Benefits
Vaginal flora balance in healthy women
In 64 healthy women taking daily L. rhamnosus GR-1 and L. reuteri RC-14 capsules (then called L. fermentum RC-14) for 60 days, 37% moved from an asymptomatic bacterial vaginosis flora to a normal lactobacilli flora versus 13% on placebo (P=0.02). Cultures showed more lactobacilli and less yeast and coliforms. A symptom questionnaire found no significant difference: 30% versus 12% reported improved vaginal well-being (P=0.17).
Vaginal flora scores after menopause
In 72 postmenopausal women with intermediate Nugent scores (4 to 6), GR-1 and RC-14 at 2.5 billion CFU each once daily for 14 days lowered the Nugent score by at least two grades in 60% of women versus 16% on placebo (p=0.0001). The Nugent score is a microscope reading of the vaginal flora, not a symptom score.
Vaginal flora with the strains versus placebo capsules
In 544 women diagnosed with bacterial vaginosis or another vaginal infection, GR-1 and RC-14 capsules (Lactogyn) taken daily for 6 weeks gave a balanced vaginal flora in 61.5% versus 26.9% on placebo (p<0.001), and 51.1% versus 20.8% six weeks later. No antibiotic is described in the abstract. The flora was read by a cytologist; no symptom scores are reported.
Use alongside a prescription antibiotic
Two placebo-controlled trials gave GR-1 and RC-14 with an antibiotic to women diagnosed with bacterial vaginosis: cure was 88% on the strains versus 40% on placebo with oral metronidazole, and 87.5% versus 50.0% with single-dose tinidazole. Every woman took the drug, so these trials do not test the strains alone, and the strains are not a replacement for prescribed treatment.
Later trials that paired the strains with an antibiotic
Two later trials found no added benefit from GR-1 and RC-14. In 99 Chinese women using metronidazole suppositories, 30-day cure was 57.69% versus 59.57% without the strains, and 90-day cure 36.54% versus 48.94%. In 65 women with HIV over 6 months, cure with metronidazole did not improve, though vaginal pH improved in women with intermediate flora.
Vaginal flora during pregnancy
Two placebo-controlled pregnancy trials of GR-1 and RC-14 found no difference from placebo. In 238 UK women dosed from early pregnancy, bacterial vaginosis rates at 18 to 20 weeks were 15% versus 9%, a nonsignificant gap. In 66 Canadian women given the strains for 12 weeks, the Nugent score returned to normal in 30% of both groups.
Urinary tract health after menopause
In 252 postmenopausal women with recurrent urinary tract infections, capsules with 1 billion CFU of GR-1 and RC-14 twice daily for 12 months did not meet the noninferiority margin against the antibiotic trimethoprim-sulfamethoxazole (3.3 versus 2.9 infections a year). There was no placebo group. E. coli antibiotic resistance rose on the antibiotic but not on the strains.
Mechanism of action
More vaginal lactobacilli during dosing
In the healthy-women trial, cultures found more vaginal lactobacilli on the strains at days 28 and 60. In the metronidazole trial, lactobacilli above 100,000 CFU per ml were recovered from 96% of women on the strains versus 53% on placebo at day 30.
Low detection of the swallowed strains
Not every trial found the strains in the vagina. In the Chinese trial the probiotic species were rarely detected in vaginal or fecal samples, and in the UK pregnancy trial the share of women colonized with the probiotic strains did not differ from placebo.
Vaginal pH
In the 6-month trial in women with HIV, women with intermediate flora on the strains were more likely to have a beneficial vaginal pH at follow-up (odds ratio 3.8, P=0.02).
Cytokines and chemokines in pregnancy
The Canadian pregnancy trial measured vaginal cytokines and chemokines. Interleukin-10 rose slightly at 28 weeks in both the probiotic and placebo groups and was not different from 13-week levels at 35 weeks, so no immune effect specific to the strains was shown.
Clinical trials
Randomized, placebo-controlled trial; daily oral capsules of L. rhamnosus GR-1 and L. fermentum RC-14 (now L. reuteri RC-14), made by Chr Hansen, for 60 days; vaginal flora scored by microscopy and culture, plus a well-being questionnaire; funded by Procter and Gamble, NSERC and the Kidney Foundation of Canada, with four authors from Procter and Gamble Healthcare Research (Reid et al. 2003, FEMS Immunol Med Microbiol)
64 healthy adult volunteers.
Flora moved from an asymptomatic bacterial vaginosis pattern to normal lactobacilli in 37% on the strains versus 13% on placebo (P=0.02). Cultures showed more lactobacilli at days 28 and 60, less yeast at day 28 and fewer coliforms at days 28, 60 and 90. No side effects were reported. On the questionnaire, 30% on the strains versus 12% on placebo reported improved vaginal well-being (P=0.17), with no difference in itchiness or odor.
Multicenter, double-blind, randomized, placebo-controlled trial in Croatia; Lactogyn capsules (L. rhamnosus GR-1 and L. reuteri RC-14, JGL) or identical placebo capsules daily for 6 weeks (no antibiotic described in the abstract); swabs read by a clinical cytologist at 6 and 12 weeks; funding is not stated in the abstract (Vujic et al. 2013, Eur J Obstet Gynecol Reprod Biol)
544 adults diagnosed with bacterial vaginosis or another vaginal infection (395 probiotic, 149 placebo).
Balanced vaginal microbiota at about 6 weeks in 61.5% on the strains versus 26.9% on placebo (p<0.001); 6 weeks later, 51.1% versus 20.8% (p<0.001). The outcome was a microscope reading of the flora; the abstract reports no symptom scores.
Randomized, double-blind, placebo-controlled trial in Nigeria; all participants took oral metronidazole 500 mg twice daily on days 1 to 7, plus L. rhamnosus GR-1 and L. reuteri RC-14 (1 billion CFU each) or placebo twice daily on days 1 to 30 (Anukam et al. 2006, Microbes Infect)
125 premenopausal adults diagnosed with bacterial vaginosis; 106 returned at day 30.
Cure at day 30 (normal Nugent score, negative sialidase test and no signs or symptoms) was 88% with the strains versus 40% with placebo (p<0.001). Lactobacilli above 100,000 CFU per ml were recovered from 96% versus 53%. Everyone took the antibiotic, so the strains were not tested alone.
Randomized, double-blind, placebo-controlled multicenter trial in Brazil; a single 2 g dose of tinidazole, then 2 capsules of L. rhamnosus GR-1 and L. reuteri RC-14 or 2 placebo capsules every morning for 4 weeks (Martinez et al. 2009, Can J Microbiol)
64 Brazilian adults diagnosed with bacterial vaginosis.
At day 28 the cure rate was 87.5% with the strains versus 50.0% with placebo (p=0.001), and a normal Nugent score was seen in 75.0% versus 34.4% (p=0.011). Everyone took the antibiotic, so the strains were not tested alone.
Randomized, double-blind, placebo-controlled trial (NCT00536848); L. rhamnosus GR-1 and L. reuteri RC-14 or placebo daily for 6 months, with metronidazole 400 mg twice daily for 10 days for those with a Nugent score of 7 to 10 (Hummelen et al. 2010, Int J Gynaecol Obstet)
65 adults with HIV and a Nugent score of 4 to 10.
Null primary result: the strains did not raise the cure rate with metronidazole. In the intermediate-flora subgroup a beneficial pH was more likely on the strains (odds ratio 3.8, P=0.02); a normal flora was not significantly more likely (odds ratio 2.4, P=0.1).
Prospective, parallel-group, randomized, controlled trial without a placebo; metronidazole vaginal suppositories for 7 days alone or with oral L. rhamnosus GR-1 and L. reuteri RC-14 for 30 days; funded by Shenzhen government research grants, and one author was employed by BGI-Shenzhen (Zhang et al. 2021, Front Cell Infect Microbiol)
126 Chinese adults with bacterial vaginosis; 52 and 47 in the analysis.
Null result: total cure at 30 days was 57.69% with the strains versus 59.57% with metronidazole alone, and at 90 days 36.54% versus 48.94% (p=0.213). Vaginal and fecal microbiota did not differ, and the probiotic species were rarely detected. No serious adverse effects were reported.
Randomized, double-blind, placebo-controlled trial at four UK maternity units; L. rhamnosus GR-1 and L. reuteri RC-14 at 2.5 billion CFU each once daily from 9 to 14 weeks' gestation to the end of gestation; funded by Barts Charity; placebo capsules came from Chr. Hansen, which reviewed the final report before submission (Husain et al. 2020, BJOG)
304 consenting adults recruited at 9 to 14 weeks' gestation; 238 in the primary analysis.
Null result: bacterial vaginosis at 18 to 20 weeks was 15% (19/123) on the strains versus 9% (10/115) on placebo (adjusted odds ratio 1.82, 95% CI 0.64 to 5.19). Colonization with the probiotic strains, E. coli, group B streptococci and other microbes did not differ.