This was a 3-year longitudinal study, Aomori in Japan. We assessed OAB symptoms and reviewed the medication records of each subject in 2016. We extracted 16S rRNA genes from fecal samples and analyzed gut microbiomes via next-generation sequencing. We evaluated the changes in urinary urgency (UU) and/or urgent urinary incontinence (UUI) from 2016 to 2019. We defined UU/UUI-progression as exacerbation of UU and/or UUI. We compared the clinical backgrounds and microbiota structure between UU/UUI-progression subjects and non-progression (controls). We assessed the impact of gut microbiome on the UU/UUI-progression via multivariate logistic regression analyses.
Figure 1
We evaluated 667 (265 male and 402 female) individuals. There were 126 UU/UUI-progression subjects. These subjects had a higher age and prevalence of proton pump inhibitor (PPI) use (14% vs. 5.4%, P = 0.003), irritable bowel syndrome (IBS), sleep disturbance, and metabolic syndrome than those without. Significant differences were found in the component structure of the microbiome between UU/UUI-progression subjects and controls (PERMANOVA, F = 2.03, R2 = 0.003, P = 0.033, Fig.1). We found 13 genera overrepresented in UU/UUI-progression subjects on the LEfSe analyses (Fig. 2). Of note, the relative abundance of genus Streptococcus (harmful bacterial genus for human health) in UU/UUI-progression subjects was significantly higher than that of controls (3.8% vs. 2.3%, P < 0.001; Fig. 3). A multivariate analysis revealed that age ≥ 65 years, current smoking, sleep disturbance, metabolic syndrome, and genus Streptococcus (Odds ratio: 1.05, P = 0.029) were independent risk factors for UU/UUI-progression. PPI use turned out to be a significant risk factor on a multivariate analysis without including genus Streptococcus.
Figure 2
In this study, we did observe significant differences in the intergroup similarity of gut microbiomes between UU/UUI-progression subjects and controls. This result implies that progression subjects may have gut dysbiosis. Furthermore, we found a relative abundance of major and harmful bacterial genus (i.e., genus Streptococcus) was an independent risk factor for UU/UUI-progression. This genus is also increased in patients with IBS. Our additional analysis also showed that subjects with IBS had a higher relative abundance of this genus than those without IBS (4.5% vs. 2.5%, P = 0.003). IBS often coexists with OAB and has been strongly associated with gut dysbiosis. Both IBS and OAB are disorders of visceral overactivity and irritability. Because IBS is thought to be deeply associated with neural substances produced by gut microbiome, it may be possible that gut dysbiosis also influences bladder function through convergent sensory pathways between bowel and bladder at a peripheral, and spinal. Considering OAB and IBS have such features, gut microbiome might be associated with the presence of OAB and exacerbation of OAB symptoms.
Figure 3
The impact of PPI use on gut microbiome might be associated with some diseases. Gastric acid inactivates ingested bacteria and acts as a barrier against bacterial migration in the upper gastrointestinal tract to the lower tract. However, PPIs have been shown to reduce gastric bactericidal activity due to their strong acid-suppressing effect, which weakens the barrier function of gastric acid. Significant differences were found in the component structure of the microbiome between PPI and non-PPI users in this study (PERMANOVA, F = 2.09, R2 = 0.003, P = 0.019). PPI use may have a strong influence on the location of bacteria in the gut and result in gut dysbiosis among PPI users. We found PPI use turned to be a significant risk factor for UU/UUI-progression when not including the relative abundance of genus Streptococcus. The relative abundance of genus Streptococcus in PPI users was significantly higher than non-PPI users (6.4% vs. 2.3%, P < 0.001). These results might suggest that PPI use contributes to increase this genus via dysbiosis in gut microbiome. In summary, PPI use might increase the risk of some diseases, including OAB symptoms through increases in this genus. However, the exact pathogenicity of genus Streptococcus for the exacerbation of OAB symptoms remains unknown. Further studies are necessary to elucidate the association between PPI use, OAB, and the gut microbiome.
Written by: Teppei Okamoto, MD, PhD, Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Read the Abstract