Natural therapeutics for urinary tract infections—a review

Background The recurrence of the urinary tract infections (UTI), following the antibiotic treatments suggests the pathogen’s resistance to conventional antibiotics. This calls for the exploration of an alternative therapy. Main body The anti-uropathogenic and bactericidal activity of many plant extracts was reported by many researchers, which involves only preliminary antibacterial studies using different basic techniques like disk diffusion, agar well diffusion, or minimum inhibitory concentration (MIC) of the crude plant extracts, but reports on the specific action of the phytoconstituents against uropathogens are limited. Vaccinium macrocarpon Aiton (cranberry) is the best-studied home remedy for UTI. Some evidences suggest that proanthocyanins present in cranberry, prevent bacteria from adhering to the walls of the urinary tract, subsequently blocking the further steps of uropathogenesis. Probiotics such as Lactobacillus and Bifidobacterium are beneficial microorganisms that may act by the competitive exclusion principle to defend against infections in the urogenital tracts. Reports on potential vaccine agents and antibodies targeting the different toxins and effecter proteins are still obscure except uropathogenic E. coli. Conclusion This review highlights some of the medicinal herbs used by aborigines to prevent or treat acute or chronic urinary tract infections, botanicals with established urobactericidal activity, clinical trials undertaken to compare the efficacy of cranberry products in UTI prevention, and other natural therapeutics reported for UTI.


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 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.

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.

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 antiadhesive 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.
The recurrence of UTI rates was reduced up to 35% in young to middle-aged women, after the use of cranberrybased 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.

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  [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 postmenopausal 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  [ 70] In vitro antiadhesion activity of cranberry (PAC) 60 μg/ml UPEC A-linked PAC were more effective than B-linked. [71] Antiadhesion activity of cranberry vs raisins 42.5 g UPEC 25-50% of reduction in adherence in cranberry gr. None in control or raisin gr. [72] In vitro antiadhesion activity of cranberry juice 27% cranberry juice (250 or 750 ml) E. coli 45% and 62% decrease in bacterial adhesion to human epithelial cell line in bacteria growing in urine of volunteers administered with 250 and 750 ml of cranberry juice, respectively. [73] Anti-adhesion activity and prevention of oxidative stress of dried cranberry juice in young women In vitro anti-adhesion assay in T24 cell line and in vivo virulence assay in C. elegans model PAC (6-120 mg) plus propolis (170-340 mg) powder E. coli Synergistic activity of propolis and proanthocyanidins [80] In vitro activity of PAC 4-1024 mg/L C. albicans Reduction in biofilm formation due to antiadherence properties and/or iron chelation at a dose of ≥ 16 mg/L PAC [81] In vitro activity of A2-linked PAC 15-100 μg/mL UPEC, P. mirabilis Up to 75% reduction of UPEC and P. mirabilis adhesion to HT1376 cell line vs. control. Also drop in motility and urease activity in P. mirabilis.

[82]
In vitro and in vivo activity of PAC 100 μg/mL P. aeruginosa Cranberry PACs significantly disrupted the biofilm formation [83] In vitro activity of oligosaccharides 0.625-10 mg/mL E. coli Reduced biofilm formation by over 50% in pathogenic form and over 60% in nonpathogenic E. coli [84] Antiadhesive activity of phenolic compounds and their metabolites derived from cranberry 100-500 μM UPEC All the metabolites showed anti-adhesive activity but procyanidin A2, significantly reduced UPEC adherence to uroepithelium at 500 μM (51.3%). [85] Ex vivo and in vitro antiadhesive activity of PAC and PAC free extract Standard cranberry extract with 1.24% PAC for ex vivo and 21% PAC for in vitro study UPEC 40-50% suppression of UPEC adhesion to human T24 bladder cells. PAC free extract did not influence biofilm and curli formation in UPEC. [86] In vivo activity of cranberry juice and its organic acids in mice Cranberry juice/bioactive compounds taken for 7 days UPEC Reduction of bacterial number in the bladder of mice drinking fresh cranberry juice, organic acids or both. [87] Das Future Journal of Pharmaceutical Sciences (2020) 6:64 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].

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 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 premenopausal 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.