Citrus aurantium L. and Its Flavonoids Regulate TNBS-Induced Inflammatory Bowel Disease through Anti-Inflammation and Suppressing Isolated Jejunum Contraction

Int J Mol Sci. 2018 Oct 7;19(10):3057. doi: 10.3390/ijms19103057.


Inflammatory bowel disease (IBD) is a serious digestive system disease, for which the clinical therapeutic choices remain limited. Dried fruits of Citrus aurantium L. (CAL) are a traditional medicine used for regulation of the digestive system. The aim of this study was to identify the regulatory effects of CAL on IBD and to clarify the mechanism of the active compounds. In trinitrobenzene sulfonic acid-induced IBD rats, 125 to 500 mg/kg of oral CAL significantly alleviated weight loss and diarrhea, decreased colitis inflammatory cell infiltration, and inhibited pro-inflammatory cytokine production. The mechanisms of characteristic flavonoids in CAL were evaluated involving inflammation and intestine contraction aspects. Naringenin, nobiletin, and hesperetin showed anti-inflammatory effects on lipopolysaccharide-induced RAW cells. The mechanism may be related to the inhibition of the tumor necrosis factor-α (TNF-α)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway to suppress cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions. Naringenin and nobiletin showed inhibitory effects on isolated jejunum contraction. The mechanism of naringenin is partly related to COX, NOS, inositol triphosphate (IP₃), and finally, to decreased jejunum motility. This study demonstrated that CAL, and its flavonoids' regulatory effects on IBD through anti-inflammation and inhibition of intestine muscle contraction, can provide basic information on developing new drugs or supplements against IBD based on CAL.

Keywords: Citrus aurantium L.; hesperetin; inflammatory; jejunum contraction; naringenin; nobiletin.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Cell Line
  • Citrus / chemistry*
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / etiology
  • Colitis, Ulcerative / metabolism
  • Cyclooxygenase 2 / metabolism
  • Flavonoids / pharmacology*
  • Flavonoids / therapeutic use
  • Gastrointestinal Motility
  • Jejunum / drug effects*
  • Jejunum / metabolism
  • Male
  • Mice
  • Muscle Contraction*
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Trinitrobenzenesulfonic Acid / toxicity
  • Tumor Necrosis Factor-alpha / metabolism


  • Anti-Inflammatory Agents
  • Flavonoids
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Trinitrobenzenesulfonic Acid
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2