The Role Of FXR In The Gastric Intestinal Metaplasia Induced By Deoxycholic Acid

A high incidence of gastric cancer is known to occur in China, and the early diagnosis of gastric carcinoma is more important to obtain good prognosis. Minute changes of gastric pits and microvascularity are common in early gastric cancer and precancerous lesions. Magnification endoscopy, chromoendoscopy and narrow band imaging (NBI) can be applied to detect those dangerous gastric lesions correctly. Intestinal metaplasia(IM) of the gastric mucosa is regarded as the precancerosis of gastric cancer. Bile acid is known as an important factor that acts to create an environment favoring the development of gastric IM. Cdx2is a specific intestinal transcription factor and plays a critical role in IM. Present researches show that FXR has special effect on gastrointestinal tumors and precancerosis. The Role of FXR in the mechanism of gastric IM induced by bile acid should be elucidated.Part I The Clinical Value of NBI and Magnification Chromoendoscopy in Diagnosis of Early Gastric Cancer and Precancerous LesionsObjectives:To investigate the clinical value of NBI and MCE in diagnosis of early gastric cancer (EGC) and precancerous lesions.Methods:One hundred and sixty two patients with188gastric lesions were enrolled and divided two groups randomly as group NBI+IC (NBI+indigo carmine) and group NBI+EP (NBI+epinephrine). Routine endoscopy followed by NBI, the chromoendoscopy (indigo carmine or epinephrine) combined magnification endoscopy was sequentially used. The quality of the gastric lesions, pits and microvascularity were evaluated. The gastric pits and microvascularity were observed and divided into corresponding patterns. The biopsy samples were taken in suspicious area. The values in diagnosis of EGC and precancerous of NBI and MCE were compared.Results:(1) There was no significant difference in detection rate of severe hyperplasia and EGC between group NBI+IC and group NBI+EP (x2=0.63, P>0.05).(2)Visualization of silhouette of gastric lesions by NBI endoscopy and chromoendoscopy were clearer than the conventional endoscopy. There was no significant difference between NBI and chromoendoscopy in both group NBI+IC and NBI+EP.(3) Visualization of gastric pit by NBI combined with magnification endoscopy (ME) was clearer than MCE and ME in both group NBI+IC and NBI+EP.(4) Visuatization of gastric mucosa microvascularity by NBI combined with ME was clearer than the ME and indigo carmine MCE in group NBI+IC; In group NBI+EP, the scores of epinephrine MCE was higher, yet no significant difference between NBI combined with ME and epinephrine MCE.(5)Compared gastric pits with histological results in188lesions of group NBI+IC and NBI+EP, Ⅰ or Ⅱ were usually found in gastric inflammation, type Ⅲ in gastric atrophy, type Ⅲ or Ⅳ in intestinal metaplasia, type Ⅳ in dysplasia and type Ⅳ or Ⅴ in EGC.(6)Compared gastric mucosa microvascularity with histological results in188lesions of group NBI+IC and NBI+EP, type Ⅰ or Ⅱ were usually found in inflammation, atrophy and intestinal metaplasia, type Ⅱ in dysplasia, type Ⅱ or Ⅲ in EGC.(7)The accuracy, sensitivity and specificity of diagnosis in gastric precancerous lesions all have insignificant deviation between NBI combined ME and MCE in both group NBI+IC and NBI+EP.(Group NBI+IC:x2=3.273, P>0.05; x2=2.057, P>0.10; x2=1.373, P>0.10; Group NBI+EP:x2=1.353, P>0.25;x2=1.153, P>0.50; x2=0.259, P>0.75).(8)The accuracy, sensitivity and specificity of diagnosis in gastric cancer all have insignificant deviation between NBI combined ME and MCE in both group NBI+IC and NBI+EP.(Group NBI+IC:x2=1.348, P>0.25; x2=1.222, P>0.50; x2=0.686, P>0.50; Group NBI+EP:x2=0.443, P>0.75; x2=1.091, P>0.50; x2=0.123, P>0.75).Conclusions:(1) NBI and MCE can capture optimal view of gastric lesion, pits and microvascularity. It is always helpful for improving the accuracy of early gastric cancer and precancerous lesions on endoscopic target biopsies.(2) Since easy to be operated, NBI system can be used as a complementary technique and it will have a wider prospect of application in the future.(3) As epinephrine has microvascularity-enhanced effect on EGCs. MCE with epinephrine is a powerful tool for assessing tumor vascularity and may contribute to the histologic diagnosis of EGCs before endoscopic treatment. Part Ⅱ The Role of FXR in the Gastric Intestinal Metaplasia Induced by Deoxycholic AcidObjectives:To study the role of Farnesoid X Receptor (FXR) in the mechanism of gastric intestinal metaplasia induced by deoxycholic acid (DCA).Methods:In vitro cultured human gastric epithelial cell line (GES-1) was induced by DCA in different concentrations for different time. Separately, MTT assay was applied to analyze the proliferation rate of GES-1cell line. Real-time PCR and Western Blot were used to analyze the mRNA and protein expression levels of FXR, Cdx2and MUC2with or without GW4064and Guggulsterone.Results:(1) DCA promoted the proliferation of GES-1with low-moderate dose (for short time. On the contrary, DCA inhibited the proliferation of GES-1with high dose for long time (P<0.05).(2) DCA up regulated the expression of FXR, Cdx2and MUC2in a dose dependent manner when treated with DCA. The highest expression levels of three genes occurred on condition of treated with DCA (400μmol/L,6h)(P<0.05). When treated with400μmol/L DCA, FXR and Cdx2had highest expression levels at6h. The highest expression level of MUC2is at12h, later than FXR and Cdx2.(P<0.05).(3)FXR agonist GW4064enhanced the three genes expression levels. Oppositely, FXR antagonist Guggulsterone attenuated their expression.(P<0.05).Conclusions:(1)DCA promoted the proliferation of GES-1with low dose for short time. DCA with high dose for long time inhibited the proliferation of GES-1cell.(2)DCA induced Cdx2expression through the FXR in GES-1cells. FXR may play an important role in the induction of gastric intestinal metaplasia and carcinogenesis induced by DCA.