Effects of Stress, Vagal Nerve Stimulation and Disease Activity on Circulating Cytokines, Quantified by an Ultrasensitive Technique, in Ulcerative Colitis: A Pilot Study

Abstract

Aims

The utility of circulating cytokine concentrations in ulcerative colitis is limited due to poor assay sensitivity. We aimed to examine the relationship of circulating cytokine concentrations, when measured by ultrasensitive detection, to disease activity, response to induction therapy, and physiological stimuli associated with mucosal injurious events.

Methods

Plasma was obtained from adult patients with ulcerative colitis in whom disease activity was assessed; before/after induction therapy; and before/after acute psychological stress and cervical transcutaneous vagal nerve/sham stimulation. Cytokines were measured using an ultrasensitive electrochemiluminescence-based multiplex assay. For stress/vagal-stimulation studies, epithelial injury was quantified by plasma concentrations of intestinal-type fatty acid-binding protein.

Results

In 12 patients in remission, 15 with mild-moderately active disease and 6 with severe colitis, concentrations of interleukin-17, IL10, interferon-γ, interleukin-8 and interleukin-6, but not tumor necrosis factor-α or interleukin-12p70, significantly reflected disease activity. In five patients in whom clinical remission was achieved with induction therapy, only interleukin-12p70 changed with a median increase of 65 (IQR 42–303)% (p = 0.006), with no consistent changes in the 10 not in remission. Vagal nerve stimulation had no effect on cytokine concentrations, but, following stress, interleukin-12p70 increased by 37 (13–60)% compared with a reduction of 29 (3–55)% following sham stimulation (p = 0.012), an effect that mirrored that of epithelial injury.

Conclusion

Multiple cytokines were detected at sub-pg/mL levels and many showed relationships to disease activity in patients with ulcerative colitis. Effects exerted by interventions associated with epithelial injury were consistently detected by changes in interleukin-12p70 concentrations, but not other cytokines.

Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12621000168853 and ANZCTR 12620000569909 [Ultrasound studies]; ClinicalTrials.gov identifier: NCT03908073