Anti-inflammatory effects of abdominal vagus nerve stimulation on experimental intestinal inflammation
Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD).
A growing body of evidence has demonstrated that unilateral electrical stimulation of the left cervical vagus nerve is a feasible treatment in a rodent model of colitis (Meregnani et al., 2011; Sun et al., 2013). Following chemically-induced colitis in rats, cervical vagus nerve stimulation (VNS) improved the disease activity index (DAI: weight and stool quality), decreased histological damage and reduced inflammatory molecular markers expressed in colonic tissue (Meregnani et al., 2011). However, the effects of VNS therapy on histology and molecular markers were only seen in areas adjacent to, but not within, the inflammatory lesion. In a subsequent colitis study, inflammatory markers were only modestly reduced by cervical VNS, and inflammatory disease parameters (DAI, histology, inflammatory cytokine production) in VNS treated tissue did not return to control levels (Sun et al., 2013).
A first, small clinical trial demonstrated efficacy cervical VNS in ileocecal Crohn’s disease patients (Bonaz et al., 2016) The majority of patients (5 of 7) responded to treatment and showed a reduction in clinical symptoms (Crohn’s DAI), improvements in molecular markers (C-reactive protein and fecal calprotectin) and endoscopy DAI score. However, two patients experienced worsening of clinical symptoms and were removed from the study (Bonaz et al., 2016). Additionally, patients reported voice alterations (dysphonia) during stimulation (Bonaz et al., 2016). Other side effects, such as coughing, pain and labored/shortness of breath (dyspnea) are frequently reported following cervical VNS in patients treated with VNS for drug resistant epilepsy (Ben-Menachem et al., 2015). Studies in epileptic children fitted with a cervical VNS report more serious complications during sleep. Stimulation-induced effects on respiration and a reduction in overall oxygen saturation was seen in the majority of patients (87.5%, 8 patients; 100%, 10 patients, respectively) (Nagarajan et al., 2003; Zaaimi et al., 2005), while stimulus-induced changes to heart rate variability are reported in 50% of patients (10 patients) (Pruvost et al., 2006; Zaaimi et al., 2007). Another study reports stimulus-induced obstructive sleep apnea (15%; 26 patients) (Khurana et al., 2007). Such off-target affects are due to the activation of low threshold cervical vagal fibers to the larynx, pharynx, heart, and lungs (discussed in detail in the discussion), while the abdominal vagus nerve is at a site below these branches and its stimulation is predicted to results in fewer off-target effects.
Although evidence for VNS therapy to treat IBD is promising, the current approach of stimulating the cervical vagus nerve has a number of clinical limitations, including potentially an undesirable side-effect profile. To overcome the limitations of cervical VNS, we hypothesized that stimulating the sub-diaphragmatic abdominal vagus nerve (Figure 1A), which is below vagal branches to the lungs and heart and closer to the end organ, will improve the therapeutic effect of VNS and have fewer off-target effects. To address this hypothesis, in this study we first developed an electrode array (in house) that was able to stimulate and record neural responses from the vagus nerve of the rats. Using this electrode array in a non-recovery experiment, referred to as the “VNS off-target experiment,” off-target effects to cardiac and respiratory rate were assessed during abdominal and cervical VNS. In a recovery experiment, referred to as the “VNS efficacy experiment,” the efficacy of abdominal VNS was assessed using a rodent model of chemically-induced intestinal inflammation (Figure 1A). Behavioral, molecular and histological markers of inflammation were evaluated to determine the efficacy of abdominal VNS, and the histology of the implanted vagus nerve examined to confirm the safety of electrode array and stimulation delivered.
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