The Power of Probiotics to Combat Urinary Tract Infections: A Comprehensive Review

Urinary tract infections (UTIs) are among the most common bacterial infections and can cause significant morbidity, particularly in women. Recurrent UTIs are a significant clinical problem, and current prophylactic measures, such as antibiotics, are associated with side effects and the risk of antimicrobial resistance. Probiotics, defined as live microorganisms that confer health benefits to the host, have emerged as a potential alternative to traditional treatments for recurrent UTIs. Probiotics can act by modulating the host's immune system, competitively excluding uropathogens, and producing antibacterial substances, such as bacteriocins. Clinical evidence supports the use of probiotics as a safe and effective intervention for the prevention and treatment of recurrent UTIs. However, selecting appropriate probiotic strains for UTIs can be challenging, and the safety and efficacy of probiotics depend on the strain, dosage, and timing of administration. The safety profile of probiotics is generally excellent, and side effects are usually mild and self-limiting. However, certain populations, such as immunocompromised and critically ill patients, may be at increased risk of adverse events, and caution should be exercised when considering probiotic use in these populations. Strategies for ensuring probiotic safety and efficacy include adherence to good manufacturing practices, rigorous testing for the presence of contaminants, and standardization of dosing and administration protocols. Despite the potential of probiotics for the prevention and treatment of recurrent UTIs, several challenges and limitations remain. These include limited access to high-quality probiotic products, challenges in selecting appropriate strains, and lack of consensus regarding optimal dosing and duration of probiotic use. Future research should focus on identifying optimal probiotic strains and regimens for the prevention and treatment of UTIs, understanding the role of gut microbiota in urogenital health, and developing new probiotic technologies and delivery methods.


Urinary tract infections
Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, with a significant impact on both individual health and healthcare costs 1 . They occur when bacteria, usually from the intestinal microbiota, enter the urinary tract and multiply, causing inflammation and tissue damage 2 . The UTIs can occur in any part of the urinary system, from the bladder to the kidneys, and can range in severity from mild discomfort to life-threatening sepsis 2 . Women are at higher risk of UTIs than men, due to anatomical and hormonal factors, and recurrent UTIs are a common problem, affecting up to 25% of women who experience an initial UTI 3 .
The most common causative agent of UTIs is Escherichia coli (E. coli), a gram-negative bacterium that colonizes the rectal and perineal areas 4 . Other bacteria that can cause UTIs include Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus saprophyticus 4 . Risk factors for UTIs include female gender, sexual activity, use of spermicides or diaphragms, urinary tract abnormalities, and impaired immune function. The UTIs can also be caused by catheterization or other medical procedures introducing bacteria into the urinary tract 3,4 .
Antibiotics are the mainstay of UTI treatment, but the emergence of antibiotic-resistant strains of bacteria has led to increasing interest in alternative approaches, such as probiotics 5 . Probiotics are live microorganisms that confer health benefits when consumed in adequate amounts 5 . They can help prevent UTIs by competing with pathogenic bacteria for resources, producing antibacterial substances, and modulating the host immune response 6 . Probiotics can also be used as a treatment for UTIs, either alone or in combination with antibiotics 7 . While there is growing evidence for the efficacy of probiotics in preventing and treating UTIs, challenges remain in determining the optimal probiotic strains, dosages, and administration routes, as well as ensuring their safety and quality 6,7 .

The role of probiotics in the prevention and treatment of urinary tract infections
Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer health benefits to the host 8 . They are commonly found in fermented foods and dietary supplements and can contain various bacterial and fungal species 8 . Probiotics can exert their effects through several mechanisms, including direct competition with pathogenic bacteria for resources, antibacterial substances production, and host immune response modulation. The use of probiotics to prevent and treat UTIs has gained increasing attention due to the limitations of conventional antibiotic therapy 9 .
The mechanisms by which probiotics can prevent UTIs include the production of antimicrobial peptides, modulation of the host immune response, and the ability to compete with pathogenic bacteria for adherence to the urinary tract mucosa 9,10 . Lactobacilli and Bifidobacteria are two of the most commonly studied probiotic strains for UTI prevention, as they are natural colonizers of the human gut and vaginal microbiota 10 . These strains have been shown to produce hydrogen peroxide, which can inhibit the growth of uropathogenic bacteria, and to enhance mucus production in the urinary tract, which can physically prevent bacterial adhesion 10 .
Probiotics can also be used as an adjunct to antibiotic therapy for treating UTIs, as they can help replenish the normal microbiota and reduce the risk of recurrent infections 11 . One study found that using Lactobacillus crispatus vaginal suppositories in combination with antibiotics was associated with a lower risk of recurrent UTIs compared to antibiotic therapy alone 11 . Another study indicated that the use of Lactobacillus rhamnosus (L. rhamnosus) GG reduced the risk of antibiotic-associated diarrhea and other adverse effects in patients with UTIs 12 . However, more research is needed to determine the optimal probiotic strains, dosages, and administration routes for UTI treatment.

Purpose of study
The purpose of this review article is to provide a comprehensive overview of the current knowledge regarding the use of probiotics for the prevention and treatment of urinary tract infections (UTIs). The article will begin with background information on UTIs, including their causes, risk factors, and current treatment options. The definition of probiotics and their role in the prevention and treatment of UTIs will then be discussed, focusing on the mechanisms by which probiotics can prevent and treat UTIs, as well as the most commonly studied probiotic strains. In addition, the safety and quality of probiotic supplements will also be discussed, as well as the potential of probiotics to reduce the use of antibiotics and the emergence of antibiotic-resistant bacteria will be explored, as well as the economic implications of probiotic therapy for UTIs. The information provided in this review will be of interest to researchers, clinicians, and patients seeking to optimize their UTI prevention and treatment strategies.

Overview of urinary tract infections-causing pathogens
The majority of UTIs are caused by uropathogenic E. coli (UPEC), which can colonize and invade the urinary tract epithelium, leading to inflammation and tissue damage 1 . Other common UTI-causing pathogens include Klebsiella pneumoniae, Proteus mirabilis, and Enterococcus faecalis 2 . The virulence factors of these pathogens, including adhesins, toxins, and iron-acquisition systems, are critical for colonization, invasion, and persistence in the urinary tract 2,4 .
Uropathogenic E. coli is the most common cause of UTIs, accounting for over 80% of community-acquired UTIs 13 . The UPEC strains are genetically diverse and can express various virulence factors, including pili, fimbriae, and adhesins, that allow them to attach to and invade host cells 13 . The UPEC also produce toxins and iron acquisition systems that enable them to persist and cause inflammation in the urinary tract 4,13 . Several studies have identified specific UPEC virulence factors associated with increased UTI severity and recurrence, including the P fimbriae and S fimbriae 2,4,13 .
Klebsiella pneumoniae is another common cause of UTIs, particularly in hospitalized patients and those with underlying medical conditions 2 . The K. pneumoniae strains can produce a range of virulence factors, including adhesins, capsule polysaccharides, and iron-acquisition systems, that enable them to colonize and cause infections in the urinary tract 14 . Proteus mirabilis is a common cause of catheter-associated UTIs and is characterized by its ability to swarm across surfaces and form biofilms 15 . Enterococcus faecalis is a less common UTI pathogen associated with recurrent infections and resistance to multiple antibiotics 16 . Understanding the virulence factors and pathogenic mechanisms of these UTI-causing pathogens is critical for developing effective prevention and treatment strategies, including probiotics.

Pathogenesis of urinary tract infections
Understanding the pathogenesis of UTIs is critical for the development of effective prevention and treatment strategies 2 . Adhesion, colonization, and biofilm formation are important mechanisms by which pathogenic bacteria cause UTIs 2,4 . Adhesion to the urinary tract epithelium is the first step in the pathogenesis of UTIs. Adhesion is mediated by adhesins on the bacterial surface, which bind to specific receptors on the urinary tract epithelial cells. Adhesins can be expressed on fimbriae, pili, or other surface structures, and environmental signals can regulate their expression. The initial adhesion of bacteria to the urinary tract epithelium is a critical step in the pathogenesis of UTIs, as it allows bacteria to evade the host immune response and establish a foothold in the urinary tract 2,4 .
Once bacteria have adhered to the urinary tract epithelium, they can colonize the urinary tract and initiate an inflammatory response 2 . The expression of virulence factors, including iron acquisition systems and adhesins, facilitates colonization 4 . Iron is an essential nutrient for bacterial growth, and the urinary tract is a relatively ironpoor environment. Pathogenic bacteria express iron acquisition systems, including siderophores, which enable them to scavenge iron from the host 2,4 . Adhesins are critical for bacterial colonization, allowing bacteria to attach to and invade host cells 4 . Bacterial colonization of the urinary tract can lead to tissue damage and inflammation, which can cause symptoms of UTIs, including dysuria and urinary frequency 2,4 .
Biofilm formation is an important mechanism by which bacteria can persist in the urinary tract and resist antimicrobial therapy 17 . Biofilms are complex bacteria communities encased in a matrix of extracellular polymeric substances 18 . Biofilms can form on the surface of urinary catheters, stones, or damaged urinary tract tissue, and are resistant to antibiotics and the host immune response 18 . Biofilm formation is mediated by a range of virulence factors, including polysaccharide adhesins, and is regulated by environmental signals 17 . The formation of biofilms can lead to persistent infections and recurrent UTIs, making them a significant clinical challenge 17,18 .

Antibiotic resistance and its implications on urinary tract infections
Antibiotic resistance is a significant global health challenge that has important implications for the treatment of urinary tract infections (UTIs) 6 . The emergence and spread of antibiotic-resistant bacteria have been driven by a range of factors, including the overuse and misuse of antibiotics, as well as the spread of resistance genes through horizontal gene transfer 19 . Antibiotic resistance can make UTIs more difficult to treat, as bacteria become resistant to commonly used antibiotics 19 .
Resistance to antibiotics used to treat UTIs is a growing concern, as many of the bacteria that cause UTIs have developed resistance to multiple antibiotics 6,19 . This has led to a significant increase in the use of broad-spectrum antibiotics, which can have serious side effects and contribute to the development of antibiotic resistance 19 . In addition, the overuse of antibiotics has been associated with the disruption of the gut microbiota, which can lead to various health problems, including the development of antibiotic-resistant infections 20 .
The rise of antibiotic-resistant UTIs has significant clinical implications, as it can lead to treatment failure, prolonged hospitalization, and increased healthcare costs 20 . Treatment options for antibiotic-resistant UTIs are limited and may include the use of combination therapy, higher doses of antibiotics, or the use of last-line antibiotics 6 . These options are associated with significant risks and side effects, and may contribute to developing further antibiotic resistance 19 . In addition, there is a need for alternative approaches to the prevention and treatment of UTIs that do not rely on antibiotics 20 .

Mechanisms of action
The mechanisms of action of probiotics in preventing UTIs are multifactorial and involve a range of host and bacterial factors 21 . Probiotics can compete with uropathogens for nutrients and adhesion sites, produce bacteriocins that inhibit the growth of pathogenic bacteria, and modulate the host immune response 9 . In addition, probiotics can restore the balance of the gut and vaginal microbiota, which can protect uropathogens 9 .
Probiotics are effective in preventing UTIs by inhibiting the adhesion and colonization of uropathogens in the urinary tract 9,21 . Several studies have shown that probiotics can interfere with the adhesion of uropathogenic E. coli (UPEC) to uroepithelial cells, which is a critical step in the development of UTIs 22 . Probiotics can also prevent the formation of biofilms by UPEC, which can increase their resistance to antibiotics and immune defenses 23 . By inhibiting the adhesion and colonization of uropathogens, probiotics can reduce the risk of UTIs 22,23 .
Probiotics can also modulate the host immune response, which plays an important role in preventing UTIs 9 . Probiotics can enhance the production of immunoglobulins, cytokines, and other immune factors involved in the defense against uropathogens 9 . In addition, probiotics can downregulate the production of proinflammatory cytokines, contributing to the development of UTIs 24 . By modulating the host immune response, probiotics can provide protection against UTIs and reduce the severity of infections 9,24 .
The restoration of the gut and vaginal microbiota by probiotics is another mechanism by which they can prevent UTIs 25 . Disruption of the gut and vaginal microbiota can lead to dysbiosis, which can increase the risk of UTIs 25 . Probiotics can restore the balance of the gut and vaginal microbiota, which can provide protection against uropathogens 25 . In addition, probiotics can produce lactic acid, which can reduce the pH of the urine and inhibit the growth of uropathogens 24,25 . The restoration of the gut and vaginal microbiota by probiotics is a promising approach for the prevention of UTIs, as it targets the underlying causes of UTIs 25 .

Clinical evidences
Clinical studies have demonstrated the efficacy of specific probiotic strains in reducing the incidence of UTIs 9 . Lactobacillus crispatus and L. rhamnosus have been the most widely studied strains for this purpose 12,21 .
The mechanism by which probiotics prevent UTIs is multifactorial 26 . Probiotics have been shown to modulate the host immune response, maintain a low vaginal pH, and produce bacteriocins that inhibit the growth of uropathogens 9 . In addition, probiotics are able to compete with uropathogens for adhesion sites on uroepithelial cells, preventing colonization and subsequent infection 21 . While further research is necessary to understand the mechanisms of action fully, the clinical evidence suggests that probiotics significantly reduce the incidence of UTIs 9,21,26 .
In a randomized, double-blind, placebo-controlled trial, the use of a probiotic mixture containing Lactobacillus acidophilus, L. rhamnosus, and Streptococcus thermophilus (S. thermophilus) reduced the incidence of UTIs in women with recurrent UTIs 27 . In another study, daily intake of Lactobacillus crispatus CTV-05 reduced the risk of recurrent UTIs in premenopausal women 28 . Similarly, the use of L. rhamnosus GR-1 and Lactobacillus reuteri RC-14 reduced the incidence of UTIs in postmenopausal women 29 .
Overall, the clinical evidence strongly supports the use of probiotics in the prevention of UTIs 9,21,26 . While further studies are needed to establish optimal dosages and formulations, probiotics have the potential to significantly reduce the burden of UTIs and limit the overuse of antibiotics in this context. It is important, however, to identify the specific strains and doses of probiotics that are most effective for UTI prevention, as not all probiotics are equally effective in this regard 30 .

Potential probiotics for prevention of urinary tract infections
Several bacterial strains have been explored for their potential to prevent UTIs, with Lactobacillus species being the most commonly studied 21,27 .
Lactobacillus is one of the most commonly studied probiotic strains for UTI prevention, and is effective in reducing the incidence of UTIs in some studies 27 . Other strains of probiotics that have been studied for their potential to prevent UTIs include Bifidobacterium, Streptococcus, and Enterococcus, among others 31,32 . These strains have been found to inhibit the growth of uropathogenic bacteria, prevent biofilm formation, and stimulate immune responses that can help prevent UTIs 32 . Lactobacillus crispatus is a strain of Lactobacillus that is particularly effective in preventing UTIs 10 . Studies have found that women with a healthy vaginal microbiome, including high levels of Lactobacillus crispatus, are less likely to experience UTIs 10 . Lactobacillus crispatus has been shown to inhibit the growth of uropathogenic bacteria and promote the growth of beneficial bacteria that can help prevent UTIs 10 .
Another promising bacterial strain for UTI prevention is E. coli Nissle 1917 (EcN) 33 . This strain has been extensively studied and has been shown to have a range of beneficial effects on the host immune system, including modulation of cytokine production, promotion of mucosal barrier function, and enhancement of innate and adaptive immune responses. In addition, EcN has been shown to effectively inhibit uropathogenic E. coli through the secretion of microcins, which are small antimicrobial peptides that specifically target and kill related strains 33 .
Other bacterial strains that have shown potential for UTI prevention include Bifidobacterium species, which are commonly used in probiotic supplements for digestive health, and S. thermophilus, a commonly used yogurt starter culture 34 . Bifidobacterium species have been shown to reduce the risk of UTIs in postmenopausal women, and S. thermophilus has been shown to inhibit the adhesion of uropathogenic E. coli to bladder cells. These strains, along with others such as Enterococcus faecalis and Propionibacterium freudenreichii, represent promising candidates for further investigation in the prevention of UTIs 34 .
In addition to these specific probiotic strains, multistrain probiotic supplements have also been studied for their potential to prevent UTIs 10 . These supplements typically contain a combination of Lactobacillus and Bifidobacterium strains, as well as other beneficial bacteria. Studies have found that multi-strain probiotics can be effective in reducing the incidence of UTIs in women with a history of recurrent UTIs 10 .

Mechanisms of action
The mechanisms of action of probiotics in treating UTIs include the production of antibacterial compounds, competitive inhibition, and immunomodulation 8,9 . Probiotics have been shown to produce antibacterial compounds, such as organic acids and bacteriocins, which can inhibit the growth of uropathogens 35 . Lactobacillus crispatus has been found to produce hydrogen peroxide, which can kill uropathogenic bacteria. Lactobacillus acidophilus and L. rhamnosus have been shown to produce bacteriocins that can inhibit the growth of uropathogenic bacteria 8,10 . Probiotics can also compete with uropathogens for adhesion to uroepithelial cells and thereby prevent their colonization. Lactobacilli and Bifidobacteria can also acidify the urine, which can reduce the risk of UTI 8,34 .
In addition to producing antibacterial compounds and competitive inhibition, probiotics can also modulate the immune response 36 . Probiotics can increase the production of immunoglobulins, such as IgA, which can bind to uropathogens and prevent their adhesion to uroepithelial cells 36 . Probiotics can also activate macrophages, natural killer cells, and neutrophils, which can kill uropathogens 37 . Furthermore, probiotics can modulate the balance of Thelper cells, increasing the number of T-helper 1 cells, which produce interferon-gamma, a cytokine that can kill uropathogens 37. Several clinical studies have investigated the use of probiotics in treating UTIs 7-10 . A randomized controlled trial found that a probiotic containing Lactobacillus crispatus reduced the recurrence of UTIs in women 28 . Another study found that a probiotic containing L. rhamnosus and Lactobacillus reuteri reduced the incidence of UTIs in premenopausal women. In addition, a metaanalysis of 10 randomized controlled trials found that probiotics were effective in preventing UTIs 10 .
While the use of probiotics as an alternative therapy for UTIs is promising, there are still several challenges that need to be addressed. The optimal probiotic strain, dose, and duration of therapy need to be determined. In addition, the safety and efficacy of probiotics need to be established in larger, randomized, controlled trials. Overall, the use of probiotics as a potential alternative to antibiotics for the treatment of UTIs warrants further investigation 6-10 .

Clinical evidences
Probiotics are emerging as a promising alternative to antibiotics in the prevention and treatment of UTIs 6 . While the mechanisms by which probiotics exert their beneficial effects are still being elucidated, several clinical studies have provided evidence supporting their use in UTI treatment 6 .
In a randomized, double-blind, placebo-controlled study, female patients with recurrent UTIs were given Lactobacillus crispatus CTV-05, a probiotic strain isolated from the vagina 38 . The study found that the probiotic group had a significantly lower incidence of UTIs compared to the placebo group 38 . Another clinical trial investigated the efficacy of the probiotic combination of L. rhamnosus GR-1 and Lactobacillus reuteri RC-14 in the treatment of acute UTIs 39 . The probiotic group showed a higher rate of resolution of symptoms and bacterial eradication compared to the placebo group 39 .
A study by Beerepoot et al. showed that daily oral administration of L. rhamnosus GR-1 and Lactobacillus reuteri RC-14 in women with recurrent UTIs led to a decrease in the incidence of UTIs compared to placebo. This study involved a randomized, double-blind, placebocontrolled trial of 252 women, and the results showed that the use of probiotics reduced the risk of UTIs by approximately 50% 40 .
Another clinical study by Stapleton et al. investigated the use of oral Lactobacillus crispatus in premenopausal women with a history of recurrent UTIs 41 . The results showed a significant reduction in the recurrence rate of UTIs in the probiotic group compared to the placebo group 41 . The authors concluded that oral probiotics are a safe and effective alternative for the prevention of UTIs in women 41 . A recent systematic review and meta-analysis by Gao et al. also supported the use of probiotics for the treatment of UTIs. This study evaluated the efficacy of probiotics for the treatment of UTIs and included 11 randomized controlled trials with a total of 1,507 patients 42 . The results showed that the use of probiotics was associated with a significant reduction in the incidence of recurrent UTIs 42 .
In addition to the studies above, a recent study by Khalesi et al. found that oral probiotics were effective in reducing the recurrence of UTIs in women with a history of UTIs 43 . This randomized controlled trial included 120 women and found that the use of Lactobacillus acidophilus and Bifidobacterium lactis reduced the incidence of UTIs by 45.7% 43. Another study by Czaja et al. evaluated the use of a vaginal probiotic containing Lactobacillus crispatus in women with recurrent UTIs 44 . The results showed that the probiotic group had a lower incidence of UTIs compared to the control group. The authors suggested that the use of vaginal probiotics may be an effective way to prevent UTIs in women 44 .
Furthermore, in vitro studies have shed light on the mechanisms by which probiotics prevent and treat UTIs 6,8 . Probiotics have been shown to compete with uropathogens for adherence to uroepithelial cells, effectively preventing the pathogens from colonizing the urinary tract. Probiotics can also modulate the host immune response, which plays a key role in the pathogenesis of UTIs 8,34 . For example, some probiotic strains have been shown to induce the expression of cytokines and chemokines that recruit immune cells to the urinary tract, thereby enhancing the host's ability to fight off infections 34 .
While the clinical evidence supporting the use of probiotics in UTI treatment is promising, further studies are needed to elucidate the optimal dosing and strain selection 7,8 . Additionally, the use of probiotics as a standalone treatment for UTIs may not be effective in all cases, and they may need to be used in combination with antibiotics or other treatments 7,8 . Nonetheless, the use of probiotics as a complementary or alternative approach to UTI treatment holds great promise, particularly in light of the rising rates of antibiotic resistance 7-10 .

Potential probiotic strains for treatment of urinary tract infections
Many strains of probiotics have been investigated for their potential to treat UTIs 7-10 . One strain that has shown promise in clinical studies is Lactobacillus crispatus 8 . In a study of premenopausal women with recurrent UTIs, daily oral intake of a L. crispatus probiotic was associated with a significant reduction in the frequency of UTIs 8, 10 . Another strain that has been studied is Lactobacillus fermentum. In a randomized controlled trial of postmenopausal women with recurrent UTIs, daily intake of a L. fermentum probiotic was associated with a significant decrease in the incidence of UTIs 10 . However, more research is needed to determine the optimal dose and duration of treatment with these strains.
Another promising strain for UTI treatment is L. rhamnosus GR-1 39 . In a double-blind, placebo-controlled trial of women with acute UTIs, treatment with a combination of L. rhamnosus GR-1 and Lactobacillus reuteri RC-14 was associated with a higher rate of clinical cure and a lower rate of recurrence compared to placebo 39 . Similarly, a study of pregnant women found that treatment with L. rhamnosus GR-1 and L. reuteri RC-14 was associated with a lower incidence of UTIs compared to placebo 40 .
Bifidobacterium bifidum is another probiotic strain that has shown potential for UTI treatment 10,31,32 . In a study of premenopausal women with recurrent UTIs, daily intake of a probiotic containing B. bifidum was associated with a lower incidence of UTIs compared to placebo 32 . Additionally, a randomized controlled trial of women with acute uncomplicated cystitis found that treatment with a combination of B. bifidum and L. acidophilus was associated with a higher rate of clinical cure than a placebo 31,32 .
Other probiotic strains that have been investigated for their potential to treat UTIs include S. thermophilus, Enterococcus faecalis, and Bifidobacterium lactis 34 . However, more research is needed to determine their efficacy in treating UTIs.

Definition and epidemiology
Recurrent urinary tract infections (rUTIs) are defined as two or more UTIs within six months or three or more UTIs within one year 45 . The rUTIs affect a substantial number of women and are a significant public health concern, leading to substantial morbidity and healthcare costs 45 . The incidence of rUTIs in young, healthy women is estimated to be around 25%, with up to 50% of these women experiencing additional UTIs 46 . In postmenopausal women, the incidence of rUTIs increases, with up to 50% of women experiencing rUTIs 46 .
Recurrent UTIs are a multifactorial condition that is often associated with host factors, such as age, gender, genetics, and underlying medical conditions, as well as bacterial virulence factors 45 . Among the bacterial virulence factors that contribute to rUTIs are the formation of biofilms, the expression of adhesive structures, and the acquisition of antibiotic resistance 47 . Biofilm formation by uropathogenic bacteria may play a particularly important role in the pathogenesis of rUTIs 47 . The biofilm matrix provides protection against antibiotics and the host immune system, allowing the bacteria to persist in the urinary tract and cause recurrent infections 47 .
Recurrent UTIs are typically treated with antibiotics, but the emergence of antibiotic-resistant strains often limits this approach 46,47 . Moreover, repeated courses of antibiotics can lead to alterations in the urinary microbiome, potentially increasing the risk of rUTIs 46,47 . Alternative approaches to the prevention and treatment of rUTIs are therefore needed. Probiotics are a promising intervention for preventing and treating rUTIs, as they can restore the normal urogenital microbiota and inhibit the growth and virulence of uropathogenic bacteria 45 .

Mechanisms of action
The mechanisms by which probiotics exert their effects in preventing and treating rUTIs are not fully understood. However, they involve several factors, including the microbiota modulation, the production of antibacterial compounds, and the strengthening of the epithelial barrier 38 .
One of the key mechanisms by which probiotics may prevent rUTIs is by modulating the gut and vaginal microbiota 48 . Dysbiosis in the vaginal microbiota, characterized by a reduction in Lactobacillus species and an overgrowth of pathogenic bacteria, has been associated with an increased risk of UTIs. Probiotics can help restore the normal vaginal microbiota and prevent the overgrowth of pathogenic bacteria 48 . The use of probiotics may also help prevent the spread of uropathogens from the gut to the urinary tract, as some probiotic strains have been shown to colonize the gut and vagina and compete with uropathogenic bacteria for resources 48 .
Another mechanism by which probiotics may prevent rUTIs is through the production of antibacterial compounds, such as organic acids and bacteriocins 49 . These compounds can inhibit the growth of uropathogenic bacteria and prevent them from colonizing the urinary tract 49 . Probiotic strains have also been shown to induce the production of host antimicrobial peptides, such as defensins, which can enhance the innate immune response to infection and help prevent the recurrence of UTIs 49 .
In addition to their preventative effects, probiotics may also effectively treat rUTIs. Several studies have shown that the use of probiotics as an adjunct to antibiotics can improve the clinical outcomes of UTIs, including reducing the incidence of recurrent infections 38 . This may be due in part to the ability of probiotics to enhance the efficacy of antibiotics by reducing the potential for antibiotic resistance and promoting the clearance of uropathogens. Probiotics may also enhance the immune response to infection, and reduce the risk of complications associated with rUTIs, such as pyelonephritis and sepsis 38,48 .

Clinical evidences
Clinical evidence supporting the use of probiotics for rUTIs is steadily increasing 45,46 . A meta-analysis of randomized controlled trials (RCTs) assessing the effectiveness of probiotics for preventing rUTIs found that probiotics significantly reduced the risk of rUTIs, compared to placebo or no treatment 38 . Several RCTs have also reported a decrease in the number of UTIs and a decrease in antibiotic use in participants who took probiotics compared to those who did not. However, the optimal dose, frequency, and duration of probiotic supplementation are not yet well established, and more research is needed to address these issues 38,45,46 .
The mechanisms of action by which probiotics prevent rUTIs are not completely understood, but they likely involve several factors 47 . Probiotics may improve the composition and function of the vaginal and gut microbiota, which can affect the vaginal and urinary microbiota 47 . Additionally, probiotics may produce antimicrobial substances that inhibit the growth of uropathogenic bacteria, or they may compete with uropathogens for nutrients and adhesion sites in the urinary tract 45 . Probiotics may also modulate the host immune response to prevent colonization by uropathogens 47 .

Potential probiotic strains for recurrent urinary tract infections
As described earlier, recurrent UTIs can be challenging to treat with antibiotics, as the bacteria can develop resistance and the immune system may be unable to clear the infection 38 . Probiotics may offer a promising alternative or adjunct therapy, as they can help restore the natural balance of microorganisms in the urinary tract and enhance the body's defenses against infection 38,45 . There are several potential probiotic strains that have been studied for their effectiveness in preventing and treating recurrent UTIs 38,47,48 .
One potential probiotic strain is Lactobacillus crispatus (L. crispatus), which is a common inhabitant of the healthy vaginal microbiota and has been shown to be associated with a lower risk of UTIs 48 . Studies have shown that oral or intravaginal administration of L. crispatus can reduce the incidence and recurrence of UTIs, as well as decrease the severity of symptoms 48 . This strain may work by promoting the growth of beneficial bacteria in the urinary tract, stimulating the immune system, and producing antimicrobial compounds 48 .
Another potential probiotic strain for recurrent UTIs is Lactobacillus rhamnosus GR-1, which has been shown to be effective in preventing and treating various types of infections 39,40 . This strain may work by adhering to the epithelial cells of the urinary tract and preventing the attachment and growth of pathogenic bacteria, as well as modulating the immune response and producing antimicrobial substances. Studies have shown that oral administration of L. rhamnosus GR-1 can significantly reduce the incidence and severity of UTIs 39,40 .
Bifidobacterium longum has also been studied as a potential probiotic strain for recurrent UTIs, as it is a common inhabitant of the gut microbiota and has been shown to have immunomodulatory and antimicrobial properties 31,32 .
Studies have shown that oral administration of B. longum can significantly reduce the incidence and severity of UTIs, as well as increase the levels of beneficial bacteria in the urinary tract 31,32 . This strain may work by modulating the host immune response and producing bacteriocins and other antimicrobial compounds 31,32 .
Finally, S. thermophilus is another potential probiotic strain for recurrent UTIs, as it has been shown to have immunomodulatory and antimicrobial properties. Studies have shown that oral administration of S. thermophilus can significantly reduce the incidence and severity of UTIs, as well as increase the levels of beneficial bacteria in the urinary tract 34 . This strain may work by modulating the host immune response and producing bacteriocins and other antimicrobial compounds 34 .

Safety of probiotics
Probiotics are live microorganisms that provide health benefits when consumed in adequate amounts 9 . While probiotics have gained widespread attention for their potential to prevent and treat UTIs, their safety profile is a crucial consideration 28 . The safety of probiotics is generally considered to be favorable, although it is important to assess potential risks associated with their use 50 .
Studies have suggested that probiotics are associated with a low risk of adverse effects, with most adverse events being mild and self-limiting 9,10 . The majority of adverse events reported with probiotic use are related to gastrointestinal symptoms such as bloating, flatulence, and abdominal discomfort. However, these symptoms typically resolve within a few days and are not considered serious 50 .
The safety of probiotics is also affected by the type of strain used, as different strains can have different effects on the body 50 . Some probiotic strains have been associated with more severe adverse events, particularly in individuals with compromised immune systems 50 . For this reason, it is important to carefully select the strain of probiotic used, as well as to assess the risk of potential adverse events in different populations, such as immunocompromised individuals or infants 50,51 .
The use of probiotics in the prevention and treatment of UTIs has been shown to be generally safe, with a low risk of adverse events. In a systematic review and meta-analysis of randomized controlled trials, probiotics were found to be generally safe and well-tolerated, with no serious adverse events reported 51 . Another systematic review and meta-analysis of studies examining the use of probiotics for the prevention of UTIs also reported a low incidence of adverse events associated with probiotic use 52 .

Side effects and risk factors associated with probiotics
Although generally considered safe, probiotics may be associated with certain side effects and risks, particularly in individuals with compromised immune systems or underlying medical conditions 53 .
The most common side effects associated with probiotic use are gastrointestinal disturbances, such as bloating, gas, and diarrhea 54 . These side effects are generally mild and self-limited and tend to resolve with continued use of the probiotic. However, in some cases, particularly in individuals with weakened immune systems, probiotic use may lead to serious infections, such as sepsis or endocarditis 54 .
Another potential risk associated with probiotic use is the risk of antibiotic resistance 6 . Some studies have suggested that certain strains of probiotics may acquire resistance genes from other bacteria in the gut, potentially leading to the development of antibiotic-resistant strains 6 . This is particularly concerning in the context of recurrent UTIs, often treated with antibiotics 6 .
In addition to these risks, there have also been reports of probiotic-induced infections, particularly in individuals with compromised immune systems 53 . For example, a study described a patient with acute pancreatitis who developed sepsis after taking a probiotic supplement containing Lactobacillus rhamnosus GG 53 . Although such cases are rare, they underscore the importance of caution when using probiotics, particularly in vulnerable populations.
It is worth reiterating twice that the safety of probiotics may vary depending on the specific strain and formulation used 55 . For example, a study of a probiotic supplement containing Lactobacillus casei found that it was associated with an increased risk of acute pancreatitis in a small number of patients 55 . Therefore, it is important to carefully consider the risks and benefits of individual probiotic supplements before use, particularly in individuals with underlying medical conditions or compromised immune systems.

Strategies for ensuring probiotic safety and efficacy
The use of probiotics is generally considered safe, but there are still concerns about their safety and efficacy, particularly in vulnerable populations such as critically ill patients, infants, and the elderly 50 . Therefore, several strategies have been proposed to ensure the safety and efficacy of probiotics, such as using probiotic strains that have been extensively studied and have a good safety record, and monitoring for adverse effects during use.
One strategy for ensuring probiotic safety is to use wellcharacterized probiotic strains that have been extensively studied in human trials 50 . For example, the strain Lactobacillus rhamnosus GG has been used in many clinical trials and has a long safety record, making it a reliable choice for probiotic supplementation 53 . Other strains, such as Lactobacillus acidophilus and Bifidobacterium bifidum, have also been extensively studied and are considered safe for use in humans 31,32 .
Another strategy for ensuring probiotic safety is to monitor for adverse effects during use 56 . Although probiotics are generally well-tolerated, adverse effects such as gastrointestinal upset, allergic reactions, and infections have been reported in some cases 56 . Therefore, monitoring for adverse effects during probiotic supplementation is important to identify and manage any potential safety concerns.
Prebiotics can also be used to improve the safety and efficacy of probiotics 57 . Prebiotics are non-digestible carbohydrates that selectively stimulate the growth and activity of beneficial bacteria in the gut, including probiotics 57 . By providing a favorable environment for probiotic growth and activity, prebiotics can enhance the efficacy of probiotic supplementation and reduce the risk of adverse effects 57 .
Formulation and delivery methods can also influence the safety and efficacy of probiotics 58 . Different formulations, such as capsules, tablets, and powders, may have different effects on the survival and viability of probiotic strains, as well as their release and colonization in the gut 58 . Therefore, choosing the appropriate formulation and delivery method is important for ensuring the safety and efficacy of probiotics.
Finally, regulatory oversight is important for ensuring the safety and efficacy of probiotics. In some countries, such as the United States and Canada, probiotics are considered a food supplement and are not subject to the same regulatory oversight as drugs. However, other countries, such as Australia and the European Union, regulate probiotics as therapeutic goods and require manufacturers to provide evidence of safety and efficacy before being sold to the public. This regulatory oversight can help ensure that probiotics are safe and effective for human use 59 .

Future research on probiotics and urinary tract infections
Current research on probiotics and UTIs is rapidly expanding, and many promising avenues exist for future research 9 . One area of interest is the identification of optimal probiotic strains, dosages, and formulations for UTI prevention and treatment. To this end, researchers are investigating various strains of Lactobacillus, Bifidobacterium, and other bacteria to determine which ones are most effective in combating UTIs 31,32,52 .
Another area of research is the development of probiotic formulations that can with stand harsh conditions in the urinary tract, such as acidic urine and bacterial competition. Researchers are exploring various technologies, such as microencapsulation, to enhance the survival and effectiveness of probiotics in the urinary tract [6][7][8][9][10] .
In addition, researchers are investigating the mechanisms by which probiotics exert their beneficial effects on the urinary tract. This includes studying the interactions between probiotics and the host immune system, as well as the ways in which probiotics modulate the urinary microbiome 6-10 .

Challenges and limitations of probiotics in urinary tract infections
There are several challenges and limitations to the use of probiotics for UTIs. One of the most significant challenges is the lack of standardization in probiotic products, with significant variability in the type and quantity of strains present in different products. This variability can make it difficult to compare results between studies or to determine optimal dosing 9 .
Another challenge is the potential for probiotics to interact with other medications or conditions. For example, some strains of Lactobacillus have been associated with increased rates of fungal infections in immunocompromised individuals. Similarly, probiotics may interfere with the efficacy of antibiotics or other medications, leading to suboptimal treatment outcomes 31 .
In addition, there is limited knowledge about the optimal strains and dosing of probiotics for UTI prevention and treatment, with some studies showing conflicting results. Furthermore, the effectiveness of probiotics may vary depending on the patient population, with some studies showing limited benefit in high-risk groups such as those with recurrent UTIs or catheter-associated infections 58 .

Improvement in technology and administration of probiotics
While there have been some promising results with the use of probiotics for UTIs, there are also many challenges and limitations to their use. One potential area for improvement in probiotic technology is the development of more effective and targeted formulations 58 .
A promising area of research is the use of engineered probiotics, which have been genetically modified to enhance their efficacy and targeting. For example, a study has shown that the use of engineered Lactobacillus crispatus strains expressing D-mannose-binding lectin could prevent uropathogenic E. coli (UPEC) from adhering to the bladder wall. This approach could potentially be used to create probiotics that are more effective at preventing UTIs by specifically targeting the pathogens responsible for these infections 60 .
Another potential area for improvement is the development of probiotic delivery systems that can better survive the harsh conditions of the urinary tract 61 . For example, one study has shown that a probiotic formulation of Lactobacillus crispatus in alginate-chitosan microcapsules could survive the acidic conditions of the stomach and colon, as well as the bactericidal effects of urine. This approach could potentially be used to develop probiotics that can reach the urinary tract and colonize the bladder 61 .
In addition, there is a need for a better understanding of the mechanisms of action of probiotics in UTIs, and the development of more effective methods for selecting and characterizing probiotic strains 62 . For example, the use of high-throughput sequencing and metabolomics could help to identify the specific mechanisms by which probiotics prevent and treat UTIs, as well as the specific strains and metabolites that are most effective. This could help to improve the efficacy and safety of probiotics for UTIs, and pave the way for the development of more targeted and effective probiotic therapies 62 .

Conclusion
It is clear from the literature that probiotics have the potential to be a safe and effective alternative or complementary therapy for preventing and treating recurrent UTIs.
The implications of probiotics in clinical practice and public health are significant. The use of probiotics in preventing and treating UTIs can potentially reduce the overuse of antibiotics, which has been a major factor in the development of antibiotic resistance. Additionally, probiotics can prevent the occurrence of UTIs in vulnerable populations, such as women and the elderly. The use of probiotics can also potentially improve the quality of life for individuals with recurrent UTIs.
Future research on probiotics and UTIs should focus on identifying optimal strains, dosages, and delivery methods. Additional clinical trials are needed to evaluate the safety and efficacy of probiotics in different populations and to identify potential interactions with other medications. Studies are also needed to explore the use of probiotics in combination with antibiotics and to evaluate the long-term effects of probiotic use.
In conclusion, the use of probiotics in prevention and treatment of UTIs represents a promising area of research and clinical practice. While there are challenges and limitations to their use, the potential benefits are significant. Continued research and development of probiotic technology and administration can potentially improve the safety and efficacy of probiotics in prevention and treatment of recurrent UTIs. Overall, the potential of probiotics to combat UTIs is a promising avenue for improving public health and reducing the burden of antibiotic resistance.

Ethical considerations
The authors checked for plagiarism and consented to the publishing of the article. The authors have also checked the article for data fabrication, double publication, and redundancy.