Urinary discomfort vs cystitis [1]

By “urinary discomfort” is meant any infection of the urinary system without complication, manifesting in healthy individuals and without associated additional sensitivity factor. Discomfort or urinary tract infection most commonly results from bacterial infections, and mainly affects adults.

Cystitis is a urinary tract infection giving rise to inflammation precisely localized in the bladder. While it can cause significant discomfort, it is usually not serious and its symptoms are characteristic: a burning sensation, low urine volume (pollakiuria) and recurrence of the urge to urinate. It is important to treat it quickly before it goes to the kidneys, making the symptoms more acute, and possibly causing fever and back pain. For this, various treatments with proven effectiveness exist.

We essentially identify 2 types of cystitis:

• simple acute cystitis (without additional sensitivity factor),
• acute cystitis at risk of complications, which include at least one factor of sensitivity (such as pregnancy or menopause in women, or even diabetes).

Simple acute cystitis can be referred to as acute relapsing cystitis when a person experiences at least 3-4 episodes in a year. To limit such recurrences, it is important to ensure good prevention and to understand to whom this public health concern is addressed.

Origin of urinary discomfort [1–3]

The urinary system is made up of our two kidneys connected to the bladder by two ureters. The bladder is also connected to the urethra, which is the outlet for urine.

This system naturally has defense mechanisms against the invasion of pathogens, and therefore against infections.

In more than 70% of cases, urinary discomfort results from a bacterial infection by a specific community: Enterobacteriaceae, and more particularly Escherichia coli (E. coli). This bacteria naturally present in the digestive tract (colon, rectum) can enter the urethra, then rise up into the bladder and adhere to the walls of the bladder causing inflammation and symptoms associated with a urinary tract infection.

An essentially feminine manifestation [3,4]

It is the anatomical differences between men and women that make women more prone to UTIs. From an anatomical point of view, the urethra of women is shorter than that of men (see diagram), but also closer to the vagina and rectum, places of natural presence of bacteria. Other factors: sex and pregnancy can also promote urinary tract infections and cystitis. The frequency of cystitis is important in women, and particularly in women of childbearing age. It is estimated that 50 to 60% of women (at least 1 in 2 women!) Contract some manifestation of urinary discomfort during their lifetime, and about 40% develop a second one within a year of the first. Some women are even prone to recurrent cystitis (3 to 4 repeats per year). Two frequency peaks are generally observed: at the start of sexual activity and after menopause with the drop in estrogen.

Solutions and associated issues

To resolve cystitis, antibiotic treatments remain to this day the most effective means from a therapeutic point of view. But faced with the emergence of antibiotic resistance [5] and the potential effect of antibiotics on the microbiota, alternative approaches are increasingly being studied [6,7] to limit recurrence without resorting to antibiotics, such as:

• Reduce the frequency of the use of antibiotics,
• Veiller à maintenir une  flore bactérienne saine pour préserver des défenses efficaces contre les pathogènes.

There are good practices published by the Haute Autorité de Santé (HAS) related to the management of cystitis [8] aimed at specifying the appropriate antibiotic treatments according to the levels of intention.

Today, non-drug prophylactic (prevention) methods for the fight against cystitis are well referenced and documented by the scientific community.

What the Research says about natural prevention alternatives

The problem of urinary discomfort in women represents such a cost to public health that the study of alternatives to prevent recurrence was initiated several years ago. At the same time, urology organizations are also working to promote potential solutions through active research on certain ingredients. Among the most cited in reference, we find cranberry (or cranberry, in French) and D-mannose [9–12]:

Cranberry
The cranberry (Vaccinium macrocarpon), also called `` american cranberry '', great lingonberry, or cranberry, is a berry particularly known for its many health benefits thanks to its content of polyphenols, in particular of the class of proanthocyanidins of the type A (category flavan-3-ols). Proanthocyanidins carry the acronym of PACs (a reference indication put forward on nutraceuticals). Among its interesting properties, cranberries may interfere with the adhesion of bacteria, acting locally in the urine [13,14]. In 2014, a clinical analysis of taking cranberry extract established the effectiveness of a standard daily dose of 36 mg of PACs [15]. A more recent meta-analysis also made it possible to conclude positively on the relevance of cranberry [16]. This compilation work highlights an important point on the perfect tolerance of the daily intake of extract standardized to 36 mg of PACs. It is important to note that the principle of standardization only applies to specific extracts, and does not apply to other types of preparations such as cranberry juice. Finally, validating the exact PAC concentration of an extract requires a reference methodology validated and institutionalized by major regulatory authorities: this is the method called BL-DMAC [17].

D-mannose  [18–20]
D-Mannose is a monosaccharide, a sugar, naturally present in the body. It is also found in our diet, especially in fruits such as cranberries. Although D-mannose is a simple sugar (like glucose), however, it is not metabolized by the body. Indeed, pharmacokinetic data on the ingestion of D-mannose has shown that at least 90% of this sugar is absorbed and reaches the bloodstream and ends up intact in the urine. Its urinary excretion is linked to its local mechanistic effects: by binding to certain pathogens such as E.coli, D-mannose would limit its adhesion to the mucosa. The compilation of clinical studies also proves the very good tolerance and efficacy of D-mannose in the form of a daily oral intake of 2 g and more.

Nutri&Co's choice

Like all of our formulas, this is of course the effectiveness that we aim for with our Cranberry Mannose formula. To effectively combat urinary discomfort, we have opted for a combination of 4 judiciously developed active ingredients:

1. High dosages without concession in reference ingredients:
   1. High dosages without concession in reference ingredients:
      
      • The patented cranberry / cranberry extract, Urophenol®, is highly specific thanks to its polyphenol profile (use of whole cranberry fruit) and the variety from which it is derived. It is supported by its own clinical study [21] based on a unique and original protocol [22], comparing the efficacy of the extract at 36 mg of PACs versus an extract with very low PACS content (2 mg). This extract therefore goes further than a simple cranberry juice low in PACs: a total of 240 mg of an extract standardized to 36 mg of PACs and analyzed according to the official BL-DMAC method that we have put in our formula,
      • Another proven ingredient: D-mannose, which we have chosen to dose at 4 g daily, which is double the smallest dose with clinically proven effectiveness. Thus, 1 single daily stick already provides the minimum effective dose of D-mannose of 2 g.
   2. 2 other extracts with additional benefits :
      
      • An extract of hibiscus flower (Hibiscus sadbariffa): the ElliroseTM extract which presents, thanks to its patented extraction process, a particular profile in organic acids (> 40%) and polyphenols (> 45%), including 'swimming pool, and known for their antimicrobial activity. In preliminary studies, analysis of the bioavailability of ElliroseTM has shown that its compounds are found intact in the urine. More recently, a clinical study was conducted on 40 women with recurrent urinary tract infections treated with 200 mg of ElliroseTM per day. The results showed that after 3 months of use, the women not only exhibited very good tolerance to the extract, but above all an improvement in the functioning of the urinary tract [23], and therefore restored urinary comfort.
      • Pomegranate extract (Punica granatum): the selected pomegranate fruit extract, Pomanox®, is patented and standardized in punicalagins (> 30%), including ellagitannins with ellagic acid. Ellagic acid is known to be metabolized in the body by the microbiota to form urolithins A and B. At the urinary level, the pomegranate seems interesting for its antibacterial activity [24–27].
   3. A format designed for optimal efficiency :
      
      • A powder formula to be diluted which encourages and promotes water intake: the first hygienic and dietary rule to apply in the event of urinary discomfort.
      • Sticks that are easy and practical to use and transport on a daily basis and which allow us a formula with a high dosage of active ingredients (which would have been impossible in the form of capsules).
      • A natural cherry flavoring to make it easier to set, and last until the end of 10 days.
      • The entire effective dose in 1 single box: 20 sticks for 10 days of intake (2 stickers per day).

   Publications

1. Wagenlehner, F.M.E.; Bjerklund Johansen, T.E.; Cai, T.; Koves, B.; Kranz, J.; Pilatz, A.; Tandogdu, Z. Epidemiology, Definition and Treatment of Complicated Urinary Tract Infections. Nat. Rev. Urol. 2020, 17, 586–600, doi:10.1038/s41585-020-0362-4.
2. 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, doi:10.1038/nrmicro3432.
3. Medina, M.; Castillo-Pino, E. An Introduction to the Epidemiology and Burden of Urinary Tract Infections. Ther. Adv. Urol. 2019, 11, 175628721983217, doi:10.1177/1756287219832172.
4. Foxman, B.; Barlow, R.; D’Arcy, H.; Gillespie, B.; Sobel, J.D. Urinary Tract Infection: Self-Reported Incidence and Associated Costs. 2000, 10, 7.
5. Zowawi, H.M.; Harris, P.N.A.; Roberts, M.J.; Tambyah, P.A.; Schembri, M.A.; Pezzani, M.D.; Williamson, D.A.; Paterson, D.L. The Emerging Threat of Multidrug-Resistant Gram-Negative Bacteria in Urology. Nat. Rev. Urol. 2015, 12, 570–584, doi:10.1038/nrurol.2015.199.
6. Colgan, R.; Williams, M. Diagnosis and Treatment of Acute Uncomplicated Cystitis. 2011, 84, 6.
7. Foxman, B.; Buxton, M. Alternative Approaches to Conventional Treatment of Acute Uncomplicated Urinary Tract Infection in Women. Curr. Infect. Dis. Rep. 2013, 15, 124–129, doi:10.1007/s11908-013-0317-5.
8. HAS Cystite Aiguë Simple, à Risque de Complication Ou Récidivante, de La Femme Available online: https://www.has-sante.fr/jcms/c_2722827/fr/cystite-aigue-simple-a-risque-de-complication-ou-recidivante-de-la-femme.
9. AFU CYSTITES RÉCIDIVANTES : DES MOYENS DE PRÉVENTION NON MÉDICAMENTEUX Available online: https://www.urofrance.org/base-bibliographique/cystites-recidivantes-des-moyens-de-prevention-non-medicamenteux.
10. Costantini, E.; Giannitsas, K.; Illiano, E. The Role of Nonantibiotic Treatment of Community-Acquired Urinary Tract Infections. Curr. Opin. Urol. 2017, 27, 120–126, doi:10.1097/MOU.0000000000000366.
11. Cai, T.; Tamanini, I.; Kulchavenya, E.; Perepanova, T.; Köves, B.; Wagenlehner, F.M.E.; Tandogdu, Z.; Bonkat, G.; Bartoletti, R.; Bjerklund Johansen, T.E. The Role of Nutraceuticals and Phytotherapy in the Management of Urinary Tract Infections: What We Need to Know? Arch. Ital. Urol. E Androl. 2017, 89, 1, doi:10.4081/aiua.2017.1.1.
12. Loubet, P.; Ranfaing, J.; Dinh, A.; Dunyach-Remy, C.; Bernard, L.; Bruyère, F.; Lavigne, J.-P.; Sotto, A. Alternative Therapeutic Options to Antibiotics for the Treatment of Urinary Tract Infections. Front. Microbiol. 2020, 11, 1509, doi:10.3389/fmicb.2020.01509.
13. Blumberg, J.B.; Camesano, T.A.; Cassidy, A.; Kris-Etherton, P.; Howell, A.; Manach, C.; Ostertag, L.M.; Sies, H.; Skulas-Ray, A.; Vita, J.A. Cranberries and Their Bioactive Constituents in Human Health. Adv. Nutr. 2013, 4, 618–632, doi:10.3945/an.113.004473.
14. González de Llano, D.; Liu, H.; Khoo, C.; Moreno-Arribas, M.V.; Bartolomé, B. Some New Findings Regarding the Antiadhesive Activity of Cranberry Phenolic Compounds and Their Microbial-Derived Metabolites against Uropathogenic Bacteria. J. Agric. Food Chem. 2019, 67, 2166–2174, doi:10.1021/acs.jafc.8b05625.
15. Jepson, R.G.; Williams, G.; Craig, J.C. Cranberries for Preventing Urinary Tract Infections. Cochrane Database Syst. Rev. 2012, doi:10.1002/14651858.CD001321.pub5.
16. Fu, Z.; Liska, D.; Talan, D.; Chung, M. Cranberry Reduces the Risk of Urinary Tract Infection Recurrence in Otherwise Healthy Women: A Systematic Review and Meta-Analysis. J. Nutr. 2017, 147, 2282–2288, doi:10.3945/jn.117.254961.
17. Haesaerts, G. Le dosage des proanthocyanidines (PAC) de cranberry dans les compléments alimentaires: enjeux et derniers développements. Phytothérapie 2010, 8, 218–222, doi:10.1007/s10298-010-0575-4.
18. Altarac, S.; Papeš, D. Use of D-Mannose in Prophylaxis of Recurrent Urinary Tract Infections (UTIs) in Women: Comment. BJU Int. 2014, 113, 9–10, doi:10.1111/bju.12492.
19. De Nunzio, C.; Bartoletti, R.; Tubaro, A.; Simonato, A.; Ficarra, V. Role of D-Mannose in the Prevention of Recurrent Uncomplicated Cystitis: State of the Art and Future Perspectives. Antibiotics 2021, 10, 10.
20. Scaglione, F.; Musazzi, U.M.; Minghetti, P. Considerations on D-Mannose Mechanism of Action and Consequent Classification of Marketed Healthcare Products. Front. Pharmacol. 2021, 12, 636377, doi:10.3389/fphar.2021.636377.
21. Babar, A.; Moore, L.; Leblanc, V.; Dudonné, S.; Desjardins, Y.; Lemieux, S.; Bochard, V.; Guyonnet, D.; Dodin, S. High Dose versus Low Dose Standardized Cranberry Proanthocyanidin Extract for the Prevention of Recurrent Urinary Tract Infection in Healthy Women: A Double-Blind Randomized Controlled Trial. BMC Urol. 2021, 21, 44, doi:10.1186/s12894-021-00811-w.
22. Asma, B.; Vicky, L.; Stephanie, D.; Yves, D.; Amy, H.; Sylvie, D. Standardised High Dose versus Low Dose Cranberry Proanthocyanidin Extracts for the Prevention of Recurrent Urinary Tract Infection in Healthy Women [PACCANN]: A Double Blind Randomised Controlled Trial Protocol. BMC Urol. 2018, 18, 29, doi:10.1186/s12894-018-0342-7.
23. Allaert, F.A. Prevention of Recurrent Cystitis in Women: Double-Blind, Placebo- Controlled Study of Hibiscus Sabdariffa L. Extract. Lett. L’Infectiologue 2010, 5.
24. Espín, J.C.; González-Barrio, R.; Cerdá, B.; López-Bote, C.; Rey, A.I.; Tomás-Barberán, F.A. Iberian Pig as a Model To Clarify Obscure Points in the Bioavailability and Metabolism of Ellagitannins in Humans. J. Agric. Food Chem. 2007, 55, 10476–10485, doi:10.1021/jf0723864.
25. Howell, A.B.; D’Souza, D.H. The Pomegranate: Effects on Bacteria and Viruses That Influence Human Health. Evid. Based Complement. Alternat. Med. 2013, 2013, 1–11, doi:10.1155/2013/606212.
26. Zam, W.; Khaddour, A. Anti-Virulence Effects of Aqueous Pomegranate Peel Extract on E. Coli Urinary Tract Infection. Prog. Nutr. 2017, 19, doi:10.23751/pn.v19i1-S.5693.
27. Ammar, O.M.A.; Ilktac, M.; Gulcan, H.O. Urolithins and Their Antimicrobial Activity: A Short Review. EMUJPharmSci 2020, 8.