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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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.