Whole-Person Approach to Urinary Tract Infection: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Luciano Garofalo.

Urobiome dysbiosis, defined as an imbalance in the microbial composition in the microenvironments along the urinary tract, is found in women with uncomplicated urinary tract infection (UTI). Historically, antibiotics have been used to address UTI. An alternative approach to uncomplicated UTI is warranted as the current paradigm fails to take urobiome dysbiosis into account and contributes to the communal problem of resistance. A whole-person, multi-modal approach that addresses vaginal and urinary tract dysbiosis may be more effective in reducing recurrent UTI.

  • UTI
  • cystitis
  • dysbiosis
  • microbiome
  • microbiota
  • urinary tract
  • urinary tract infection
  • urobiome
  • vaginal microbiome
  • alternative medicine

1. Introduction

Each year approximately 97 million outpatient visits are associated with antibiotic prescriptions, more of which are given for urinary tract infection (UTI) than any other diagnosis [1,2][1][2]. Urine culture and sensitivity testing are not recommended as the standard of care in the clinical diagnosis of UTI [3], and the management protocol is often irrespective of any clearly identifiable pathogen. Research has shown that antibiotic use is associated with an increased risk of recurrent UTI [4]. Moreover, antibiotic use within the past six months is a contributing risk factor for harboring resistant uropathogen isolates [5] and can facilitate cross-resistance when prescribed alongside non-antibiotics [6].
Trimethoprim–sulfamethoxazole (TMP–SMX) was recommended as first-line therapy in the treatment of acute uncomplicated bacterial cystitis by the Infectious Diseases Society of America guideline released in 2011 [7]. However, as TMP–SMX resistance has since escalated to a pooled worldwide average of 23.6% [8], providers may resort more to fluoroquinolones, causing an increase in the incidence of fluoroquinolone resistance among uropathogens, including ciprofloxacin-resistant Escherichia coli [9]. Fluoroquinolone resistance begets increasingly more dangerous infections such as hospital-acquired pneumonia and complicated UTI [10]. Exposure to fluoroquinolones has been associated with a more than 6-fold increased risk of acquiring C. difficile colitis [11]. Comparatively, patients who received TMP–SMX had a 2-fold higher risk of C. difficile colitis [11]. As the rates of incidence, recurrence, and therapeutic resistance of UTI rise, UTI treatment recommendations continue to evolve as part of the wider antibiotic stewardship effort.
Investigations into the efficacy of alternative therapies such as botanicals and probiotics have mostly been reduction-based, focusing on the impact of the substitute intervention on a singular physiological system in isolation. Many botanicals possess active constituents with antimicrobial properties or anti-adhesive effects that can aid in the treatment of UTI; however, more attention should be given to the complex mechanisms of action of complementary therapies as an integrative approach to Whole-Person Health (WPH).

1.1. Prevalence

UTI accounts for upwards of 10.5 million visits to physician offices and emergency departments per year and represents a significant portion of ambulatory healthcare costs [13][12]. UTI disproportionately affects women, with half of all women self-reporting at least one UTI by age 32 and 20–30% of women experiencing a second UTI within six months of initial infection [14][13]. These estimates do not include asymptomatic bacteriuria (ABU), occurring in 1% of schoolgirls, ≥2% of pregnant women, and about 20% of elderly individuals of both sexes [15][14]. Asymptomatic bacteriuria (ASB) is defined as the presence of ≥105 colony-forming units per mL of one or more bacterial species, irrespective of pyuria, in a urine specimen from a patient without signs or symptoms of UTI [16][15].

1.2. Pathophysiology

Infection typically begins when coliform bacteria contaminate the periurethral area and colonize the urethra through the expression of virulence and adhesion factors. From there, infection ascends to the bladder where bacterial multiplication is accomplished through the release of toxins and proteases that feed off host nutrients and instigate an inflammatory response [17][16]. By evading host immune surveillance, uropathogens can subsequently ascend to the kidneys, again attaching via adhesins or pili to colonize the renal epithelium and then produce tissue-damaging toxins [18][17].

1.3. Diagnostic Criteria

UTIs are categorized as either uncomplicated (simple) or complicated. Simple UTI, or simple cystitis, occurs primarily in otherwise healthy females of childbearing age. The prominent risk factors are prior UTI, new sexual partners (within the last year), vaginal infection, prolonged withholding of urine, and use of diaphragms or spermicides [19][18]. Complicated UTI is characterized by factors that disturb normal structure and function of the urinary tract, including indwelling catheters, anatomic variations or history of surgery in the urinary tract, renal insufficiency, neurogenic bladder, diabetes, pregnancy, and immunocompromised state (drug-induced, inherited, etc.). UTI in males is much less common and generally categorized as complicated [20][19].

1.4. Cystitis as a Spectrum of Etiologies

Lower urinary tract symptoms can present similarly for a variety of non-infectious urological disorders as well as UTI. Chronic bladder inflammation is subject to central sensitization and can have a variety of host- or environmentally mediated triggers [21][20]. For this reason, it can be difficult to distinguish bacterial infection from interstitial cystitis or other non-infectious etiologies in the primary care setting, especially for UTI that is considered recurrent or chronic. As a result, many patients with cystitis of non-infectious etiology receive unnecessary antibiotic prescriptions.
Bacteriuria in the absence of symptoms does not justify antibiotic prescription unless in a pregnant female [22][21]. Uropathogenic bacteria are found with increasing frequency in the urine as patients age due to compounding factors such as menopause, immunosenescence, and recurrent colonization by drug-resistant bacteria. These changes influence the urobiome and the etiology of cystitis, thus indicating different treatment approaches for older versus younger females [23][22]. ABU is common in the elderly and treating it with antibiotics is no longer recommended due to both a lack of mortality benefit and harm of antibiotic overuse [24][23].
Innate immunity, barrier defenses, and the urobiome may play more of a role than specific immunity in protecting the urinary tract from infection [25][24]. The urinary tract, and especially the bladder, has several physical, chemotactic, and immune-mediated barriers to infection. The urogenital epithelium is turned over at a high rate relative to other tissue due in part to the regular passing of acidic urine as well as the local immune system’s normal function. At a normal pH of 5.5 or less, urine helps discourage bacterial growth, and mucosal tissue in the urinary tract produces organic acids to combat pathogens. Unlike the body’s typical Th1-dominant response to bacterial invasion, the uroepithelium produces a Th2-dominant response, allowing for quicker overturn of compromised uroepithelium but generating progressively weaker bactericide and bacteriostasis [26][25].
Thus, the syndrome of cystitis, whether or not it is accompanied by a bacterial infection, can have one or several compounding etiologies (e.g., infection, dysbiosis, uroepithelial dysfunction, or central sensitization). These can be difficult to assess accurately in the clinical setting, especially for chronic and recurrent cases. Antibiotics can address pathogen overgrowth and resulting inflammation; however, they may also exacerbate dysbiosis, drive resistance, or contribute to the imbalance of other systems.

1.5. The Urobiome

The urinary tract has a microbiome whose taxa is similar to that of the gut, with Lactobacillus being the most commonly occurring species [27,28,29][26][27][28]. Alterations in the urinary microbiota have been linked to non-infectious urologic diseases, such as neurogenic bladder dysfunction, interstitial cystitis, and urgency urinary incontinence [30][29]. Urine from patients with interstitial cystitis exhibits lower bacterial diversity and a higher abundance of Lactobacillus when compared to healthy controls [31][30]. These findings suggest that some cases of “suspected UTI” could be symptomatic expressions of microbial dysbiosis, which might only be exacerbated by antibiotics. Additionally, the use of low-dose, prophylactic antibiotics to prevent recurrent infection could further contribute to pathogenic resistance evolution by creating bacterial persister cells. Persister cells are genetically similar to previous generations but exhibit a greater fitness and virulence, which serves to optimize their permanent colonization in the indigenous microbial environment [32][31].
Advancements in metagenomics have allowed us to explore the gut microbiome as a potential reservoir for resistant pathogens. The high alpha diversity of microbiota within this ecosystem easily facilitates the horizontal transfer of antimicrobial resistance genes to susceptible pathogens. The concept of this “resistome” may offer more knowledge beyond the epidemiologic considerations of clinical isolates alone [33][32]. The intestinal microbiota composition varies between different niche environments along the length of the digestive tract, influencing metabolism, intestinal epithelial cell proliferation and permeability, and modulating the immune response, either directly or through crosstalk. As such, dysbiosis of the gut microbiome has been linked to a multitude of diseases beyond the intestinal environment, including many in the urinary tract. Moreover, microbial metabolites in the gut and other organs distal to the kidneys, bladder, and urethra are likely to influence the urinary microbiome and its homeostasis [34][33].
Metabolomic assay analysis suggests that species population may not be as important as the resultant metabolic pathways created [35][34]. Individual populations can differ in composition but perform the same functions to preserve environmental homeostasis. Recurrent UTI may be associated with an inability to reconstitute the normal microbiota, either as a result of long-term antibiotic use or other underlying host factors [36][35]. Ideally, microbial diversity allows for sustained essential metabolic activity within the microenvironment. A microbiome consisting of multiple species of bacteria with the ability to perform the same functions serves as an insurance policy against bacterial death due to pharmaceutical and environmental disturbances.

2. Whole-Person Approach to UTI

While up to 50% of uncomplicated cystitis cases spontaneously resolve within one week [37][36], medical attention and intervention are still important. In addition to the risk of worsening infection such as pyelonephritis, symptoms may take longer to clear without treatment and the length of time to symptom resolution is not tolerable for many patients [38][37]. Trials have compared ibuprofen alone to antibiotics and other therapies, hypothesizing that palliating symptoms will make the natural resolution of cystitis more tolerable and spare antibiotic usage [39,40][38][39]. While infection may resolve at similar rates when using ibuprofen compared to antibiotics, higher symptom burden and incidence of pyelonephritis are still consequences that require consideration [41][40].
These challenges elucidate the need for alternative therapies that provide symptomatic relief, have antipathogenic properties, and do not perpetuate recurrent infection. Investigations into the microbial diversity and population of the urobiome between healthy individuals and those with acute bacterial cystitis have prompted an interest in probiotic supplementation as a therapy for recurrent cystitis [42][41]. Several botanical and nutritional therapies, many of which originated in traditional medicine systems, have gained attention as promising alternative therapeutic models for cystitis. While most antibiotics employ a single pharmacologic mechanism to fight bacteria, botanicals generally contain a complex array of phytochemicals that have evolved in response to diverse threats, possibly yielding robustness against the development of targeted resistance [43][42]. Finally, urogenital hygiene and hydration are significant yet clinically undervalued contributors to urinary tract health that can be leveraged through behavioral interventions [44][43]. Altogether, these alternative approaches may be combined to target several mechanisms of action and address compounding etiologies for both acute and recurrent/chronic cystitis (see Table 1).
Table 1. Whole-Person Approach to Uncomplicated UTI and Urobiome Health.

Therapy

Strategy

Mechanism

References

Lactobacillus spp.

(Probiotics)

Decrease pathogenic bacteria by competing with pathogenic microbes for nutrients and space;

May provide healthy microbial metabolites.

Urobiome support

Anti-adhesion

Anti-inflammatory

[45,46,47,48,49,50,51]

[44][45][46][47][48][49][50]

D-mannose

Inhibits pathological bacterial adhesion to uro-epithelium.

Anti-adhesion

[52,5153,54,][5255,][5356,57]

[][54][55][56]

Cranberry

Increases growth of beneficial bacteria and decreases growth of pathogenic bacteria.

Urobiome support

Anti-adhesion

Anti-septic

Anti-inflammatory

Diuresis

[58,59,60,61,62,63,64,65,66,67,68,69,70,71]

[57][58][59][60][61][62][63][64][65][66][67][68][69][70]

Arctostaphylos uva-ursi

Increases urine flow to decrease pathogenic bacteria.

Anti-septic

Anti-inflammatory

Diuresis

[72,73,74,75,76,77,78,79]

[71][72][73][74][75][76][77][78]

Sexual hygiene & Contraception choice

Slow contamination.

Anti-contamination

pH level maintenance

[80,81,82]

[79][80][81]

Hydration

Increases urine flow to clear pathogenic bacteria.

Urobiome support

Anti-contamination

Diuresis

pH level maintenance

[83]

[82]

Diet

Increase growth of beneficial bacteria; slow contamination; decrease growth and adhesion of pathogens

Anti-contamination

Urobiome support

Anti-inflammatory

Anti-adhesion

[84,85,86,87,88,89,90,91,92]

[83][84][85][86][87][88][89][90][91]

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