Effects of a supplement associating Lactobacillus strains and proanthocyanidin-rich plant extracts against recurrent uncomplicated, urinary tract infections: A prospective, controlled study

Abstract

Purpose

Recurrent cystitis, particularly common in women, substantially diminishes patient quality of life and represents a major clinical practice and public health burden. Increasing development of resistance to antibiotics has encouraged the search for alternative treatments. The benefits of a food supplement associating two Lactobacillus strains with proanthocyanidin A-rich cranberry and cinnamon extracts were evaluated in 80 women with a history of cystitis recurrence.

Materials and Methods

Post-inclusion recurrence frequency was compared between women taking the investigated supplement daily for 6 months and non-supplemented women, based on patient-completed Acute Cystitis Symptom Score (ACSS) questionnaires.

Results

Two-thirds (64.9%) of supplemented women experienced no further episodes of cystitis during the first 6 months of the study compared to only one-third (31.6%) of non-supplemented women (p=0.004), the difference between the two groups being significant from 3 months onward. ACSS scores revealed significantly fewer and less severe urinary symptoms in supplemented women, as well as a significantly reduced impact of these symptoms on quality of life (p<0.0001).

Conclusions

The results shown by extensive data on women suffering from recurrent cystitis, collected over 8 months, indicate that taking the tested supplement daily for 6 months can provide significant benefits in terms of recurrence frequency, symptoms, and quality of life. The study is registered on the ClinicalTrials.gov site under the identifier NCT04987164.

Graphical Abstract

INTRODUCTION

Urinary tract infections (UTIs) constitute the second most common type of bacterial infection [1,2]. They represent a major public health issue, engendering a substantial deterioration in patient quality of life and placing a considerable burden on clinical practices and the public health system. They are particularly common in women, in whom the lifetime risk of a symptomatic UTI is around 50% and the estimated recurrence rate is 20%–40% within 3–4 months of the initial infection [1,3,4]. Most UTIs are expressed as acute uncomplicated cystitis (AUC) [5].

The principal causative agent is uropathogenic Escherichia coli (UPEC), responsible for 70%–95% of both sporadic and recurrent UTIs [6]. Antibiotics are commonly prescribed for both initial and recurrent UTIs, but their repeated use may favor the emergence of multidrug-resistant bacteria and may also adversely affect the microbiota [7,8]. The identification of effective nonantibiotic treatments, particularly for recurrent UTIs, is a high priority and the use of probiotics and plant extracts is attracting increasing interest.

The food supplement evaluated in our study contains cranberry and cinnamon extracts, as well as two strains of Lactobacillus, a beneficial bacterial component of the gut and vaginal microbiota. Women with no history of UTIs tend to have a Lactobacillus-dominated vaginal microbiota, whereas a Lactobacillus-depleted vaginal microbiota is a risk factor for UPEC colonization and UTIs [2,9]. Previous in vitro studies demonstrated inhibition of growth of the UPEC strain CIP 548T by each of the strains contained in the food supplement evaluated in our study, namely Lactobacillus helveticus LA401 and Lactiplantibacillus plantarum LA402, as well as a complementary inhibitory effect of the two strains cultured together with E. coli (PiLeJe Laboratoire, unpublished data on file). LA402 was additionally shown to maintain a high residual viability in the presence of the cinnamon and cranberry extracts present in the supplement.

Cranberries have traditionally been used to combat UTIs and their ability to decrease the risk of recurrent UTIs in healthy women has been confirmed in clinical trials [10,11,12] and acknowledged in several systematic reviews and meta-analyses [3,13,14,15,16]. The benefits of cranberry products are particularly evident in women with recurrent UTIs [13,14]. Bacterial adherence to the bladder epithelium is a key event in UTI pathogenesis and in vitro studies have shown that cranberry-derived proanthocyanidins (PAC), particularly A-type PAC, inhibit the adherence of uropathogenic Pfimbriated E. coli to human uroepithelial cells [17,18,19,20]. Like cranberries, cinnamon also includes Atype PAC and an in vitro study demonstrated both a PAC dose-dependent inhibitory effect of cinnamon extracts on E. coli adherence to isolated human bladder epithelial cells and a synergistic inhibitory effect of combined cinnamon and cranberry extracts on this adherence [21].

The objective of this study was to investigate the ability of a 6-month supplementation with a food supplement comprising cranberry and cinnamon extracts plus L. helveticus LA401 and L. plantarum LA402 to reduce the frequency of recurrent cystitis episodes in women having experienced recurrent cystitis prior to their inclusion. Data concerning symptoms and quality of life were collected over a total period of 8 months, using the Acute Cystitis Symptom Score (ACSS) questionnaire. The ACSS has been validated in numerous languages including American English [22] and French [23]. It has proven to be a valuable tool for the initial diagnosis of AUC in clinical studies and medical practice, as well as constituting a validated patient-reported outcome measure (PROM) enabling the assessment of treatments in women experiencing recurrent cystitis [22,24,25,26].

MATERIALS AND METHODS

1. Study design and ethics statement

This prospective, controlled study compared the number of symptomatic episodes of AUC (primary endpoint), urinary discomfort and the impact of this factor on quality of life, between two groups of women respectively taking and not taking the food supplement evaluated (Fig. 1). The study was conducted in conformity with the reference methodology of the National Commission for Data Computerization and Freedom (CNIL) and Good Clinical Practices. It was authorized by the local Ethics Committee (Comité de Protection des Personnes Sud Med II) (approval number: 221C07) on March 12, 2021 and notified to the French Medicines Agency (ANSM) on August 27, 2021. It is registered on the ClinicalTrials.gov site under the identifier NCT04987164.

Fig. 1. Study design. eCRF, electronic case report form.

2. Supplementation

The supplementation evaluated comprised two tablets per day of a food supplement containing in total 100 mg of cranberry extract and 320 mg of cinnamon extract (together supplying 36 mg of PAC-A), plus 5×10⁹ colony-forming units of the strains L. helveticus LA401 and L. plantarum LA402 (marketed by PiLeJe Laboratoire under the names Feminabiane CBU, Feminabiane CU, Ladybiane CBU, Feminabiane CU-UC, or Balans Plus Cranberry duo). The cranberry extract comprised a powder prepared from an aqueous extract of cranberries (Vaccinium macrocarpon) standardized to contain ≥15% A2-type PACs (Brunswick Laboratories 4-di-methylaminocinnamaldehyde [BL-DMAC] method). The cinnamon extract combined a delipidated powder of Cinnamomum cassia bark (a supercritical CO₂ extraction co-product) with a hydroalcoholic bark extract (ethanol: water 70:30, dried bark: dried extract 3:1). The extract was standardized to contain ≥8% A2-type PACs (BL-DMAC) and did not contain any essential oil.

3. Study population

Women were recruited from a panel of volunteers constituted by a French contract research organization, CEN (Dijon, France) (Fig. 1). Inclusion began on November 18, 2021 and last patient last visit occured on August 4, 2022. Potentially eligible women were invited to attend the clinical investigation center where the investigator fully explained the nature of the study (inclusion visit). Eligible women expressing their willingness to participate in the study were allocated to receive or not receive the food supplement.

Inclusion criteria:

• • Women aged between 18 years and 65 years;

• • Reporting at least two episodes of symptomatic cystitis (manifested by a burning sensation and/or pain or discomfort during urination [score ≥1 for ACSS item 3] AND frequent abnormal urination [pollakiuria] and/or urgent urination [score ≥1 for ACSS item 1 and/or item 2]) during the past 6 months, confirmed as being of bacterial origin (documented by urine analysis or an antibiotic prescription, or validated by a physician in at least one case), and having had a significant effect on quality of life (ACSS for the “quality of life” domain ≥3);

• • Giving their consent to participate in the study.

Exclusion criteria:

• • Urinary discomfort having a severe impact on quality of life (ACSS for the “quality of life” domain >7);

• • Antibiotic treatment or prebiotic or probiotic supplementation either ongoing or within the month preceding inclusion;

• • Prophylactic intake of cranberry juice within 15 days before inclusion;

• • Recourse to local estrogen treatment during 3 months prior to inclusion;

• • Presence of diabetes mellitus, immunosuppressive disease, or pelvic floor anomalies, presence or history of renal pathology;

• • Ongoing or planned pregnancy, or breast-feeding;

• • Known allergy to plants of the cranberry family or to any of the components of the supplement.

4. Outcome measures

The two study groups were compared on the basis of the responses recorded by each woman in the ACSS questionnaire [22,25,26]. The ACSS questionnaire is a simple diagnostic tool developed on the hypothesis that AUC can be diagnosed with a high probability based on the presence or absence of six typical symptoms (during the past 24 hours) and their severity (absence of any symptom [0 point], mild [1 point], moderate [2 points], or severe [3 points]) [22].

The six typical symptoms described in the ACSS questionnaire are as follows:

• • Frequent urination of small amounts of urine

• • Sudden and uncontrollable urge to urinate

• • Feeling a burning pain when urinating

• • Impression of incomplete bladder emptying

• • Feeling pain in the lower abdomen not associated with urination

• • Seeing blood in the urine

The total number of points calculated for the domain “typical symptoms” ranges from 0 (no symptom) to 18 (maximum symptom severity). The ACSS questionnaire also includes two additional domains: “differential symptoms”, comprising four items suggestive of an infection located in an adjacent organ (e.g., urethra, vagina, kidneys), for a total number of points ranging from 0 (no symptom) to 12 (maximum symptom severity), and “quality of life”, comprising three items for a total number of points ranging from 0 (no discomfort related to urinary symptoms and no impact of these symptoms on everyday activities and work, or on social activities) to 9 (severe discomfort/impact) [22]. The global score, comprising the sum of the sub-scores of the three domains, therefore ranges from 0 to 39.

5. Primary endpoint

The primary endpoint was the number of symptomatic cystitis episodes declared by each of the two study groups from inclusion up to 6 months (corresponding to the supplementation period). Symptomatic cystitis episodes were defined according to the patient-completed ACSS questionnaire on the basis of:

• • A burning sensation and/or pain or discomfort during urination (score ≥1 for item 3) as well as at least one of the following symptoms:

• • Frequent, abnormal urination (pollakiuria) or urgent urination (score ≥1 for item 1 and/or item 2).

The number of episodes declared up to 3 months was also evaluated, as well as the number of episodes declared up to the end of the study at 8 months, to assess persistence of the effect of supplementation.

6. Secondary endpoints

• • Discomfort during urination and its impact on quality of life (ACSS score and sub-scores);

• • Intensity of urinary symptoms (“typical symptoms” sub-score and total ACSS);

• • Time from inclusion to onset of the declared symptomatic cystitis episodes and the interval between episodes.

Patient satisfaction with the supplementation was recorded as “unsatisfied”, “fairly satisfied”, and “satisfied to very satisfied” at the end of 1, 3, and 6 months of supplementation (or no supplementation) and at 2 months after the end of the supplementation period (i.e., at 8 months).

7. Statistical analyses

The required sample size was based on the hypothesis of a mean of two symptomatic episodes of cystitis during the 6 months prior to the study and an estimated decrease of 1.5 episodes in this frequency among women receiving the supplement compared with 0.5 episodes among those not receiving the supplement at 6 months (corresponding to the end of the supplementation period). To demonstrate a difference of one episode between the two groups, with an alpha risk of 0.05 and a power of 80%, assuming a standard deviation (SD) of 1.5 in the number of episodes, it was estimated that 36 women would be required in each group, corresponding to a total study population of 72 women. Assuming a 10% rate of incomplete data files or discontinuation of the study before 6 months, the target study population was set at 80 women.

The study data were analyzed using SAS version 9.4 (SAS Institute). Continuous variables are presented as mean±SD, categorical variables being presented as percentages. The statistical significance of differences between the two study groups was determined by different tests depending on the normality or non-normality of the data distribution. In all tests, p<0.05 were considered statistically significant. The efficacy population was defined as all subjects evaluable for the primary endpoint and meeting the inclusion criteria and none of the exclusion criteria. The safety population comprised all subjects having taken at least one dose of the supplement.

RESULTS

1. Characteristics at the inclusion visit

A total of 80 women were included in the study, five women being subsequently excluded (Fig. 2). The population analyzed for efficacy therefore comprised 75 women in total, 37 in the supplemented group and 38 in the non-supplemented group. Characteristics determined at the inclusion visit did not differ to a statistically significant extent between these two groups except for the proportion of postmenopause women, which was significantly higher in the group receiving the supplement (Table 1). Overall, the data recorded at the inclusion visit confirmed that the women enrolled were indeed experiencing recurrent cystitis. In addition, the majority of these women had taken an antibiotic for symptomatic cystitis episodes within the 6 months prior to inclusion (excluding the month before inclusion in accordance with exclusion criteria). The antibiotic prescribed was principally fosfomycin, the first-line antibiotic recommended for the treatment of AUC in France [27].

Fig. 2. Study flow chart.

Table 1. Patient characteristics at the inclusion visit.

Characteristic	Supplemented (n=37)	Not supplemented (n=38)	p-value
Age (y)	42.5±12.6 (19–64)	39.4±9.8 (20–58)	NS
Weight (kg)	69.7±17.2	64.9±11.6	NS
Body mass index (kg/m²)	26.3±6.8	23.8±4.3	NS
Post-menopause (%)	32.4	13.2	0.046*
Number of symptomatic cystitis episodes during the 6 months prior to inclusion	2.2±1.4	2.0±0.9	NS
Global ACSS for the episodes of urinary discomfort experienced during the 6 months prior to inclusion	16.9±5.9	18.0±3.9	NS
Sub-score for the “typical symptoms” domain of the ACSS questionnaire for the episodes of urinary discomfort experienced during the 6 months prior to inclusion	9.6±3.3	10.4±2.5	NS
Sub-score for the “differential symptoms” domain of the ACSS questionnaire for the episodes of urinary discomfort experienced during the 6 months prior to inclusion	1.9±2.1	1.7±1.7	NS
Sub-score for the “quality of life” domain of the ACSS questionnaire for the episodes of urinary discomfort experienced during the 6 months prior to inclusion	5.4±1.8	5.9±1.7	NS
Total score on the ACSS questionnaire during the past 24 hours	2.7±3.6	2.8±3.9	NS
Percentage of women having taken at least one antibiotic treatment during the 6 months prior to inclusion for a cystitis-related urinary infection episode	75.3	78.7	NS
Percentage of women having taken at least one food supplement for a urinary infection episode during the 6 months prior to inclusion	6.2	10.7	NS
Percentage of women having undergone a laboratory urine test related to a urinary infection episode within the 6 months prior to inclusion	43.2	45.3	NS
Percentage of women for whom a urinary infection was confirmed by the laboratory urine test	100.0	91.2	NS

Values are presented as mean±standard deviation (range), mean±standard deviation only, or %.

NS, not statistically significant; ACSS, Acute Cystitis Symptom Score.

^*p<0.05.

2. Number of symptomatic cystitis episodes recorded from inclusion up to 6 months (primary endpoint)

From inclusion up to 6 months, substantially fewer supplemented women experienced recurrence of cystitis compared to non-supplemented women (Fig. 3). It is noteworthy that the difference between the two groups was significant from 3 months onward. From 0 to 3 months, 81.1% of women in the supplemented group experienced no episode of cystitis compared with 57.9% in the non-supplemented group; conversely, 42.1% of women in the non-supplemented group experienced at least one episode of cystitis compared with only 18.9% of women in the supplemented group (p=0.03, chi-squared test).

Fig. 3. Percentages of women experiencing symptomatic cystitis episodes during the first 6 months of the study in the supplemented and non-supplemented groups. The percentages of women experiencing ≥1 episode of cystitis during the study in the two groups was calculated as the sum of the percentages experiencing 1, 2, and 3 or more episodes (shaded box on the right-hand side of the figure). p=0.004 for comparison of distribution in the two groups according to the number of episodes 0 vs. ≥1 (Fisher’s test); p=0.0302 for comparison of distribution in the two groups according to the number of episodes 0, 1, 2, or 3 and more (Fisher’s test).

Comparison of the mean number of episodes recorded during the 6 months preceding inclusion and that recorded from inclusion up to 6 months inclusive showed a statistically significant decrease in the supplemented group (Table 2). From inclusion up to 6 months, the mean number of episodes recorded was 0.9 in the supplemented group and 1.7 in the non-supplemented group. This difference was statistically significant according to the non-parametric Mann–Whitney test (p=0.0048), but not according to Student’s t-test, owing to one woman in the supplemented group who reported 15 episodes from inclusion up to 6 months (the extreme value for this group). When this woman was excluded from the analysis, the mean number of episodes in the supplemented group fell to 0.5, resulting in a statistically significant difference between the two groups using Student’s t-test (p=0.0031).

Table 2. Mean number of symptomatic cystitis episodes recorded during the 6 months preceding inclusion and that recorded during the first 6 months of the study (corresponding to the period of supplementation in the group allocated to receive the supplement).

Group		No. of episodes during the 6 months preceding inclusion	No. of episodes from inclusion up to 6 months	Delta	p-valuea
Supplemented		2.2±1.4	0.9±2.5	-1.3±3.0	0.01*
	95% CI	1.7, 2.7	0.1, 1.8	-2.3, -0.3
Non-supplemented		2.0±0.9	1.7±2.0	-0.3±2.0	0.34
	95% CI	1.7, 2.3	1.0, 2.3	-1.0, 0.3

Values are presented as mean±standard deviation or 95% CI.

CI, confidence interval.

^a:Paired Student’s t-test for intragroup comparison of the number of episodes before versus after inclusion.

^*p<0.05.

Analysis of the number of symptomatic cystitis episodes between inclusion and the end of the study at 8 months showed persistence of the benefit of supplementation up to 2 months after this was discontinued. The results differed little from those obtained during the first 6 months of the study shown in Fig. 3.

There was no difference between the two groups in the time to onset of the first episode of symptomatic cystitis after inclusion, or in the interval between two successive episodes of cystitis.

3. Discomfort during urination and its impact on quality of life

The ACSS questionnaire was completed whenever a woman experienced an episode of symptomatic cystitis and on the following days until symptom resolution, between inclusion and the end of the study at 8 months. During this period, 36 symptomatic cystitis episodes were recorded in the supplemented group and 68 in the non-supplemented group, corresponding to 67 days and 175 days of crisis, respectively.

According to the ACSS questionnaires completed during symptomatic cystitis episodes, the total score and subscores were significantly reduced in the supplemented group (Fig. 4), except for the “differential symptoms” domain sub-score (as expected since this sub-score is used to rule out potential diseases other than recurrent uncomplicated cystitis). Statistically significant differences in favor of the supplemented group were observed for four of the typical symptoms (Fig. 5). Globally, the impact of urinary symptoms on quality of life was less in supplemented women than in non-supplemented women (Fig. 6).

Fig. 4. Discomfort during urination and its impact on quality of life in the supplemented and non-supplemented groups during recurrent symptomatic episodes of cystitis. Mean ACSS questionnaire total score and “typical symptoms”, “differential symptoms”, and “quality of life” domain sub-scores for symptomatic cystitis episodes reported between inclusion and end of the study at 8 months. A total of 36 episodes were recorded in the supplemented group and 68 in the non-supplemented group, corresponding to 67 days and 175 days of crisis, respectively. A total of 58 ACSS questionnaires were completed in the supplemented group and 138 in the non-supplemented group; 46 missing data. ACSS, Acute Cystitis Symptom Score. ^***p<0.0001.

Fig. 5. Effect of supplementation on the intensity of “typical symptoms” for symptomatic cystitis episodes reported between inclusion and end of the study at 8 months. A total of 36 symptomatic cystitis episodes were recorded in the supplemented group and 68 in the non-supplemented group, corresponding to 67 days and 175 days of crisis, respectively. A total of 58 ACSS questionnaires were completed in the supplemented group and 138 in the non-supplemented group; 46 missing data. Statistically significant differences between the supplemented and non-supplemented groups were observed for the symptoms “frequent emission of small amounts of urine”, “sudden uncontrollable urge to urinate”, “burning pain when urinating”, and “feeling of incomplete bladder emptying” (ACSS questions 1 to 4). No difference was observed for the two other typical symptoms (“blood in urine” and “pain in the lower abdomen not associated with urination”). ACSS, Acute Cystitis Symptom Score.

Fig. 6. Repercussions of urinary symptoms on quality of life for symptomatic cystitis episodes reported between inclusion and the end of the study at 8 months. A total of 36 symptomatic cystitis episodes were recorded in the supplemented group and 68 in the non-supplemented group, corresponding to 67 days and 175 days of crisis, respectively. A total of 58 ACSS questionnaires were completed in the supplemented group and 138 in the non-supplemented group; 46 missing data. The overall distribution of women between the different levels of urinary discomfort and repercussion of urinary symptoms on their quality of life in the two groups differed significantly (p<0.0001 for severity of urinary discomfort, impact on everyday activities/work and impact on social activities; Fisher’s test). ACSS, Acute Cystitis Symptom Score.

4. Satisfaction, compliance and tolerance

Overall, 97.3% of women reported satisfaction at the end of the 6-month supplementation period and all women at the end of the 8-month study. The mean rate of compliance with supplementation was 98.3%±4.0%. The food supplement was well tolerated, only 4 (10.8%) of the 37 women receiving this supplement declaring adverse events. With respect to the urogenital sphere, one case of vaginal irritation and one case of mycosis were reported, with no evident causal link to the supplement.

DISCUSSION

Advantageous features of this study comprise the robustness of the data collected and the fact that the results are based on a major effort to monitor symptoms over a long period. Specifically, the study protocol allowed the collection of a considerable amount of data on the symptoms and quality of life of women experiencing recurrent uncomplicated cystitis during a period of 8 months. The ACSS questionnaire used in the study constitutes a validated PROM that allowed assessment of the benefits of a 6-month intake of a food supplement containing PAC A-rich cranberry and cinnamon extracts plus the Lactobacillus strains, L. helveticus LA401, and L. plantarum LA402. It is also important to highlight the excellent compliance observed during the 6 months of supplementation and the high overall level of satisfaction.

Comparisons of the frequency of symptomatic cystitis episodes between the supplemented and non-supplemented groups consistently indicated a benefit of supplementation. This benefit persisted up to the end of the study, two months after the end of the supplementation period. Importantly, supplementation led to a statistically significant improvement in quality of life compared to no supplementation with respect to both everyday/work activities and social activities assessed by the ACSS questionnaire. The supplementation was well tolerated.

Lower incidences of clinical UTIs were also seen in patients allocated to cranberry juice intake in a 24-week randomized, placebo-controlled study [12] as well as in patients receiving a probiotic combining a cranberry extract with two Lactobacillus strains (L. acidophilus PXN 35 and L. plantarum PXN 47) in a 26-week randomized, placebo-controlled study [2]. This study conducted in women experiencing recurrent UTI showed a significantly lower rate of recurrence after 26 weeks of probiotic vs. placebo supplementation, with a longer median time to recurrence and a shorter duration of recurrent episodes [2]. Similarly, a randomized 90-day study comparing the number of UTI episodes in premenopausal women with a history of recurrent UTIs receiving respectively no treatment, a combination of L. paracasei, cranberry and D-mannose once a day for 10 days per month, or the same combination daily, showed substantially and significantly higher rates of UTI episodes in the control group than in either of the groups receiving the combination treatment. The rate of UTI episodes did not differ significantly between these last two groups, despite the large disparity in dosing schedules [6]. In that study, all patients received fosfomycin for two consecutive days prior to enrolment to eliminate any existing infection at baseline.

The effects observed in our study could be explained by the ability of the product’s active ingredients to limit the growth and adhesion of pathogens. In previous studies, we showed that L. helveticus LA401 and L. plantarum LA402 inhibited the growth of a uropathogenic strain of E. coli (PiLeJe Laboratoire, unpublished data on file) and that cinnamon inhibited the adhesion of E. coli to epithelial cells, a synergistic inhibitory effect on adhesion being observed when cinnamon and cranberry extracts were combined [21]. In addition, it has been shown that uropathogens can form quiescent intracellular reservoirs in bladder cells, which may explain cystitis recurrences [28]. Long-term use of the food supplement tested might neutralize the pathogens originating from these foci as soon as they are reactivated, thus preventing the development of recurrent episodes of cystitis. This supplement might also prevent the development of quiescent pathogen reservoirs, as previously documented for cranberry extracts [29]. Its effects observed in this study might also involve other mechanisms of action. For example, cinnamon and cranberry extracts have been shown to have anti-biofilm activity [30,31], while Lactobacillus strains have well known beneficial effects on the immune system, including anti-inflammatory effects [32], effects that have also been described for cinnamon [33] and cranberry extracts [34]. Congestion around uropathogens, the production of bacteriocins, hydrogen peroxide and lactic acid, and the acidic environment caused by lactic acid are other mechanisms of action of lactobacilli that may come into play in this context [32]. Whatever the mechanisms of action involved, limiting infectious episodes would lead to a reduction in the symptoms associated with infection and consequently an improvement in quality of life, as women would no longer be hampered in their daily lives by the infection and its symptoms. Recurrent cystitis can indeed be a severely debilitating condition [35]. The impact on women suffering from recurrent cystitis includes, of course, not only the pain and urinary symptoms associated with each episode, but also the potential development of a more serious UTI (e.g., pyelonephritis), disability precluding work and activities of daily living, deterioration in psychosocial parameters, with a risk of depression and anxiety, and side effects of antibiotics whether used for short-term treatment or long-term prophylaxis [35]. The availability of alternative solutions to counteract the recurrence of these UTIs is therefore essential.

Overall, the results of our study are consistent with those of previous studies investigating the benefits of various Lactobacillus species and cranberry extracts separately or in combination in women presenting recurrent UTIs. The principal limitations of our comparative study were its open design and lack of placebo comparison. Allocation was also by blocks of 10 rather than smaller blocks. Furthermore, the number of post-menopause women, potentially at higher risk of UTIs owing to hormonal changes affecting vaginal fluid composition and the vaginal microbiota [9,36], was substantially and statistically significantly higher in the supplemented group compared to the non-supplemented group. This discrepancy might have led to an underestimation of the benefit of supplementation. Nonetheless, we observed a significant difference between the two groups in favor of supplementation, as regards the percentage of women experiencing recurrence of cystitis.

CONCLUSIONS

In conclusion, 6-month intake of the tested food supplement achieved clinically and statistically significant benefits in women experiencing recurrent symptomatic cystitis episodes in terms of frequency of recurrence, symptoms and quality of life.