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The Gut-Vagina-Bladder-Axis and UTIs

Here at Invivo Healthcare we are committed to raising awareness of under-discussed health complaints and the evidence-based microbiome solutions which can help individuals to live their lives to the full. Urinary tract infections (UTIs) are one such example. This article explores how nurturing the urinary microbiome via modulation of the gut-vagina-bladder axis holds great promise for improving the lives of many.


ecosystem
Urinary Tract Infections: The Problem

UTIs are one of the most common types of infection which pose a significant burden on the quality of life of millions1. They are eight times more prevalent in women than men and 50-60% of adult women will experience at least one uncomplicated UTI during their lifetime2,3. This common type of UTI drives a range of deeply uncomfortable symptoms, not least significant pain upon urination, blood in urine, and incontinence, in the absence of functional or anatomical impairment of the urinary tract or significant impairment of kidney function. There is a spike in prevalence during the years of maximum sexual activity which is usually between 18-39 years, as well as with increasing age to the degree that around 10% of postmenopausal women report having experienced a UTI episode during the previous year4. Other at-risk groups include infants, pregnant women, patients with catheters, and diabetics, to name just a few3. The societal need for effective solutions for the prevention and management of UTIs could not be more evident.

One of the most significant issues with uncomplicated UTIs is their propensity to become recurrent. Recurrent uncomplicated UTIs (rUTIs) involve the occurrence of two or more symptomatic episodes within six months or three or more within 12 months. In fact, around 30% of women experience a UTI recurrence within six months of their first episode4 and this can go on to put an immense burden on emotional as well as physical health, which is certainly what we see in clinical practice. An important observational study assessing the quality of life (QoL) impact of rUTIs found that 61.9% of patients (n=575) exhibited some degree of depression5. Another major cause of concern is the serious complications which can arise from UTIs, not least pyelonephritis (when the infection reaches the kidneys) and sepsis (when the infection reaches the blood), both of which require hospital admission and urgent treatment.

With the growing problem of antibiotic resistance, it is staggering to learn that around one in three women will experience at least one UTI treated with antibiotics by just 24 years of age3. With the treatment of UTIs so heavily dependent on antibiotics, complementary solutions with demonstrated efficacy for urinary tract health are a necessity and this is the conclusion of several researchers in the field1,2.

The Urinary Microbiome

It was long believed that the urinary tract was sterile except in the case of active infections, which we know to be driven by a range of uropathogens (microbes which cause infection of the urinary tract), including uropathogenic Escherichia coli (E. coli) (UPEC), Enterococcus faecalis, Proteus mirabilis, Staphylococcus saprophyticus, Pseudomonas aeruginosa, Klebsiella, and Candida albicans. Thanks to technological advancements, namely the development of next generation sequencing (NGS) DNA analysis, it is now understood that the urinary tract is inhabited by non-infection-associated micro-organisms too and actually has its own microbial community6,7. The urinary microbiome appears to be dominated by Lactobacillus, followed by other genera to a lesser degree, including Streptococcus, Staphylococcus, Corynebacteria, Escherichia, Aerococcus, and Gardnerella. While it is important to recognise that research into the urinary microbiome is still in its infancy, there is no doubt that the urinary microbiome has a formative impact on urinary tract health, for better or for worse8,9.

Introducing the Gut-Vagina-Bladder-Axis

We often talk about the crosstalk and interconnectedness between the different microbiome niches in the human body, primarily how the oral, vaginal, and gut microbiome influence each other and, in turn, the health of us, the human, in which these microbes reside. This is especially relevant when it comes to the urinary microbiome and the overall health of the urinary tract given the complex crosstalk that occurs via the gut-vagina-bladder axis10. The gut-kidney axis also exists, whereby gut dysbiosis can drive various renal disorders such as chronic kidney disease (CKD) and kidney stones10.

It is well-established that the gut microbiome can affect the health of most, if not all, organs within the human body11. This is certainly the case for the organs of the urinary tract. Composition of the gut microbiome can impact that of the urinary microbiome due to the ability of intestinal bacteria to translocate from the perianal region up towards the vagina and urethra12. A key example of this is E. coli and Enterococcus which have been identified in the gut microbiome of those prone to UTIs13–15. Intestinal uropathogens can translocate from the gut to the urinary tract after being shed in the faeces. They are able to ascend to the bladder following colonisation of the periurethral region and go on to grow and multiply after successful adhesion and colonisation of the bladder epithelium. Such translocation of bacteria might help to account for the increased prevalence of UTIs in women bearing in mind the close proximity of the urethra to the anus, the shortness of the female urethra, and the warm and moist environment of the perineum and vagina which may foster the overgrowth of uropathogenic bacteria16.

On the other side of the equation, a state of eubiosis in the gut (a balanced microbiome) with high relative abundance of two key commensal bacterial taxa – Faecalibacterium and Romboutsia – is associated with a decreased risk of UTIs, especially Enterobacter mediated17. Thus, the research available to date demonstrates that the gut microbiome can either have a protective or pathogenic effect on urinary tract health and is an important microbiome site to support for those prone to UTIs.

Moving now to the vagina-bladder axis, comparison of the vaginal and urinary microbiomes has shown that they significantly overlap, with Lactobacillus being the most abundant genus in both, followed by an overlap of other strains such as Gardnerella, Prevotella, and Ureaplasma18. It is therefore unsurprising that one of the most common vaginal health conditions, bacterial vaginosis (BV), is strongly associated with an increased risk of UTIs16.

BV is associated with an overgrowth of anaerobic bacteria, such as Gardnerella vaginalis, alongside a depleted Lactobacillus colony and an alkaline vaginal pH. Gardnerella vaginalis, for example, has been identified in the urinary microbiome of those with UTIs19. Animal studies have demonstrated the capacity of this strain to trigger damage to the bladder surface and re-activate latent E. coli and trigger an E. coli mediated rUTI20. Similar to the gut, the vaginal microbiome can therefore act as a reservoir for uropathogens, such as Gardnerella vaginalis, which can then ascend into the urinary tract. This finding is reinforced by the fact women with rUTIs usually have a high abundance of E. coli in their vaginal microbiome as well21.

Such crosstalk along the gut-vagina-bladder axis is likely mediated by prior disruption of protective Lactobacilli colonies which otherwise have a formative role in staving off opportunistic bacterial overgrowth in the gut, vaginal, and urinary microbiome. For instance, high relative abundance of Lactobacilli in the vaginal microbiome of postmenopausal women has been shown to reduce the risk of vaginal colonisation with E. coli,22 which may then confer a protective benefit against UTIs. Such depletion of Lactobacilli can be driven by various environmental and endogenous stimuli, ranging from low oestrogen during the menopause22 to antibiotic use,23 which disrupts these niches in the body and makes it easier for opportunistic bacteria to proliferate and migrate into the urinary tract.

How to Support the Gut-Vagina-Bladder Microbiome

…Recognizing factors that affect both the gut and vaginal microbiota is indispensable for understanding the pathogenesis of UTI, and designing interventions to prevent it.
Meštrović, T., et al (2020)10

We could not agree more. To support the prevention and management of UTIs, we need to restore balance to the urinary ecosystem by harmonising the gut-bladder-vagina axis. The following steps can be useful:

  • For those with rUTIs, conducting a microbiome test to comprehensively assess the vaginal and/or gut microbiome can be an important screening tool to detect reservoirs of UTI-implicated opportunistic microbes, such as E. coli, Enterococcus faecalis, and Gardnerella vaginalis. This can then pave the way for targeted microbiome interventions to bring balance back to these microbiome sites, as guided by a health professional, which might in turn help to re-balance the urinary microbiota.
  • There has been a lot of research attention into the potential benefit of targeted probiotic supplementation for reducing the risk of UTIs24,25. In vitro research has highlighted the ability of an oral probiotic blend consisting of L. plantarum W21, L. acidophilus W22, L. salivarius W24, L. casei W56, L. helveticus W74, L. pentosus W2 (KCA1), and L. brevis W63 to inhibit the growth of various uropathogens, including E. coli, C. albicans, S. aureus, and P. aeruginosa. This likely occurs via a wide range of mechanisms, including the production of antibacterial agents such as lactic acid, hydrogen peroxide, and bacteriocins, competition with uropathogens for attachment sites and nutrients, and strengthening the epithelial barrier to improve its resilience to infection.
  • Explore additional natural interventions to help inhibit adhesion of uropathogens to the lining of the urinary tract, including cranberry,2 D-mannose,26 and hibiscus27.
  • At the same time, it is imperative to identify and address the systemic drivers of low resilience of the urinary tract to infection. These include, but are not limited to, blood glucose dysregulation, low immunity, dehydration, and impaired structural integrity of the urothelium (lining of the urinary tract) which are arise due to a lack of oestrogen (e.g. during the menopause) and insufficient nutrient status, especially vitamin A, C, zinc, and vitamin D. Indeed, vitamin D has the ability to stimulate production of anti-microbial substances in the urinary epithelium, notably cathelicidin, when exposed to pathogenic bacteria which may help to strengthen the mucosal immunity of the urinary tract and make it more resilient to infection28,29.
References

  1. Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary tract infections [Internet]. Vol. 11, Therapeutic Advances in Urology. SAGE Publications Inc.; 2019 [cited 2021 Apr 19]. Available from: /pmc/articles/PMC6502976/
  2. Al-Badr A, Al-Shaikh G. Recurrent urinary tract infections management in women: A review [Internet]. Vol. 13, Sultan Qaboos University Medical Journal. Sultan Qaboos University; 2013 [cited 2021 Apr 21]. p. 359–67. Available from: /pmc/articles/PMC3749018/
  3. Foxman B. Epidemiology of urinary tract infections: Incidence, morbidity, and economic costs. Am J Med [Internet]. 2002 Jul 8 [cited 2021 Apr 21];113(1 SUPPL. 1):5–13. Available from: https://pubmed.ncbi.nlm.nih.gov/12113866/
  4. Alós JI. Epidemiology and etiology of urinary tract infections in the community. Antimicrobial susceptibility of the main pathogens and clinical significance of resistance. Enferm Infecc Microbiol Clin [Internet]. 2005 Dec 3 [cited 2021 Apr 19];23(SUPPL.4):3–8. Available from: https://pubmed.ncbi.nlm.nih.gov/16854352/
  5. Renard J, Ballarini S, Mascarenhas T, Zahran M, Quimper E, Choucair J, et al. Recurrent Lower Urinary Tract Infections Have a Detrimental Effect on Patient Quality of Life: a Prospective, Observational Study. Infect Dis Ther [Internet]. 2015 Mar 1 [cited 2021 Apr 19];4(1):125–35. Available from: https://pubmed.ncbi.nlm.nih.gov/25519161/
  6. Thomas-White K, Brady M, Wolfe AJ, Mueller ER. The Bladder Is Not Sterile: History and Current Discoveries on the Urinary Microbiome [Internet]. Vol. 11, Current Bladder Dysfunction Reports. Current Medicine Group LLC 1; 2016 [cited 2021 Apr 28]. p. 18–24. Available from: https://pubmed.ncbi.nlm.nih.gov/27182288/
  7. Whiteside SA, Razvi H, Dave S, Reid G, Burton JP. The microbiome of the urinary tract - A role beyond infection [Internet]. Vol. 12, Nature Reviews Urology. Nature Publishing Group; 2015 [cited 2021 Apr 28]. p. 81–90. Available from: https://pubmed.ncbi.nlm.nih.gov/25600098/
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  9. Bao Y, Al KF, Chanyi RM, Whiteside S, Dewar M, Razvi H, et al. Questions and challenges associated with studying the microbiome of the urinary tract [Internet]. Vol. 5, Annals of Translational Medicine. AME Publishing Company; 2017 [cited 2021 Apr 27]. Available from: /pmc/articles/PMC5300849/
  10. Meštrović T, Matijašić M, Perić M, Čipčić Paljetak H, Barešić A, Verbanac D. The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside. Diagnostics [Internet]. 2020 Dec 22 [cited 2021 Apr 29];11(1):7. Available from: https://pubmed.ncbi.nlm.nih.gov/33375202/
  11. Ahlawat S, Asha, Sharma KK. Gut–organ axis: a microbial outreach and networking [Internet]. Letters in Applied Microbiology. Blackwell Publishing Ltd; 2020 [cited 2021 Apr 29]. Available from: https://sfamjournals.onlinelibrary.wiley.com/doi/full/10.1111/lam.13333
  12. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options [Internet]. Vol. 13, Nature Reviews Microbiology. Nature Publishing Group; 2015 [cited 2021 Apr 19]. p. 269–84. Available from: https://pubmed.ncbi.nlm.nih.gov/25853778/
  13. Moreno E, Andreu A, Pigrau C, Kuskowski MA, Johnson JR, Prats G. Relationship between Escherichia coli strains causing acute cystitis in women and the fecal E. coli population of the host. J Clin Microbiol [Internet]. 2008 Aug [cited 2021 Apr 29];46(8):2529–34. Available from: https://pubmed.ncbi.nlm.nih.gov/18495863/
  14. Katouli M. Population structure of gut Escherichia coli and its role in development of extra-intestinal infections [Internet]. Vol. 2, Iranian Journal of Microbiology. Tehran University of Medical Sciences; 2010 [cited 2021 Apr 29]. p. 59–72. Available from: /pmc/articles/PMC3279776/
  15. Magruder M, Sholi AN, Gong C, Zhang L, Edusei E, Huang J, et al. Gut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection. Nat Commun [Internet]. 2019 Dec 1 [cited 2021 Apr 29];10(1):1–9. Available from: https://doi.org/10.1038/s41467-019-13467-w
  16. Sumati A, Saritha N. Association of urinary tract infection in women with bacterial vaginosis. J Glob Infect Dis [Internet]. 2009 [cited 2021 Apr 29];1(2):151. Available from: /pmc/articles/PMC2840952/
  17. Magruder M, Edusei E, Zhang L, Albakry S, Satlin MJ, Westblade LF, et al. Gut commensal microbiota and decreased risk for Enterobacteriaceae bacteriuria and urinary tract infection. Gut Microbes [Internet]. 2020 Nov 9 [cited 2021 Apr 29];12(1):1805281. Available from: https://www.tandfonline.com/doi/full/10.1080/19490976.2020.1805281
  18. Komesu YM, Dinwiddie DL, Richter HE, Lukacz ES, Sung VW, Siddiqui NY, et al. Defining the relationship between vaginal and urinary microbiomes. In: American Journal of Obstetrics and Gynecology [Internet]. Mosby Inc.; 2020 [cited 2021 Apr 29]. p. 154.e1-154.e10. Available from: http://www.ajog.org/article/S0002937819310105/fulltext
  19. Lewis AL, Gilbert NM. Roles of the vagina and the vaginal microbiota in urinary tract infection: evidence from clinical correlations and experimental models. GMS Infect Dis [Internet]. 2020 [cited 2021 Apr 29];8:Doc02. Available from: /pmc/articles/PMC7186798/
  20. Gilbert NM, O’Brien VP, Lewis AL. Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease. PLoS Pathog [Internet]. 2017 Mar 1 [cited 2021 Apr 29];13(3). Available from: https://pubmed.ncbi.nlm.nih.gov/28358889/
  21. Navas-Nacher EL, Dardick F, Venegas MF, Anderson BE, Schaeffer AJ, Duncan JL. Relatedness of Escherichia coli colonizing women longitudinally. Mol Urol [Internet]. 2001 [cited 2021 Apr 29];5(1):31–6. Available from: https://pubmed.ncbi.nlm.nih.gov/11689149/
  22. Pabich WL, Fihn SD, Stamm WE, Scholes D, Boyko EJ, Gupta K. Prevalence and Determinants of Vaginal Flora Alterations in Postmenopausal Women. J Infect Dis [Internet]. 2003 Oct 1 [cited 2021 Apr 29];188(7):1054–8. Available from: https://pubmed.ncbi.nlm.nih.gov/14513427/
  23. Georgieva R, Yocheva L, Tserovska L, Zhelezova G, Stefanova N, Atanasova A, et al. Antimicrobial activity and antibiotic susceptibility of Lactobacillus and Bifidobacterium spp. intended for use as starter and probiotic cultures. Biotechnol Biotechnol Equip [Internet]. 2015 [cited 2021 Apr 29];29(1):84–91. Available from: /pmc/articles/PMC4434095/
  24. Stapleton AE, Au-Yeung M, Hooton TM, Fredricks DN, Roberts PL, Czaja CA, et al. Randomized, placebo-controlled phase 2 trial of a lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis [Internet]. 2011 May 15 [cited 2021 Apr 29];52(10):1212–7. Available from: https://pubmed.ncbi.nlm.nih.gov/21498386/
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  26. Kranjčec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: A randomized clinical trial. World J Urol [Internet]. 2014 Feb [cited 2021 Apr 29];32(1):79–84. Available from: https://pubmed.ncbi.nlm.nih.gov/23633128/
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  28. Gombart AF. The vitamin D-antimicrobial peptide pathway and its role in protection against infection [Internet]. Vol. 4, Future Microbiology. NIH Public Access; 2009 [cited 2021 Apr 29]. p. 1151–65. Available from: /pmc/articles/PMC2821804/
  29. Chromek M, Slamová Z, Bergman P, Kovács L, Podracká L, Ehrén I, et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med [Internet]. 2006 Jun 4 [cited 2021 Apr 29];12(6):636–41. Available from: https://www.nature.com/articles/nm1407

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