Rose Willemze

Acetylcholine-producing T cells in the intestine regulate antimicrobial peptide expression and microbial diversity

The cholinergic anti-inflammatory pathway reduces systemic tumor necrosis factor (TNF) via acetylcholine-producing memory T cells in the spleen. These choline acetyltransferase (ChAT)-expressing T cells are also found in the intestine, where their function is unclear. We aimed to characterize these cells in mouse and human intestine and delineate their function. We made use of the ChAT-enhanced green fluorescent protein (eGFP) reporter mice. CD4Cre mice were crossed to ChATfl/fl mice to achieve specific deletion of ChAT in CD4+ T cells. We observed that the majority of ChAT-expressing T cells in the human and mouse intestine have characteristics of Th17 cells and coexpress IL17A, IL22, and RORC The generation of ChAT-expressing T cells was skewed by dendritic cells after activation of their adrenergic receptor β2 To evaluate ChAT T cell function, we generated CD4-specific ChAT-deficient mice. CD4ChAT-/- mice showed a reduced level of epithelial antimicrobial peptides lysozyme, defensin A, and ang4, which was associated with an enhanced bacterial diversity and richness in the small intestinal lumen in CD4ChAT-/- mice. We conclude that ChAT-expressing T cells in the gut are stimulated by adrenergic receptor activation on dendritic cells. ChAT-expressing T cells may function to mediate the host AMP secretion, microbial growth and expansion.

Neuronal control of experimental colitis occurs via sympathetic intestinal innervation

Vagus nerve stimulation is currently clinically evaluated as a treatment for inflammatory bowel disease. However, the mechanism by which this therapeutic intervention can have an immune‐regulatory effect in colitis remains unclear. We determined the effect of intestine‐specific vagotomy or intestine‐specific sympathectomy of the superior mesenteric nerve (SMN) on dextran sodium sulfate (DSS)‐induced colitis in mice. Furthermore, we tested the efficacy of therapeutic SMN stimulation to treat DSS‐induced colitis in rats.

β-Blocker use is associated with a higher relapse risk of inflammatory bowel disease: a Dutch retrospective case–control study

Objective Inflammatory bowel disease (IBD) is a multifactorial disease and many factors may influence the disease course, like the concomitant use of medication. An example thereof is the use of &bgr;-blockers, antagonizing &bgr;-adrenergic receptors. &bgr;-adrenergic receptor activation has potent anti-inflammatory effects on the immune system. We addressed whether an association exists between the use of beta-blockers and the course of IBD, defined by the risk of a disease relapse in patients with IBD. Patients and methods In this retrospective case–control study, we used a population-based cohort of patients with IBD. We identified colitis relapses using IBD medication prescriptions as a proxy. We calculated the number of relapses per 100 person-years and compared this between patients with IBD using &bgr;-blockers and patients with IBD not using &bgr;-blockers. We used Cox proportional hazards models with shared frailty to compare the relative relapse risk between both groups. Results A total of 250 patients with IBD were included, of which 30 patients used a &bgr;-blocker for at least 3 months. With the Cox proportional hazards model with shared frailty, adjusted for age and sex, we observed a 54% (hazard ratio: 1.54; 95% confidence interval: 1.05–2.25; P=0.03) higher risk of a relapse in the group of patients with IBD using &bgr;-blockers versus the group not using &bgr;-blockers. Conclusion Even in this limited cohort study, we show that patients with IBD using &bgr;-blockers have an increased relapse risk. Indeed, concomitant medication use seems to be a factor that can influence the course of IBD, and this should be acknowledged while making decisions about treatment of IBD and follow-up.

Adrenergic innervation regulates intestinal microbiota diversity via generation of cholinergic Th17 lymphocytes

Background: Although, it is usually difficult to differentiate multiple system atrophy (MSA) from Parkinson’s disease (PD), we have previously reported that post-void residuals and sphincter electromyography were useful for differentiation 1), . However, we did not know which is more appropriate in differentiating MSA from PD. Aims: We aimed to perform receiver operating characteristic analysis to determine the ability of sphincter electromyography (mean duration) and post-void residuals (free flow study and pressure-flow study) for distinguishing multiple system atrophy from Parkinson’s disease. Methods: We retrospectively reviewed 241 case records where both urodynamic study and sphincter electromyography were performed in patients with multiple system atrophy (n = 147) and Parkinsons disease (n = 94). We performed receiver operating characteristic analysis of the data sets. Results: The area under the curve (AUC) used to differentiate multiple system atrophy from Parkinson’s disease was 0.79 in post-void residuals during pressure flow study, 0.73 in post-void residuals during freeflow study and 0.69 in mean duration of sphincter electromyography, respectively; these values were statistically significant. Conclusion: The present results suggested that post-void residuals were more appropriate than mean duration of sphincter electromyography in differentiating MSA from PD. In particular, the AUC in postvoid residuals under pressure flow study was larger than that of under free-flow study. 1) Yamamoto T, Sakakibara R, Uchiyama T, Yamaguchi C, Ohno S, Nomura F, Yanagisawa M, Hattori T, Kuwabara S. Time-dependent changes and gender differences in urinary dysfunction in patients with multiple system atrophy. Neurourol Urodyn. 2014 Jun;33(5):516-23. 2) Yamamoto T, Sakakibara R, Uchiyama T, Yamaguchi C, Nomura F, Ito T, YanagisawaM, YanoM, Awa Y, Yamanishi T, Hattori T, Kuwabara S. Receiver operating characteristic analysis of sphincter electromyography for parkinsonian syndrome. Neurourol Urodyn. 2012 Sep;31(7):1128-34.

The sympathetic mesenteric nerve regulates experimental colitis

Background. The autonomic nervous system plays a regulatory role in the immune response. It has been established that norepinephrine (NE) has anti-inflammatory effects on dendritic cell activation, which is a critical event in colitis pathophysiology. Our aim was to investigate the effect of sympathetic nerve activity on experimental colitis. Methods. 1) In a T-cell transfer colitis model, using Rag1 mice, sympathectomy was achieved chemically using 6-hydroxydopamine (6-OHDA) or surgically by cutting the supra mesenteric nerve (Sx). 2) In a dextran sodium sulfate (DSS) induced colitis model, mice underwent Sx or Sx combined with gastrointestinal-selective vagotomy (Cx) to assess the additive effect of the vagus nerve. Colitis was evaluated by histology and mRNA levels of inflammatory cytokines, along with clinical parameters such as weight loss and diarrhea. Ileal NE was measured by mass spectrometry. Results. 6-OHDA as well as Sx caused a significant decrease in ileal NE levels. In Rag1, but not in wild type mice, Sx caused clinical signs of spontaneous colitis from day 8 and a significant increase of pro-inflammatory cytokines IL-1β and IL-6. 6-OHDA similarly elicited signs of colitis, but inflammatory cytokines were not significantly elevated. In DSS induced colitis, Cx aggravated colitis and increased IL-1β and IL-6 expression in the distal colon. Sx alone did not significantly affect IL-1β and IL-6 expression. Conclusion. Sympathetic innervation maintains homeostasis in the gut. Mucosal NE levels are critical determinants in maintaining mucosal tolerance towards luminal microbiota. Our data may explain how neuronal damage and plasticity contributes to pathology in IBD.