Background

Urinary tract infection (UTI) is a condition when any part of the urinary tract (urethra, bladder, ureter, and kidney) gets infected with bacteria or occasionally with fungus that evades the host defense barrier and colonize the urinary tract. The effect of UTI ranges from a mild self-limiting sickness to acute sepsis, with a mortality rate of 20-40% [1], which increases inexplicably with age. Both the sexes are prone to develop UTI with a female to male ratio of 2:1 in patients older than 70 years as compared to a 50:1 ratio in younger population [2]. It is the second most common infection after respiratory tract infections. Different methods are practiced to treat and prevent chronic and recurrent UTI, i.e., taking antibiotics, bioactive natural foods, using probiotics, and maintaining good personal hygiene, but still, they are yet to be addressed successfully. As UTI is generally caused by bacteria, they are most frequently treated with antibiotics. But, the type of medication and length of treatment depends on type of bacteria, its level of susceptibility, history, symptoms, and immune status of the patient.

It is not known, what percentage of people are now using alternative therapies, but certainly large numbers of women are drinking cranberry juice or using herbal remedies to enhance their immune status or taking probiotics to restore the normal vaginal flora, which usually gets disturbed after an antibiotic therapy. Vaccine development for organisms other than E. coli still remains obscure [3]. Cranberry, mannose, and probiotics are frequently used for recurrent UTI, and berberine and uva ursi are prescribed for acute UTI. Potassium salt supplements reduce dysuria by alkalinizing the urine. Application of estriol cream and supplement of vitamins A and C were considered to be effective to prevent UTI [4]. Generally, people drink plenty of water to flush out the infectious bacteria. Application of curd water around the urethra can help in getting rid of urinary burning sensation. This present review enlists some ethnobotanicals, which are reported to be beneficial for UTI and other urinary disorders. It covers a list of potential herbs with urobactericidal activity, the in vitro/in vivo and clinical trial studies reported to prove the efficacy of cranberry in treating UTI. It also represents the synopsis of relevant natural therapeutics, those are proven to be useful in both prevention and cure of urological disorders.

Methods

Intense review of literature on the prevalence, mechanism of urinary tract infection, risk factors, preventive measures, and natural therapeutics for UTI were carried out using different databases like Google, Pubmed, and Sciencedirect. The keywords like the preventive and therapeutic role of different plants and their products in uropathogenesis, medicinal plants for acute and recurrent UTI, natural remedies, therapeutics for UTI, and anti-uropathogenic activity of medicinal plants, role of cranberry in acute and recurrent UTI were accessed from Medline, Google, Pubmed, and from different books, electronic, and printed journals, available in the library of Berhampur University, Utkal University, Institute of Life Sciences, and Regional Medical Research Center, Bhubaneswar, Odisha. The different keywords like urinary tract infection, uropathogenic bacteria, uropathogenesis, and UPEC are used in Google, Pubmed, and www.asm.org websites. The language chosen was English and both research and review articles were taken into account.

Botanicals used for UTI

Therapeutic botanicals are defined as plants and their products with medicinal value. Indigenous plants are used for various ailments since time immemorial by mankind and probably we had learned this art from animals, since they have the inherent ability to use natural products for their different health ailments. These natural products are rich in diverse bioactive compounds, which form the basis for the development of new pharmaceuticals. There are immense advantages of using therapeutic botanicals like lesser side effects, more patient approval, less costly, and can be renewed naturally [5]. There are many reports that phytochemicals act as multi-drug resistance inhibitors/modulators that augment the effect of commonly used antibiotics [6, 7]. Diuretics like Solidago spp (goldenrod) herb, Levisticum officinale (lovage) root, Petroselinum crispus (parsley) fruit, and Urtica dioica (stinging nettle) increase urine volume in both healthy and people with urinary disorders that help in flushing out the probable threats. People, who consume antiseptic and anti-adhesive herbs like Arctostaphylos uva-ursi (uva ursi), Juniperus spp (Juniper) leaf, and fruit of Vaccinium macrocarpon (cranberry) excrete antimicrobial compounds, which may directly kill microbes or interfere with their adhesion to epithelial cells, thereby protecting against acute and chronic UTI [8]. The roots of Mahonia aquifolium (Pursh) Nutt. (Oregon grape) (Berberidaceae) and Hydrastis canadensis L. (Goldenseal) (Ranunculaceae) are rich in berberine. Berberine is an important drug against many bacteria and combat infections by preventing the bacteria (E. coli and Proteus species) from adhering to the host cell [9], which suggests their potent role in treating UTI.

Supplement of aqueous extract of corn (Zea mays L.) silk (outer thread-like part) to UTI patients significantly reduced the symptoms by reducing the number of RBCs, pus cells, and crystals in urine without any side effects [10]. It is rich in diverse therapeutic compounds [11]. Plants belonging to family Apiaceae, Fabaceae, Malvaceae followed by Asteraceae and Cucurbitaceae were found to be very effective against UTI [12]. Ethnomedicinal use of some plants against recurrent and chronic UTI is listed in Table 1.

Table 1 Directory of some important ethnomedicinal plants/plant parts used for UTI
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Botanicals with anti-uropathogenic activity

Few Jordanian plants were reported to have antibiotic resistance-modifying activity against MDR E. coli. Especially, methanol extracts of the plant parts improved the effects of cephalexin, doxycycline, neomycin, chloramphenicol, and nalidixic acid against both the standard and resistant strains of E. coli. Extracts of Anagyris foetida L. (Fabaceae) and Lepidium sativum L. (Apiaceae) had differential activity against the standard and resistant strains as it decreased the activity of amoxicillin against the standard strain but increased the activity against resistant strains. Edible plants like Gundelia tournefortii L. (Asteraceae), Eruca sativa Mill. (Brassicaceae), and Origanum syriacum L. (Lamiaceae), augmented clarithromycin activity against the resistant E. coli strain. Perhaps these antibiotics and plant extracts may be prescribed together to treat infections caused by MDR E. coli [24]. There are numerous reports for the anti-uropathogenic and urobactericidal activities of various plants and their products, which are listed in Table 2.

Table 2 List of medicinal plants with anti-uropathogenic potential
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Cranberry: a potent uroprotective agent

For centuries, cranberries have been used as a treatment for urinary tract diseases and its antibacterial activity was reported long back [60]. It contains > 80% water, 10% carbohydrates (glucose and fructose) [61], and other phytoconstituents like anthocyanins, flavonoids, terpenoids, catechins, organic acids (citric acid, malic acid, and quinic acid, etc.) with small amount of ascorbic acid, benzoic acid, glucuronic acids [62]. Quinic acid was suggested to be responsible for excretion of hippuric acid in urine in large amounts, which is an antibacterial agent and also has the ability to acidify the urine [63, 64]. Moreover, the elucidation of the UTI pathogenesis has opened a new vista to understand the mode of action of cranberry as an anti-adhesive prophylactic and therapeutic agent for UTI [65].

Escherichia coli strains isolated from urine (UPEC) attached three times more efficiently to uroepithelial cells than E. coli isolated from other experimental sources like stool, sputum, or wound. This proves a unique population of E. coli strain responsible for UTI [66]. Antiadherence activity against gram-negative bacteria isolated from urine and other medical sources was observed in volunteers administered with cranberry juice cocktail or urine and uroepithelial cells obtained after drinking the cocktail, which proves its efficacy in treating UTI [66]. Consumption of different cranberry products helped young and elderly women in preventing and protecting them against UTI [67].

The anthocyanidin/proanthocyanidin biocompounds present in cranberry are reported often to be potent antiadhesive compounds. Since cranberry inhibits the adhesion of type I and P-fimbriated uropathogens (e.g., uropathogenic E. coli) to the uroepithelium, thus, weaken colonization and succeeding infection [68]. Figure 1 depicts the molecular mechanism of antiadhesive property of proanthocyanidins. Due to lack of proper standardization of cranberry products, it becomes extremely complicated to compare products or correlate the results [69]. The in vitro and in vivo studies were summarized in Table 3.

Fig. 1
figure 1

Type 1 or P-fimbriae inhibitors (e.g., proanthocyanins) are shown as green balls interfering with binding of bacterial fimbriae to uroepithelial cell

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Table 3 In vitro/in vivo activity of cranberries against UTI causing bacteria
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The recurrence of UTI rates was reduced up to 35% in young to middle-aged women, after the use of cranberry-based compounds. But, in groups with complicated UTI (i.e., young and elderly patients, or patients with neurogenic bladder or with chronic indwelling catheters), the potency of cranberry was unclear. However, these compounds cannot be taken for a longer duration as they have some undesirable effects like weight gain, gastrointestinal problems, and harmful interactions with other drugs [69]. Clinical trials were often complicated and results are not satisfactory in patients with complicated UTI, whereas, cranberry uptake significantly prevented acute cystitis in high-risk females [88]. The clinical trials undertaken with cranberry were summarized in Table 4.

Table 4 Clinical trials of cranberry products for UTI prevention in different populations
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Cinnamom verum J. Presl. (cinnamon): a potent botanical for complicated UTI

Chronic recurrent UTI was resulted in patients with urinary catheters due to biofilm formation by MDR UPEC. Trans-cinnamaldehyde (0%, 1%, 1.25%, or 1.5%) was reported to prevent UPEC biofilm formation both on plate culture and indwelling catheters. When trans-cinnamaldehyde was used in catheter lock solution, it inactivated UPEC biofilm formation on catheters. Since the test concentrations had no cytotoxic effects on human bladder epithelial cells, it can be used as a surface coating for catheters or in catheter lock solution to prevent UTI [115]. Trans-cinnamaldehyde significantly reduced uroepithelial cell attachment and invasion by UPEC by inhibiting the expression of major genes associated with its attachment and invasion to host tissue [116]. These findings support the use of cinnamon as a natural remedy for UTI.

Arctostaphylos uva-ursi (L.) Spreng (bearberry)

Arctostaphylos uva-ursi (uva ursi), also known as bearberry or upland cranberry, is a useful herb for bladder infection. Bearberry leaves and preparations made from them have significant antibacterial activity (especially against E. coli) and astringent activity due to its arbutin content and diuretic properties. In a double-blind study of 57 women, five of twenty-seven women had a recurrence in the placebo group while none of thirty women had a recurrence in the uva ursi group after 1 year [117]. Schindler et al. reported that the total amount of urinary excretion of arbutin metabolites (hydroquinone) remained same in all the three groups, after the administration of a single oral dose of bearberry leaves extract or film-coated tablets or an aqueous solution in a randomized crossover study (n = 16) [118].

Probiotics

Probiotics are helpful in establishing and maintaining normal ecology of the vagina, urethra, and bladder and a proper bladder pH and preventing recurrent UTI, which was supported by various in vivo and in vitro studies. Lactobacilli are present predominantly in the urogenital flora of healthy reproductive-aged women. But, the flora is disturbed following long term antibiotic administration and post menstruation temporarily and in post-menopausal women permanently. Supplement of Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14 appears to be most effective in reducing the risk of intestinal and urogenital infections [119]. The antagonistic activity of five probiotic lactobacilli (L. rhamnosus, L. fermentum, L. acidophilus, L. plantarum, and L. paracasei) and two bifidobacteria (Bifidobacterium lactis, B. longum) against six target pathogens were estimated using different assays. Pyelonephritic E. coli was highly suppressed by L. rhamnosus and both bifidobacterial strains [120]. One hundred thirty-nine women (mean age: 30.5 years) with acute UTI were compared with 185 women of similar age with no episodes of UTIs for 5 years. Frequent consumption of fresh juices, especially berry juices, and fermented milk products containing probiotic bacteria decreased the risk of recurrence of UTI in fertile women. So, dietary supplements can be used to prevent UTI [121].

Preincubation of the uroepithelial cells with Lactobacillus bacterial cell wall fragments inhibited the adherence and colonization of gram-negative uropathogens either completely or partially, which prevented the onset of UTI in female rats. Since the lipoteichoic acid present in the bacterial cell wall is responsible for the adherence of the Lactobacillus cells to uroepithelial cells but its steric hindrance blocked the adherence of uropathogens [122, 123]. Seven strains of lactic acid bacteria (L. paracasei, L. salivarius, two Pediococcus pentosaceus strains, two L. plantarum strains, and L. crispatus) and their fermented probiotic products exhibited clear zones of inhibition against UPEC. This suggests their potential role in adjuvant therapy for prevention and treatment of UTI. The growth of UPEC strains was significantly inhibited after co-culture with lactic acid bacteria and probiotic products in human urine. Oral administration of probiotic products also abrogated the number of viable UPEC in the urine of UPEC-challenged BALB/c mice [124].

Vaccines

Adhesin-based vaccines were very effective in blocking host–pathogen interactions, thereby preventing the establishment of disease [125,126,127]. In addition to the UPEC adhesins (i.e., pili, fimbriae), adhesins from P. mirabilis, and E. faecalis were also reported as vaccine targets [128]. Vaccination with HlyA (UPEC pore-forming toxin) reduced the rate of renal scaring compared to controls, though it could not prevent UPEC colonization of the kidneys [129]. Several urease inhibitors, i.e., acetohydroxamic acid (AHA), phosphoramidites, benzimidazoles have been used as potent drugs for UTI treatment against urease producing bacterial species like P. mirabilis and S. saprophyticus [130]. Pilicides (type 1 pilus assembly inhibitor) and mannosides (pili function inhibitor) block UPEC colonization, invasion, and biofilm formation and prevent UTI [131, 132].

Discussions

Antibiotics are frequently used to treat and prevent acute and recurrent UTI, but their repeated use can result in dysbiosis of vaginal and intestinal normal flora, as well as antibiotic resistance due to the high mutation ability and horizontal gene transfer capability of different pathogens. Moreover, different mechanisms are used by uropathogens for survival in the bladder under stresses such as starvation and immune responses. Uropathogens undergo morphological changes, invade uroepithelial cells, and form biofilms to persist and cause recurrent infections. Extracellular DNA, exopolysaccharides, pili, flagella, and other adhesive fibers create a niche for a bacterial community that is secluded from antimicrobial agents, immune responses, and other stresses [133]. Thus, it is high time to seek alternative methods for the prevention and treatment of UTIs.

Diuretic botanicals like Asparagus officinalis L. (asparagus), Betula spp. (birch) Elymus repens (L.) Gould (synonym: Agropyron repens) (couch grass), Solidago virgaurea L. (goldenrod), and Equisetum arvense L. (horsetail) work against UTI by increasing urinary volume and supposedly flushing bacteria out of the urinary tract. Ayurvedic herbs like Tribulus terrestris L., Boerhavia diffusa L., Tinospora cordifolia (Willd.) Miers, and Santalum album L. are used since time immemorial for UTI in India. The tribes of Odisha state, India, use the roots of Adiantum lunulatum Burm. f, Argemone mexicana L., Clausena excavata Burm. f, Mimosa pudica L., epicarp of Cucumis melo L., and seeds of Cucumis sativus L. for UTIs. These herbs have proven anti-uropathogenic activities, which were reported enormously by different researchers. However, reports on anti-uropathogenic activity of specific phytoconstituents or their mode of action at the molecular level on uropathogens like enzyme or protein inhibition or degradation, cell membrane, or cell wall disruption or dysfunction of other vital organs of uropathogens are limited. Though the herbal remedies are considered safe to use without any significant side effects yet they are slow in action to be effective in serious acute infections, but they are more effective in preventing recurrence and safeguarding against the post-infectious sequelae.

The safety and efficacy of a product containing two probiotic strains of Lactobacilli plus cranberry extract was reported for impeding recurrent UTIs in pre-menopausal adult women. After 26 weeks, in a randomized, double-blind, placebo-controlled pilot study, a significantly lower number of women experienced recurrent UTIs (9.1 vs 33.3%), those who were administered with the product as compared to placebo [134]. In another study, the efficacy and safety of standardized cranberry capsules as prophylaxis in children with recurrent UTI was reported, where children on cranberry compared to the control group experienced significantly lower percentage of recurrent UTIs, with no side effects. A declined trend of E. coli infections was observed in the cranberry group (83.3% vs. 66.6%), though it was not significant (p = 0.28) [135].

Root extract of Hemidesmus indicus R. Br. (Indian sarsaparilla) (Asclepiadaceae) and seed extract of P. granatum (pomegranate) were reported to have urobactericidal activity against different uropathogens, clinically isolated from patients suffering from urinary tract infections, i.e., Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, and Klebsiella pneumonia [59, 136, 137]. Along with the presence of therapeutic antioxidants, i.e., phenolic compounds, tannins, steroids, terpenes, coumarins, and flavonoids, the extracts were found to be rich in natural glycosides, which are supposed to act as molecular decoys to prevent adhesion of pathogenic bacteria to host cell, thereby inhibiting the future pathogenesis. However, further research is required to confirm it. Till date, there are many reports on scientific evaluations and clinical trials of natural therapeutics for UTI, but they have serious limitations in study design and data interpretation. Most of the products mentioned in this review are based on “in vitro” studies; therefore, more clinical trials should be undertaken in order to assess the efficacy of these alternative preventions and therapeutic methods in humans.

Conclusion

Uroprotective role of cranberry was reported by maximum researchers, yet they suffer from serious drawbacks and fail to prove that cranberry use can prevent or treat acute and recurrent UTI. So, further investigation should focus on the molecular action of various phytochemicals present in cranberry and other potential berries against different uropathogens and uropathogenesis. Supplementation of probiotics was also proven to be effective in both acute and recurrent UTI. However, scientific validation with efficient clinical trial reports will strengthen the practice of using these traditional resources, which will help us in preventing these common yet very discomforting ailments.