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Review

A Bird’s-Eye View of the Pathophysiologic Role of the Human Urobiota in Health and Disease: Can We Modulate It?

by
Emilio Jirillo
1,
Raffaele Palmirotta
1,
Marica Colella
1,2,* and
Luigi Santacroce
1
1
Interdisciplinary Department of Medicine, Section of Microbiology and Virology, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy
2
Doctoral School, eCampus University, 22060 Novedrate, Italy
*
Author to whom correspondence should be addressed.
Pathophysiology 2024, 31(1), 52-67; https://doi.org/10.3390/pathophysiology31010005
Submission received: 15 December 2023 / Revised: 22 January 2024 / Accepted: 23 January 2024 / Published: 1 February 2024
(This article belongs to the Topic Human Anatomy and Pathophysiology, 2nd Volume)
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Abstract

:
For a long time, urine has been considered sterile in physiological conditions, thanks to the particular structure of the urinary tract and the production of uromodulin or Tamm–Horsfall protein (THP) by it. More recently, thanks to the development and use of new technologies, i.e., next-generation sequencing and expanded urine culture, the identification of a microbial community in the urine, the so-called urobiota, became possible. Major phyla detected in the urine are represented by Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Particularly, the female urobiota is largely represented by Lactobacillus spp., which are very active against urinary pathogenic Escherichia (E.) coli (UPEC) strains via the generation of lactic acid and hydrogen peroxide. Gut dysbiosis accounts for recurrent urinary tract infections (UTIs), so-called gut–bladder axis syndrome with the formation of intracellular bacterial communities in the course of acute cystitis. However, other chronic urinary tract infections are caused by bacterial strains of intestinal derivation. Monomicrobial and polymicrobial infections account for the outcome of acute and chronic UTIs, even including prostatitis and chronic pelvic pain. E. coli isolates have been shown to be more invasive and resistant to antibiotics. Probiotics, fecal microbial transplantation, phage therapy, antimicrobial peptides, and immune-mediated therapies, even including vaccines for the treatment of UTIs, will be described.

1. Introduction

Current investigations into human microbiota and microbiome have greatly contributed to better understanding the beneficial roles of microorganisms, which colonize many districts of our body [1]. Alteration of the equilibrium between protective and pathogenic bacteria (dysbiosis), e.g., in the gut and in the urinary tract, may lead to a condition of disease. The link between microbiota and metabolic/immune activities represents the major focus of this emerging field [2,3,4,5]. In particular, the bacterial components of the microbiota can, via their metabolic products, directly or indirectly modulate the function of many cell types, even including immune cells, ultimately eradicating pathogens.
The old belief that urine is a sterile environment has prevented for a long time further investigation of the presence of the urinary microbiota, the so-called urobiota. Only over the last decade has the existence of a complex microbial community in the urine been acknowledged [6,7]. In this regard, the use of new technologies, such as next-generation sequencing and expanded quantitative urine culture, has allowed for new accomplishments to be made in the field of urobiota [8]. According to Shoemaker, in urine samples, the most common bacteria detected are the following: Lactobacillus, Streptococcus, Gardnerella, Staphylococcus, and Corynebacterium. In addition, other bacteria, such as Burkholderia, Klebsiella, Prevotella, and Veilonella, are detectable, even at lower levels [9], thus contributing to the microbial diversity that is the major feature of human urine, whose composition depends on several factors. For instance, in pre-menopausal women, Lactobacillus spp. are very dominant, while in post-menopausal women, Mobiluncus levels are increased [10].
Also, aging seems to exert its impact on the composition of urobiota, since in individuals over 70 years of age, uncommon bacteria are found in the urine, i.e., Proteiniphilum, Saccharofermentans, and Parvimonas [11,12,13,14].
Other factors, which may contribute to differences in the composition of the urobiota, are represented by the collecting mode of urinary samples. From the analysis of a series of reports, it appears that suprapubic aspiration and transurethral catheterization are the best modalities for collecting samples since both procedures avoid contamination from the genitals [15,16,17,18].
From a pathogenic point of view, shifts in the microbial community of the urobiota may lead to a urinary tract infection (UTI) [19,20]. In this respect, the prevalence of uropathogenic strains of Escherichia coli may account for chronic infections. Women are affected by UTIs more than men, due to a shorter urethra and hormonal changes, as in the case of lower estrogen amounts in post-menopausal women [21,22,23].
Furthermore, the abuse of antibiotic treatment often causes alterations in the urobiota with the development of antimicrobial resistance and chronic recurrent cystitis [24,25].
Quite interestingly, the gut microbiota has been shown to account for the majority of UTIs, with Escherichia (E.) coli as the prevalent uropathogen [26]. Through clonal tracking, evidence has been provided that UTIs are very often preceded by an exaggerated growth of uropathogens [27]. Moreover, a link between vaginal and urinary microbial strains (Lactobacillus, E. coli, and Streptcoccus (S.) anginosus) has been reported, thus indicating the coexistence of a urogenital microbiota in women [28].
Recurrent (r) UTIs are mainly caused by uropathogenic E. coli (UPEC) strains, which colonize the periurethral area, then move up to the urethra, and ultimately reach the bladder [14,29,30,31]. Recurrent UTIs are very often monomicrobial infections, but in some cases, they are polymicrobial infections with Enterococcus (E.) faecalis and UPEC strains acting as major etiologic factors [32]. Polymicrobial biofilms characterize rUTIs with E. faecalis, Proteus (P.) mirabilis, and Klebsiella (K.) pneumoniae as dominant organisms [33,34]. Furthermore, polymicrobial interactions in the context of biofilms are responsible for antibiotic resistance, i.e., against ciprofloxacin and trimethoprim [35,36].
Chronic prostatitis (CP) is very common in men under age 50, and some studies have reported an increase in Burkholderia cenocepacia in the course of CP [37,38,39]. Another study by Shoskes reported the association of CP with the gut microbiota also in view of higher counts of Clostridia and Bacteroidia in CP patients in comparison to controls [40].
Antibiotic therapy still represents the best treatment to combat UTIs. However, the misuse or abuse of antibiotics has permitted the occurrence of multi-antibiotic-resistant bacteria [41].
Therefore, different approaches are currently under investigation in order to restore the subverted urobiota [42].
E. coli 83972 has been shown to compete with UPEC isolates, and its introduction in neurogenic bladders decreased the frequency of UTIs. Moreover, Lactobacillus (L.) cispatus administration was very effective in the prevention of UTIs [43,44].
Also, fecal microbiota transplantation in patients with rUTIs decreased the colonization of multi-antibiotic-resistant bacterial strains, while increasing antibiotic susceptibility to uropathogens [45].
Among bacterial inhibitors, experimental evidence has been provided that mannosides operate as receptor analogs and prevent the binding of UPEC fimbriae to epithelial cells in the bladder [46]. Another strategy is based on the administration of ceragenins that are able to enhance the function of endogenous LL-37, an antimicrobial peptide (AMP) [47,48].
The aim of the present review is to describe the urobiota functions in health and disease, also to provide information on novel therapeutic approaches to combat UTIs, with probiotics and bacterial by-products, especially in the case of antibiotic resistance. Finally, immune-mediated therapeutic attempts will be described, even including the application of new vaccines.

2. The Composition of the Urobiota

The urobiota is composed of a core of bacteria with four major phyla, Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria [49]. Of note, Actinobacteria and Bacteroidetes are lacking in the male urobiota, with Corynebacterium as a dominant strain [50].
In general terms, microbial composition male urobiota resembles that present in the skin microbiota [51]. Moreover, changes in the male urobiota composition also depend on concurrent disease, since Propionibacterium acnes strains are prevalent in patients with prostatic cancer, whereas Enterobacteriaceae and Actinobacteria dominate in benign prostate tumors [52,53].
The female urobiota resembles that of the vaginal microbiota with a prevalence of Lactobacillus spp. [54]. Lactobacillus spp. play a protective role against UPEC pathogens via their by-products, such as lactic acid and hydrogen peroxide [55,56]. Conversely, in pre-menopause women, reduced levels of Lactobacillus correlate with urinary incontinence as an indication of urobiota imbalance [57,58]. Of note, female urobiota resembles that of the skin during menstruation, while after sexual intercourse, an increase in Staphylococcus and Streptococcus has been reported [59].
Gardnerella (G.) vaginalis, that is very abundant in bacterial vaginosis, correlates with a decrease in Lactobacillus spp. when it is present at high levels in the female urobiota, thus exposing women to UTI development, pyelonephritis, and renal infections [60,61]. The composition of the urobiota is depicted in Figure 1.

3. The Impact of the Gut Microbiota on UTI Occurrence

Several pieces of evidence support the concept that the gut microbiota is involved in the pathogenesis of UTIs [62,63,64]. For instance, increased levels of Enterobecteriaceae and E. coli in the gut have been associated with UTI recurrence [65,66].
UPEC strains can colonize the urinary tract in view of their surface factors and secreted virulence factors. Among surface factors, type 1 and P fimbriae account for adhesion to host cells, biofilm formation, and the release of cytokines, respectively [67]. On the other hand, secreted virulence factors comprise hemolysins, cytotoxic necrotizing factors 1, and siderophores, which are responsible for intracellular survival, iron acquisition, and tissue damage [68,69].
Extraintestinal pathogenic E. coli (ExPEC), when ingested with food and/or water, are neutralized by the gut epithelium, but in the case of intestinal epithelium dysfunction, they overcome the gut barrier and translocate to the urinary tract [70].
Moreover, antibiotic-induced dysbiosis facilitates the translocation of ExPEC to extraintestinal sites, even including the urinary tract [71]. Quite interestingly, endotoxemia resulting from gut dysbiosis has been detected in the course of stress and depression associated with rUTIs [72]. Clinically, women with uncomplicated rUTIs have been found to have gut dysbiosis with decreased levels of Lactobacillus spp. and Bifidobacteria along with increased numbers of E. coli, Clostridium, and Staphylococcus spp. [72]. In support of the above data, a gut–bladder syndrome has been reported, thus indicating the passage of pathogens from the gut to the bladder [73].
Recently, a positive association has been reported between urobiota and overactive bladder, a neuromuscular dysfunction predominated by the presence of urinary urgency, suggesting a possible role of urinary dysbiosis in this common condition. However, it seems to be worsened by an overlapping viral infection that can also affect bacterial diversity and composition. There are very limited studies with non-uniform results, but a constant feature is the difference in the microbial population of the gut and genito-urinary tract between individuals with urge urinary incontinence and healthy people. For further information, readers should refer to the recent studies conducted by [74,75,76].

4. Urobiota Alteration in UTIs and Pathogenetic Mechanisms

In the course of UTIs, a variety of bacteria have been identified in urobiota by current DNA sequencing methods. According to Price et al. and Kenneally et al., in aged people, immunocompromised individuals, patients with indwelling devices, and those who have received previous antibiotic treatment, urobiota is characterized by a dramatic decrease in E. coli, Enterococcus, Staphylococcus, G. vaginalis, and Lactobacillus, paralleled by an increase in Pseudomonas aeruginosa, Aerococcus urinae, and Proteus mirabilis [74,75]. Within this framework, there is evidence that bacteria originating from the gastrointestinal tract or urogenital epithelial niches create the so-called intracellular bacterial communities (IBCs) in the bladder wall, as observed in acute cystitis and rUTI patients [76].
UPEC strains contributing to the formation of IBCs belong to phylogroups A, B1, B2, C, E, F, and D, with B2 and D endowed with stronger virulence and higher levels of multidrug resistance [77,78].
Thanks to modern technologies, it has been discovered that UTIs also constitute polymicrobial infections with E. faecalis and UPEC strains as dominant bacteria [79].
Of note, L-ornithine is secreted by E. faecalis with the subsequent stimulation of E. coli’s iron uptake pathway and related biofilm formation [79,80]. Also, catheter-associated UTIs (CAUTIs) are polymicrobial in nature, and E. coli isolates are more invasive with increased resistance to antibiotics [81]. In the same direction, P. mirabilis and E. faecalis biofilms are resistant to various antibiotics, such as aminoglycosides, fluroquinolones, and carbapenems [82]. In particular, P. mirabilis produces urease, leading to crystalline biofilm formation on catheters and resistance against pre-coated antimicrobial agents [83]. In sum, the above cited pathogenetic mechanisms account for disease progression and more severe adverse effects in comparison to monomicrobial infections [84].
Prostate infections are caused by various bacterial strains, i.e., E. coli, Pseudomonas, Klebsiella, Enterococcus, Enterobacter, Proteus, and Serratia, and can be divided into acute bacterial, chronic bacterial, asymptomatic inflammatory prostatitis, and chronic pelvic pain [85].
The above pathogens replace the prostate microbiota, that is mainly represented by Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes [86,87,88]. Despite the fact that the prostate is not connected to the gut microbiota, it can be reached by intestinal post-biotics, such as endotoxins or lipopolysaccharides (LPSs), from the cell wall of Gram-negative bacteria [89].
In this respect, prostate cancer cells express on their membrane Toll-like receptor (TLR)4, that is the specific receptor for LPSs and whose activation accounts for the release of proinflammatory cytokines, vascular endothelial growth factor, and CCL2 [90,91]. Furthermore, E. coli strains isolated from chronic prostatitis patients modify the prostatic milieu, promoting tumor growth [92]. Conversely, evidence has been provided that small RNAs isolated from Pseudomonas spp. are not correlated with prostate cancer development and may retard metastatic dissemination [93].
From a pathogenic point of view, immune response in the course of prostatitis is able to promote a massive liberation of proinflammatory cytokines and enzymes, e.g., collagenase or glucuronidase, that contribute to prostate damage [94].
The relationship between urobiota and bladder cancer has been the subject of a previous investigation in terms of bacteria which may promote tumor growth. However, in a recent review, the role of urinary bacteria able to arrest cancer progression has been pointed out with special reference to their capacity to reinforce immunosurveillance [95]. The authors conclude that the exact mechanisms of the anti-neoplastic protection afforded by bacteria require further study.
The pathogenesis of UTIs is expressed in Figure 2.

5. New Therapeutic Approaches to Modulate the Urobiota and Prevent UTIs

Until recently, antibiotic treatment has represented the most appropriate therapy to defeat UTIs. However, the misuse and abuse of antibiotics have increased the number of antibiotic-resistant uropathogens, thus affecting the microbicidal activity of these drugs. For this reason, novel therapeutic approaches are under investigation to restore the urobiota [96,97].

5.1. Probiotics

Probiotics have largely been used for correcting the gut microbiota in view of their ability to inhibit pathogen colonization, modulate host immune response, and maintain epithelial barrier integrity [98,99,100]. Therefore, probiotics have also been used in UTIs. For instance, Lactobacillus spp., when administered via intravaginal suppository, could prevent the outcome of UTIs [101]. L. crispatus is able to secrete lactic acid, which is highly microbicidal against C. trachomatis (C.t.), as well as Candida albicans [102,103,104].
L. rhamnosus has been shown to be very effective in UTIs, downregulating UPEC virulence, even including NF-kB activation, P, and type 1 fimbriae, as well as preventing the formation of biofilms [105,106,107]. Moreover, the intravesical administration of L. rhamnosus has been demonstrated to be beneficial in patients with neurogenic lower urinary tract infections [108].
E. coli Nissle 1917, a non-pathogenic strain, is currently used as a preventative probiotic agent against UTIs in view of its ability to antagonize other uropathogens [109].
Actually, this bacterium possesses catechol microcins, which support bacterial competitiveness by binding ferric iron under iron-limited circumstances [110,111].
E. coli 83972 is an attenuated strain, which differentiates from the E. coli strains detected in UTIs, thanks to fim deletions and papG point mutations, which reduce its motility and account for the absence of P, type 1, and F1c fimbriae [112]. This bacterium is able to colonize the urinary tract, outperforming uropathogens and decreasing UTI risk [113,114].
Another avirulent E. coli strain, HU217, has been used to coat urinary catheters, thus reducing the incidence rates of infection in patients [115].
Of note, both prebiotics and synbiotics have been used in a few clinical trials in patients with UTIs [116,117]. Further studies are needed to validate the efficacy of these agents.

5.2. Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) is based on the transfer of healthy stool to the intestinal lumen of a given patient with the attempt to restore the antibiotic-mediated subversion of the gut microbiota. Application of the FMT in patients with recurrent Clostridioides difficile infection and UTIs has led to an increased antibiotic susceptibility of the uropathogens, E. coli and Klebsiella, so it has been proposed for selected patients [118]. Similarly, in patients with irritable bowel syndrome and rUTIs, FMT has reduced pathogenic strains in stool, while it has also attenuated UTI symptoms [119].

5.3. Phage Therapy

Phage therapy for UTIs is based on the use of lytic proteins, phage cocktails, and phages associated with antibiotics [120]. In a human murine model, the combination of a phage with antibiotics (TMP-SMX and ciprofloxacin) reduced the biofilm biomass and a multi-drug-resistant strain of Acinetobacter baumannii [121]. The synergistic effect seems to rely on the inhibition of dihydrofolate reductase, DNA topoisomerase II and IV, with a faster phage expansion and bacterial cell lysis [122]. Also, the association between anti-Pseudomonas phages and E. coli HU2117, a derivative of E. coli 83972, was very effective in the prevention of P. aeruginosa biofilm in urinary catheters [123].
Pyophage, a commercial preparation, has been shown to be very effective in the treatment of UTIs [124,125]. The intravesical administration of Pyophage in patients with UTIs has been very effective as an antibiotic treatment, even if further trials are required to fully validate this type of treatment [125].

5.4. Antimicrobial Peptides

AMPs are produced by the urothelium in the urinary tract, and, among them, human cathelicidin (LL-37), human-beta defensin (HBD), and human-alpha defensin 5 (HD-5) have been clinically evaluated. Selected probiotics and nutraceuticals could be used to induce an increased production and release of these molecules, offering new therapeutic and prophylactic tools for urinary diseases [126,127,128,129,130,131].
LL-37 exerts protective effects in the course of UTIs, and, in particular, it suppresses biofilm formation by the inhibition of CsgA polymerization, a subunit of curly fimbriae, which generates resistance in UPC strains [132,133,134].
Alpha-defensins possess an elevated antimicrobial potential, and the recombinant HD5 has been shown to be highly microbicidal against several uropathogens [135].
HBD-1 and HBD-2 are present in the urinary tract, and, in particular, HBD-2 is very effective against E. faecalis [136]. Cecropin A, derived from the wax moth, Galleria Mellonella, has been demonstrated to be active against biofilm-forming UPEC strains [137]. However, more research is needed to define the potential of HBDs in the urinary tract.

5.5. Bacteriocins

Bacteriocins also belong to AMPs and are defined as ribosomal synthetized peptides by both Gram-positive and Gram-negative bacteria [138]. The dramatic increase in multi-drug-resistant Gram-negative bacteria has prompted more research in the field of Gram-negative bacteriocins. Colicins and microcins are major Gram-negative bacteriocins, with the former having a higher molecular weight (>20 kDa) and the latter being characterized by a lower molecular weight (<10 kDa).
Colicins are synthetized by more than 50% E. coli strains and employ various mechanisms to destroy bacteria, i.e., membrane permeabilization via voltage-dependent channels, cellular nuclease degradation, and the inhibition of peptidoglycan synthesis [139]. Clinically, colicins are able to reduce biofilm generation in urinary catheters, and their antibacterial activity can be increased, combining a lubricant with colicin SR4 or using L. brevis DT24, which expresses colicin E2 [140,141,142]. Furthermore, bioengineered nisin variants S29A and S29G, model bacteriocins, exhibited a higher potency against Shigella and Pseudomonas spp. [143,144,145].
Pheromonicin results from the combination of a channel-forming colicin 1a and its cognate immunity protein from E. coli with a pheromone-encoding gene from S. aureus and exhibits specific activity against S. aureus [146].
Chimeric bacteriocins have also been demonstrated to be very effective in the killing of E. coli and P. aeruginosa [147,148].
Microcins are AMPs encoded by plasmids or chromosomes and show antibacterial activity against Enterobacteriaceae spp. [149]. They act via the inhibition of bacterial enzymes, membrane permeabilization, and the exploitation of membrane components [149,150]. The insertion of microcin H47 and microcin M into E. coli Nissle 1917 enhanced their activity against UPEC strains [151,152].
In terms of bioengineering, the insertion of non-canonical amino acids into microcin J25 gave rise to several variants with similar or even higher microbicidal activity in comparison with the wild counterpart [153,154]. Also, the combination of chitosan nanoparticles with microcin J25 generated a stable nano-antimicrobial effective against both Gram-positive and Gram-negative bacteria [155].
In Figure 3, bacteria and bacterial by-products as novel biotherapeutics are described.

5.6. Inhibitors of Bacterial Virulence

Mannosides are small molecules able to function as receptor analogs that can bind fimbriae, thus preventing UPEC-host cell interactions, as seen in murine infection models and human kidney cells [156,157,158]. Then, targeting bacterial type 1 pilus fimh adhesins with mannosides selectively depleted uropathogenic E. coli from the gut, potentially reducing UTI incidence [159].

5.7. Immune-Mediated Therapies

There is evidence that LL-37 accounts for neutrophil, macrophage, and T lymphocyte responsiveness in UTIs [160]. In this respect, synthetic antimicrobials, ceragenins, have been shown to enhance LL-37 activity in the urinary tract [161,162]. Moreover, a prolyl-hydroxylase inhibitor, GB-004, was able to regulate the hypoxia-inducible factor-1 alpha, reducing the inflammatory infiltrate in murine UTIs [163]. The above cited studies suggest the possibility of reinforcing the immune response or decreasing the inflammatory profile in the urinary tract.
IL-22, a member of the IL-10 cytokine superfamily, has been shown to regulate the microbiota and the expression of AMPs in human urothelial cells [164,165]. According to the studies of Sonnenberg et al. and Schirinzi et al., IL-22 may be used to control UTI infections, reducing the inflammatory burden [165,166].
Vaccines composed of UPEC antigens have been proposed, such as ExPEC4V, which targets the O-polysaccharide chain of a pathogenic strain of E. coli LPSs in women rUTIs [167]. Furthermore, the sublingual spray vaccine, Uromune, composed of heat-inactivated lysates of E. coli, E. faecalis, K. pneumonia, and P. vulgaris, could prevent UTIs in women, with only 10% of the vaccinated group undergoing UTIs within 12 months after vaccination [168].
In Figure 4, molecular and immune-mediated approaches to treat UTIs are described.

6. Conclusions

The urobiota represents the microbial community of the urinary tract. It interacts with the microbiota of the gastrointestinal and genital tracts, regulating local and systemic immune responsiveness. Dysbiosis of the urobiota can lead to UTIs, which may be complicated by antibiotic-resistant bacterial strains. In this regard, several therapeutic attempts are at present being investigated for the restoration of the urobiota. Besides biotherapeutics, i.e., probiotics and FMT procedure, immune-mediated approaches are under study, using AMPs and targeting cytokines, such as IL-22, for controlling inflammation, as well as bacterial colonization during UTIs. Finally, an emerging field is represented by the use of vaccines that target the O-polysaccharide chain of ExPEC LPSs with encouraging results in rUTI women, even if further clinical data are necessary to validate vaccine efficacy.

Author Contributions

Concept and design: E.J. and L.S. Acquisition, analysis, and interpretation of data: E.J. and M.C. Drafting of the manuscript: E.J. and L.S. Critical revision of the manuscript for important intellectual content: All the authors. Administrative, technical, or material support: R.P. and L.S. Supervision: E.J. and L.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All relevant data are reported in the manuscript.

Acknowledgments

The authors express their gratitude to Giuseppe Divittorio and Michelangelo Ferri, Interdisciplinary Department of Medicine, for their valuable help in data collection.

Conflicts of Interest

The authors declare no conflicts of interest.

List of Abbreviations

CAUTICatheter-associated UTI
CPChronic prostatitis
ExPECExtraintestinal pathogenic Escherichia coli
FMTFecal Microbiota Transplantation
HBDHuman-beta defensin
HD5Human-alpha defensin 5
IBCsIntracellular bacterial communities
ILInterleukin
LPSsLipopolysaccharides
RRecurrent
UTIsUrinary tract infections
UPECUropathogenic Escherichia coli
ThT helper
TREGT regulatory cells

References

  1. Sleator, R.D. The human superorganism—Of microbes and men. Med. Hypotheses 2010, 74, 214–215. [Google Scholar] [CrossRef]
  2. Magrone, T.; Jirillo, E. The interplay between the gut immune system and microbiota in health and disease: Nutraceutical intervention for restoring intestinal homeostasis. Curr. Pharm. Des. 2013, 19, 1329–1342. [Google Scholar] [CrossRef]
  3. Rizzetto, L.; Fava, F.; Tuohy, K.M.; Selmi, C. Connecting the immune system, systemic chronic inflammation and the gut microbiome: The role of sex. J. Autoimmun. 2018, 92, 12–34. [Google Scholar] [CrossRef]
  4. Visconti, A.; Le Roy, C.I.; Rosa, F.; Rossi, N.; Martin, T.C.; Mohney, R.P.; Li, W.; de Rinaldis, E.; Bell, J.T.; Venter, J.C.; et al. Interplay between the human gut microbiome and host metabolism. Nat. Commun. 2019, 10, 4505. [Google Scholar] [CrossRef]
  5. De Santis, S.; Cavalcanti, E.; Mastronardi, M.; Jirillo, E.; Chieppa, M. Nutritional Keys for Intestinal Barrier Modulation. Front. Immunol. 2015, 6, 612. [Google Scholar] [CrossRef] [PubMed]
  6. Wolfe, A.J.; Toh, E.; Shibata, N.; Rong, R.; Kenton, K.; FitzGerald, M.; Mueller, E.R.; Schreckenberger, P.; Dong, Q.; Nelson, D.E.; et al. Evidence of Uncultivated Bacteria in the Adult Female Bladder. J. Clin. Microbiol. 2012, 50, 1376–1383. [Google Scholar] [CrossRef] [PubMed]
  7. Jones, J.; Murphy, C.P.; Sleator, R.D.; Culligan, E.P. The urobiome, urinary tract infections, and the need for alternative therapeutics. Microb. Pathog. 2021, 161 Pt B, 105295. [Google Scholar] [CrossRef]
  8. Gasiorek, M.; Hsieh, M.H.; Forster, C.S. Utility of DNA Next-Generation Sequencing and Expanded Quantitative Urine Culture in Diagnosis and Management of Chronic or Persistent Lower Urinary Tract Symptoms. J. Clin. Microbiol. 2019, 58, e00204-19. [Google Scholar] [CrossRef] [PubMed]
  9. Shoemaker, R.; Kim, J. Urobiome: An outlook on the metagenome of urological diseases. Investig. Clin. Urol. 2021, 62, 611–622. [Google Scholar] [CrossRef] [PubMed]
  10. Curtiss, N.; Balachandran, A.; Krska, L.; Peppiatt-Wildman, C.; Wildman, S.; Duckett, J. Age, menopausal status and the bladder microbiome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2018, 228, 126–129. [Google Scholar] [CrossRef] [PubMed]
  11. Brubaker, L.; Wolfe, A.J. The new world of the urinary microbiota in women. Am. J. Obstet. Gynecol. 2015, 213, 644–649. [Google Scholar] [CrossRef]
  12. Yıldırım, S.; Shoskes, D.; Kulkarni, S.; Laguna, P. Urinary microbiome in uncomplicated and interstitial cystitis: Is there any similarity? World J. Urol. 2020, 38, 2721–2731. [Google Scholar] [CrossRef] [PubMed]
  13. Brubaker, L.; Wolfe, A.J. The female urinary microbiota, urinary health and common urinary disorders. Ann. Transl. Med. 2017, 5, 34. [Google Scholar] [CrossRef]
  14. Barber, A.E.; Norton, J.P.; Spivak, A.M.; Mulvey, M.A. Urinary tract infections: Current and emerging management strategies. Clin. Infect Dis. 2013, 57, 719–724. [Google Scholar] [CrossRef]
  15. Cho, I.; Blaser, M.J. The human microbiome: At the interface of health and disease. Nat. Rev. Genet. 2012, 13, 260–270. [Google Scholar] [CrossRef] [PubMed]
  16. Bajic, P.; Van Kuiken, M.E.; Burge, B.K.; Kirshenbaum, E.J.; Joyce, C.J.; Wolfe, A.J.; Branch, J.D.; Bresler, L.; Farooq, A.V. Male Bladder Microbiome Relates to Lower Urinary Tract Symptoms. Eur. Urol. Focus 2020, 6, 376–382. [Google Scholar] [CrossRef]
  17. Pallares-Mendez, R.; Cervantes-Miranda, D.E.; Gonzalez-Colmenero, A.D.; Ochoa-Arvizo, M.A.; Gutierrez-Gonzalez, A. A Perspective of the Urinary Microbiome in Lower Urinary Tract Infections—A Review. Curr. Urol. Rep. 2022, 23, 235–244. [Google Scholar] [CrossRef] [PubMed]
  18. Thomas-White, K.J.; Kliethermes, S.; Rickey, L.; Lukacz, E.S.; Richter, H.E.; Moalli, P.; Zimmern, P.; Norton, P.; Kusek, J.W.; Wolfe, A.J.; et al. Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence. Am. J. Obstet. Gynecol. 2017, 216, 55.e1–55.e16. [Google Scholar] [CrossRef]
  19. Zandbergen, L.E.; Halverson, T.; Brons, J.K.; Wolfe, A.J.; de Vos, M.G.J. The Good and the Bad: Ecological Interaction Measurements between the Urinary Microbiota and Uropathogens. Front. Microbiol. 2021, 12, 659450. [Google Scholar] [CrossRef]
  20. Guglietta, A. Recurrent urinary tract infections in women: Risk factors, etiology, pathogenesis and prophylaxis. Futur. Microbiol. 2017, 12, 239–246. [Google Scholar] [CrossRef]
  21. Abelson, B.; Sun, D.; Que, L.; A Nebel, R.; Baker, D.; Popiel, P.; Amundsen, C.L.; Chai, T.; Close, C.; DiSanto, M.; et al. Sex differences in lower urinary tract biology and physiology. Biol. Sex. Differ. 2018, 9, 45. [Google Scholar] [CrossRef] [PubMed]
  22. Alperin, M.; Burnett, L.; Lukacz, E.M.; Brubaker, L. The mysteries of menopause and urogynecologic health: Clinical and scientific gaps. Menopause 2019, 26, 103–111. [Google Scholar] [CrossRef] [PubMed]
  23. Kmiec, D.; Nchioua, R.; Sherrill-Mix, S.; Stürzel, C.M.; Heusinger, E.; Braun, E.; Gondim, M.V.P.; Hotter, D.; Sparrer, K.M.J.; Hahn, B.H.; et al. CpG Frequency in the 5′ Third of the env Gene Determines Sensitivity of Primary HIV-1 Strains to the Zinc-Finger Antiviral Protein. mBio 2020, 11, e02903-19. [Google Scholar] [CrossRef] [PubMed]
  24. Kostakioti, M.; Hultgren, S.J.; Hadjifrangiskou, M. Molecular blueprint of uropathogenic Escherichia coli virulence provides clues toward the development of anti-virulence therapeutics. Virulence 2012, 3, 592–593. [Google Scholar] [CrossRef] [PubMed]
  25. Raz, R. Postmenopausal women with recurrent UTI. Int. J. Antimicrob. Agents 2001, 17, 269–271. [Google Scholar] [CrossRef]
  26. Magruder, M.; Sholi, A.N.; Gong, C.; Zhang, L.; Edusei, E.; Huang, J.; Albakry, S.; Satlin, M.J.; Westblade, L.F.; Crawford, C.; et al. Gut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection. Nat. Commun. 2019, 10, 5521. [Google Scholar] [CrossRef]
  27. Thänert, R.; Reske, K.A.; Hink, T.; Wallace, M.A.; Wang, B.; Schwartz, D.J.; Seiler, S.; Cass, C.; Burnham, C.-A.D.; Dubberke, E.R.; et al. Comparative Genomics of Antibiotic-Resistant Uropathogens Implicates Three Routes for Recurrence of Urinary Tract Infections. mBio 2019, 10, e01977-19. [Google Scholar] [CrossRef]
  28. Thomas-White, K.; Forster, S.C.; Kumar, N.; Van Kuiken, M.; Putonti, C.; Stares, M.D.; Hilt, E.E.; Price, T.K.; Wolfe, A.J.; Lawley, T.D. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nat. Commun. 2018, 9, 1557. [Google Scholar] [CrossRef] [PubMed]
  29. Santacroce, L.; Colella, M.; Charitos, I.A.; Di Domenico, M.; Palmirotta, R.; Jirillo, E. Microbial and Host Metabolites at the Backstage of Fever: Current Knowledge about the Co-Ordinate Action of Receptors and Molecules Underlying Pathophysiology and Clinical Implications. Metabolites 2023, 13, 461. [Google Scholar] [CrossRef]
  30. Terlizzi, M.E.; Gribaudo, G.; Maffei, M.E. UroPathogenic Escherichia coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-antibiotic Antimicrobial Strategies. Front. Microbiol. 2017, 8, 1566. [Google Scholar] [CrossRef] [PubMed]
  31. Priadko, K.; Romano, L.; Olivieri, S.; Romeo, M.; Barone, B.; Sciorio, C.; Spirito, L.; Morelli, M.; Crocetto, F.; Arcaniolo, D.; et al. Intestinal microbiota, intestinal permeability and the urogenital tract: Is there a pathophysiological link? J. Physiol. Pharmacol. 2022, 73, 575–585. [Google Scholar] [CrossRef]
  32. Fourcade, C.; Canini, L.; Lavigne, J.P.; Sotto, A. A comparison of monomicrobial versus polymicrobial Enterococcus faecalis bacteriuria in a French University Hospital. Eur. J. Clin. Microbiol. Infect. Dis. 2015, 34, 1667–1673. [Google Scholar] [CrossRef] [PubMed]
  33. Werneburg, G.T.; Nguyen, A.; Henderson, N.S.; Rackley, R.R.; Shoskes, D.A.; Le Sueur, A.L.; Corcoran, A.T.; Katz, A.E.; Kim, J.; Rohan, A.J.; et al. The Natural History and Composition of Urinary Catheter Biofilms: Early Uropathogen Colonization with Intraluminal and Distal Predominance. J. Urol. 2020, 203, 357–364. [Google Scholar] [CrossRef] [PubMed]
  34. Mukherjee, K.; Amsel, D.; Kalsy, M.; Billion, A.; Dobrindt, U.; Vilcinskas, A. MicroRNAs regulate innate immunity against uropathogenic and commensal-like Escherichia coli infections in the surrogate insect model Galleria mellonella. Sci. Rep. 2020, 10, 2570. [Google Scholar] [CrossRef] [PubMed]
  35. Orazi, G.; O’Toole, G.A. “It Takes a Village”: Mechanisms Underlying Antimicrobial Recalcitrance of Polymicrobial Biofilms. J. Bacteriol. 2019, 202, e00530-19. [Google Scholar] [CrossRef] [PubMed]
  36. Zhang, L.; Foxman, B.; Manning, S.D.; Tallman, P.; Marrs, C.F. Molecular epidemiologic approaches to urinary tract infection gene discovery in uropathogenic Escherichia coli. Infect. Immun. 2000, 8, 2009–2015. [Google Scholar] [CrossRef]
  37. Schwager, S.; Agnoli, K.; Köthe, M.; Feldmann, F.; Givskov, M.; Carlier, A.; Eberl, L. Identification of Burkholderia cenocepacia strain H111 virulence factors using nonmammalian infection hosts. Infect. Immun. 2013, 81, 143–153. [Google Scholar] [CrossRef]
  38. Arzola, J.M.; Hawley, J.S.; Oakman, C.; Mora, R.V. A case of prostatitis due to Burkholderia pseudomallei. Nat. Rev. Endocrinol. 2007, 4, 111–114. [Google Scholar] [CrossRef]
  39. Organ, M.; Grantmyre, J.; Hutchinson, J. Burkholderia cepacia infection of the prostate caused by inoculation ofcontaminated ultrasound gel during transrectal biopsy of the prostate. Can. Urol. Assoc. J. 2010, 4, 58–60. [Google Scholar] [CrossRef]
  40. Shoskes, D.A.; Altemus, J.; Polackwich, A.S.; Tucky, B.; Wang, H.; Eng, C. The Urinary Microbiome Differs Significantly between Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Controls as Well as between Patients with Different Clinical Phenotypes. Urology 2016, 92, 26–32. [Google Scholar] [CrossRef]
  41. Santacroce, L.; Di Domenico, M.; Montagnani, M.; Jirillo, E. Antibiotic Resistance and Microbiota Response. Curr. Pharm. Des. 2023, 29, 356–364. [Google Scholar] [CrossRef] [PubMed]
  42. Chen, Y.-C.; Lee, W.-C.; Chuang, Y.-C. Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection. Int. J. Mol. Sci. 2023, 24, 7055. [Google Scholar] [CrossRef] [PubMed]
  43. Santacroce, L.; Palmirotta, R.; Bottalico, L.; Charitos, I.A.; Colella, M.; Topi, S.; Jirillo, E. Crosstalk between the Resident Microbiota and the Immune Cells Regulates Female Genital Tract Health. Life 2023, 13, 1531. [Google Scholar] [CrossRef] [PubMed]
  44. Kim, D.S.; Lee, J.W. Urinary Tract Infection and Microbiome. Diagnostics 2023, 13, 1921. [Google Scholar] [CrossRef]
  45. Tariq, R.; Pardi, D.S.; Tosh, P.K.; Walker, R.C.; Razonable, R.R.; Khanna, S. Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection Reduces Recurrent Urinary Tract Infection Frequency. Clin. Infect. Dis. 2017, 65, 1745–1747. [Google Scholar] [CrossRef] [PubMed]
  46. Kalas, V.; Hibbing, M.E.; Maddirala, A.R.; Chugani, R.; Pinkner, J.S.; Mydock-McGrane, L.K.; Conover, M.S.; Janetka, J.W.; Hultgren, S.J. Structure-Based Discovery of Glycomimetic FmlH Ligands As Inhibitors of Bacterial Adhesion During Urinary Tract Infection. Proc. Natl. Acad. Sci. USA 2018, 115, E2819–E2828. [Google Scholar] [CrossRef] [PubMed]
  47. Mitchell, G.; Silvis, M.R.; Talkington, K.C.; Budzik, J.M.; Dodd, C.E.; Paluba, J.M.; Oki, E.A.; Trotta, K.L.; Licht, D.J.; Jimenez-Morales, D.; et al. Ceragenins and Antimicrobial Peptides Kill Bacteria through Distinct Mechanisms. mBio 2022, 13, e0272621. [Google Scholar] [CrossRef] [PubMed]
  48. Chromek, M.; Slamová, Z.; Bergman, P.; Kovács, L.; Podracká, L.; Ehrén, I.; Hökfelt, T.; Gudmundsson, G.H.; Gallo, R.L.; Agerberth, B.; et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat. Med. 2006, 12, 636–641. [Google Scholar] [CrossRef]
  49. Colella, M.; Topi, S.; Palmirotta, R.; D’agostino, D.; Charitos, I.A.; Lovero, R.; Santacroce, L. An Overview of the Microbiota of the Human Urinary Tract in Health and Disease: Current Issues and Perspectives. Life 2023, 13, 1486. [Google Scholar] [CrossRef]
  50. Karstens, L.; Asquith, M.; Davin, S.; Stauffer, P.; Fair, D.; Gregory, W.T.; Rosenbaum, J.T.; McWeeney, S.K.; Nardos, R. Does the Urinary Microbiome Play a Role in Urgency Urinary Incontinence and Its Severity? Front. Cell. Infect. Microbiol. 2016, 6, 78. [Google Scholar] [CrossRef]
  51. E Fouts, D.; Pieper, R.; Szpakowski, S.; Pohl, H.; Knoblach, S.; Suh, M.-J.; Huang, S.-T.; Ljungberg, I.; Sprague, B.M.; Lucas, S.K.; et al. Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. J. Transl. Med. 2012, 10, 174. [Google Scholar] [CrossRef] [PubMed]
  52. Mak, T.N.; Sfanos, K.S.; Brüggemann, H. Draft Genome Sequences of Two Strains of Propionibacterium acnes Isolated from Radical Prostatectomy Specimens. Genome Announc. 2013, 1, e01071-13. [Google Scholar] [CrossRef]
  53. Shrestha, E.; White, J.R.; Yu, S.-H.; Kulac, I.; Ertunc, O.; De Marzo, A.M.; Yegnasubramanian, S.; Mangold, L.A.; Partin, A.W.; Sfanos, K.S. Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer. J. Urol. 2018, 199, 161–171. [Google Scholar] [CrossRef] [PubMed]
  54. Pearce, M.M.; Zilliox, M.J.; Rosenfeld, A.B.; Thomas-White, K.J.; Richter, H.E.; Nager, C.W.; Visco, A.G.; Nygaard, I.E.; Barber, M.D.; Schaffer, J.; et al. The female urinary microbiome in urgency urinary incontinence. Am. J. Obstet. Gynecol. 2015, 213, 347.e1–347.e11. [Google Scholar] [CrossRef] [PubMed]
  55. A Cadieux, P.; Burton, J.; Devillard, E.; Reid, G. Lactobacillus by-products inhibit the growth and virulence of uropathogenic Escherichia coli. J. Physiol. Pharmacol. 2009, 60 (Suppl. S6), 13–18. [Google Scholar] [PubMed]
  56. Charitos, I.A.; Topi, S.; Gagliano-Candela, R.; De Nitto, E.; Polimeno, L.; Montagnani, M.; Santacroce, L. The Toxic Effects of Endocrine Disrupting Chemicals (EDCs) on Gut Microbiota: Bisphenol A (BPA) A Review. Endocr. Metab. Immune Disord. Drug Targets 2022, 22, 716–727. [Google Scholar] [CrossRef]
  57. Gümüş, D.; Yüksek, F.K.; Sefer, Ö.; Yörük, E.; Uz, G.; Küçüker, M.A. The roles of hormones in the modulation of growth and virulence genes’ expressions in UPEC strains. Microb. Pathog. 2019, 132, 319–324. [Google Scholar] [CrossRef]
  58. Price, T.K.; Wolff, B.; Halverson, T.; Limeira, R.; Brubaker, L.; Dong, Q.; Mueller, E.R.; Wolfe, A.J. Temporal Dynamics of the Adult Female Lower Urinary Tract Microbiota. mBio 2020, 11, e00475-20. [Google Scholar] [CrossRef]
  59. Gholiof, M.; Adamson-De Luca, E.; Wessels, J.M. The female reproductive tract microbiotas, inflammation, and gynecological conditions. Front. Reprod. Health 2022, 9, 963752. [Google Scholar] [CrossRef]
  60. Morrill, S.; Gilbert, N.M.; Lewis, A.L. Gardnerella vaginalis as a Cause of Bacterial Vaginosis: Appraisal of the Evidence from in vivo Models. Front. Cell. Infect. Microbiol. 2020, 10, 168. [Google Scholar] [CrossRef]
  61. O’Brien, V.P.; Joens, M.S.; Lewis, A.L.; Gilbert, N.M. Recurrent Escherichia coli Urinary Tract Infection Triggered by Gardnerella vaginalis Bladder Exposure in Mice. J. Vis. Exp. 2020, 166, e61967. [Google Scholar] [CrossRef]
  62. Flores-Mireles, A.L.; Walker, J.N.; Caparon, M.; Hultgren, S.J. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol. 2015, 13, 269–284. [Google Scholar] [CrossRef] [PubMed]
  63. Stapleton, A.E.; Au-Yeung, M.; Hooton, T.M.; Fredricks, D.N.; Roberts, P.L.; Czaja, C.A.; Yarova-Yarovaya, Y.; Fiedler, T.; Cox, M.; Stamm, W.E. Randomized, Placebo-Controlled Phase 2 Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent Urinary Tract Infection. Clin. Infect. Dis. 2011, 52, 1212–1217. [Google Scholar] [CrossRef] [PubMed]
  64. Colella, M.; Charitos, I.A.; Ballini, A.; Cafiero, C.; Topi, S.; Palmirotta, R.; Santacroce, L. Microbiota revolution: How gut microbes regulate our lives. World J. Gastroenterol. 2023, 29, 4368–4383. [Google Scholar] [CrossRef] [PubMed]
  65. Meštrović, T.; Matijašić, M.; Perić, M.; Paljetak, H.; Barešić, A.; Verbanac, D. The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside. Diagnostics 2020, 11, 7. [Google Scholar] [CrossRef] [PubMed]
  66. Forde, B.M.; Roberts, L.W.; Phan, M.-D.; Peters, K.M.; Fleming, B.A.; Russell, C.W.; Lenherr, S.M.; Myers, J.B.; Barker, A.P.; Fisher, M.A.; et al. Population dynamics of an Escherichia coli ST131 lineage during recurrent urinary tract infection. Nat. Commun. 2019, 10, 3643. [Google Scholar] [CrossRef]
  67. Khonsari, M.S.; Behzadi, P.; Foroohi, F. The prevalence of type 3 fimbriae in Uropathogenic Escherichia coli isolated from clinical urine samples. Meta Gene 2021, 28, 100881. [Google Scholar] [CrossRef]
  68. Behzadi, P. Classical chaperone-usher (CU) adhesive fimbriome: Uropathogenic Escherichia coli (UPEC) and urinary tract infections (UTIs). Folia Microbiol. 2020, 65, 45–65. [Google Scholar] [CrossRef]
  69. Hozzari, A.; Behzadi, P.; Khiabani, P.K.; Sholeh, M.; Sabokroo, N. Clinical cases, drug resistance, and virulence genes profiling in Uropathogenic Escherichia coli. J. Appl. Genet. 2020, 61, 265–273. [Google Scholar] [CrossRef]
  70. Ghosh, S.; Whitley, C.S.; Haribabu, B.; Jala, V.R. Regulation of Intestinal Barrier Function by Microbial Metabolites. Cell. Mol. Gastroenterol. Hepatol. 2021, 11, 1463–1482. [Google Scholar] [CrossRef]
  71. Stepanova, N. How Advanced Is Our Understanding of the Role of Intestinal Barrier Dysfunction in the Pathogenesis of Recurrent Urinary Tract Infections. Front. Pharmacol. 2022, 13, 780122. [Google Scholar] [CrossRef]
  72. Trzeciak, P.; Herbet, M. Role of the Intestinal Microbiome, Intestinal Barrier and Psychobiotics in Depression. Nutrients 2021, 13, 927. [Google Scholar] [CrossRef]
  73. Montagnani, M.; Bottalico, L.; Potenza, M.A.; Charitos, I.A.; Topi, S.; Colella, M.; Santacroce, L. The Crosstalk between Gut Microbiota and Nervous System: A Bidirectional Interaction between Microorganisms and Metabolome. Int. J. Mol. Sci. 2023, 24, 10322. [Google Scholar] [CrossRef]
  74. Whiteside, S.A.; Razvi, H.; Dave, S.; Reid, G.; Burton, J.P. The microbiome of the urinary tract—A role beyond infection. Nat. Rev. Urol. 2015, 12, 81–90. [Google Scholar] [CrossRef]
  75. Hsu, L.-N.; Hu, J.-C.; Chen, P.-Y.; Lee, W.-C.; Chuang, Y.-C. Metabolic Syndrome and Overactive Bladder Syndrome May Share Common Pathophysiologies. Biomedicines 2022, 10, 1957. [Google Scholar] [CrossRef] [PubMed]
  76. Nardos, R.; Leung, E.T.; Dahl, E.M.; Davin, S.; Asquith, M.; Gregory, W.T.; Karstens, L. Network-Based Differences in the Vaginal and Bladder Microbial Communities between Women with and without Urgency Urinary Incontinence. Front. Cell. Infect. Microbiol. 2022, 12, 759156. [Google Scholar] [CrossRef]
  77. Biggel, M.; Xavier, B.B.; Johnson, J.R.; Nielsen, K.L.; Frimodt-Møller, N.; Matheeussen, V.; Goossens, H.; Moons, P.; Van Puyvelde, S. Horizontally acquired papGII-containing pathogenicity islands underlie the emergence of invasive uropathogenic Escherichia coli lineages. Nat. Commun. 2020, 11, 5968. [Google Scholar] [CrossRef] [PubMed]
  78. Löffler, B.; Tuchscherr, L.; Niemann, S.; Peters, G. Staphylococcus aureus persistence in non-professional phagocytes. Int. J. Med. Microbiol. 2014, 304, 170–176. [Google Scholar] [CrossRef]
  79. Keogh, D.; Tay, W.H.; Ho, Y.Y.; Dale, J.L.; Chen, S.; Umashankar, S.; Williams, R.B.; Chen, S.L.; Dunny, G.M.; Kline, K.A. Enterococcal Metabolite Cues Facilitate Interspecies Niche Modulation and Polymicrobial Infection. Cell Host Microbe 2016, 20, 493–503. [Google Scholar] [CrossRef] [PubMed]
  80. Topi, S.; Bottalico, L.; Charitos, I.A.; Colella, M.; Di Domenico, M.; Palmirotta, R.; Santacroce, L. Biomolecular Mechanisms of Autoimmune Diseases and Their Relationship with the Resident Microbiota: Friend or Foe? Pathophysiology 2022, 29, 507–536. [Google Scholar] [CrossRef]
  81. Croxall, G.; Weston, V.; Joseph, S.; Manning, G.; Cheetham, P.; McNally, A. Increased human pathogenic potential of Escherichia coli from polymicrobial urinary tract infections in comparison to isolates from monomicrobial culture samples. J. Med. Microbiol. 2011, 60 Pt 1, 102–109. [Google Scholar] [CrossRef]
  82. Magruder, M.; Edusei, E.; Zhang, L.; Albakry, S.; Satlin, M.J.; Westblade, L.F.; Malha, L.; Sze, C.; Lubetzky, M.; Dadhania, D.M.; et al. Gut commensal microbiota and decreased risk for Enterobacteriaceae bacteriuria and urinary tract infection. Gut Microbes 2020, 12, 1805281. [Google Scholar] [CrossRef] [PubMed]
  83. Bottery, M.J.; Matthews, J.L.; Wood, A.J.; Johansen, H.K.; Pitchford, J.W.; Friman, V.-P. Inter-species interactions alter antibiotic efficacy in bacterial communities. ISME J. 2022, 16, 812–821. [Google Scholar] [CrossRef] [PubMed]
  84. Short, F.L.; Murdoch, S.L.; Ryan, R.P. Polybacterial human disease: The ills of social networking. Trends Microbiol. 2014, 22, 508–516. [Google Scholar] [CrossRef] [PubMed]
  85. Khan, F.U.; Ihsan, A.U.; Khan, H.U.; Jana, R.; Wazir, J.; Khongorzul, P.; Waqar, M.; Zhou, X. Comprehensive overview of prostatitis. Biomed. Pharmacother. 2017, 94, 1064–1076. [Google Scholar] [CrossRef] [PubMed]
  86. Miyake, M.; Ohnishi, K.; Hori, S.; Nakano, A.; Nakano, R.; Yano, H.; Ohnishi, S.; Owari, T.; Morizawa, Y.; Itami, Y.; et al. Mycoplasma genitalium Infection and Chronic Inflammation in Human Prostate Cancer: Detection Using Prostatectomy and Needle Biopsy Specimens. Cells 2019, 8, 212. [Google Scholar] [CrossRef]
  87. Salachan, P.V.; Rasmussen, M.; Fredsøe, J.; Ulhøi, B.; Borre, M.; Sørensen, K.D. Microbiota of the prostate tumor environment investigated by whole-transcriptome profiling. Genome Med. 2022, 14, 9. [Google Scholar] [CrossRef]
  88. Munteanu, R.; Feder, R.-I.; Onaciu, A.; Munteanu, V.C.; Iuga, C.-A.; Gulei, D. Insights into the Human Microbiome and Its Connections with Prostate Cancer. Cancers 2023, 15, 2539. [Google Scholar] [CrossRef]
  89. Salminen, S.; Collado, M.C.; Endo, A.; Hill, C.; Lebeer, S.; Quigley, E.M.M.; Sanders, M.E.; Shamir, R.; Swann, J.R.; Szajewska, H.; et al. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 649–667, Erratum in Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 551. [Google Scholar] [CrossRef]
  90. Shukla, S.; MacLennan, G.T.; Fu, P.; Patel, J.; Marengo, S.R.; Resnick, M.L.; Gupta, S. Nuclear Factor-κB/p65 (Rel A) Is Constitutively Activated in Human Prostate Adenocarcinoma and Correlates with Disease Progression. Neoplasia 2004, 6, 390–400. [Google Scholar] [CrossRef]
  91. Jain, S.; Suklabaidya, S.; Das, B.; Raghav, S.K.; Batra, S.K.; Senapati, S. TLR4 activation by lipopolysaccharide confers survival advantage to growth factor deprived prostate cancer cells. Prostate 2015, 75, 1020–1033. [Google Scholar] [CrossRef] [PubMed]
  92. Simons, B.W.; Durham, N.M.; Bruno, T.C.; Grosso, J.F.; Schaeffer, A.J.; E Ross, A.; Hurley, P.J.; Berman, D.M.; Drake, C.G.; Thumbikat, P.; et al. A human prostatic bacterial isolate alters the prostatic microenvironment and accelerates prostate cancer progression. J. Pathol. 2015, 235, 478–489. [Google Scholar] [CrossRef] [PubMed]
  93. Feng, Y.; Ramnarine, V.R.; Bell, R.; Volik, S.; Davicioni, E.; Hayes, V.M.; Ren, S.; Collins, C.C. Metagenomic and metatranscriptomic analysis of human prostate microbiota from patients with prostate cancer. BMC Genom. 2019, 20, 146. [Google Scholar] [CrossRef] [PubMed]
  94. Kopa, Z.; Wenzel, J.; Papp, G.K.; Haidl, G. Role of granulocyte elastase and interleukin-6 in the diagnosis of male genital tract inflammation. Andrologia 2005, 37, 188–194. [Google Scholar] [CrossRef] [PubMed]
  95. Russo, A.E.; Memon, A.; Ahmed, S. Bladder Cancer and the Urinary Microbiome—New Insights and Future Directions: A Review. Clin. Genitourin. Cancer, 2024; Epub ahead of print. [Google Scholar] [CrossRef]
  96. Inchingolo, F.; Santacroce, L.; Cantore, S.; Ballini, A.; Del Prete, R.; Topi, S.; Saini, R.; Dipalma, G.; Arrigoni, R. Probiotics and EpiCor® in human health. J. Biol. Regul. Homeost. Agents 2019, 33, 1973–1979. [Google Scholar] [CrossRef] [PubMed]
  97. Lev-Sagie, A.; Goldman-Wohl, D.; Cohen, Y.; Dori-Bachash, M.; Leshem, A.; Mor, U.; Strahilevitz, J.; Moses, A.E.; Shapiro, H.; Yagel, S.; et al. Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nat. Med. 2019, 25, 1500–1504. [Google Scholar] [CrossRef] [PubMed]
  98. Kim, S.-K.; Guevarra, R.B.; Kim, Y.-T.; Kwon, J.; Kim, H.; Cho, J.H.; Kim, H.B.; Lee, J.-H. Role of Probiotics in Human Gut Microbiome-Associated Diseases. J. Microbiol. Biotechnol. 2019, 29, 1335–1340. [Google Scholar] [CrossRef]
  99. Tkhruni, F.N.; Aghajanyan, A.E.; Balabekyan, T.R.; Khachatryan, T.V.; Karapetyan, K.J. Characteristic of Bacteriocins of Lactobacillus rhamnosus BTK 20-12 Potential Probiotic Strain. Probiotics Antimicrob. Proteins 2020, 12, 716–724. [Google Scholar] [CrossRef]
  100. van Hemert, S.; Meijerink, M.; Molenaar, D.; A Bron, P.; de Vos, P.; Kleerebezem, M.; Wells, J.M.; Marco, M.L. Identification of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood mononuclear cells. BMC Microbiol. 2010, 10, 293. [Google Scholar] [CrossRef]
  101. Santacroce, L.; Man, A.; Charitos, I.A.; Haxhirexha, K.; Topi, S. Current knowledge about the connection between health status and gut microbiota from birth to elderly. A narrative review. Front. Biosci. 2021, 26, 135–148. [Google Scholar] [CrossRef]
  102. Edwards, V.L.; Smith, S.B.; McComb, E.J.; Tamarelle, J.; Ma, B.; Humphrys, M.S.; Gajer, P.; Gwilliam, K.; Schaefer, A.M.; Lai, S.K.; et al. The Cervicovaginal Microbiota-Host Interaction Modulates Chlamydia trachomatis Infection. mBio 2019, 10, e01548-19. [Google Scholar] [CrossRef]
  103. Niu, X.-X.; Li, T.; Zhang, X.; Wang, S.-X.; Liu, Z.-H. Lactobacillus crispatus Modulates Vaginal Epithelial Cell Innate Response to Candida albicans. Chin. Med. J. 2017, 130, 273–279. [Google Scholar] [CrossRef]
  104. Man, A.; Ciurea, C.N.; Pasaroiu, D.; Savin, A.-I.; Toma, F.; Sular, F.; Santacroce, L.; Mare, A. New perspectives on the nutritional factors influencing growth rate of Candida albicans in diabetics. An in vitro study. Mem. Inst. Oswaldo. Cruz. 2017, 112, 587–592. [Google Scholar] [CrossRef]
  105. Petrova, M.I.; Imholz, N.C.E.; Verhoeven, T.L.A.; Balzarini, J.; Van Damme, E.J.M.; Schols, D.; Vanderleyden, J.; Lebeer, S. Lectin-Like Molecules of Lactobacillus rhamnosus GG Inhibit Pathogenic Escherichia coli and Salmonella Biofilm Formation. PLoS ONE 2016, 11, e0161337. [Google Scholar] [CrossRef] [PubMed]
  106. Karlsson, M.; Scherbak, N.; Khalaf, H.; Olsson, P.-E.; Jass, J. Substances released from probiotic Lactobacillus rhamnosus GR-1 potentiate NF-κB activity in Escherichia coli-stimulated urinary bladder cells. FEMS Immunol. Med. Microbiol. 2012, 66, 147–156. [Google Scholar] [CrossRef] [PubMed]
  107. Beerepoot, M.A.J.; ter Riet, G.; Nys, S.; van der Wal, W.M.; de Borgie, C.A.J.M.; de Reijke, T.M.; Prins, J.M.; Koeijers, J.; Verbon, A.; Stobberingh, E.; et al. Lactobacilli vs. antibiotics to prevent urinary tract infections: A randomized, double-blind, noninferiority trial in postmenopausal women. JAMA Intern. Med. 2012, 172, 704–712. [Google Scholar] [CrossRef] [PubMed]
  108. Groah, S.L.; Rounds, A.K.; Ljungberg, I.H.; Sprague, B.M.; Frost, J.K.; Tractenberg, R.E. Intravesical Lactobacillus rhamnosus GG is safe and well tolerated in adults and children with neurogenic lower urinary tract dysfunction: First-in-human trial. Ther. Adv. Urol. 2019, 11, 1756287219875594. [Google Scholar] [CrossRef] [PubMed]
  109. Kenneally, C.; Murphy, C.P.; Sleator, R.D.; Culligan, E.P. The urinary microbiome and biological therapeutics: Novel therapies for urinary tract infections. Microbiol. Res. 2022, 259, 127010. [Google Scholar] [CrossRef] [PubMed]
  110. Thomas, X.; Destoumieux-Garzón, D.; Peduzzi, J.; Afonso, C.; Blond, A.; Birlirakis, N.; Goulard, C.; Dubost, L.; Thai, R.; Tabet, J.-C.; et al. Siderophore Peptide, a New Type of Post-translationally Modified Antibacterial Peptide with Potent Activity. J. Biol. Chem. 2004, 279, 28233–28242. [Google Scholar] [CrossRef] [PubMed]
  111. Vassiliadis, G.; Destoumieux-Garzón, D.; Lombard, C.; Rebuffat, S.; Peduzzi, J. Isolation and characterization of two members of the siderophore-microcin family, microcins M and H47. Antimicrob. Agents Chemother. 2010, 54, 288–297. [Google Scholar] [CrossRef] [PubMed]
  112. Zdziarski, J.; Brzuszkiewicz, E.; Wullt, B.; Liesegang, H.; Biran, D.; Voigt, B.; Grönberg-Hernandez, J.; Ragnarsdottir, B.; Hecker, M.; Ron, E.Z.; et al. Host Imprints on Bacterial Genomes—Rapid, Divergent Evolution in Individual Patients. PLoS Pathog. 2010, 6, e1001078. [Google Scholar] [CrossRef]
  113. Roos, V.; Ulett, G.C.; Schembri, M.A.; Klemm, P. The Asymptomatic Bacteriuria Escherichia coli Strain 83972 Outcompetes Uropathogenic E. coli Strains in Human Urine. Infect. Immun. 2006, 74, 615–624. [Google Scholar] [CrossRef]
  114. Stork, C.; Kovács, B.; Rózsai, B.; Putze, J.; Kiel, M.; Dorn, Á.; Kovács, J.; Melegh, S.; Leimbach, A.; Kovács, T.; et al. Characterization of Asymptomatic Bacteriuria Escherichia coli Isolates in Search of Alternative Strains for Efficient Bacterial Interference against Uropathogens. Front. Microbiol. 2018, 9, 214. [Google Scholar] [CrossRef]
  115. Trautner, B.W.; Hull, R.A.; Thornby, J.I.; Darouiche, R.O. Coating Urinary Catheters with an Avirulent Strain of Escherichia coli as a Means to Establish Asymptomatic Colonization. Infect. Control. Hosp. Epidemiol. 2007, 28, 92–94. [Google Scholar] [CrossRef] [PubMed]
  116. Veziant, J.; Bonnet, M.; Occean, B.V.; Dziri, C.; Pereira, B.; Slim, K. Probiotics/Synbiotics to Reduce Infectious Complications after Colorectal Surgery: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Nutrients 2022, 14, 3066. [Google Scholar] [CrossRef]
  117. Bustamante, M.; Oomah, B.D.; Oliveira, W.P.; Burgos-Díaz, C.; Rubilar, M.; Shene, C. Probiotics and prebiotics potential for the care of skin, female urogenital tract, and respiratory tract. Folia Microbiol. 2020, 65, 245–264. [Google Scholar] [CrossRef] [PubMed]
  118. Baek, O.D.; Hjermitslev, C.K.; Dyreborg, L.; Baunwall, S.M.D.; Høyer, K.L.; Rågård, N.; Hammeken, L.H.; Povlsen, J.V.; Ehlers, L.H.; Hvas, C.L. Early Economic Assessment of Faecal Microbiota Transplantation for Patients with Urinary Tract Infections Caused by Multidrug-Resistant Organisms. Infect. Dis. Ther. 2023, 12, 1429–1436. [Google Scholar] [CrossRef] [PubMed]
  119. Hocquart, M.; Pham, T.; Kuete, E.; Tomei, E.; Lagier, J.C.; Raoult, D. Successful Fecal Microbiota Transplantation in a Patient Suffering From Irritable Bowel Syndrome and Recurrent Urinary Tract Infections. Open Forum Infect. Dis. 2019, 6, ofz398. [Google Scholar] [CrossRef] [PubMed]
  120. Malik, S.; Sidhu, P.K.; Rana, J.; Nehra, K. Managing urinary tract infections through phage therapy: A novel approach. Folia Microbiol. 2020, 65, 217–231. [Google Scholar] [CrossRef]
  121. Grygorcewicz, B.; Wojciuk, B.; Roszak, M.; Łubowska, N.; Błażejczak, P.; Jursa-Kulesza, J.; Rakoczy, R.; Masiuk, H.; Dołęgowska, B. Environmental Phage-Based Cocktail and Antibiotic Combination Effects on Acinetobacter baumannii Biofilm in a Human Urine Model. Microb. Drug Resist. 2021, 27, 25–35. [Google Scholar] [CrossRef]
  122. Chegini, Z.; Khoshbayan, A.; Vesal, S.; Moradabadi, A.; Hashemi, A.; Shariati, A. Bacteriophage therapy for inhibition of multi drug-resistant uropathogenic bacteria: A narrative review. Ann. Clin. Microbiol. Antimicrob. 2021, 20, 30. [Google Scholar] [CrossRef]
  123. Liao, K.; Lehman, S.; Tweardy, D.; Donlan, R.; Trautner, B. Bacteriophages are synergistic with bacterial interference for the prevention of Pseudomonas aeruginosa biofilm formation on urinary catheters. J. Appl. Microbiol. 2012, 113, 1530–1539. [Google Scholar] [CrossRef]
  124. Catte, A.; Ramaswamy, V.K.; Vargiu, A.V.; Malloci, G.; Bosin, A.; Ruggerone, P. Common recognition topology of mex transporters of Pseudomonas aeruginosa revealed by molecular modelling. Front. Pharmacol. 2022, 13, 1021916. [Google Scholar] [CrossRef]
  125. Leitner, L.; Ujmajuridze, A.; Chanishvili, N.; Goderdzishvili, M.; Chkonia, I.; Rigvava, S.; Chkhotua, A.; Changashvili, G.; McCallin, S.; Schneider, M.P.; et al. Intravesical bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: A randomised, placebo-controlled, double-blind clinical trial. Lancet Infect. Dis. 2021, 21, 427–436. [Google Scholar] [CrossRef]
  126. Magrone, T.; Russo, M.A.; Jirillo, E. Dietary Approaches to Attain Fish Health with Special Reference to their Immune System. Curr. Pharm. Des. 2018, 24, 4921–4931. [Google Scholar] [CrossRef]
  127. Nagy-Bota, M.C.; Man, A.; Santacroce, L.; Brinzaniuc, K.; Pap, Z.; Pacurar, M.; Pribac, M.; Ciurea, C.N.; Pintea-Simon, I.A.; Kovacs, M. Essential Oils as Alternatives for Root-Canal Treatment and Infection Control against Enterococcus faecalis—A Preliminary Study. Appl. Sci. 2021, 11, 1422. [Google Scholar] [CrossRef]
  128. Spencer, J.D.; Schwaderer, A.L.; Becknell, B.; Watson, J.; Hains, D.S. The innate immune response during urinary tract infection and pyelonephritis. Pediatr. Nephrol. 2014, 29, 1139–1149. [Google Scholar] [CrossRef] [PubMed]
  129. Hiratsuka, T.; Nakazato, M.; Ihi, T.; Minematsu, T.; Chino, N.; Nakanishi, T.; Shimizu, A.; Kangawa, K.; Matsukura, S. Structural Analysis of Human β-Defensin-1 and Its Significance in Urinary Tract Infection. Nephron 2000, 85, 34–40. [Google Scholar] [CrossRef] [PubMed]
  130. Chromek, M. The role of the antimicrobial peptide cathelicidin in renal diseases. Pediatr. Nephrol. 2015, 30, 1225–1232. [Google Scholar] [CrossRef] [PubMed]
  131. Zasloff, M. Antimicrobial Peptides, Innate Immunity, and the Normally Sterile Urinary Tract. J. Am. Soc. Nephrol. 2007, 18, 2810–2816. [Google Scholar] [CrossRef] [PubMed]
  132. Babikir, I.H.; Abugroun, E.A.; Bilal, N.E.; Alghasham, A.A.; Abdalla, E.E.; Adam, I. The impact of cathelicidin, the human antimicrobial peptide LL-37 in urinary tract infections. BMC Infect. Dis. 2018, 18, 17. [Google Scholar] [CrossRef] [PubMed]
  133. Gupta, S.; Jackson, A.; DaJusta, D.; McLeod, D.; Alpert, S.; Jayanthi, V.; McHugh, K.; Schwaderer, A.; Becknell, B.; Ching, C. Urinary antimicrobial peptides: Potential novel biomarkers of obstructive uropathy. J. Pediatr. Urol. 2018, 14, 238.e1–238.e6. [Google Scholar] [CrossRef]
  134. Mao, X.; Yao, R.; Guo, H.; Bao, L.; Bao, Y.; Xu, Y.; Sun, J.; Guo, S.; Shi, Y.; Liu, S.; et al. Polysaccharides extract from Vaccaria segetalis seeds inhibits kidney infection by regulating cathelicidin expression. J. Ethnopharmacol. 2021, 267, 113505. [Google Scholar] [CrossRef]
  135. Wang, Y. The Function of OmpA in Escherichia coli. Biochem. Biophys. Res. Commun. 2002, 292, 396–401. [Google Scholar] [CrossRef]
  136. Kandaswamy, K.; Liew, T.H.; Wang, C.Y.; Huston-Warren, E.; Meyer-Hoffert, U.; Hultenby, K.; Schröder, J.M.; Caparon, M.G.; Normark, S.; Henriques-Normark, B.; et al. Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis. Proc. Natl. Acad. Sci. USA 2013, 110, 20230–20235. [Google Scholar] [CrossRef]
  137. Fenner, A. Antimicrobial peptide derived from moths can eradicate UPEC biofilms and could offer a novel therapeutic option. Nat. Rev. Urol. 2020, 17, 191. [Google Scholar] [CrossRef] [PubMed]
  138. Cotter, P.D.; Ross, R.; Hill, C. Bacteriocins—A viable alternative to antibiotics? Nat. Rev. Genet. 2013, 11, 95–105. [Google Scholar] [CrossRef]
  139. Hirakawa, H.; Suzue, K.; Tomita, H. Roles of the Tol/Pal System in Bacterial Pathogenesis and Its Application to Antibacterial Therapy. Vaccines 2022, 10, 422. [Google Scholar] [CrossRef]
  140. Trautner, B.W. Management of catheter-associated urinary tract infection. Curr. Opin. Infect. Dis. 2010, 23, 76–82. [Google Scholar] [CrossRef]
  141. Roy, S.M.; Riley, M.A. Evaluation of the potential of colicins to prevent extraluminal contamination of urinary catheters by Escherichia coli. Int. J. Antimicrob. Agents 2019, 54, 619–625. [Google Scholar] [CrossRef]
  142. Trivedi, D.; Jena, P.K.; Seshadri, S. Colicin E2 Expression in Lactobacillus brevis DT24, A Vaginal Probiotic Isolate, against Uropathogenic Escherichia coli. ISRN Urol. 2014, 2014, 869610. [Google Scholar] [CrossRef]
  143. Field, D.; Hill, C.; Cotter, P.D.; Ross, R.P. The dawning of a ‘Golden era’ in lantibiotic bioengineering. Mol. Microbiol. 2010, 78, 1077–1087. [Google Scholar] [CrossRef]
  144. Healy, B.; Field, D.; O’connor, P.M.; Hill, C.; Cotter, P.D.; Ross, R.P. Intensive mutagenesis of the nisin hinge leads to the rational design of enhanced derivatives. PLoS ONE 2013, 8, e79563. [Google Scholar] [CrossRef]
  145. Yuan, J.; Zhang, Z.-Z.; Chen, X.-Z.; Yang, W.; Huan, L.-D. Site-directed mutagenesis of the hinge region of nisinZ and properties of nisinZ mutants. Appl. Microbiol. Biotechnol. 2004, 64, 806–815. [Google Scholar] [CrossRef] [PubMed]
  146. Santacroce, L.; Charitos, I.A.; Bottalico, L. A successful history: Probiotics and their potential as antimicrobials. Expert. Rev. Anti-Infect. Ther. 2019, 17, 635–645. [Google Scholar] [CrossRef] [PubMed]
  147. Kageyama, M.; Kobayashi, M.; Sano, Y.; Masaki, H. Construction and characterization of pyocin-colicin chimeric proteins. J. Bacteriol. 1996, 178, 103–110. [Google Scholar] [CrossRef] [PubMed]
  148. Gupta, S.; Bram, E.E.; Weiss, R. Genetically Programmable Pathogen Sense and Destroy. ACS Synth. Biol. 2013, 2, 715–723. [Google Scholar] [CrossRef] [PubMed]
  149. Rebuffat, S. Ribosomally synthesized peptides, foreground players in microbial interactions: Recent developments and unanswered questions. Nat. Prod. Rep. 2022, 39, 273–310. [Google Scholar] [CrossRef] [PubMed]
  150. Santacroce, L.; Imbimbo, C.; Ballini, A.; Crocetto, F.; Scacco, S.; Cantore, S.; Di Zazzo, E.; Colella, M.; Jirillo, E. Testicular Immunity and Its Connection with the Microbiota. Physiological and Clinical Implications in the Light of Personalized Medicine. J. Pers. Med. 2022, 12, 1335. [Google Scholar] [CrossRef] [PubMed]
  151. Rodríguez, E.; Laviña, M. The proton channel is the minimal structure of ATP synthase necessary and sufficient for microcin h47 antibiotic action. Antimicrob. Agents Chemother. 2003, 47, 181–187. [Google Scholar] [CrossRef] [PubMed]
  152. Patzer, S.I.; Baquero, M.R.; Bravo, D.; Moreno, F.; Hantke, K. The colicin G, H and X determinants encode microcins M and H47, which might utilize the catecholate siderophore receptors FepA, Cir, Fiu and IroN. Microbiology 2003, 149, 2557–2570. [Google Scholar] [CrossRef]
  153. Parker, J.K.; Davies, B.W. Microcins reveal natural mechanisms of bacterial manipulation to inform therapeutic development. Microbiology 2022, 168, 001175. [Google Scholar] [CrossRef]
  154. Piscotta, F.J.; Tharp, J.M.; Liu, W.R.; Link, A.J. Expanding the chemical diversity of lasso peptide MccJ25 with genetically encoded noncanonical amino acids. Chem. Commun. 2015, 51, 409–412. [Google Scholar] [CrossRef]
  155. Yu, H.; Ma, Z.; Meng, S.; Qiao, S.; Zeng, X.; Tong, Z.; Jeong, K.C. A novel nanohybrid antimicrobial based on chitosan nanoparticles and antimicrobial peptide microcin J25 with low toxicity. Carbohydr. Polym. 2021, 253, 117309. [Google Scholar] [CrossRef]
  156. Mydock-McGrane, L.; Cusumano, Z.; Han, Z.; Binkley, J.; Kostakioti, M.; Hannan, T.; Pinkner, J.S.; Klein, R.; Kalas, V.; Crowley, J.; et al. Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections. J. Med. Chem. 2016, 59, 9390–9408. [Google Scholar] [CrossRef]
  157. Ballini, A.; Charitos, I.A.; Cantore, S.; Topi, S.; Bottalico, L.; Santacroce, L. About Functional Foods: The Probiotics and Prebiotics State of Art. Antibiotics 2023, 12, 635. [Google Scholar] [CrossRef]
  158. Guiton, P.S.; Cusumano, C.K.; Kline, K.A.; Dodson, K.W.; Han, Z.; Janetka, J.W.; Henderson, J.P.; Caparon, M.G.; Hultgren, S.J. Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice. Antimicrob. Agents Chemother. 2012, 56, 4738–4745. [Google Scholar] [CrossRef] [PubMed]
  159. Spaulding, C.N.; Klein, R.D.; Ruer, S.; Kau, A.L.; Schreiber, H.L.; Cusumano, Z.T.; Dodson, K.W.; Pinkner, J.S.; Fremont, D.H.; Janetka, J.W.; et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 2017, 546, 528–532. [Google Scholar] [CrossRef] [PubMed]
  160. Han, Q.; Guo, M.; Zheng, Y.; Zhang, Y.; De, Y.; Xu, C.; Zhang, L.; Sun, R.; Lv, Y.; Liang, Y.; et al. Current Evidence of Interleukin-6 Signaling Inhibitors in Patients with COVID-19: A Systematic Review and Meta-Analysis. Front. Pharmacol. 2020, 11, 615972. [Google Scholar] [CrossRef] [PubMed]
  161. Wnorowska, U.; Piktel, E.; Durnaś, B.; Fiedoruk, K.; Savage, P.B.; Bucki, R. Use of ceragenins as a potential treatment for urinary tract infections. BMC Infect. Dis. 2019, 19, 369. [Google Scholar] [CrossRef] [PubMed]
  162. Krakowska, A.; Cedzyński, M.; Wosiak, A.; Swiechowski, R.; Krygier, A.; Tkaczyk, M.; Zeman, K. Toll-like receptor (TLR2, TLR4) polymorphisms and their influence on the incidence of urinary tract infections in children with and without urinary tract malformation. Central Eur. J. Immunol. 2022, 47, 260–266. [Google Scholar] [CrossRef]
  163. Lin, A.E.; Beasley, F.C.; Olson, J.; Keller, N.; Shalwitz, R.A.; Hannan, T.J.; Hultgren, S.J.; Nizet, V. Role of Hypoxia Inducible Factor-1α (HIF-1α) in Innate Defense against Uropathogenic Escherichia coli Infection. PLoS Pathog. 2015, 11, e1004818. [Google Scholar] [CrossRef] [PubMed]
  164. Qi, X.; Yun, C.; Sun, L.; Xia, J.; Wu, Q.; Wang, Y.; Wang, L.; Zhang, Y.; Liang, X.; Wang, L.; et al. Gut microbiota–bile acid–interleukin-22 axis orchestrates polycystic ovary syndrome. Nat. Med. 2019, 25, 1225–1233. [Google Scholar] [CrossRef] [PubMed]
  165. Sonnenberg, G.F.; Monticelli, L.A.; Alenghat, T.; Fung, T.C.; Hutnick, N.A.; Kunisawa, J.; Shibata, N.; Grunberg, S.; Sinha, R.; Zahm, A.M.; et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 2012, 336, 1321–1325. [Google Scholar] [CrossRef] [PubMed]
  166. Sabih, A.; Leslie, S.W. Complicated Urinary Tract Infections. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2023. [Google Scholar]
  167. Huttner, A.; Hatz, C.; Dobbelsteen, G.v.D.; Abbanat, D.; Hornacek, A.; Frölich, R.; Dreyer, A.M.; Martin, P.; Davies, T.; Fae, K.; et al. Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: A randomised, single-blind, placebo-controlled phase 1b trial. Lancet Infect. Dis. 2017, 17, 528–537. [Google Scholar] [CrossRef] [PubMed]
  168. Lorenzo-Gómez, M.F.; Padilla-Fernã¡Ndez, B.; Garcãa-Cenador, M.B.; Virseda-Rodrãguez, J.; Martãn-Garcãa, I.; Sã¡Nchez-Escudero, A.; Vicente-Arroyo, M.J.; Mirón-Canelo, J.A. Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections. Front. Cell. Infect. Microbiol. 2015, 5, 50. [Google Scholar] [CrossRef]
Pathophysiology 31 00005 g001
Figure 1. Composition of the urobiota in health and disease. In female urobiota, Lactobacillus spp. play a protective role against urinary pathogenic Escherichia coli (UPEC) strains via release of lactic acid and hydrogen peroxide, while Gardnerella vaginalis may cause a re-emergence of UPEC strains in experimental UTIs. In male urobiota, Propionibacterium acnes and Enterobacteriaceae and Actinobaculum urinale are associated with malignant and benign prostate tumor, respectively. Taken together, these data indicate the different roles of urobiota phyla, ranging from protection to induction of infections and/or tumors.
Figure 1. Composition of the urobiota in health and disease. In female urobiota, Lactobacillus spp. play a protective role against urinary pathogenic Escherichia coli (UPEC) strains via release of lactic acid and hydrogen peroxide, while Gardnerella vaginalis may cause a re-emergence of UPEC strains in experimental UTIs. In male urobiota, Propionibacterium acnes and Enterobacteriaceae and Actinobaculum urinale are associated with malignant and benign prostate tumor, respectively. Taken together, these data indicate the different roles of urobiota phyla, ranging from protection to induction of infections and/or tumors.
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Figure 2. Pathogenesis of UTIs. IBCS are endowed with more virulence and higher levels of resistance to antibiotics. In polymicrobial infections, secretion of L-ornithine causes overgrowth of UPECs and resistance to antibiotics, as in the case of catheter-associated UTIs. In prostate infections, secretion of LPSs maintains the chronicity of disease.
Figure 2. Pathogenesis of UTIs. IBCS are endowed with more virulence and higher levels of resistance to antibiotics. In polymicrobial infections, secretion of L-ornithine causes overgrowth of UPECs and resistance to antibiotics, as in the case of catheter-associated UTIs. In prostate infections, secretion of LPSs maintains the chronicity of disease.
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Figure 3. Bacteria and bacterial by-products as novel biotherapeutics. Probiotics and fecal microbiota transplantation are very active in preventing the risk of UTIs, outperforming uropathogens. Phages are active in combination with antibiotics or E. coli Hu2117 in the prevention of UTIs. Antimicrobial peptides and bacteriocins are bacterial by-products with microbicidal potential against uropathogens.
Figure 3. Bacteria and bacterial by-products as novel biotherapeutics. Probiotics and fecal microbiota transplantation are very active in preventing the risk of UTIs, outperforming uropathogens. Phages are active in combination with antibiotics or E. coli Hu2117 in the prevention of UTIs. Antimicrobial peptides and bacteriocins are bacterial by-products with microbicidal potential against uropathogens.
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Figure 4. Use of receptor antagonists, immune molecules, and vaccines in the prevention of UTIs. Mannosides prevent the binding of fimbriae to host cells, thus reducing the incidence of UTIs. LL-37, hypoxia-inducible factors, and IL-22 are immune molecules that are able to reduce the inflammatory infiltrate in the course of UTIs. ExPEC4V and Uromune vaccines are under investigation for the prevention of UTIs in women.
Figure 4. Use of receptor antagonists, immune molecules, and vaccines in the prevention of UTIs. Mannosides prevent the binding of fimbriae to host cells, thus reducing the incidence of UTIs. LL-37, hypoxia-inducible factors, and IL-22 are immune molecules that are able to reduce the inflammatory infiltrate in the course of UTIs. ExPEC4V and Uromune vaccines are under investigation for the prevention of UTIs in women.
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Jirillo, E.; Palmirotta, R.; Colella, M.; Santacroce, L. A Bird’s-Eye View of the Pathophysiologic Role of the Human Urobiota in Health and Disease: Can We Modulate It? Pathophysiology 2024, 31, 52-67. https://doi.org/10.3390/pathophysiology31010005

AMA Style

Jirillo E, Palmirotta R, Colella M, Santacroce L. A Bird’s-Eye View of the Pathophysiologic Role of the Human Urobiota in Health and Disease: Can We Modulate It? Pathophysiology. 2024; 31(1):52-67. https://doi.org/10.3390/pathophysiology31010005

Chicago/Turabian Style

Jirillo, Emilio, Raffaele Palmirotta, Marica Colella, and Luigi Santacroce. 2024. "A Bird’s-Eye View of the Pathophysiologic Role of the Human Urobiota in Health and Disease: Can We Modulate It?" Pathophysiology 31, no. 1: 52-67. https://doi.org/10.3390/pathophysiology31010005

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