Therapeutic ultrasound attenuates DSS-induced colitis through the cholinergic anti-inflammatory pathway

Abstract

Background: Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD) characterized by uncontrolled immune response, diarrhoea, weight loss and bloody stools, where sustained remission is not currently achievable. Dextran Sulphate Sodium (DSS)-induced colitis is an animal model that closely mimics human UC. Ultrasound (US) has been shown to prevent experimental acute kidney injury through vagus nerve (VN) stimulation and activation of the cholinergic anti-inflammatory pathway (CAIP). Since IBD patients may present dysfunctional VN activity, our aim was to determine the effects of therapeutic ultrasound (TUS) in DSS-induced colitis. Methods: Acute colitis was induced by 2% DSS in drinking water for 7 days and TUS was administered to the abdominal area for 7 min/day from days 4-10. Clinical symptoms were analysed, and biological samples were collected for proteomics, macroscopic and microscopic analysis, flow cytometry and immunohistochemistry. Findings: TUS attenuated colitis by reducing clinical scores, colon shortening and histological damage, inducing proteomic tolerogenic response in the gut during the injury phase and early recovery of experimental colitis. TUS did not improve clinical and pathological outcomes in splenectomised mice, while α7nAChR (α7 nicotinic acetylcholine receptor-indicator of CAIP involvement) knockout animals presented with disease worsening. Increased levels of colonic F4/80 + α7nAChR + macrophages in wild type mice suggest CAIP activation. Interpretation: These results indicate TUS improved DSS-induced colitis through stimulation of the splenic nerve along with possible contribution by VN with CAIP activation. Fund: Intramural Research Programs of the Clinical Centre, the National Institute of Biomedical Imaging and Bioengineering at the NIH and CAPES/Brazil.

S‐Allylcysteine Inhibits PhIP/DSS‐Induced Colon Carcinogenesis through Mitigating Inflammation, Targeting Keap1, and Modulating Microbiota Composition in Mice

“…Moreover, DSS causes spleen weight gain. [ 42 ] Additionally, colitis predisposes the colon to the development of cancer and promotes all stages of tumorigenesis. [ 43 ] Studies have revealed that the anti‐inflammatory properties of SAC may be related to its ability to decrease NF‐κB activation, thus leading to a blocked inflammatory signaling cascade.…”

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

“…A recent publication by Cotero et al reported that engagement of the CAP was possible with non-invasive peripheral focused ultrasound (FUS), which resulted in lower cytokine expression and inflammation (Cotero et al, 2019). Moreover, it was reported in the same year that non-focused ultrasound targeting the entire right side of a mouse between the axilla and the hip improved mild IBD symptoms, possibly by activating the splenic nerve and the CAP (Nunes et al, 2019). Whether FUS neuromodulation of targeted peripheral ganglion or plexus provides a more efficacious use of the new technology and reduces more severe IBD models/symptomology has not been investigated.…”

“…Weight loss was assessed relative to baseline weights. (Cotero et al, 2019), unlike previous ultrasound applications that required a transducer to be swept across an organ (Gigliotti et al, 2013) or left in place as unfocused ultrasound with a 5 cm 2 footprint (Nunes et al, 2019).…”

Bilobalide Alleviated Dextran Sulfate Sodium-Induced Experimental Colitis by Inhibiting M1 Macrophage Polarization Through the NF-κB Signaling Pathway

“…The DSS acts as a negatively charged water-soluble sulfated polysaccharide with a highly variable molecular weight ranging from 5 to 1,400 kDa (Chassaing et al, 2014). Through the alteration in the concentration and the frequency of DSS administration, acute, chronic, and relapsing models of intestinal inflammation may be achieved (Di Martino et al, 2016;Nunes et al, 2019). Notably, a closely resembled human ulcerative colitis (UC) is regarded as the most severe murine colitis that is induced through the administration of 40 to 50 kDa DSS in drinking water (Okayasu I et al, 1990).…”