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Crohn's disease (CD) is a chronic intestinal disturbance mediated by mucosal immune hyperactivity that is often associated with the formation of stenosis. No reliable solution to stenosis CD exists so far. Therefore, we generated carboxymethyl chitosan oligosaccharide (CMCOS) as a new promising therapy and investigate its efficacy in an improved rat CD model. CMCOS was synthesized by enzymatic hydrolysis, and its biosafety was evaluated in vivo. The rat model of stenosis CD was optimized by an orthogonal experiment of 75 or 100 mg/kg trinitrobenzenesulfonic acid (TNBS) in a 50 or 75% ethanol enema. The therapeutic efficacy of CMCOS on the rat model of stenosis CD was investigated and compared with the commercial drug 5-aminosalicylic acid over a 28 day period of disease progression. The rat model of stenosis CD was well established by intracolonic administration of 75 mg/kg TNBS in 75% ethanol. CMCOS significantly alleviated CD symptoms morphologically, hematologically, and pathologically, promoting functional recovery of intestinal epithelium in a dose-dependent manner. CMCOS reduced infiltrations of inflammatory cells by regulating the IL-17A/PPAR-γ pathway and reduced fibro-proliferation and fibrodegeneration of the colon tissue by downregulating the TGF-β1/WT1 pathway. 75 mg/kg TNBS in a 75% ethanol enema induces a rat model of stenosis CD suitable for preclinical pathology and pharmacological studies. The safety, antifibrosis, and functional repair performance of CMCOS make it a promising candidate for the treatment of stenosis CD.

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