Impact of Oral Administration of Four Lactobacillus Strains on Nugent Score – Systematic Review and Meta-Analysis
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Wageningen Academic Beneficial Microbes, 2019; 10(5): 483-496 Publishers Impact of oral administration of four Lactobacillus strains on Nugent score – systematic review and meta-analysis M. de Vrese1#, C. Laue2, E. Papazova2, L. Petricevic3 and J. Schrezenmeir2,4* 1Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Department of Microbiology and Biotechnology; Hermann-Weigmann-Straβe 1, 24117 Kiel, Germany; 2Clinical Research Center, Schauenburgerstraβe 116, 24118 Kiel, Germany; 3Department of Obstetrics and Fetomaternal Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria; 4University Medicine, Langenbeckstraβe 1, 55131 Mainz, Germany; [email protected]; #retired Received: 28 September 2018 / Accepted: 9 February 2019 © 2019 Wageningen Academic Publishers RESEARCH ARTICLE OPEN ACCESS Abstract We aimed at assessing the evidence for an effect on vaginal dysbiosis by oral administration of a mixture of Lactobacillus strains isolated from vaginal microbiota. For this purpose, we systematically reviewed the literature for randomised clinical trials (RCTs) in which the effect of oral administration of a mixture of four Lactobacillus strains (Lactobacillus crispatus LbV 88 (DSM 22566), Lactobacillus gasseri LbV 150N (DSM 22583), Lactobacillus jensenii LbV 116 (DSM 22567) and Lactobacillus rhamnosus LbV96 (DSM 22560)) on vaginal dysbiosis was examined based on Nugent score. Four RCTs were identified: a double-blind (DB)-RCT in 60 male-to-female transsexual women with neovagina; an open label RCT in 60 pregnant women with herpes virus infection; a DB-RCT in 36 women with bacterial vaginosis; a DB-RCT in 22 postmenopausal breast cancer patients receiving chemotherapy. Only in the three DB-RCTs Nugent score was assessed. The meta-analysis of these trials showed a significant reduction of Nugent score by probiotics compared to placebo in the fixed (standardised mean differences (SMD) -0.561; confidence interval (CI) -0.935 to -0.186; P=0.004 and random effect models (SMD -0.561; CI -0.935 to -0.186; P=0.004). The odds ratio (OR) of the cases presenting with improved Nugent score after probiotics compared to placebo treatment showed a significant effect in the fixed (OR=3.936; CI 1.702 to 9.100; P=0.001) and random effect model (OR=3.902; CI 1.681 to 9.059; P=0.001) Cochran’s Q and I2 statistics showed no heterogeneity. This meta-analysis indicates that the oral intake of the pertinent Lactobacillus strains improves the microbial pattern in vaginal dysbiosis. Keywords: probiotics, lactobacilli, vaginal microbiota, Nugent score 1. Introduction spontaneous abortions (Donders et al., 2000; Harmanli et al., 2000; Hauth et al., 2003; Hillebrand et al., 2002; Hillier The normal, acidic, vaginal milieu of adult women is et al., 1996; Klebanoff et al., 2004; Larsson et al., 1990; maintained by microbiota predominantly consisting of Leitich et al., 2003; Macones et al., 2004; Petricevic et al., lactobacilli (particularly of Lactobacillus crispatus and 2014; Simhan et al., 2005; Swidsinski et al., 2013). Lactobacillus jensenii). Under various conditions, such as bacterial vaginosis and chemotherapy, the vaginal Oral and/or local administration of lactic acid producing microbiota may be impaired. Bacterial vaginosis (BV) is bacteria and in particular of (so-called probiotic) lactobacilli characterised by a depletion of lactobacilli in favour of such as Lactobacillus rhamnosus GR-1 and Lactobacillus anaerobic bacteria, by decreased H2O2- and lactic acid reuteri RC-14 has been demonstrated to facilitate positive concentrations and by an increase in pH above 4.5. This alterations of vaginal microbiota in healthy women, to is associated with increased risk for urogenital infections, improve or restore an impaired vaginal microbiota or to obstetric complications and (in pregnant women) augment the efficacy of antibiotic treatment in women ISSN 1876-2883 print, ISSN 1876-2891 online, DOI 10.3920/BM2018.0129 483 M. de Vrese et al. with BV (Anukam et al., 2006; Martinez et al., 2009; Reid Search strategy and data extraction and Bocking, 2003). In order to improve the efficacy of the treatment of BV, potential candidate lactobacilli were We searched PUBMED/MEDLINE, EMBASE, and the isolated from the vaginal microbiota of healthy women COCHRANE library for eligible articles without publication using a number of selection criteria, namely: date or language restrictions. Using the search term (in Boolean notation) ‘(lactobacillus OR lactobacilli) AND Catalase and oxidase activity, growth under aerobic and (vaginal OR vagina) AND (microbiota OR microflora), anaerobic conditions, acidification capacity, production we found 685 potentially relevant articles. The number of extracellular hydrogen peroxide, glycogen utilisation, decreased to 215 papers when the search was restricted to bile salt tolerance and growth inhibition of pathogens the above-mentioned lactobacilli species (full search term (Escherichia coli, Gardnerella vaginalis, Candida krusei, ‘(lactobacillus OR lactobacilli) AND (vaginal OR vagina) Candida albicans and Candida glabrata strains), absence AND (microbiota OR microflora) AND (crispatus OR of antibiotic resistances, mucin degradation, β-haemolysis gasseri OR jensenii OR rhamnosus)’. If the search was as well as glycosidase and arylamidase activity (Domig et limited to articles that examined the combination of all al., 2014). four species, or if the four lactobacilli strains were added to the search term either individually or in combination Four Lactobacillus strains (L. crispatus LbV 88, Lactobacillus (additional term ‘LbV OR LbV88 OR LbV 150N OR LbV116 gasseri LbV 150N, L. jensenii LbV 116 and L. rhamnosus LbV OR LbV96’), only six or four articles remained. Of these, 96, fulfilling these criteria (De Seta et al., 2014; Domig et two studies (Kiss et al., 2007; Martinez-Pena et al., 2013) al., 2014) were isolated by Kiss et al. (2007). This mixture were rejected on the basis of the abstract because they had was tested in several RCT pilot studies (Anoshina, 2016; not investigated health effects of all four species. Kaufmann et al., 2014; Laue et al., 2018; Marschalek et al., 2017) showing positive effects on the vaginal microbial A full-text search for one or all of the four strains mentioned pattern and, in one study, an improvement of the cure rate using Google Scholar yielded the same result. A manual in BV. It is commercially available as a food supplement search of the lists of references of retrieved articles as well (European Patent EP2509610B1). However, due to the low as inquiries to individual authors provided no further number of women examined, the studies mostly missed the articles. A request to the patent holder of the mixture of required level of significance. the four lactobacilli strains mentioned above confirmed the completeness of our list of four RCTs carried out according So, we aimed at assessing the overall evidence for an to the criteria for good research and publication practice effect of oral administration of these Lactobacillus strains (Figure 1). isolated from vaginal microbiota on vaginal dysbiosis. For this purpose, we performed a systematic review and Eligibility criteria meta-analysis of randomised clinical trials (RCTs) in which the effect of oral administration of a mixture of these We included randomised clinical trials (RCTs) in which Lactobacillus strains on vaginal dysbiosis was examined the effect of oral administration of the complete mixture based on Nugent score. of the four Lactobacillus strains (L. crispatus LbV 88 (DSM 22566), L. gasseri LbV 150N (DSM 22583), L. jensenii LbV Nugent score (>3) was used for defining vaginal dybiosis, 116 (DSM 22567) and L. rhamnosus LbV96 (DSM 22560)) since the global burden of vaginal dysbiosis was assessed on vaginal dysbiosis was assessed based on Nugent score. in studies based on Nugent score and since the extent of dysbiosis (no or low abundance of lactobacilli; increased Quality assessment bacterial diversity) in molecular studies correlated well with the Nugent score and with vaginal pH (Van de Wijgert The methodological quality of each study was estimated and Jespers, 2017). independently by both investigators (MV and JS) with respect to the method of randomisation, random allocation 2. Materials and methods concealment, blinding of treatment allocation, and study withdrawals Systematic literature searches and data extraction were performed by two investigators (JS and MV) independently Publication bias from each other. To visually identify publication bias or other small study effects, we used funnel plots of the standard error versus the standardised mean difference (SMD) or the odds ratio (OR), respectively (Light and Pillemer, 1984). 484 Beneficial Microbes 10(5) Improvement of vaginal dysbiosis by probiotic lactobacilli Calculation of effect measures and data synthesis 3. Results Statistical evaluation and meta-analysis were done using Studies identified the program MedCalc Statistical Software version 18.2.1 (MedCalc Software, Ostend, Belgium; http://www.medcalc. Overall, the literature search initially identified four RCTs, org). The authors of all three lastly identified studies representing data from 178 subjects (Figure 1 and Table 1): provided their raw data. For effect measures, we considered 1. Kaufmann et al. (2014), a DB-RCT in 60 male-to-female the mean difference ± standard deviation in absolute change transsexual women with penile linked neovagina; of the Nugent score between