The intestinal epithelium is continuously exposed to potentially harmful antigens, pathogens, toxins and air pollutants, and premature enterocytes are vulnerable to these exogenous and endogenous stimuli.Chitosan oligosaccharide (COS), a degradation product of chitosan with anti-oxidative, anti-inflammatory and anti-bacterial effects, may be a good source material for the development of a potent therapeutic agent against inflammatory responses.This study was conducted to investigate the effects of dietary COS on the intestinal inflammatory response and the calcium-sensing receptor (CaSR)and nuclear factor-kappa B (NF-κB) signaling pathways that may be involved using a lipopolysaccharide (LPS)-challenged piglet model.A total of 40 piglets (Duroc × Landrace × Large Yorkshire) weaned at 28 days were used in a 2 × 2 factorial design; the main factors were dietary treatment (basal or COS) and inflammatory challenge (LPS or saline).Piglets were fed the basal diet or the basal diet plus 300 μg/kg COS for a 21-d period.On d 14 and 21 after the initiation of treatment, the challenged group received an intraperitoneal injection ofEscherichia coli LPS (E.coli serotype 055∶B5)at 60 and 80 μg/kg BW, respectively, and the unchallenged group was injected with the same amount of sterilized saline.Two hours following the injection with LPS or saline, serum and intestinal samples were obtained.Serum concentrations of cytokines as well as histopathological grading, abundance of cytokine mRNA and expressions of CaSR and NF-κB pathway proteins were determined.The results showed that dietary supplementation with COS significantly alleviated histopathological injury induced by LPS which indicated by lesser mononuclear cell and polymorphonuclear cell infiltration, erosion and epithelial hyperplasia.Piglets fed the COS diet had lower serum concentrations ofTNF-α, IL-6 and IL-8as well as lower abundances of proinflammatory cytokines (IL-1β, IL-6, IL-8 etc) mRNA but higher anti-inflammatory cytokines (IL-4, TGF-β 1) mRNA in the jejunum and ileum compared with piglets fed the basal diet among LPS-challenged piglets (P < 0.05).Dietary supplementation with COS increased the expression of CaSR and PLCβ2 proteins in the jejunum and ileum of both saline-and LPS-treated piglets but decreased the expression ofp-NF-κB, IKKα/β and Iκ B proteins in the jejunum and ileum of LPS-challenged piglets (P < 0.05).These findings indicate that COS may be able to reduce the intestinal inflammatory response, concomitant with the activation of CaSR and the inhibition of NF-κB signaling pathways under an inflammatory stimulus.Further studies will be needed to elucidate the mechanisms that regulate homeostasis and cross-talk between CaSR and the NF-κB-mediated inflammatory pathway in health and disease.