3. UTI and Urinary Microbiome
The study of the urine microbiome is becoming increasingly important due to the fact that changes in its composition have been linked to the development of many illnesses, mainly UTIs. UTIs are the body’s second most frequent bacterial infection, accounting for around 8.1 million medical visits each year [
36]. UTIs are prevalent in women and commonly reoccur. According to the National Health and Nutrition Examination Survey III data, UTIs occur in 53,067 cases per 100,000 women throughout their lifetime, compared to 13,689 cases per 100,000 males [
37]. The greatest gender disparity comes between the ages of 16 and 35, when women are about 35 times more likely to be impacted [
37]. Women have a greater incidence of urinary colonization than men. Anatomically, the vaginal cavity and rectal opening are located in close proximity to the urethral opening. Additionally, women have more wet periurethral regions, which are suitable growing grounds for bacteria [
38]. Due to the shorter urethral length, the bacteria entering the urethra are more likely to ascend to the female bladder than the male bladder [
38]. Uropathogenic
E. coli (UPEC) is responsible for about 80% of infections. Although virulence characteristics like sticky fimbriae play a role in UPEC pathogenesis, predisposing host variables also play a role in UTIs, especially in people who have repeated episodes [
39]. UTI is defined as an infection of the urethral cavity followed by an infection of the lower urinary tract up to the bladder, resulting in urethritis and cystitis, respectively [
40]. When infections cause pyelonephritis in the kidneys they can even spread via the bloodstream, resulting in systemic infection (urosepsis) [
41].
Patients with culture-confirmed UTI should receive oral antibiotics, depending on their clinical status [
42]. Sulphonamides or first-generation cephalosporins are the most often prescribed oral antibiotics. However, there is rising worry about urinary pathogen resistance to these antibiotics, as seen by the increasing frequency of therapeutic failures following empiric therapy [
43]. Recent examination of the impact of antibiotic prophylaxis on urinary microbiota [
6] showed that when the urinary microbiota of preventive trimethoprim-sulfamethoxazole therapy and a healthy control group were compared, the antibiotic group substantially increased the number of pathogenic species while decreasing microbial diversity relative to the healthy control group. These results emphasize the need to show sensitivity when choosing optimum preventive regimens and indicate that probiotic prophylaxis may be more successfully explored. [
6,
44]. The comparative genomic analyses were performed on
E. coli isolates from adult female bladders without signs of lower UTI, with a clinical diagnosis of UTI, or with lower urinary tract symptoms (LUTS) [
45]. The genetic compositions of the
E. coli isolates or the makeup of the complete urobiome was unable to differentiate between the urinary microbiomes of persons with UTI and those without LUTS [
45]. This study suggests that UTI symptoms linked with
E. coli detection are more likely the result of microbiome composition. Recently, the study comparing urine next-generation sequencing (NGS) of patients with acute uncomplicated cystitis (AUC) and recurrent cystitis (RC) revealed differences in microbiome patterns [
46]. Transurethrally obtained urine specimens from the RC group had substantially more microbiome diversity than the AUC group.
Pseudomonas,
Acinetobacter, and
Enterobacteriaceae were identified in the urine NGS findings for the AUC group, while
Sphingomonas,
Staphylococcus,
Streptococcus, and
Rothia spp. were detected in the RC group [
46]. Significant variations in bacterial diversity and patterning were seen between AUC and RC patients. This study suggests that AUC can be considered a transient infection produced by a single pathogenic organism, while dysbiosis seems to play a more significant role in the pathophysiology of RC [
46,
47]. RC may be linked with urinary tract dysbiosis, but more study is necessary [
46,
48].
Numerous UTIs go unreported and untreated, particularly in older individuals who frequently have polymicrobial UTI samples. The presence of significant uropathogenic species in mixed culture urine samples from older individuals, as well as resistance to first-line antibiotics with potentially enhanced resistance to ciprofloxacin and trimethoprim, was described [
49,
50]. Most notably, the study demonstrates that
E. coli isolated from polymicrobial UTI samples is statistically more invasive than
E. coli recovered from monomicrobial culture samples in in vitro epithelial cell infection tests [
51].
E. coli contamination in polymicrobial UTI samples may offer an elevated danger to human health [
51]. Furthermore, the function of
enterococci in the pathogenesis of polymicrobial infections provides insight into the bacterial cooperation process. When virulent
enterococci were evaluated in the presence or absence of
E. coli strains in the in vivo
Caenorhabditis elegans model, a synergistic impact on virulence was seen when
enterococci and
E. coli were compared to
enterococci alone or
E. coli alone [
52].
Enterococcus faecalis has the ability to modify its immediate environment via signaling, therefore promoting the growth of other coinfecting organisms [
52]. Increasing reports support that a single external pathogenic bacterial invasion is insufficient to account for UTI-associated disease in humans. Both an imbalance in the urine microbiota repertoire and polymicrobial pathogenic causes should be correlated.
Lactobacilli species such as
L. crispatus,
L. iners, and so on are commensal bacteria that reside in healthy females [
30]. These
Lactobacilli deficits have been linked to the colonization of UTI-causing uropathogens [
2,
7]. Predisposition to get UTI is linked with a decline of
Lactobacillus iners in the patients who develop postoperative UTI [
29,
53]. The change in the urine microbiota, in conjunction with other risk factors (age and estrogen levels) contributes to the development of postoperative UTI with uropathogens such as
E. coli,
Klebsiella pneumoniae, and
Pseudomonas aeruginosa [
29,
53]. The vaginal microbiome can influence the host’s susceptibility to UTI. According to the clinical study on young women with a history of recurrent UTIs, women with recurrent UTIs become more resistant when their vaginal microbiome is modified with probiotics such as
Lactobacillus crispatus [
54]. Intravaginal probiotic treatment with
L. crispatus showed significant reduction in recurrent UTI associated with high-level vaginal colonization with
L. crispatus [
54]. The regulatory effect of the vaginal microbiome on UTI was further supported by the report that women who have bacterial vaginosis as a result of anaerobic
Gardnerella vaginalis overgrowth experience more UTI than women who have healthy microbial communities consisting primarily of
Lactobacillus [
55]. Clinical studies indicate that the makeup of a woman’s vaginal microbiome has an effect on her susceptibility to recurrent UTI [
56]. Bladder exposure to
G. vaginalis induces
E. coli egress from latent intracellular
E. coli reservoirs in the bladder and increases the risk of life-threatening
E. coli [
56].
G. vaginalis exposures were sufficient to induce bladder epithelial apoptosis and exfoliation, as well as interleukin-1 receptor-mediated kidney damage that persisted after
G. vaginalis clearance from the urinary system [
56]. This study provides the etiology of recurrent UTI, in which illness may be triggered by brief but potent urinary tract exposures to vaginal bacteria. Altogether, increasing evidence support the notion that single invasion by an external pathogenic bacterium fails to explain UTI-associated pathology in humans. The complete understanding of UTI needs to consider both an imbalance in the urine microbiota repertoire and polymicrobial pathogenic sources [
2,
57].
4. Bladder Cancer and Urinary Microbiome
Limited research has been conducted on the bladder microbiome involvement in urological cancers. Recent studies indicate that the human microbiome can affect cancer formation, however the function of microbes in bladder cancer pathogenesis has not been investigated. According to a study comparing urine samples from healthy people to bladder cancer patients using 16S rRNA sequencing, an abundance of the genus
Streptococcus in bladder cancer patients was detected [
78]. Bladder urothelial carcinoma (UBC) is the sixth most common kind of cancer globally [
79]. UBC can be categorized as non-muscle invasive, muscle invasive, or locally advanced/metastatic [
80]. UBC is characterized by a heterogeneous tumor cell population and surrounding tumor microenvironment (TME). Given that the microbiota has been linked to the formation of cancer in a variety of tissues, urinary microbiome is also implicated in UBC. Only a few studies have examined the relevance of the microbiome in urologic malignancy.
Several studies were performed to define and compare the bladder cancer patients’ urine microbiota to that of healthy controls. The potential changes in the extracellular matrix caused by the microbiota and the subsequent inflammation may play a role in carcinogenesis [
81]. This study recruiting male bladder cancer patients and non-neoplastic controls collected midstream urine. Cancer patients’ urine samples were enriched with some bacterial genera (e.g.,
Acinetobacter,
Anaerococcus, and
Sphingobacterium), but showed a decrease in others (e.g.,
Serratia,
Proteus, and
Roseomonas) [
81]. Enrichment of
Herbaspirillum,
Porphyrobacter, and
Bacteroides was identified in cancer patients with a high risk of recurrence and progression, suggesting that these genera might serve as risk stratification biomarkers [
81]. Another study was performed to analyze bacterial populations using 16S sequencing in mid-stream urine specimens obtained from male patients diagnosed with bladder cancer and healthy, age-matched males [
82]. Although microbial diversity and overall microbiome composition did not change substantially between groups, the study detected more abundant operational taxonomic units (OTUs) belonging to the genus
Fusobacterium as a potential protumorigenic pathogen enriched in the bladder cancer group. OTUs from the genera
Veillonella,
Streptococcus, and
Corynebacterium were less prevalent in the bladder cancer group [
82]. An additional study reported that the midstream urine samples from bladder cancer patients exhibited a higher abundance of
Actinomyces than the control group. The study suggested that the increased prevalence of
Actinomyces europaeus in bladder cancer patient samples may be diagnostic of bladder cancer [
83]. More recently, bladder cancer patients’ urine microbiota was compared to that of healthy controls by utilizing 16S rRNA sequencing of voided urine samples. Bacterial populations were analyzed using 16S sequencing in urine specimens taken from bladder cancer patients and healthy, age-matched controls [
82]. While microbial diversity and overall microbiome composition did not vary substantially across groups, the genus
Fusobacterium was substantially enriched in the bladder cancer group and can be considered as a potential protumorigenic pathogen [
82]. In healthy urines, the genera
Veillonella,
Streptococcus, and
Corynebacterium were more prevalent [
82]. However, owing to the small sample size, more research is required to establish if the urine microbiota is linked with bladder cancer.
Although these studies performed on the bladder cancer patients suggest the potential relationship between the bladder microbiome and bladder cancer, these studies collected voided urine specimens (midstream urine samples) which mischaracterized the urinary bladder microbiome for the urogenital microbiota [
6,
7]. A further comparative study of microbial communities in urine obtained via suprapubic aspiration or transurethral catheter should be performed in order to examine the contribution of the urinary bladder microbiome in bladder cancer. A recent study evaluated the need to carefully compare the microbiome profiles linked with the urine and bladder mucosa in bladder cancer patients. Tissue samples were obtained from patients after transurethral excision of cancer tissue [
11]. Simultaneously, urine samples were collected from the same individuals by transurethral resectoscopy. As “five suspicious genera,”
Akkermansia,
Bacteroides,
Clostridium sensustricto,
Enterobacter, and
Klebsiella were overrepresented in tissue samples compared to urine [
11]. This study discovered significant differences in some taxa, suggesting that the bladder tissue microbiota and the urine microbiota may differ to some extent [
2,
11]. Greater knowledge of the microbiome’s function in the development and progression of bladder cancer may open the way for novel treatment approaches. The urine microbiota may serve as a biomarker for bladder cancer and as a therapeutic target. Finally,
Table 1 contains a description of the major bacterial genera found in individuals with urinary diseases.
Table 1. A summary of the bacterial genera reported in individuals with urinary disease.
Disorder |
Subjects |
Specimens |
More Abundant Microbiome than Control Group |
References |
UI/OAB |
Women with MUI |
Catheterized urine |
No difference in Lactobacilli, but six bacterial community types identified |
[59] |
Women undergoing POP/ SUI surgery |
Catheterized urine |
OAB group: Atopobium vaginae, Finegoldia magna |
[77] |
Women with OAB |
Midstream urine and vaginal swab |
OAB group: Proteus (Less: Lactobacillus) |
[76] |
Women undergoing SUI surgery |
Voided or catheterized urine |
Hormone-negative women: (Less Lactobacillus, Gardnerella) |
[83] |
Women with OAB |
Catheterized urine |
OAB group: Sneathia, Staphylococcus, Proteus, Helcococcus, Gemella, Mycoplasma, Aerococcus |
[84] |
Women with daily UUI |
Catheterized urine |
UUI group: Sphingomonadales, Chitinophaga, Brevundimonas, Cadidatus Planktoluna, Alteromonadaceae, Elizabethkingia, Methylobacterium, Caldicellulosiruptor, Stenotrophomonas(less: Prevotella, Comamonadaceae, Nocardioides, Mycobacterium) |
[62] |
Women seeking UUI treatment |
Catheterized urine |
UUI group: Actinobaculum, Actinomyces, Aerococcus, Arthrobacter, Corynebacterium, Gardnerella, Oligella, Staphylococcus, Streptococcus |
[8] |
IC/BPS |
Women with IC/BPS |
Midstream urine |
IC/BPS group: Lactobacillus gasseri (less Corynebacterium) |
[68] |
Women with IC/BPS |
Midstream urine |
No difference in genus |
[85] |
Women with IC/BPS |
Midstream urine and vaginal swab |
No difference in genus |
[86] |
Women with IC/BPS |
Catheterized urine |
IC group: (less Lactobacillus acidophilus) |
[69] |
Women with IC/BPS |
Stool and vaginalswab |
IC/BPS group: (less Eggerthella sinensis, Colinsella aerofaciens, F. prausnitzii, Odoribacter splanchnicus, Lactonifactor longoviformis) |
[87] |
Women with IC/BPS |
Midstream urine |
No difference in genus |
[88] |
Women with IC |
Midstream urine |
IC group: -more Lactobacillus |
[89] |
UTI |
Women with acute cystitis or recurrent cystitis |
Catheterized urine |
Acute cystitis group: Pseudomonas, Acinetobacter, Enterobacteriaceae Recurrent cystitis group: Sphingomonas, Staphylococcus, Streptococcus, Rothia spp |
[46] |
postoperative urinary tract infection patients |
Catheterized urine and vaginal swab |
Patient group: Escherichia coli, Klebsiella pneumoniae, P. aeruginosa (Less Lactobacillus iners) |
[90] |
Bladder cancer |
Bladder cancer patients |
Midstream urine |
Bladder cancer group: Actinomyces europaeus |
[91] |
Men with non-muscle invasive bladder cancer |
Midstream urine |
Bladder cancer group: Fusobacterium, Actinobaculum, Facklamia, Campylobacter |
[82] |
Men with bladder cancer |
Midstream urine |
Bladder cancer group: Acinetobacter, Anaerococcus, Sphingobacterium (Less: Serratia, Proteus, Roseomonas) |
[81] |
Urothelial carcinoma patients |
Midstream urine |
Bladder cancer group: Streptococcus, Pseudomonas, Anaerococcus |
[78] |