| 【Background】One of the most common malignant tumors of the gastrointestinal tract is gastric cancer（GC）.The occurrence of intestinal type GC is in accordance with the"Correa model",namely,non-atrophic gastritis,atrophic gastritis,intestinal metaplasia（IM）,atypical hyperplasia,and finally progression to early GC,in which IM is the key link in the transformation of normal gastric mucosa from benign to malignant.According to the pathological characteristics,IM can be divided into complete IM and incomplete IM,and also,IM can be classified as mild IM,moderate IM,and severe IM according to the area of intestinalization or the number of cupped cells.Numerous studies have demonstrated that the risk of GC in incomplete IM or severe IM is significantly greater,therefore,IM intervention is the first step to prevent gastric cancer,and it is especially important to clarify the risk factors associated with the occurrence of IM.Currently,IM-related risk factors are not fully understood.National and international studies have confirmed that HP infection,age,high-salt diet and other factors are closely related to gastric mucosa IM,while it is still controversial whether gender,smoking,tea consumption and bile reflux are related to the occurrence of gastric mucosa IM.In particular,the relationship between bile reflux and gastric mucosa IM is currently controversial,and previous studies have only classified bile reflux as present or absent,without grading endoscopic bile reflux,and the conclusions have yet to be further validated.Therefore,this study further investigated the relationship between endoscopic bile reflux scale and other factors and gastric mucosal IM,aiming to provide evidence for early prevention and treatment of IM.Bile reflux gastritis（BRG）is a disease of inflammatory changes of gastric mucosa caused by excessive bile reflux into the stomach through the pylorus,which can lead to a series of clinical symptoms,and several studies have found that excessive reflux of bile acids into the stomach is closely associated with an increased risk of GC.In addition,cellular experiments have confirmed that bile acid stimulation can induce intestinal metaplasia of gastric epithelial cells,therefore,we speculate that bile acid in gastric juice may induce the development of gastric mucosa IM,especially incomplete IM or severe IM,leading to the occurrence of GC.However,it is unclear whether there is a correlation between bile acid concentration in gastric juice and gastric mucosa IM and the pathological classification and severity of IM,which is the focus of this study.In addition,the molecular mechanism of bile acid-induced intestinal metaplasia of gastric epithelial cells is still unclear.The activation of Caudal Homobox transcription factor 2（CDX2）,an intestine-specific transcription factor,is considered to have played an important role in the onset of IM,which is directly related to the progression of IM.SRY related HMG box-2（SOX2）is a key transcription molecule closely related to gastric differentiation,which has an opposite expression pattern to CDX2,and the two constitute a regulatory network that may play a significant regulatory role in the progression of IM.Farnesoid X receptor（FXR）and G protein-coupled bile acid receptor 5（TGR5）are the two most essential receptors mediating the action of bile acids,which can promote IM by activating their receptors.The four factors mentioned above are closely related to the occurrence of bile acid-induced IM,but their expression in IM tissue and their relationship with bile acid concentration in gastric juice are still unclear.Based on this,this study will further explore the relationship between bile acid concentration in gastric juice and IM and the relevant molecular mechanism.【Objective】1.To explore the relationship between IM and age,sex,smoking history,drinking history,eating habits,history of concomitant diseases,HP infection,endoscopic bile reflux scale and other related variables.2.To study the relationship between the concentration of bile acid in gastric juice and gastric mucosa IM,the pathological classification and severity of IM,and the related molecular mechanism.【Methods】1.97 patients with IM verified by pathology and 97 patients with chronic non-atrophic or chronic atrophic gastritis confirmed by endoscopy at the endoscopy center of our hospital were chosen as the study participants between November 2021 and October2022,and they were divided into IM group and non-IM group.We created a questionnaire to gather clinical information from the two groups,including their age,gender,Body mass index（BMI）,smoking and drinking histories,level of education,family history of gastric cancer,dietary habits,and history of concomitant diseases.HP infection was measured by13C urea breath test or rapid urease test,and bile reflux was graded under endoscope.The correlation between each variable and IM was analyzed by univariate and multivariate logistic regression analysis.2.The patients with bile reflux gastritis confirmed by gastroscopy at our hospital’s Endoscopy Center from March 2022 to December 2022 were chosen as the study subjects,and the patients suspected of having IM were evaluated by pathology.A total of 54 cases of bile reflux gastritis with IM were collected,and respectively 54 cases of age-and sex-matched healthy individuals,gastritis without bile reflux and bile reflux gastritis without IM were selected.They were divided into healthy control group,gastritis without bile reflux group,bile reflux gastritis without IM group and bile reflux gastritis with IM group,to analyze the difference of bile acid concentration in gastric juice of different groups.And then we selected patients with bile reflux gastritis as the research object,measured the concentration of bile acid in gastric juice,analyzed its correlation with the occurrence rates of IM in bile reflux gastritis,and determined the difference in the expression of FXR,TGR5,CDX2,SOX2 in gastric mucosa,and analyzed the correlation between the concentration of bile acid in gastric juice and the expression of FXR,TGR5,CDX2,SOX2 in gastric mucosa.Further,the relationship between bile acid concentration in gastric juice and pathological classification and severity of IM in patients with bile reflux gastritis was analyzed.【Results】1.The univariate logistic regression analysis demonstrated statistically significant differences between the two groups in terms of age,sex,smoking history,high-salt diet,spicy and stimulating diet,vegetables,fruits,tea drinking,HP infection,bile reflux（P<0.05）,while there was no significant difference in BMI,drinking history,education level,high-fat diet,pickled or smoked food diet,coffee,hypertension,hyperlipidemia,diabetes,family history of gastric cancer,gastric surgery history,and medication history（P>0.05）.The statistically significant variables in the univariate logistic regression analysis were added to the multivariate logistic regression analysis,and the results indicated age≥60 years（OR,4.050;95%CI 1.372-12.615;P=0.037）,high-salt diet（OR,3.605;95%CI 1.791-7.527;P=0.003）,HP infection（OR,4.022;95%CI 2.096-7.954;P<0.001）,II degree bile reflux（OR,3.470;95%CI 1.420-8.946;P=0.025）and III degree bile reflux（OR,16.922;95%CI 5.343-66.940;P<0.001）were independent risk factors for gastric mucosal IM,and increased vegetable intake（OR,0.296;95%CI 0.149-0.570;P=0.003）was the independent protective factor for gastric mucosal IM.2.The bile acid concentration in gastric juice of patients in healthy control group,gastritis without bile reflux group,bile reflux gastritis without IM group and bile reflux gastritis with IM group were 19.45（8.60,87.57）μmol/L、23.65（15.35,102.07）μmol/L、421.60（212.75,757.18）μmol/L and 1040.55（666.62,1916.35）μmol/L,respectively,and bile acid concentration in gastric juice of bile reflux gastritis with IM group was significantly higher than that of other three groups（P<0.05）,and bile acid concentration in gastric juice of bile reflux gastritis without IM group was significantly higher than thatof healthy control group and gastritis without bile reflux group（P<0.05）.Patients with bile reflux gastritis were divided equally into low concentration group,medium concentration group and high concentration group according to the concentration of bile acid.The incidence rate of IM in the three groups was 22.2%,41.7%and 86.1%respectively.There was a significantly higher incidence rate of IM in the high concentration group than in the medium and low concentration groups（P<0.05）.Bile reflux gastritis patients with IM were divided equally into low concentration group and high concentration group according to the concentration of bile acid.The incidence of incomplete IM in the two groups was 25.9%and 63.0%,respectively.There was a significantly higher incidence of incomplete IM in the high concentration group than in the low concentration group（P<0.05）,and the incidence of mild,moderate,and severe IM in the low concentration group was 59.3%,33.3%,and 7.4%,respectively,and the incidence of mild,moderate and severe IM in the high concentration group was 37.0%,44.4%and 18.5%,respectively,and the two groups were not significantly different with respect to the severity of IM（P>0.05）.The expression of FXR,TGR5,CDX2 and SOX2 in gastric mucosa of patients with bile reflux gastritis were tested by immunohistochemistry.The results showed that the high expression rates of four factors in bile reflux gastritis with IM group were 57.4%,51.9%,53.7%and 55.6%,respectively,and the high expression rates of four factors in bile reflux gastritis without IM group were 11.1%,14.8%,5.6%and 83.3%,respectively.The high expression rates of FXR,TGR5 and CDX2 in tissues with bile reflux gastritis with IM were remarkably higher than those without IM,and the high expression rate of SOX2was remarkably lower than that of tissues without IM（P<0.05）.At the same time,we analyzed the relationship between bile acid concentration in gastric juice and the expression of four factors.The results showed that bile acid concentration in gastric juice of patients with bile reflux gastritis was significantly positively correlated with the expression of FXR,TGR5 and CDX2 in tissues（P<0.05）,and was significantly negatively correlated with the expression of SOX2 in tissues（P<0.05）,and patients in the high concentration group had significantly higher expression rates of FXR,TGR5,and CDX2 in their gastric mucosa tissues than patients in the medium and low concentration groups（P<0.05）,and had significantly lower expression rates of SOX2 in their gastric mucosa tissues than patients in the medium and low concentration groups（P<0.05）.In addition,we further analyzed the correlation between the expression of FXR,TGR5,SOX2 and CDX2 in gastric mucosa of patients with bile reflux gastritis with IM.The results showed that the expression of FXR,TGR5 and CDX2 was significantly positive correlation（P<0.05）,and the expression of SOX2 and CDX2 was significantly negative correlation（P<0.05）.【Conclusions】1.Age,sex,smoking history,high-salt diet,spicy and stimulating diet,tea drinking,HP infection,bile reflux may be risk factors for gastric mucosal IM,and increased intake of vegetables and fruits may be protective factors for gastric mucosal IM,and age≥60years,high-salt diet,HP infection,II degree bile reflux and III degree bile reflux were independent risk factors for gastric mucosal IM,and increased vegetable intake is the independent protective factor for gastric mucosal IM.2.The bile acid concentration in gastric juice of patients with bile reflux gastritis with IM is significantly elevated.High concentration of bile acid may promote the occurrence of IM by regulating the expression of FXR,TGR5,CDX2 and SOX2,and when the concentration is higher,incomplete IM is more likely to occur.The relationship between the bile acid concentration in gastric juice and the severity of IM has not been found. |
PDF Full Text Request