Urobiota and urinary tract infections in liver cirrhosis

   The urobiome is being actively studied, diagnostics are being improved and new markers of inflammatory diseases of the urinary tract are being searched for, despite the fact that most microorganisms are unidentified and their functions remain not fully understood.

   The aim of the study was to study the composition of the urinary tract microbiota (urobiota) in patients with liver cirrhosis, depending on the presence of urinary tract infection.

   Material and methods. A prospective cohort single-center study was conducted on 48 patients with liver cirrhosis (30 men, 18 women), who, in addition to standard studies, underwent metagenomic sequencing of urine and feces. The average age of the examined patients was 50.5 years, there were 16 and 32 patients with and without urinary tract infection, respectively. High-performance sequencing was performed using the MiSeq genetic analyzer (Illumina, USA) using a protocol based on the analysis of variable regions of the 16s rRNA gene. Data analysis was performed using the Kraken2 algorithm. The significance level of α is assumed to be 0.05. The study is registered in Clinicaltrials.gov (NCT05335213).

   The results and their discussion. The dominant phylotypes of the urobiota in patients with liver cirrhosis are Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, among which Proteobacteria predominate (more than 50 %). The beta diversity of the urinary tract microbiota has significant differences in patients without or with urinary tract infection (p = 0.001). Urinary tract infection increases the density of such taxa in urine as Gammaproteobacteria, including Escherichia, Klebsiella, Acinetobacter, Enterobacter, as well as Bacilli, Synergistia, Deltaproteobacteria, Epsilonproteobacteria, Acidithiobacillia and decreases the density of Prevotella, Clostridioides, Brevundimonas, Delftia, Stenotrophomonas, Streptococcus (p < 0.05).

   Conclusions. Microbiological identification based on the method of metagenomic sequencing made it possible to identify more than 1,000 types of microorganisms in the urine of patients with liver cirrhosis, including uncultivated ones, and a characteristic bacterial pattern of urinary tract infection, which expands the understanding of the pathogenesis and diagnostic possibilities of urinary tract infections and creates prerequisites for substantiating the directions of microbiota modulation and personalization of patient treatment.

1. Almas S., Carpenter R.E., Rowan C., Tamrakar V.K., Bishop J., Sharma R. Advantage of precision metagenomics for urinary tract infection diagnostics. Front. Cell. Infect. Microbiol. 2023;13:1221289. doi: 10.3389/fcimb.2023.1221289

2. Kim D.S., Lee J.W. Urinary tract infection and microbiome. Diagnostics (Basel). 2023;13(11):1921. doi: 10.3390/diagnostics13111921

3. Gupta K. Urinary tract infection challenges: beyond the basics. Infect. Dis. Clin. North Am. 2024;38(2):229–394. doi: 10.1016/S0891-5520(24)00017-5

4. Zheng H., Wang C., Yu X., Zheng W., An Y., Zhang J., Zhang Y., Wang G., Qi M., Lin H., Wang F. The role of metabolomics and microbiology in urinary tract infection. Int. J. Mol. Sci. 2024;25(6):3134. doi: 10.3390/ijms25063134

5. Pierre J.F., Akbilgic O., Smallwood H., Cao X., Fitzpatrick E.A., Pena S., Furmanek S.P., Ramirez J.A., Jonsson C.B. Discovery and predictive modeling of urine microbiome, metabolite and cytokine biomarkers in hospitalized patients with community acquired pneumonia. Sci. Rep. 2020;10(1):13418. doi: 10.1038/s41598-020-70461-9

6. Malaeva E.G. Urinary tract infections and microbiota. Problemy zdorov’ya i ekologii = Health and Environment Issues. 2021;18(3):5–14. [In Russian]. doi: 10.51523/2708-6011.2021-18-3-1

7. Brubaker L., Wolfe A.J. The female urinary microbiota, urinary health and common urinary disorders. Ann. Transl. Med. 2017;5(2):34. doi: 10.21037/atm.2016.11.62

8. Engel D.R., Wagenlehner F.M.E., Shevchuk О. Scientific advances in understanding the pathogenesis, diagnosis, and prevention of urinary tract infection in the past 10 years. Infect. Dis. Clin. North Am. 2024;38(2):229–240. doi: 10.1016/j.idc.2024.03.002

9. Ceprnja M., Oros D., Melvan E., Svetlicic E., Skrlin J., Barisic K., Starcevic L., Zucko J., Starcevic A. Modeling of urinary microbiota associated with cystitis. Front. Cell. Infect. Microbiol. 2021;11:643638. doi: 10.3389/fcimb.2021.643638

10. Magruder M., Sholi A.N., Gong C., Zhang L., Edusei E., Huang J., Albakry S., Satlin M.J., Westblade L.F., Crawford C., … Lee J.R. Gut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection. Nat. Commun. 2019;10(1):5521. doi: 10.1038/s41467-019-13467-w

11. Keogh D., Tay W.H., Ho Y.Y., Dale J.L., Chen S., Umashankar S., Williams R.B.H., Chen S.L., Dunny G.M., Kline K.A. Enterococcal metabolite cues facilitate interspecies niche modulation and polymicrobial infection. Cell Host Microbe. 2016;20(4):493–503. doi: 10.1016/j.chom.2016.09.004

12. Perez-Carrasco V., Soriano-Lerma A., Soriano M., Gutiérrez-Fernández J., Garcia-Salcedo J.A. Urinary microbiome: yin and yang of the urinary tract. Front. Cell. Infect. Microbiol. 2021;11:617002. doi: 10.3389/fcimb.2021.617002

13. Grine G., Lotte R., Chirio D., Chevalier A., Raoult D., Drancourt M., Ruimy R. Co-culture of Methanobrevibacter smithii with Еnterobacteria during urinary infection. EBioMedicine. 2019;43:333–337. doi: 10.1016/j.ebiom.2019.04.037

14. Lingiah V.A., Pyrsopoulos N.T. Bacterial infections in cirrhotic patients in a tertiary care hospital. J. Clin. Transl. Hepatol. 2021;9(1):32–39. doi: 10.14218/JCTH.2020.00076

15. Reuken P.A., Stallmach A., Bruns T. Mortality after urinary tract infections in patients with advanced cirrhosis – relevance of acute kidney injury and comorbidities. Liver Int. 2013;33(2):220–230. doi: 10.1111/liv.12029

16. Neugent M.L., Hulyalkar N.V., Nguyen V.H., Zimmern P.E., de Nisco N.J. Advances in understanding the human urinary microbiome and its potential role in urinary tract infection. mBio. 2020;11(2):e00218–e00220. doi: 10.1128/mBio.00218-20

17. 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(10):1745–1747. doi: 10.1093/cid/cix618

18. Malaeva E.G., Stoma I.O. Possibilities and prospects of modification of the intestinal microbiome. Arkhiv vnutrnney meditsiny = Archive of Internal Medicine. 2022;12(5):341–351. [In Russian]. doi: 10.20514/2226-6704-2022-12-5-341-351

19. 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. doi: 10.3390/pathophysiology31010005

20. Maslennikov R., Ivashkin V., Efremova I., Alieva A., Kashuh E., Tsvetaeva E., Poluektova E., Shirokova E., Ivashkin K. Gut dysbiosis is associated with poorer long-term prognosis in cirrhosis. World. J. Hepatol. 2021;13(5):557–570. doi: 10.4254/wjh.v13.i5.557

21. Dubourg G., Morand A., Mekhalif F., Godefroy R., Corthier A., Yacouba A., Diakite A., Cornu F., Cresci M., Brahimi S., … Raoult D. deciphering the urinary microbiota repertoire by culturomics reveals mostly anaerobic bacteria from the gut. Front. Microbiol. 2020;11:513305. doi: 10.3389/fmicb.2020.513305

22. Gaston J.R., Johnson A.O., Bair K.L., White A.N., Armbruster C.E. Polymicrobial interactions in the urinary tract: is the enemy of my enemy my friend? Infect. Immun. 2021:IAI.00652-20. doi: 10.1128/IAI.00652-20

23. Sturov N.V., Popov S.V., Zhukov V.A., Lyapunova T.V. Correction of gut microbiota in urinary tract infection (a review). Farmakologiya & farmakoterapiya = Pharmacology & Pharmacotherapy. 2022;(3):24–27. [In Russian]. doi: 10.46393/27132129_2022_3_24

24. Sturov N.V., Popov S.V., Zhukov V.A. Pathogenetic role and possibilities for correction of gut microbiota disorders in urinary tract infections. Antibiotiki i khimioterapiya = Antibiotics and Chemotherapy. 2021;66(7–8):100–108. [In Russian]. doi: 10.24411/0235-2990-2021-66-7-8-100-108