Bioactive Compounds in Natural Remedies and Functional Foods for Managing Recurrent Urinary Tract Infections in Postmenopausal Women

Abstract

Hormonal and age-related physiological changes significantly predispose postmenopausal women to recurrent urinary tract infections (rUTIs). The low estrogen levels characteristic of menopause can lead to genitourinary syndrome, which disrupts vaginal microbiota, weakens urinary defenses, and increases susceptibility to infections. A history of rUTIs, diabetes mellitus, sexual activity, and estrogen therapy is among the key risk factors for rUTIs. These factors may compromise urinary tract defenses, enabling bacterial colonization and infection. Given that frequent antibiotic treatment can lead to antimicrobial resistance, bioactive natural compounds are promising alternatives for UTI management. This review explores the role of bioactive compounds in natural remedies and functional foods as potential non-antibiotic approaches for rUTI management in postmenopausal women. Key bioactive compounds, including benzoic acid, proanthocyanidins, D-mannose, arbutin, phytoestrogens, berberine, vitamin C, and oleuropein, inhibit bacterial adherence and support urinary health. Functional foods enriched with these compounds, along with probiotics and cranberry products, may enhance urinary health and quality of life in postmenopausal women. However, due to the paucity of corroborating evidence, further well-designed clinical research is essential to validate efficacy, determine safety, and establish evidence-based dietary recommendations for UTI prevention.

INTRODUCTION

Menopause is commonly experienced by women aged 45 to 55 years [1] and results from reduced secretion of the ovarian hormones estrogen and progesterone. This occurs as the finite store of ovarian follicles is depleted. Women in the menopausal transition and postmenopausal period are affected by vasomotor symptoms, urogenital atrophy, sexual dysfunction, somatic symptoms, cognitive difficulty, sleep disturbance, and psychological problems [2].

According to Taga et al. [3], during the perimenopausal period, many women experience a range of symptoms, including hot flashes, sweating, changes in skin and mucous membranes, and mental health issues. These symptoms, mainly due to a decrease in female sex hormones, can significantly reduce quality of life. In addition, postmenopausal women are more susceptible to urinary tract infections (UTIs) [4], cardiovascular morbidity, dyslipidemia, hypertension, central obesity, and diabetes, partly due to estrogen deprivation [5].

Currently, a variety of menopausal symptoms and indicators associated with structural changes in the vagina, vulva, and lower urinary tract are collectively referred to as the genitourinary syndrome of menopause (GSM). GSM includes symptoms related to the genitalia and sexual organs, as well as urinary symptoms such as urgency, dysuria, and recurrent UTIs (rUTIs) [6]. rUTI are defined as three episodes of UTI in the previous 12 months or two episodes in the last 6 months [7].

Twenty-nine percent of postmenopausal women reported urinary incontinence, and 50% of them had genitourinary disorders. Dyspareunia, dryness, itching, and vaginal discharge are other clinical signs [8]. UTIs include acute pyelonephritis (an upper UTI) and acute cystitis (a lower UTI) [9]. UTIs are the second most common medical condition requiring attention and treatment in primary and secondary care settings. Its incidence is significantly higher in older women [6]. These infections are classified as either symptomatic (defined on the basis of symptoms and a positive urine culture) or asymptomatic (defined on the basis of a positive culture alone) [10].

Risk factors for complex UTIs are variable and multiple. The main risk factors affecting postmenopausal women include reduced estrogen secretion, a history of rUTIs, oral estrogen supplementation, diabetes, incomplete bladder emptying (e.g., cystocele), previous urogenital surgery, the genetically determined trait of not secreting ABO histo-blood group antigens, and frequent or high-dose use of estrogen creams [4,11,12,13].

In postmenopausal women, UTIs are common and cause significant morbidity and financial costs. The risk factors for UTI in healthy postmenopausal women living in the community have not been thoroughly described, although they have been extensively studied in younger women and older, debilitated women [4]. With the challenges posed by traditional therapies and the rise of antibiotic resistance, there is growing interest in exploring bioactive compounds from natural sources as potential alternatives.

Bioactive compounds such as benzoic acid, proanthocyanidins (PACs), fructose, D-mannose, oleuropein, arbutin, phytoestrogens, and berberine from various natural sources have demonstrated antibacterial properties against UTIs, as evidenced by both clinical studies and traditional use [14,15,16,17]. This review aims to explore the potential of bioactive compounds in developing functional food products specifically designed to manage UTIs in postmenopausal women. By integrating insights from recent studies, we highlight innovative dietary strategies that could offer sustainable and effective interventions for this population, addressing a growing health concern with natural, food-based solutions.

CHANGES AT MENOPAUSE PREDISPOSING TO URINARY TRACT INFECTION

A reduction in serum estrogen levels is associated with menopause. Estrogen receptors are expressed in the trigone of the bladder, the epithelium of the urethra and vagina, and the levator ani muscle of the pelvic floor [18]. When estrogen levels decline, the body undergoes several changes, including atrophy of the vulval, vaginal, lower urinary tract epithelium, a decline in detrusor function, and fibrosis of the bladder wall. Additionally, increased sensitivity to neurotransmitters such as norepinephrine leads to weakening of the pelvic floor muscles, increased post-void residual urine, and a decreased sensory threshold in the distal bladder [18]. Urethral closure pressure and Valsalva leak-point pressure are also reduced, contributing to urinary urgency [19].

According to Jung and Brubaker [20], the urogenital microbiota undergoes significant changes with age, frequently diminishing a woman's natural defenses against UTIs. Menopause is therefore a major risk factor for rUTIs. The pathophysiology of a single acute UTI in premenopausal women differs substantially from the pathogenesis of rUTIs in postmenopausal women.

In healthy premenopausal women, Lactobacillus species largely colonize the vagina, relying on glycogen produced by vaginal epithelial cells [4,20]. Lactobacilli ferment glycogen to produce lactic acid, which inhibits the growth of other bacteria, maintaining a protective vaginal microbiome and preventing dysbiosis and infection [21]. The GSM is characterized by changes in the urogenital epithelium associated with postmenopausal estrogen deficiency. This results in decreased production of epithelial glycogen, which subsequently reduces Lactobacillus colonization and lactic acid production. The rise in vaginal pH further increases susceptibility to uropathogen colonization and infection [20,22].

According to Hu et al. [4], a population-based case-control study was conducted among women aged 55 to 75 years who were enrolled in a large staff-model health maintenance organization. In this study, the primary pathogens causing UTIs were Escherichia coli (82.0%), followed by Group B Streptococcus (2.7%), Enterococcus (2.6%), Klebsiella species (5.0%), Proteus species (3.6%), and various other organisms (4.2%) responsible for the remaining infections. Women experiencing GSM due to these changes may exhibit symptoms such as nocturia, urgency, post-void dribbling, dysuria, hematuria, dyspareunia, vulvovaginal itching, and increased susceptibility to UTIs [23].

MECHANISM OF LOWER URINARY TRACT INFECTION

Bacteria colonize the area around the meatus and the distal urethra [13]. The colonization then progresses up the urethra to the bladder. Bladder colonization and infection begin when bacteria bind to the epithelial tissues of the bladder wall. This is an important distinction, as bacteria in the urinary tract (bacteriuria) may be present in the urine unbound and without symptoms (asymptomatic bacteriuria). To cause a bladder infection, the bacteria possess various adhesive organelles on their surface that facilitate adhesion and subsequent invasion of the bladder epithelial cells [24].

After entering the uroepithelial cells, the bacteria rapidly proliferate to form small clusters known as intracellular bacterial communities. Eventually, these bacteria aggregate to create biofilms, which are organized communities that display collective behavior. Biofilms protect the bacteria by concealing them within their matrix, shielding the communities from external stresses and making them resistant to host immune responses. Over time, bacteria detach from the biofilm and reattach to other uroepithelial sites, establishing new reservoirs of infection. During this process, the infection may remain dormant for weeks without symptoms. As a result, infections can persist for extended periods even after antibiotic treatment. A rare alternative pathway of infection is vesicoenteric fistula, in which the bladder acquires infection directly from neighboring organs. In such cases, urine cultures often reveal multiple organisms rather than a single pathogen [13].

RISK FACTORS FOR URINARY TRACT INFECTION

Postmenopausal women with a history of recurrent urinary tract infections

More recently, a case-control study done by Raz et al. [25] compared 53 age- and community-matched women without a history of UTI to 149 postmenopausal women with a history of rUTIs. The results showed that women with rUTIs were more likely than the control group to have experienced UTIs during their premenopausal years.

The finding by Foxman et al. [11] that a history of UTIs in the previous year increases the risk by seven to 18 times is consistent with previous research in premenopausal and postmenopausal women. A study conducted among women aged 40 to 65 reported that having three or more UTIs at any point in the past increased the risk nearly six-fold, while having at least one UTI within the past 12 months raised the risk 14-fold. These findings clearly indicate that, in both preand postmenopausal women, a history of UTIs is a significant predictor of current infection risk [26].

Sexual activity

According to Hu et al. [4], sexual activity remains a substantial risk factor for postmenopausal women in good health, although with a smaller magnitude of effect. Fewer than one sexual encounter per week was not associated with an increased risk of UTI, whereas women who reported sexual activity once a week or more were at higher risk. However, because higher-frequency sexual activity was less common, it was difficult to evaluate its effect fully. While sexual activity is a significant risk factor for younger women, neither this cohort nor another study of older age groups demonstrated the same strong association [11]. Sexual activity is believed to increase UTI risk by introducing new infectious organisms from the partner, damaging periurethral tissues, and transferring potential uropathogens into the bladder. Nonetheless, the incidence of UTIs among postmenopausal women does not vary significantly with sexual frequency, ranging between 7.7% and 9.2%. One possible explanation is an age-related increase in immunity. Although risk estimates are substantially lower than those observed in younger women, studies still report a positive association between symptomatic cystitis and sexual activity in postmenopausal women [4,11,26].

Diabetics

Patients with diabetes have higher rates of UTIs and bacteriuria compared to those without diabetes. Among adults with diabetes, women with type 2 diabetes are at the greatest risk of developing UTIs. The increased susceptibility observed in insulin-dependent women may reflect a longer disease duration or a more severe form of diabetes compared to non-insulin-dependent patients. Peripheral neuropathy, a common complication of diabetes, can contribute to uropathies that promote bacterial growth and increase residual urine volume [26].

Previous research on the incidence of acute cystitis has suggested several possible mechanisms, including increased adhesion of type 1 fimbriated E. coli to uroepithelial cells [27], reduced leukocyte and cytokine concentrations in the urine of diabetic women, and a higher incidence of vaginal E. coli colonization among women receiving insulin therapy [28]. In postmenopausal women, insulin-treated diabetes appears to be a potentially modifiable risk factor for acute cystitis; however, a lifetime history of UTIs remains the strongest predictor [12].

Oral estrogen supplementation

According to Hu et al. [4], most women use oral estrogen to manage postmenopausal symptoms. Approximately 40% of participants reported taking oral estrogen supplements in the month prior to enrollment for the study, and 97% of these women were prescribed conjugated estrogens or esterified estrogen (Estratab, Solvay). The daily estrogen dose varied, with a maximum of 2.5 mg/day and a modal dose of 0.625 mg/day. Women receiving more than 0.625 mg/day had an increased risk of developing UTIs compared to those not undergoing estrogen therapy. In contrast, lower estrogen doses showed no association with either an increased or decreased risk of UTIs.

Additional risk factors include atrophic vaginitis, urine incontinence, significant post-void residual volumes, and other mechanical or physiological conditions that impair incomplete bladder emptying, such as cystocele [29], as well as previous urogenital surgery and the genetically determined trait of not secreting ABO histo-blood group antigens [13]. Furthermore, women who reported more frequent and higher use of estrogen creams had an increased risk of infection, as estrogen cream use has been associated with a higher incidence of acute cystitis. Vaginal creams may contribute to UTI risk by introducing infectious agents into the vagina [12,13].

MANAGEMENT AND TREATMENT

Treatments for urinary tract infection

According to Jung and Brubaker [20], oral antibiotics are the primary treatment for treating acute UTI in postmenopausal women with a confirmed diagnosis of rUTI. Table 1 [20,30,31,32,33] summarizes an evidence-based approach to treating UTI in adult women with rUTI. The advantages of initiating empiric antibiotics immediately include rapid symptom relief and decrease bladder inflammation. However, these advantages must be balanced against the possibility of unnecessary or inappropriate antibiotic usage, which could contribute to the spread of antibiotic resistance. Symptom alleviation is essential. Regardless of the antibiotic used, sufficient hydration and bladder- specific and general pain medications are advised. Phenazopyridine is a particularly effective local bladder analgesic [30,34]. Nonsteroidal anti-inflammatory medicines have been investigated as both an adjunct and a substitute for UTI antibiotics. Ibuprofen can reduce antibiotic use; however, researchers noticed a little increase in the burden of symptoms during the initial treatment [30].

Table 1. Treatment of UTI in adult women with rUTI.

Type	Name [31]	Dosing
Symptom relief	Pyridium	100–200 mg TID × 2 days
	Ibuprofen	400 mg TID × 3 days
1st line antibiotic	Nitrofurantoin monohydrate/macrocrystals	100 mg BID × 5 days
	Trimethoprim/sulfamethoxazole	160/800 mg BID × 3 days
	Fosfomycin	3 g × 1 dose
2nd line antibiotic	Ciprofloxacin	250 mg BID × 3 days or 500 mg ER daily × 3 days
	Beta-lactams	3–7 days course
Self-start antibiotic	Nitrofurantoin monohydrate/macrocrystals	100 mg BID × 5 days
	Trimethoprim/sulfamethoxazole	160/800 mg BID × 3 days
	Fosfomycin	3 g × 1 dose

rUTI: recurrent urinary tract infection, TID: ter in die (three times a day), BID: bis in die (twice a day), ER: extended release.

Data from the articles of Jung and Brubaker (Climacteric 2019;22:242-9), Gágyoret al. (BMJ 2015;351:h6544), Gupta et al. (Clin Infect Dis 2011; 52:e103-20), Arabyat et al. (Expert Opin Drug Saf 2015; 14: 1653-60), Falagas et al. (Lancet Infect Dis 2010; 10:43-50) [20,30,31,32,33].

When selecting a UTI antibiotic, efficacy, collateral effects, and side effects should all be considered. Nitrofurantoin and trimethoprim/sulfamethoxazole are acceptable first-line medicines with proven efficacy and low collateral damage. Trimethoprim/sulfamethoxazole should only be used if community resistance is known [31].

According to Schaeffer and Stuppy [35], certain women may be eligible for self-start therapy, in which the patient appropriately detects her UTI symptoms and begins previously prescribed medications. The choice of a self-start antibiotic is based on resistance trends from previous cultures, local community antibiotic resistance, symptom relief effectiveness, and medication tolerance. Patient empowerment through active treatment participation, as well as reduced anxiety, phone calls, clinic visits, and laboratory testing, is among the advantages of self-starting therapy. There is a small chance of improper antibiotic exposure, such as when the uropathogen is resistant to her regular medication.

Prevention method for urinary tract infection

UTIs are among the most common bacterial diseases, requiring effective prevention strategies. Key approaches include functional foods (e.g., cranberry products), probiotics, estrogen therapy in postmenopausal women, methenamine salts, and antibiotic prophylaxis (Fig. 1).

Fig. 1. Preventive methods for UTIs, highlighting key approaches such as cranberry tablets, antibiotics, probiotics, methenamine salts, and estrogen therapy. UTIs: urinary tract infections, PACs: proanthocyanidins.

Estrogen therapy

Postmenopausal estrogen decline reduces glycogen in the vaginal epithelium, decreasing Lactobacillus spp. and increasing vaginal pH, which favors uropathogen colonization [22,36,37]. Vaginal estrogen therapy restores epithelial glycogen, encourages Lactobacillus recolonization, promotes lactic acid production, and lowers vaginal pH, thereby reinstating the urogenital microbiota and reducing rUTI recurrence.

Clinical trials demonstrate that vaginal estriol or estradiol significantly decreases UTI episodes and improves urogenital symptoms. For example, women receiving vaginal estriol experienced only 0.5 UTI incidents annually compared to 5.9 in the placebo group; vaginal pH decreased from 5.5 ± 0.7 to 3.6 ± 1.0, and Lactobacillus colonized 60% of treated women within 1 month [12,38]. Similarly, estradiol vaginal rings reduced urogenital symptoms and maintained 45% of women free of UTIs after 36 weeks versus 20% in the placebo group [38,39].

Functional foods and probiotics

Cranberry products

Cranberries are widely used for UTI prevention [40,41,42,43]. Their bioactive compounds include fructose, present in all fruit juices, and A-type PACs, unique to Vaccinium berries [16,44,45]. PACs inhibit E. coli adhesion to uroepithelial cells, preventing colonization and infection, without directly killing bacteria. Anti-adhesive effects can be observed within a few hours of ingestion and last several hours [16].

Daily consumption of 450–720 mL of cranberry juice has been reported to slightly acidify urine and increase urinary hippuric acid excretion, although bacteriostatic activity against E. coli may be limited in some healthy individuals [16,46,47]. Effervescent cranberry tablets with vitamin C improve absorption, gastrointestinal tolerance, and patient adherence, and may be especially beneficial for postmenopausal women [48].

Other Vaccinium berries, such as blueberries, bilberries, lingonberries, and huckleberries, are being investigated for UTI prevention. Blueberries, containing mostly B-type PACs, appear approximately one-third as effective as cranberries in anti-adhesive activity; however, higher consumption levels may compensate for lower efficacy [49]. Limited studies on lingonberry juice suggest potential benefits, but more research is needed [50].

Probiotics

Regular intake of fermented milk products containing Lactobacillus has been associated with a lower risk of rUTIs, whereas raw milk does not show the same effect [51]. Lactobacillus species can colonize the human gut, displace coliform bacteria, reduce UTI recurrence, and restore urogenital flora when administered intravaginally or orally. Phase 2 clinical trials indicate that vaginal Lactobacillus crispatus may be effective in reducing rUTIs in premenopausal women [20,52].

Methenamine salts

Methenamine is hydrolyzed in acidic urine to release formaldehyde, acting as a nonspecific urinary antiseptic. This bacteriostatic activity is independent of bacterial resistance, making methenamine useful for long-term prophylaxis. Cochrane reviews indicate its efficacy in individuals with normal urinary tracts and non-neuropathic bladders, with few reported adverse events [53].

Antibiotics

Antibiotics given on a daily or post-coital basis are useful preventive measures. When women experience coitally-associated UTI, the rate of UTI is decreased by post-coital medications. When compared to a placebo, daily continuous antibiotic prophylaxis for 6–12 months lowers the incidence of UTI, when there is no post-coital relationship with rUTI. Intravesical antibiotic instillations are a useful tool when previously stated preventative measures have not been successful in preventing rUTI episodes [20].

To minimize the possibility of systemic adverse effects, this method delivers the antibiotic directly to the bladder (instillation period of at least 1 hour) with minimal systemic absorption. The antibiotic gentamicin has been the subject of the greatest research (Table 2) [10,14,20,53,54,55,56,57,58].

Table 2. Prevention of UTI in adult women with recurrent UTI.

Type		Dosing
Vaginal estrogen		Estradiol (Vagifem, Ferring Pharmaceuticals) 10 mcg × 2/week
	Tablet	Estradiol (Estrace, Pfizer) 0.5 mg × 2/week
	Cream	Conjugated vaginal estrogens (Premarin, Pfizer) 0.5 mg × 2/week
	Ring	Estradiol (Estring, Pfizer) 2 mg every 3 months
D-mannose		2 g dissolved in 200 mL water daily
Methenamine		1 g twice a day
Antibiotics-continuous		50–100 mg daily
	Nitrofurantoin monohydrate/macrocrystals	40/200 mg daily to every 3 days 100 mg daily
	Trimethoprim/sulfamethoxazole	125–250 mg daily, 3 g every 10 days
	Trimethoprim	-
	Cephalexin	-
	Fosfomycin	-
Vaginal probiotic		Daily × 5 days, then weekly × 10 week
Vitamin C		1–3 g three to four times per day
Cranberry		Two capsules daily

UTI: urinary tract infection.

Data from the articles of Raz and Stamm (N Engl J Med 1993; 329: 753-6), Kranjčec et al. (World J Urol 2014; 32: 79-84), Lee et al. (Cochrane Database Syst Rev 2012; 10: CD003265), Hooton (Int J Antimicrob Agents 2001; 17:259-68), Perrotta et al. (John Wiley & Sons, Ltd., 2005), Stapleton et al. (Clin Infect Dis 2011; 52: 1212-7), Schwenger et al. (Cochrane Database Syst Rev 2015; 2015: CD008772) [10,14,53,55,56,57,58].

BIOACTIVE COMPOUNDS FOR THE TREATMENT OF URINARY TRACT INFECTIONS

Bioactive compounds play a vital role in the prevention and management of rUTIs, particularly in postmenopausal women. These compounds are known for their anti-bacterial, anti-inflammatory, and urogenital health activities. Phytoestrogens, plant derived estrogen compounds, along with berberine and oleuropein which are also known for their antimicrobial activity, D-mannose and PACs which prevent bacterial binding in urinary tract, arbutin, benzoic acid, and fructose which can be beneficial for urinary tract, are some of the bioactive compounds. Another contribution is from vitamin C as it makes the urine acidic and provides uncomfortable conditions for bacteria (Fig. 2).

Fig. 2. Bioactive compounds relevant for preventing recurrent urinary tract infections in postmenopausal women, including phytoestrogen, berberine, proanthocyanidin, D-mannose, arbutin, oleuropein, benzoic acid, fructose, and vitamin C, along with their chemical structure.

Benzoic acid

Benzoic acid occurs naturally in many foods and is also widely used as a preservative due to its antibacterial and antifungal properties [59,60]. Its relevance to UTIs was first observed in the late 19th century, when German physicians reported that cranberry consumption increased hippuric acid excretion in urine [16]. Cranberries are a good source of benzoic acid, which is metabolized and excreted in the urine as hippuric acid [16]. Hippuric acid was historically believed to explain the protective effect of cranberries, as it can act as a bacteriostatic agent and contribute to urinary acidification. Early studies showed that hippuric acid inhibited E. coli growth at a minimum concentration of 0.02 mmol/L at pH 5.0, though its antimicrobial activity decreased approximately five-fold when the pH increased to 5.6 [16].

However, modern evidence indicates that hippuric acid alone provides only a modest contribution to UTI prevention. Its bacteriostatic activity at physiological concentrations and typical urinary pH levels appears insufficient to account for cranberry's clinical effects. Instead, other cranberry-derived compounds, particularly PACs, are now recognized as the main contributors to anti-adhesion activity against E. coli [61].

Proanthocyanidin

PACs are polyphenolic compounds belonging to the flavonoid family, widely distributed in plants such as berries, grapes, nuts, seeds, and pine bark [62]. Cranberries are particularly rich in PACs, especially A-type structures, which distinguish them from the more common B-type PACs found in other fruits [15].

The relevance of PACs to UTI prevention lies in their ability to interfere with the adhesion of E. coli, the predominant uropathogen. In vitro studies demonstrated that cranberry PACs strongly inhibit P-fimbriae-mediated adhesion of uropathogenic E. coli to uroepithelial cells, thereby preventing colonization and reducing biofilm formation. This anti-adhesive mechanism is distinct from conventional antibiotics and is considered the primary contributor to cranberry's protective role, rather than urinary acidification by hippuric acid [44,63].

Clinical evidence for PACs remains mixed. A Cochrane systematic review concluded that cranberry products may modestly reduce the risk of rUTIs, particularly in women with frequent infections, but results across trials were inconsistent due to variability in PAC content, product formulations (juices, capsules, tablets), and patient compliance [64]. Moreover, the stability of PACs is influenced by pH, temperature, and light exposure, which contributes to substantial variation in the bioactive levels of commercially available cranberry products [13].

Fructose

Fructose, which is naturally present in all fruit juices, has been proposed to interfere with mannose-sensitive fimbrial adhesins of uropathogenic E. coli [16]. In vitro evidence suggests that monosaccharides such as fructose may act as competitive inhibitors of the FimH adhesin, thereby reducing bacterial attachment to uroepithelial cells [65]. Despite these mechanistic observations, there is no robust clinical evidence that fructose alone prevents UTIs. Its effect is therefore considered modest and likely supportive, acting in combination with other cranberry-derived bioactives such as PACs rather than as an independent therapeutic agent.

D-mannose

D-mannose, a naturally occurring monosaccharide found in fruits and available as a dietary supplement has been studied for its role in preventing rUTIs in women. D-mannose acts by specifically binding to the FimH adhesin of E. coli, thereby preventing bacterial adhesion to the bladder urothelium, a critical step in UTI pathogenesis. Clinical evidence suggests that D-mannose is more effective than placebo in reducing UTI recurrence over a 6-month period and demonstrates comparable efficacy to low-dose nitrofurantoin (50 mg/day) [14]. However, evidence is still limited by the small number of large-scale and long-term randomized controlled trials (RCTs), highlighting the need for further studies to confirm its efficacy and safety profile.

Oleuropein

Oleuropein, a secoiridoid glycoside found abundantly in the Oleaceae (e.g., olive leaves), Gentianaceae, and Cornaceae families, is a product of terpene secondary metabolism that serves as a precursor for various indole alkaloids [66]. Oleuropein and its hydrolytic metabolites exhibit broad-spectrum antimicrobial activity, including inhibition of E. coli. Beyond direct bacterial growth inhibition, oleuropein has been reported to disrupt established biofilms, a key virulence factor contributing to rUTIs [67]. Preclinical studies and nutraceutical investigations support its antimicrobial, antioxidant, and anti-inflammatory properties, although clinical trials specifically addressing UTI prevention or treatment remain limited [17].

Arbutin

Arbutin, a glycosylated hydroquinone derivative found in the leaves of Arctostaphylos uva-ursi (bearberry, also known as umbabazane), has been shown to exert antibacterial effects in the urinary tract [13]. Following ingestion, arbutin is metabolized to hydroquinone and related compounds, which are excreted in the urine and contribute to its antimicrobial activity. Owing to these properties, arbutin has been traditionally used for urinary disorders, and it has received official recognition from Commission E of the German Federal Institute for Drugs and Medical Devices for the treatment of lower urinary tract inflammation [68]. Pharmacokinetic studies confirm the urinary excretion of hydroquinone following bearberry extract intake [69]. Despite this supportive data, clinical evidence specifically evaluating its efficacy for UTI prevention or treatment remains limited, with few RCTs conducted to date.

Phytoestrogen

Phytoestrogens are plant-derived compounds that structurally resemble 17β-estradiol. Four major classes, isoflavones, stilbenes, coumestans, and lignans are recognized as phytoestrogens [70]. In postmenopausal women, phytoestrogens may help prevent UTIs by restoring the vaginal epithelium, promoting Lactobacillus colonization, lowering vaginal pH, reinforcing the epithelial barrier, and enhancing innate antimicrobial defenses. These effects collectively reduce the likelihood of E. coli adherence and colonization in the urinary tract [71].

Although oral formulations are the most commonly used route, they are associated with delayed absorption, stability issues, and variable patient compliance. Liquid forms may also exhibit delayed onset of action. Effervescent tablets have been proposed as an alternative to improve bioavailability and patient convenience [72]. RCTs support the benefits of phytoestrogens for GSM, suggesting an indirect protective effect against UTIs, although direct evidence for UTI prevention remains limited [42].

Berberine

Berberine is an isoquinoline alkaloid found in several plants, including barberry (Berberis vulgaris), tree turmeric (Berberis aristata), Oregon grape (Berberis aquifolium), goldenthread (Coptis chinensis), and goldenseal root (Hydrastis canadensis). These plants have a long history of use in traditional Chinese, Ayurvedic, and other medical systems worldwide. Berberine exhibits broad antimicrobial activity against bacteria, fungi, viruses, protozoa, and helminths. Early studies suggested low antibiotic potency in isolates, leading to the assumption that berberine was ineffective; however, more recent evidence indicates that synergistic interactions with other plant compounds enhance its ability to reach bacterial targets and exert antimicrobial effects [13]. Despite promising preclinical and broad antimicrobial data, evidence specifically supporting its efficacy in UTIs remains limited, and variable absorption and study heterogeneity pose challenges for interpretation [43,45].

Vitamin C

Vitamin C (ascorbic acid), found in citrus fruits and available as a dietary supplement, has been suggested to reduce the incidence of UTIs by acidifying urine and supporting immune function. Evidence from a RCT in pregnant women showed that daily intake of 100 mg of ascorbic acid reduced UTI incidence from approximately 29.1% to 12.7% over 3 months [73]. However, there is currently no robust evidence supporting its use for preventing rUTIs in postmenopausal women, and long-term dosing and safety remain unclear.

Several other substances such as vitamin A, bromelain, nettle, Oregon grape, plantain, horsetail, horseradish, and green tea have been proposed as potential urinary tract supportive agents. Nonetheless, scientific evidence regarding their antibacterial efficacy or clinical benefits is limited, and further rigorous research is required before recommending their use for UTI prevention (Table 3) [13,14,17,42,43,45,61,64,65,69,73].

Table 3. Overview of non-antibiotic compounds used for urinary tract infection prevention, including sources, mechanisms of action, clinical evidence, limitations, and key references.

Compound	Source	Mechanism of action	Clinical evidence	Limitation	Key reference
Benzoic acid	Cranberries	Excreted as hippuric acid → lowers urinary pH, bacteriostatic	Historically linked to UTI prevention; weak evidence today	Minimal modern validation	Pilcher et al. [61]
PAC	Cranberries, blueberries	Inhibit Escherichia coli adhesion, reduce biofilm	RCTs show modest benefit	Variable PAC content; mixed results	Williams et al. [64]
Fructose	Fruit juices	Hypothesized to interfere with mannose-sensitive fimbrial adhesion (based on in vitro lectin/fimbriae binding models)	No robust clinical trials; evidence largely indirect or mechanistic	Weak alone; mostly supportive role	Hung et al. [65]
D-mannose	Fruits, supplements	Blocks E. coli fimbriae adhesion	RCT showed comparable efficacy to nitrofurantoin	Few large-scale, long-term trialslong-term trials	Kranjčec et al. [14]
Oleuropein	Olive leaves	Antimicrobial, antioxidant, anti-inflammatory	Preclinical and nutraceutical studies supportive	Limited UTI-specific trials	Gorzynik-Debicka et al. [17]
Arbutin	Bearberry leaves	Hydrolyzed to hydroquinone → antibacterial	Pharmacokinetic study: arbutin/hydroquinone excretion in humans after bearberry extract intake	Few RCTs; no strong clinical trials specifically for UTI effectiveness	Schindler et al. [69]
Phytoestrogens	Soy, flaxseed, clover	Mimic estrogen, restore vaginal epithelium & Lactobacillus	RCTs show benefit for GSM; indirect UTI benefit	Limited direct UTI evidence	Gray et al. [42]
Berberine	Berberis spp., Coptis spp.	Antimicrobial, anti-biofilm	Broad human data for antimicrobial effects in different infections; review shows some benefit, though UTI-specific data are sparse	Variable absorption; UTI-specific efficacy less well documented; heterogeneity in studies	Migkos et al. [43], Imenshahidi and Hosseinzadeh [45]
Vitamin C	Citrus fruits, supplements	Acidifies urine,	RCT in pregnant women showed that daily intake of 100 mg ascorbic acid reduced UTI incidence from ~29.1% down to ~12.7% over 3	Weak evidence in postmenopausal women; only one RCT, risk of bias; unclear dosing/safety long-term	Ochoa-Brust et al. [73]

UTI: urinary tract infection, PAC: proanthocyanidin, RCT: randomized controlled trial, GSM: genitourinary syndrome of menopause.

CONCLUSION

This review highlights functional foods and natural remedies containing bioactive compounds for the potential management of rUTIs among postmenopausal women. Compounds such as D-mannose, phytoestrogens, PACs, and berberine show promising activity in inhibiting bacterial adherence and supporting urinary health. Functional foods and dietary supplements enriched with these compounds, combined with cranberry products and probiotics, may provide complementary, non-antibiotic approaches to urinary health. Nevertheless, current clinical evidence remains limited, with variability in study design, dosing, and formulations. Further well-designed RCTs are required to confirm efficacy, determine standardized dosing, and establish long-term safety. In addition, potential adverse effects, interactions with commonly prescribed medications, and inconsistency in bioactive compound content across commercial products should be carefully considered. Addressing these limitations through rigorous clinical research will be essential to develop evidence-based dietary guidelines and inform the safe use of functional foods and targeted nutritional supplements for urinary health in postmenopausal women.