Non‐invasive peripheral focused ultrasound neuromodulation of the celiac plexus ameliorates symptoms in a rat model of inflammatory bowel disease

Abstract

Individuals suffering from inflammatory bowel disease (IBD) experience significantly diminished quality of life. Here, we aim to stimulate the celiac plexus with noninvasive peripheral focused ultrasound (FUS) to modulate the enteric cholinergic antiinflammatory pathway. This approach may have clinical utility as an efficacious IBD treatment given the non-invasive and targeted nature of this therapy. We employed the dextran sodium sulfate (DSS) model of colitis, administering lower (5%) and higher (7%) doses to rats in drinking water. FUS on the celiac plexus administered twice a day for 12 consecutive days to rats with severe IBD improved stool consistency scores from 2.2 ± 1 to 1.0 ± 0.0 with peak efficacy on day 5 and maximum reduction in gross bleeding scores from 1.8 ± 0.8 to 0.8 ± 0.8 on day 6. Similar improvements were seen in animals in the low dose DSS group, who received FUS only once daily for 12 days. Moreover, animals in the high dose DSS group receiving FUS twice daily maintained colon length (17.7 ± 2.5 cm), while rats drinking DSS without FUS exhibited marked damage and shortening of the colon (13.8 ± 0.6 cm) as expected. Inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-17, tumour necrosis factor-α and interferon-γ were reduced with DSS but coincided with control levels after FUS, which is plausibly due to a loss of colon crypts in the former and healthier crypts in the latter. Lastly, overall, these results suggest non-invasive FUS of peripheral ganglion can deliver precision therapy to improve IBD symptomology.

Ultrasound Neuromodulation of the Spleen Has Time-Dependent Anti-Inflammatory Effect in a Pneumonia Model

“…This protective effect has been shown by activating CAP prophylactically or immediately following injury in multiple models of severe inflammation or trauma, including sepsis, haemorrhagic shock, postoperative ileus, and kidney ischemia reperfusion injury ( 1 , 6 , 19 , 21 , 40 , 45 , 46 ). The protective effect has also been shown in models of chronic and pathological inflammation, including collagen-induced and serum transfer models of arthritis and DSS-induced colitis ( 20 , 27 , 35 , 39 ). However, the activity of CAP, and the effect of stimulating the CAP pathway during progression of a local or acute infection has not previously been measured.…”

“…These investigations have included models of endotoxemia ( 18 , 21 ), sepsis ( 21 ), hemorrhagic shock ( 45 ), postoperative ileus ( 46 ), and kidney ischemia reperfusion injury ( 40 ). This hypothesis has also been tested in models of inflammatory disease [such as collagen- or serum-induced arthritis ( 27 , 39 ) and chemical-induced colitis ( 35 )], in which the CAP pathway is activated to provide an anti-inflammatory effect in the presence of chronic inflammatory disease. In each of these models, electrical ( 2 ), ultrasonic ( 28 ), or pharmaceutical ( 32 ) activation of CAP resulted in reduced cytokine production and disease-alleviating therapeutic effects.…”

Manipulation of the inflammatory reflex as a therapeutic strategy

“…68 This pathway has recently been termed the ''enteric-CAP.'' 69 Thus, the vagus nerve once again appears key to the a7nAChR-mediated effects in IBD. Further research has suggested that the vagus nerve is capable of inducing a7nAChR-independent anti-colitic effects, such as by the recruitment of regulatory T cells (Tregs).…”

“… 66 However, VNS, which has demonstrated efficacy in models of IBD, 67 has also been shown to reduce bowel inflammation independently of splenic innervation, and instead via cholinergic stimulation of α7nAChR-expressing resident macrophages in the gut. 68 This pathway has recently been termed the “enteric-CAP.” 69 Thus, the vagus nerve once again appears key to the α7nAChR-mediated effects in IBD. Further research has suggested that the vagus nerve is capable of inducing α7nAChR-independent anti-colitic effects, such as by the recruitment of regulatory T cells (Tregs).…”

Research-Based Product Innovation to Address Critical Unmet Needs of Patients with Inflammatory Bowel Diseases

“…Modalities to enable more targeted and less invasive neuromodulation, including ultrasound, could expand the appeal of this approach, as proposed by GE Research and other groups. 188 , 193 , 194 …”