibiotic treatment. The odds ratio in favour of active treatment over placebo in preventing diarrhea associated with antibiotics was 0.39 for S. boulardii and 0.34 for lactobacilli.

Clostridium difficile-associated diarrhea (CDAD)

Clostridium difficile is a common cause of diarrhea associated with treatment with antimicrobial and/or antibiotic medication and can potentially progress to colitis, pseudomembranous colitis, toxic megacolon and death. In spite of antimicrobial therapy, recurrence is common. The S. boulardii strain of bacteria is being used to restore microbial balance and inhibit C. difficile proliferation and has been used as an adjunct to vancomycin treatment.

A 2005 systematic review of RCTs conducted to assess the effectiveness of probiotic therapy in the prevention or treatment of C. difficile-associated diarrhea (CDAD) reported that the benefit of probiotic therapy was seen in two studies and restricted to subgroups characterised by severe CDAD and increased use of vancomycin. Due to the heterogeneity in choice and dose of probiotic and in the criteria for diagnosing CDAD, synthesising further information from the eight studies was difficult, leaving the authors to conclude that better designed and larger studies are required.

UROGENITAL INFECTIONS

Probiotics are widely used to decrease the frequency of recurrent bacterial vaginosis and candidal vulvovaginitis, and have undergone clinical testing that supports this use. They are administered both orally and intravaginally. Additionally, lactobacilli play a significant role in the prevention of UTIs. One study using intravaginal administration of probiotics such as Lactobacillus GR-1 and B-54 or RC-14 strains twice weekly for 2 weeks and then monthly for 2 months demonstrated that treatment resulted in 45% less UTIs than placebo and improved the maintenance of normal flora. A significant reduction in UTI rate was also reported in a randomised double-blind study involving 55 premenopausal women. The study investigated the effectiveness of treatment for 1 year with a weekly suppository containing either 0.5 g L. rhamnosus GR-1 and L. fermentum B-54 or a Lactobacillus growth factor. Treatment resulted in the UTI rate decreasing by 73% and 79%, respectively, with no adverse effects reported.

The mechanisms by which Lactobacillus spp. reduce bacterial vaginosis and UTIs appear to involve anti-adhesion factors, byproducts such as hydrogen peroxide and bacteriocins lethal to pathogens, and perhaps immune modulation or signalling effects. Bifidobacteria in particular are considered well suited to this activity and have, therefore, been investigated for their effects in the treatment of female genitourinary infections.

Oral supplementation

Several studies have confirmed that lactobacilli administered orally can survive the gastrointestinal tract and colonise the genitourinary tract, thus enhancing the normal vaginal lactobaccilli.

In a study of 10 women whose vaginal bacterial flora was abnormal and who had suffered repeated bacterial vaginosis, yeast infections and/or UTIs, a regimen was prescribed of ingesting 109 viable Lactobacillus GR-1 and RC-14 bacteria each day. In a majority of patients with symptoms of suprapubic and micturition pain, frequency, dysuria and urgency, or vaginal irritation, the symptoms disappeared within 1-2 weeks and all the patients remained healthy for several months following treatment.

A randomised study of 42 healthy women compared treatment with either L. rhamnosus GR-1 plus L. fermentum RC-14 or L. rhamnosus GG alone. On assessment, the vaginal flora was normal in 40% of cases and 14 patients had asymptomatic bacterial vaginosis. Oral treatment with 108 viable L. rhamnosus GR-1 and L. fermentum RC-14 once and twice daily re-established a healthy vaginal flora in up to 90% of patients, and 7 of 11 patients with bacterial vaginosis converted to normal or intermediate scores within 1 month. Treatment with L. rhamnosus GG failed to have an effect. Another study by Reid and Bruce suggests that oral administration of L. rhamnosus GR-1 and L. fermentum RC-14 can result in vaginal colonisation even more quickly: within 7 days. Their study also found that colonisation can be maintained for up to 10 weeks after treatment cessation in some individuals.

Similar results were obtained in a randomised placebo-controlled study of 64 healthy women testing oral administration of L. rhamnosus GR-1 and L. fermentum RC-14, which found that the probiotics can restore asymptomatic bacterial vaginosis microflora to normal lactobacilli colonised microflora and reduce pathogenic bacteria. Significant results were obtained after 60 days’ treatment with no adverse effects reported.

Probiotic-enriched dairy products

A small randomised study of 46 participants showed that ingestion of 150 mL L. acidophilus-enriched yoghurt was associated with an increased prevalence of colonisation of the rectum and vagina by the bacteria and may have contributed to reduced episodes of bacterial vaginosis. Another crossover study of 33 women with recurrent vaginitis found that daily ingestion of 240 mg yoghurt containing L. acidophilus for 1 year decreased both candidal colonisation and infection.

IRRITABLE BOWEL SYNDROME

People suffering from IBS sometimes experience symptoms of abdominal cramping and either diarrhea or constipation or a combination of both. Although the aetiology of IBS is still unknown, there is growing suspicion that there is a persistent, mild inflammatory state with changes in mucosal function or structure and an associated imbalance of intestinal flora. This imbalance can lead to inefficient metabolism of nutrients and the formation of gas and short-chain fatty acids, both of which induce propulsive contractions and accelerate colonic transit or enhance fluid and sodium absorption in the colon. As such, clinical trials have been conducted to clarify the role of probiotics in this condition, so far producing promising results.

In a 4-week, double-blind placebo-controlled trial, 60 people with IBS were treated with L. plantarum or placebo. The patients recorded their own gastrointestinal function, starting 2 weeks before the study and continuing throughout the study period. Twelve months after the end of the study, all patients were asked to complete a questionnaire. The study showed significant reductions in intestinal flatulence in the treatment group compared with placebo. At the 12-month follow-up, patients in the test group maintained a better overall gastrointestinal function than control patients.

In another study, 40 patients were randomly assigned either L. plantarum 299V in liquid suspension or placebo over a period of 4 weeks. All patients treated with the probiotic reported resolution of their abdominal pain as compared with 11 patients from the placebo group. There was also a trend towards normalisation of stool frequency in constipation for 6 of 10 patients treated with the probiotic compared with 2 of 11 treated with placebo. With regard to all IBS symptoms, an improvement was noted in 95% of patients in the active group compared with 15% of patients in the placebo group (P< 0.0001).

INFLAMMATORY BOWEL DISEASES

Probiotics are also being used as adjunctive therapy for Crohn’s disease and inflammatory bowel disease.

Pouchitis

Pouchitis is the most common long-term complication of ileal pouch-anal anastomosis in patients with underlying ulcerative colitis. Clinical symptoms of pouchitis are not specific, and they can be caused by other conditions such as rectal cuff inflammation and irritable pouch syndrome. Therefore, to make an accurate diagnosis, endoscopic evaluation, together with symptom assessment, is necessary. Although antibacterial therapy can induce and maintain remission, probiotics can also be used to maintain clinical remission and prevent relapse in patients with relapsing or chronic pouchitis. According to one review, there is now strong evidence to support the therapeutic use of probiotics in postoperative pouchitis.

HELICOBACTER PYLORI INFECTION

A review of 13 clinical trials of probiotics and H. pylori infection summarises the results as follows.

• In six trials involving a total of 180 patients, sole treatment with probiotics produced positive results in five studies. In three trials, there were significantly reduced breath-test readings and in two others some patients were cleared of infection.

• In seven further trials of 682 patients, probiotics were added to a therapeutic regimen of antibiotics, resulting in an increased cure rate in two studies, and reduced side-effects in four. Trials in which fermented milk products or whole cultures of lactobacilli were used tended to show better results than when the probiotic was taken in the form of bacteria alone.

It must be noted that not all the studies were randomised, double-blind and placebo-controlled, and some involved only small numbers of patients. However, the positive results obtained suggest that probiotics may have a place as adjunctive treatment in H. pylori infections and possibly in prophylaxis.

ATOPIC DERMATITIS AND ECZEMA

Probiotics have the potential to moderate inflammatory and immune responses and strengthen the intestinal barrier function, three actions that are useful in addressing the underlying pathophysiological processes involved in atopic dermatitis (AD) and eczema. The use of probiotic therapy to prevent allergic disease has been demonstrated in studies using L. rhamnosus GG in neonates, whereas studies in infants and children with established AD have found that probiotics reduce the severity of the condition. Prevention of allergy A randomised, double-blind placebo-controlled study showed that perinatal administration of probiotics (L. rhamnosus GG) reduced the development of atopic eczema in children by 50% during the first 2 years of life. Some 1 59 mothers were randomly allocated to receive 2 capsules of placebo or 1010 viable L. rhamnosus GG daily for 4 weeks before expected delivery. After delivery, capsules were taken for 5 months. During lactation either the mother or the infant consumed the preparations. In a 4-year follow-up study, it was revealed that the preventive effect of the probiotic on atopic eczema extended beyond infancy.

Treatment of established allergy

A randomised, double-blind study of 55 young children (aged 5-18 months) with moderate or severe atopic AD found that treatment with L. fermentum VRI-033 PCC (1 x 109; Probiomics) twice daily produced a significant reduction in the Severity Scoring of Atopic Dermatitis (SCORAD) index. At week 15, 92% of children receiving probiotics had a SCORAD index that was significantly better than baseline compared with the placebo group (n = 17, 53%) (P = 0.01). Another randomised double-blind study has found that supplementation of infant formulas with viable but not heat-inactivated L. GG may have benefits for the management of atopic eczema and cow’s milk allergy.

According to two other placebo-controlled studies, it appears that people with greater allergic responses may be better suited to treatment and experience superior effects. Rosenfeldt et al found that treatment with two Lactobacillus strains (lyophilised L. rhamnosus 19070-2 and L. reuteri DSM 122450) given in combination for 5 weeks to children aged 1-13 years with AD resulted in 55% experiencing improvement. Interestingly, the total SCORAD score did not change significantly. Allergic patients with a positive skin prick test response and increased IgE levels experienced a more pronounced response to treatment. Similarly, a study by Sistek et al (2005) found that a combination of two probiotics (Lactobacillus rhamnosus and Bifidobacteria lactis) given to children with established AD effectively reduced the SCORAD index among the food-sensitised children, but not in other children. Children in this study received 2 x 1010 colony-forming units/g of probiotic or placebo daily as a powder mixed with food or water.

HIGH CHOLESTEROL

Probiotics modestly reduce cholesterol levels in healthy subjects and may have stronger effects in people with hyperlipidaemia.

A meta-analysis of six studies of a probiotic dairy product containing Enterococcus faecium found that the fermented yoghurt product produced a 4% decrease in total cholesterol and a 5% decrease in LDL-cholesterol.

In another study, 32 subjects with serum total cholesterol ranging from 5.7 to 7.25 mg/dL were randomly assigned to two treatments: (1) intake of a low-fat drinking yoghurt prepared with two ordinary yoghurt starters (Streptococcus thermophilus and Lactobacillus delbrueckii subsp. Bulgaricus: placebo group); and (2) intake of a low-fat drinking yoghurt prepared with the two yoghurt starters plus Bifidobacterium longum strain BL1 (probiotic group). After intake for 4 weeks at 3 x 100 mL/day, reduction of serum total cholesterol was observed in approximately half of the probiotic group subjects; a particularly significant decrease in serum total cholesterol was found among subjects with moderate hypercholesterolaemia (serum total cholesterol > 6.2 mg/dL). The serum lipid concentrations in the placebo group subjects were almost stable during the experimental periods.

A crossover study of 29 healthy women, aged 19-56 years, found that the long-term daily consumption of 300 g of two different types of yoghurt over a period of 21 weeks increased the serum concentration of HDL-cholesterol and led to the desired improvement of the LDLHDL-cholesterol ratio. The normal yoghurt contained 3.5% fat and starter cultures of S. thermophilus and L. lactis, whereas the probiotic yoghurt was enriched with L. acidophilus 145, B. longum 913 and 1% oligofructose. The mean serum concentration of total cholesterol and the LDL-cholesterol was not influenced by the normal yoghurt (P > 0.05). However, both the normal and the probiotic yoghurt increased the HDL concentration significantly, by 0.3 mmol/L (P = 0.002) and decreased the LDLHDL ratio from 3.24 to 2.48 (P = 0.001).

A recent controlled, randomised double-blind study of 36 heavy smokers found that 400 mL/day of a rose hip drink containing L. plantarum 299v (5 x 107 colony-forming units/mL) led to a reduction in cardiovascular disease risk factors. Significant decreases in SBP, leptin, and fibrinogen (P < 0.001) were recorded in the experimental group. No such changes were observed in the control group. Decreases in F(2)-isoprostanes (markers of oxidative stress) (37%) and IL-6 (42%) were also noted in the experimental group in comparison with baseline. Monocytes isolated from subjects treated with L. plantarum showed significantly reduced adhesion (P < 0.001) to endothelial cells.