Blocking Interleukin‐6 signalling ameliorates gastrointestinal dysfunction in the mdx model of Duchenne Muscular Dystrophy

GI hypomotility, pseudo obstruction and constipation have been reported in patients with Duchenne muscular dystrophy. Although the pathology is attributed to dystrophin deficiency in abdominal skeletal muscle and the associated lack of mobility, smooth muscle and enteric neurons are also deficient in dystrophin. Hence, the study aims were to assess GI function in the mdx mouse and determine if the pathophysiological changes could be ameliorated with therapeutic interventions. Stress‐induced defecation rates, colonic morphology and colonic contractile activity were compared between wild‐type (WT) and mdx mice. Saline‐treated control mdx mice were compared with mdx mice receiving either monoclonal anti‐IL‐6 receptor antibodies (xIL‐6R, 0.3mg/kg), or the corticotropin‐releasing factor 2 receptor agonist, urocortin 2 (uro2, 30µg/kg) or both. Mdx mice have significantly slower rates of defecation in response to an open field stressor. Morphologically, their colon lengths are shorter and their colonic muscle layers are thicker. Colonic contractions evoked by IL‐6 were increased in mdx mice and this was attenuated by prior incubation with tetrodotoxin. Abnormal faecal output in mdx mice was normalised by xIL‐6R treatment and xIL‐6R alone or xIL‐6R and uro2 normalises colonic length. Moreover, the amplitude of IL‐6‐evoked colonic contractions was significantly reduced by xIL‐6R, uro2 or co‐treatment. This is likely to be related to the observed decrease in colonic expression of IL‐6R protein. These data suggest that the loss of dystrophin from colonic smooth muscle and/or enteric neurons in mdx mice results in altered GI morphology and function. However, GI function and morphology can be normalised by in vivo treatment with xIL‐6R and/or uro2.