Key pointsr Hyperactivity of the stress system and low-grade immune activation characterize the functional bowel disorder irritable bowel syndrome (IBS).r These studies show that interleukin (IL)-6 and IL-8 and the stress hormone corticotropin-releasing factor (CRF), present in IBS plasma, have functional effects on gastrointestinal activity by stimulating myenteric neurons and colonic contractions.r Moreover, in the Wistar Kyoto rat model of IBS, which exhibits altered gastrointestinal motility and visceral pain sensitivity, blocking IL-6 and/or CRF1 receptors alleviates these IBS-like symptoms.r Underlying these effects are altered colonic protein expression of tight junction proteins which regulate gut barrier function and the T-type calcium channel Ca V 3.2, which has been linked to visceral pain.r These findings demonstrate the importance of the enteric nervous system and intestinal physiology in bowel dysfunction. AbstractThe search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg −1 I.P) with or without the CRFR1 antagonist antalarmin (10 mg kg −1 I.P). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel Ca V 3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.

Objectives The burden often associated with informal caregiving for patients with dementia is associated with negative effects on health, both physiologically and in terms of caregiver cognition. There is wide variation in the level of burden experienced by dementia caregivers. To better understand caregiver burden, it is thus important to understand the factors associated with level of burden. Methods In the current study, we collected carer burden and putative associated factors at baseline, 6 and 12 months. Hierarchical regression was used to assess the impact of these factors on caregiver burden. We assessed self-reported carer burden, patient behavioural and safety issues, and level of difficulty associated with providing assistance with activities of daily living (ADL). Patients’ age was also recorded, and trained nurses assessed patient cognitive performance using the quick mild cognitive impairment screen. Results At baseline, patients’ age, cognition and ADLs were associated with burden, and safety and challenging behaviour were both significantly associated with burden independent of the other factors. Change in burden was associated with change in carer-reported safety at 6-month follow-up, and with change in safety and change in carer-reported challenging behaviours at 12-month follow-up. Conclusions Safety issues and challenging behaviours are associated with carer burden, even after accounting for cognitive and functional impairment in the person with dementia. As dementia progresses, monitoring these factors may help to inform stress-management strategies for caregivers.

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Treatment which neutralizes peripheral IL-6 signaling and stimulates CRFR2 recovers force-generating capacity and the ability to perform mechanical work in mdx diaphragm muscle. These findings may be important in the search for therapeutic targets in DMD. Muscle Nerve 56: E134-E140, 2017.

An intact gut epithelium preserves the immunological exclusion of "non-self" entities in the external environment of the gut lumen. Nonetheless, information flows continuously across this interface, with the host immune, endocrine, and neural systems all involved in monitoring the luminal environment of the gut. Both pathogenic and commensal gastrointestinal (GI) bacteria can modulate centrally-regulated behaviors and brain neurochemistry and, although the vagus nerve has been implicated in the microbiota-gut-brain signaling axis, the cellular and molecular machinery that facilitates this communication is unclear. Studies were carried out in healthy Sprague-Dawley rats to understand cross-barrier communication in the absence of disease. A novel colonic-nerve electrophysiological technique was used to examine gut-to-brain vagal signaling by bacterial products. Calcium imaging and immunofluorescent labeling were used to explore the activation of colonic submucosal neurons by bacterial products. The findings demonstrate that the neuromodulatory molecule, glucagon-like peptide-1 (GLP-1), secreted by colonic enteroendocrine L-cells in response to the bacterial metabolite, indole, stimulated colonic vagal afferent activity. At a local level indole modified the sensitivity of submucosal neurons to GLP-1. These findings elucidate a cellular mechanism by which sensory L-cells act as cross-barrier signal transducers between microbial products in the gut lumen and the host peripheral nervous system.

These findings confirm the importance of dystrophin in normal GI function and implicate IL-6 as an important regulator of GI motility in the mdx mouse. Inhibition of IL-6 signaling may offer a potential new therapeutic strategy for treating DMD-associated GI symptoms.

This study aimed to quantify the effect of cardiac hypertrophy induced with isoprenaline and caffeine on reflex regulation of renal sympathetic nerve activity by the arterial and cardiopulmonary baroreceptors. Male Wistar rats, untreated or given water containing caffeine and subcutaneous (s.c.) isoprenaline every 72 h for 2 weeks or thyroxine s.c. for 7 days, were anaesthetized and prepared for measurement of renal sympathetic nerve activity or cardiac indices. Both isoprenaline-caffeine and thyroxine treatment blunted weight gain but increased heart weight and heart weight to body weight ratio by 40 and 14% (both P < 0.01), respectively. In the isoprenaline-caffeine group, the maximal rate of change of left ventricular pressure and the contractility index were higher by 17 and 14% (both P < 0.01), respectively, compared with untreated rats. In the isoprenaline-caffeine-treated rats, baroreflex gain curve sensitivity was depressed by approximately 30% (P < 0/05), while the mid-point blood pressure was lower, by 15% (P < 0/05), and the range of the curve was 60% (P < 0.05) greater than in the untreated rats. An acute intravenous infusion of a saline load decreased renal sympathetic nerve activity by 42% (P < 0.05) in the untreated rats but had no effect in the isoprenaline-caffeine-or the thyroxinetreated groups. The isoprenaline-caffeine treatment induced cardiac hypertrophy with raised cardiac performance and an associated depression in the reflex regulation of renal sympathetic nerve activity by both high-and low-pressure baroreceptors. The thyroxine-induced cardiac hypertrophy also blunted the low-pressure baroreceptor-mediated renal sympatho-inhibition. These findings demonstrate that in cardiac hypertrophy without impaired cardiac function, there is a blunted baroreceptor control of renal sympathetic outflow.

Background Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon‐like peptide 1 (GLP‐1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP‐1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP‐1 receptor agonist, and if this differs in a rat model of IBS. Methods Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains. Key Results Circulating GLP‐1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin‐4, a GLP‐1 receptor agonist, are potentiated by a ghrelin receptor (GHSR‐1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin‐4 to alter smooth muscle function was modified by a GHSR‐1 agonist in both strains. Gut‐brain signaling via GLP‐1–mediated activation of vagal afferents was also potentiated by the GHSR‐1 agonist. Conclusions & Inferences These findings support a temporal interaction between ghrelin and GLP‐1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP‐1. While the sensitizing effects of the GHSR‐1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.