Introduction

Recurrent urinary tract infections (rUTIs) affect up to 25% of women worldwide¹, with risk of antibiotic-related side effects and multi-drug resistance. Several gut pathobionts, mainly Enterobacteriaceae, are responsible for nearly 90% of all UTIs, and gut microbiome imbalance has recently appeared as a main pathogenic pathway of UTIs². Untargeted probiotics have provided conflicting results in this setting,^3-5 and current evidence does not support their use.⁶ Gut microbiome testing are emerging as a promising diagnostic tool to target microbiome and offer a personalized therapeutic strategy, but their real value is unknown.

Aims & Methods

Our aim is to evaluate whether targeting gut microbiome is an effective strategy to prevent rUTIs derived from gut pathobionts.
In this pilot study, we included consecutive patients with rUTIs derived from gut pathobionts referring at our outpatient microbiome clinic in 2022.
All patients underwent a commercially available stool microbiome testing (XMICROGem from XBIOGem) based on 16S rRNA analysis, performed as already described⁷. Then, patients received a targeted therapy based on results of the gut microbiome testing, with the aim of restoring a balanced microbiota. Non-adsorbable antibiotics were used to downregulate pathobionts’ abundance, while prebiotics and probiotics were given to boost the abundance of specific taxa and/or to compete with pathobionts. Patients were followed up at least 12 weeks after the end of therapy.
We collected the following data of patients: age, gender, presence of gastrointestinal (GI) symptoms (assessed with GSRS), taxa responsible of UTIs; specific characteristics of gut microbiome (alpha diversity, abundance of Enterobacteriaceae, Escherichia, Klebsiella, Bifidobacteria, Akkermansia, and short-chain fatty acid producers including Lachnospiraceae, Faecalibacterium, Roseburia, Butyrivibrio); specific therapies given after testing, including non-adsorbable antibiotics, prebiotics, and probiotic strains. The primary outcome was the recurrence of UTIs, and the secondary outcome was gastrointestinal symptoms, at 12-week follow-up.

Results

Twelve patients were enrolled in the study period (n= 11 females, mean age 40 years). Of them, 11 (92%) presented with GI symptoms (67% with bloating, 50% with constipation, 50% with abdominal pain, 42% with dyspepsia, 17% with diarrhea). rUTIs were caused by E. coli in 11 patients and E. faecalis in one patient. The gut microbiome testing showed a decrease of alpha diversity in two patients (17%), of Akkermansia in eight patients (67%) and of SCFA-producers in seven patients (58%), as well as increased Proteobacteria in seven patients (58%). Moreover, Bacteroidetes were increased in four patients (33%) while Firmicutes were decreased in two patients (17%). Ten patients underwent rifaximin (83%) and two paromomycin (17%). E. coli Nissle 1917 was used in seven patients (58%), five in combination with an Enterococcus faecium-based strain,one in combination with Lactobacillus crispatus M247, and one in combination with both. Multi-strains probiotics were used in 7 patients (58%). Prebiotics were administered in seven patients. At 12-week follow-up, nine patients (75%) were free from new episodes of UTIs, and eight patients (73%) experienced an improvement of GI symptoms.

Conclusion

A precision medicine strategy based on gut microbiome testing may be a promising approach to treat rUTIs and ameliorate associated GI symptoms. Well designed, randomized and larger studies are needed to confirm our preliminary findings.

References

1. Meena, J., Thomas, C. C., Kumar, J., Raut, S. & Hari, P. Non-antibiotic interventions for prevention of urinary tract infections in children: a systematic review and meta-analysis of randomized controlled trials. Eur J Pediatr 180, 3535–3545 (2021).
2. Thänert, R. et al. Comparative Genomics of Antibiotic-Resistant Uropathogens Implicates Three Routes for Recurrence of Urinary Tract Infections. mBio 10, e01977-19 (2019).
3. Abdullatif, V. A. et al. Efficacy of Probiotics as Prophylaxis for Urinary Tract Infections in Premenopausal Women: A Systematic Review and Meta-Analysis. Cureus 13, e18843 (2021).
4. Grin, P. M., Kowalewska, P. M., Alhazzan, W. & Fox-Robichaud, A. E. Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis. Can J Urol 20, 6607–6614 (2013).
5. New, F. J., Theivendrampillai, S., Juliebø-Jones, P. & Somani, B. Role of Probiotics for Recurrent UTIs in the Twenty-First Century: a Systematic Review of Literature. Curr Urol Rep 23, 19–28 (2022).
6. EAU Guidelines on Urological Infections - THE GUIDELINE - Uroweb. Uroweb - European Association of Urology https://uroweb.org/guidelines/urological-infections/chapter/the-guideline.

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.