Urinary cytokines in women with refractory detrusor overactivity: A longitudinal study of rotating antibiotic versus placebo treatment

Abstract

Over 50% of women with detrusor overactivity (DO), who do not respond to therapy have been shown to have bacteriuria, which may stimulate the release of inflammatory cytokines than can enhance nerve signalling, leading to symptoms of urgency. This study made use of a consecutive series of urine samples collected from women with refractory DO, who participated in a clinical trial of rotating antibiotic therapy. The aim was to determine the effect of bacteriuria and antibiotic treatment on the levels of urinary cytokines, and to correlate the cytokine concentration with patient outcome measures relating to urgency or urge incontinence. The urinary cytokines chosen were IL-1α, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, CXCL10 (IP-10), MCP-1 and TNF-α. The presence of bacteriuria stimulated a significant increase in the concentrations of IL-1α (P 0.0216), IL-1 receptor antagonist (P 0.0264), IL-6 (P 0.0003), IL-8 (P 0.0043) and CXCL-10 (P 0.009). Antibiotic treatment significantly attenuated the release of IL-1α (P 0.005), IL-6 (P 0.0027), IL-8 (P 0.0001), IL-10 (P 0.049), and CXCL-10 (P 0.042), i.e. the response to the presence of bacteria was less in the antibiotic treated patients. Across the 26 weeks of the trial, antibiotic treatment reduced the concentration of five of the nine cytokines measured (IL-1α, IL-6, IL-8, IL-10 and CXCL-10); this did not reach significance at every time point. In antibiotic treated patients, the urinary concentration of CXCL-10 correlated positively with four of the six measures of urgency. This study has shown that cytokines associated with activation of the innate immune system (e.g. cytokines chemotactic for or activators of macrophages and neutrophils) are reduced by antibiotic therapy in women with refractory DO. Antibiotic therapy is also associated with symptom improvement in these women, therefore the inflammatory response may have a role in the aetiology of refractory DO.

Urinary Tract Infection in Overactive Bladder: An Update on Pathophysiological Mechanisms

“…Using samples collected as part of the phase IIb trial described above, we were able to investigate the mechanisms behind the improvement in outcomes in the OAB patients. Our follow-up analysis of the trial cohort revealed that cytokines associated with activation of the innate immune system are reduced by antibiotic therapy in women with OAB ( Chen et al, 2021b ). In particular, antibiotic treatment was associated with significant reductions of pro-inflammatory cytokines IL-1α, IL-1Ra, IL-6, IL-8, and CXCL-10 and the anti-inflammatory cytokine IL-10, which are all cytokines typically present in UTIs ( Sundac et al, 2016 ).…”

“…This variability is further compounded by the relatively small number of patients included in these studies. Despite these issues, there is a growing consistency in the evidence for elevations in pro-inflammatory cytokines TNF-α ( Tyagi et al, 2010 ; Ma et al, 2016 ; Chen et al, 2019 ), MCP-1 ( Tyagi et al, 2010 ; Chen et al, 2019 ; Farhan et al, 2019 ; Ghoniem et al, 2020 ) and MIP-1 ( Tyagi et al, 2010 ; Ma et al, 2016 ) as well as reductions in anti-inflammatory cytokines IL-10, IL-1 receptor antagonist, and IL-4 ( Ma et al, 2016 ; Tyagi et al, 2016 ; Pillalamarri et al, 2018 ) in OAB patients. A shift in the balance of these cytokines to a more pro-inflammatory state, and a lack of anti-inflammatory cytokines in women with OAB, may allow an inflammatory response to proliferate, thus contributing to the pathogenesis of the disease ( Pillalamarri et al, 2018 ).…”