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Additional file 4. Supplementary methods.

Additional file 3: Fig. S1. Regulatory component annotation of 665 DNA methylation (DNAm) sites. A) DNAm sites annotated with active or inactive chromatin states were enriched in different blood cell types. B) DNAm sites annotated with histone markers were enriched in different blood cell types. Reference of active chromatin states: active transcription start site (TSS)-proximal promoter states (TssA, TssAFlnk), a transcribed state at the 5′ and 3′ ends of genes showing both promoter and enhancer signatures (TxFlnk), actively transcribed states (Tx, TxWk), enhancer states (Enh, EnhG), and a state associated with zinc finger protein genes (ZNF/Rpts). Reference of inactive chromatin states: constitutive heterochromatin (Het), bivalent regulatory states (TssBiv, BivFlnk, EnhBiv), repressed polycomb states (ReprPC, ReprPCWk), and quiescent state (Quies). Reference histone marker: H3K4me1 is enriched at active and primed enhancers; H3K4me3 is a modification that is associated with transcriptionally active/poised chromatin.

Additional file 4: Fig. S2. Manhattan plots of colocalization between intestinal cis-eQTLs and mbQTLs. Six pairs of cis-eQTLs and mbQTLs with PPH4 > 0.5 were plotted for illustration: MUC1–CARNFORCAT.PWY, MUC1–PWWY.7237, CD40–PYRIDNUCSYN.PWY, CD40–PWY.5101, CD40–PWY.0845 and PRKAB1–P164.PWY. All microbial pathways were annotated by MetaCyc database ( https://metacyc.org/ ). The x-axis shows the chromosomal positions while the y-axis indicates the –log10 P values of SNPs.

Supplemental material, sj-docx-1-tag-10.1177_17562848231158549 for Gastrointestinal injury induced by immunomodulators: A review article by Pingxin Zhang, Ren Mao, Chuhan Zhang, Yun Qiu and Minhu Chen in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848231165129 for Neutrophil-to-lymphocyte ratio for predicting postoperative recurrence in Crohn’s disease patients with isolated anastomotic lesions by Rirong Chen, Chao Li, Kang Chao, Yizhe Tie, Jieqi Zheng, Huili Guo, Zhirong Zeng, Li Li, Minhu Chen and Shenghong Zhang in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848231170947 for Early transmural healing and its predictors assessed by magnetic resonance enterography in patients with Crohn’s disease receiving ustekinumab by Longyuan Zhou, Cicong Hu, Ruonan Zhang, Yun Qiu, Yu Wang, Zishan Liu, Baili Chen, Yao He, Zhirong Zeng, Xuehua Li, Ren Mao and Minhu Chen in Therapeutic Advances in Gastroenterology

Additional file 1: Fig S1. The mRNA expression heatmap of cadherin family in colonic epithelium of CD patients. Fig S2. PCDH20 expression in inflamed tissue of CD patients and successful construction of DSS and TNBS colitis. a Decreased expression of PCDH20 in inflamed tissue of CD patients. b-c Successful construction of TNBS colitis, greater weight loss, shortened colon length. d-g Successful construction of DSS colitis, greater weight loss, higher disease activity index, shortened colon length, and higher myeloperoxidaseactivity. Each group n > 3. * p

Supplemental material, sj-docx-1-tag-10.1177_17562848231158549 for Gastrointestinal injury induced by immunomodulators: A review article by Pingxin Zhang, Ren Mao, Chuhan Zhang, Yun Qiu and Minhu Chen in Therapeutic Advances in Gastroenterology

Additional file 1. Supplementary Methods.

Supplemental material, sj-docx-1-tag-10.1177_17562848231165129 for Neutrophil-to-lymphocyte ratio for predicting postoperative recurrence in Crohn’s disease patients with isolated anastomotic lesions by Rirong Chen, Chao Li, Kang Chao, Yizhe Tie, Jieqi Zheng, Huili Guo, Zhirong Zeng, Li Li, Minhu Chen and Shenghong Zhang in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848231170947 for Early transmural healing and its predictors assessed by magnetic resonance enterography in patients with Crohn’s disease receiving ustekinumab by Longyuan Zhou, Cicong Hu, Ruonan Zhang, Yun Qiu, Yu Wang, Zishan Liu, Baili Chen, Yao He, Zhirong Zeng, Xuehua Li, Ren Mao and Minhu Chen in Therapeutic Advances in Gastroenterology

Additional file 5. Peer review history.

Supplemental material, sj-docx-1-tag-10.1177_17562848221116666 for Anti-TNF-α agents for refractory intestinal Behçet’s disease: case series and meta-analysis by Shukai Zhan, Caiguang Liu, Na Li, Tong Li, Zhenyi Tian, Min Zhao, Dongxuan Wu, Minhu Chen, Zhirong Zeng and Xiaojun Zhuang in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848221089096 for Development and validation of a non-invasive biomarker-based model to identify endoscopic recurrences of Crohn’s disease by Gaoshi Zhou, Rirong Chen, Yueyun Jiang, Li Li, Jieqi Zheng, Chao Li, Shenghong Zhang and Minhu Chen in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848221116666 for Anti-TNF-α agents for refractory intestinal Behçet’s disease: case series and meta-analysis by Shukai Zhan, Caiguang Liu, Na Li, Tong Li, Zhenyi Tian, Min Zhao, Dongxuan Wu, Minhu Chen, Zhirong Zeng and Xiaojun Zhuang in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848221089096 for Development and validation of a non-invasive biomarker-based model to identify endoscopic recurrences of Crohn’s disease by Gaoshi Zhou, Rirong Chen, Yueyun Jiang, Li Li, Jieqi Zheng, Chao Li, Shenghong Zhang and Minhu Chen in Therapeutic Advances in Gastroenterology

Additional file 1: Materials and Methods. Figure S1. Inflammation parameters after induction of acute colitis with TNBS in mice. Table S1. Histologic grading of biopsy specimens in Crohn’s disease. Table S2. Nancy index system in ulcerative colitis. Table S3. DAI of the control and TNBS-treated mice with acute colitis. Table S4. Macroscopic damage score of the control and TNBS-treated mice with acute colitis.

Objective To present results of the Kyoto Global Consensus Meeting, which was convened to develop global consensus on (1) classification of chronic gastritis and duodenitis, (2) clinical distinction of dyspepsia caused by Helicobacter pylori from functional dyspepsia, (3) appropriate diagnostic assessment of gastritis and (4) when, whom and how to treat H. pylori gastritis. Design Twenty-three clinical questions addressing the above-mentioned four domains were drafted for which expert panels were asked to formulate relevant statements. A Delphi method using an anonymous electronic system was adopted to develop the consensus, the level of which was predefined as ≥80%. Final modifications of clinical questions and consensus were achieved at the face-to-face meeting in Kyoto. Results All 24 statements for 22 clinical questions after extensive modifications and omission of one clinical question were achieved with a consensus level of >80%. To better organise classification of gastritis and duodenitis based on aetiology, a new classification of gastritis and duodenitis is recommended for the 11th international classification. A new category of H. pylori -associated dyspepsia together with a diagnostic algorithm was proposed. The adoption of grading systems for gastric cancer risk stratification, and modern image-enhancing endoscopy for the diagnosis of gastritis, were recommended. Treatment to eradicate H. pylori infection before preneoplastic changes develop, if feasible, was recommended to minimise the risk of more serious complications of the infection. Conclusions A global consensus for gastritis was developed for the first time, which will be the basis for an international classification system and for further research on the subject.

OBJECTIVES: The global prevalence of IBS is difficult to ascertain, particularly in light of the heterogeneity of published epidemiological studies. The aim was to conduct a literature review, by experts from around the world, of community-based studies on IBS prevalence. DESIGN: Searches were conducted using predetermined search terms and eligibility criteria, including papers in all languages. Pooled prevalence rates were calculated by combining separate population survey prevalence estimates to generate an overall combined meta-prevalence estimate. The heterogeneity of studies was assessed. RESULTS: 1451 papers were returned and 83, including 288 103 participants in 41 countries, met inclusion criteria. The mean prevalence among individual countries ranged from 1.1% in France and Iran to 35.5% in Mexico. There was significant variance in pooled regional prevalence rates ranging from 17.5% (95% CI 16.9% to 18.2%) in Latin America, 9.6% (9.5% to 9.8%) in Asia, 7.1% (8.0% to 8.3%) in North America/Europe/Australia/New Zealand, to 5.8% (5.6% to 6.0%) in the Middle East and Africa. There was a significant degree of heterogeneity with the percentage of residual variation due to heterogeneity at 99.9%. CONCLUSIONS: The main finding is the extent of methodological variance in the studies reviewed and the degree of heterogeneity among them. Based on this, we concluded that publication of a single pooled global prevalence rate, which is easily calculated, would not be appropriate or contributory. Furthermore, we believe that future studies should focus on regional and cross-cultural differences that are more likely to shed light on pathophysiology.

Multiple studies have shown that IL23 cytokine plays an essential role in the development of autoimmune diseases by activating IL17-producing helper T (Th17) cells. Given that the susceptibility loci in IL23R for Crohn's disease (CD) is present in Western population and not in Asian population; we screened the IL23R gene by DNA sequencing to identify susceptibility loci in a selected CD cohort and confirmed it in all our subjects (134 CD and 131 controls). A novel nonsynonymous SNP (p.Gly149Arg, c.445GA) and 35 single nucleotide polymorphisms (SNPs) were identified. Among them, only rs11465788 was implicated in CD susceptibility (P = 4.9 x 10(-4), OR = 0.30). Genotype-phenotypic interaction analysis showed that rs11465788 is associated with nonstricturing and nonpenetrating disease behaviour in CD patients (P = 0.015). Our results provide the evidence that rs11465788 may influence the susceptibility and clinical features of CD in Chinese population.

In this paper, we investigated Cdx2 and claudin-2 expression in pathological paraffin tissues of sinus ventriculi from gastroscopic biopsy to determine the correlation between the expressions of these 2 genes during gastric carcinogenesis by immunochemical ABC technique. Altogether, we analyzed 108 chronic superficial gastritis, 55 chronic atrophic gastritis, 109 intestinal-type metaplasia, 93 dysplasia and 52 gastric intestinal-type adenocarcinoma samples. Our results indicated that the percentage of Cdx2-positive cases was 0% (0/108) for chronic superficial gastritis, 0% (0/55) for chronic atrophic gastritis, 90.83% (99/109) for intestinal-type metaplasia, 51.61% (48/93) for dysplasia and 61.54% (32/52) for gastric intestinal-type adenocarcinoma, primarily expressed in the cell nucleus and partly in the cytoplasm (p < 0.05); interestingly, the percentage for the intestine-type metaplasia was markedly high. The percentage of claudin-2-positive cases was 0% (0/108) for chronic superficial gastritis, 0% (0/55) for chronic atrophic gastritis, 0% (0/109) for intestinal-type metaplasia, 35.48% (33/93) for dysplasia and 71.15% (37/52) for gastric intestinal-type adenocarcinoma, primarily in the cell membrane and gradually increased in the multistage process of gastric carcinogenesis (p < 0.05). Significant correlations were found between claudin-2 and Cdx2 protein expression in dysplasia and intestine-type adenocarcinoma (r = 0.112, p < 0.05). Thus, there may be a correlation between the expression of claudin-2 and Cdx2 in stages of dysplasia and cancer.

OBJECTIVE: To evaluate the effects of intravenous infusion of omeprazole and H2-receptor antagonists on 24-h intragastric pH levels in patients with bleeding duodenal ulcers. METHODS: Fifty patients with active bleeding duodenal ulcers were randomly assigned to receive one of four treatment regimens: 40 mg omeprazole by intravenous infusion every 12 h, 40 mg famotidine intravenously every 12 h, 50 mg ranitidine intravenously every 6 h, 200 mg cimetidine intravenously every 6 h. Intragastric pH values were monitored in each subject at the baseline level and continuously for 24 h after treatment. RESULTS: Only the omeprazole group produced mean and median intragastric pH values of above 6. The famotidine group had mean and median intragastric pH values above 4. In the other two groups, pH values were both below 4. The mean percentages of time that intragastric pH levels were < 4, < 5 and < 6 over the 24 h period in each of the treatment groups were found to increase in the following order (smallest percentage to largest percentage): omeprazole, famotidine, ranitidine and cimetidine. CONCLUSIONS: The effect of intravenous use of omeprazole in active duodenal ulcer bleeding is superior to that of H2-receptor antagonists and the increase in intragastric pH is maintained for a longer period.

Up to approximately 40% to 50% of patients discontinue thiopurine therapy during the course of inflammatory bowel disease (IBD). We investigated the role of the metabolite thiopurine in IBD treatment. This was a prospective study. IBD patients receiving azathioprine (AZA) were prospectively included. Thiopurine methyltransferase (TPMT) genotypes were examined before therapy, and thiopurine metabolite levels were examined at weeks 2, 4, 8, 12, 24, and 48. In total, 132 patients were included. The frequency of leucopenia increased at 6-thioguanine nucleotide (6-TGN) levels ≥420 pmol/8 × 108 RBC (odds ratio [OR] = 7.9; 95% confidence interval (95%CI): 3.5–18.0; P

Not all of the adverse effects to thiopurine therapy can be explained by thiopurine methyltransferase (TPMT) polymorphisms. This study was intended to evaluate the value of TPMT genotype and phenotype measurement during the first year of thiopurine therapy.Consecutive patients with inflammatory bowel disease (IBD) who were receiving azathioprine or 6-mercaptopurine were followed up for 12 months. TPMT genotypes and phenotypes were examined in patients with IBD before thiopurine therapy and in unrelated healthy volunteers by polymerase chain reaction and high-performance liquid chromatography.A total of 199 patients and 300 healthy volunteers were included at 2 centers. Forty-seven of the 199 patients (23.62%) exhibited adverse effects during the entire course of thiopurine therapy. Two (1%) patients carrying TPMT*3C developed leucopenia at week 4 of azathioprine treatment. The TPMT*3C had a specificity of 100% (163/163) but a sensitivity of 5.56% (2/36) for predicting leucopenia. The calculated optimal cutoff activity for high TPMT activity and decreased TPMT activity was 4.75 U/mL red blood cells. The risk of leucopenia increased in the decreased TPMT group (odds ratio: 20.25; 95% confidence interval: 2.19-187.17; P = 0.004) and increased more during the initial 3 months of thiopurine therapy (odds ratio: 34.80; 95% confidence interval: 3.71-326.77; P = 0.001). Leucopenia occurred more frequently in the patients cotreated with 5-aminosalicylates than in those not cotreated (32.81% versus 11.11%, respectively, P0.001).The results of this study suggest that the value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia, and that phenotyping is a more cost-effective tool that can be successfully used in patients. The coadministration of 5-aminosalicylates results in a high frequency of leucopenia in patients receiving azathioprine or 6-mercaptopurine.

Silybin, a natural antioxidant, has been traditionally used against a variety of liver ailments. To investigate its effect and the underlying mechanisms of action on non-alcoholic fatty liver in rats, we used 60 4-6-week-old male Sprague-Dawley rats to establish fatty liver models by feeding a high-fat diet for 6 weeks. Hepatic enzyme, serum lipid levels, oxidative production, mitochondrial membrane fluidity, homeostasis model assessment-insulin resistance index (HOMA-IR), gene and protein expression of adiponectin, and resistin were evaluated by biochemical, reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Compared with the model group, silybin treatment (26.25 mg·kg(-1)·day(-1), started at the beginning of the protocol) significantly protected against high-fat-induced fatty liver by stabilizing mitochondrial membrane fluidity, reducing serum content of alanine aminotransferase (ALT) from 450 to 304 U/L, decreasing hepatic malondialdehyde (MDA) from 1.24 to 0.93 nmol/mg protein, but increasing superoxide dismutase (SOD) and glutathione (GSH) levels from 8.03 to 9.31 U/mg protein and from 3.65 to 4.52 nmol/mg protein, respectively. Moreover, silybin enhanced the gene and protein expression of adiponectin from 215.95 to 552.40, but inhibited that of resistin from 0.118 to 0.018. Compared to rosiglitazone (0.5 mg·kg(-1)·day(-1), started at the beginning of the protocol), silybin was effective in stabilizing mitochondrial membrane fluidity, reducing SOD as well as ALT, and regulating gene and protein expression of adiponectin (P < 0.05). These results suggest that mitochondrial membrane stabilization, oxidative stress inhibition, as well as improved insulin resistance, may be the essential mechanisms for the hepatoprotective effect of silybin on non-alcoholic fatty liver disease in rats. Silybin was more effective than rosiglitazone in terms of maintaining mitochondrial membrane fluidity and reducing oxidative stress.

OBJECTIVE: To investigate the effect of eradicating Helicobacter pylori on the development and reversion of atrophic gastritis in an animal study. METHODS: One hundred and ten grade II C57BL/6 female mice were randomly divided into experimental (60 mice) and control (50 mice) groups. The mice in the experimental group were infected with the SS1 H. pylori strain, then randomly subdivided into group A and group B (30 mice in each group). Group A and group B received a dose of standard bismuth triple therapy 6 and 12 months after infection, respectively. Ten mice in each group were killed before the therapy, then at 3 and 6 months after completion of the therapy (a total of 30 mice). The histopathological features of the glandular stomach were graded using a method analogous to the Sydney system and kinetic changes in the mucosal epithelial cells of the glandular stomach were examined using anti-BrdU immunohistochemical staining and flow cytometry. RESULTS: All mice that received eradication therapy tested negative for Helicobacter pylori. Significant improvement in chronic active gastritis was observed after the eradication of H. pylori in both groups A and B. Atrophic changes were not seen at any time interval in group A, whereas in group B, atrophic changes were seen 12 months after H. pylori infection and no significant changes in the degree of atrophy were observed 3 and 6 months after the eradication of H. pylori. The cell kinetic indices (S-phase cell percentage, proliferation index and labeling index) in the experimental group before the eradication of H. pylori were significantly higher than those in the control group at any time (P 0.05). CONCLUSIONS: The present study suggests that the eradication of H. pylori can reduce gastric mucosal inflammation and change the epithelial cell kinetics of the stomach. It was found that early treatment can prevent the formation of mucosal atrophy. When atrophy has established, eradication of H. pylori can no longer reverse the change but may prevent its progress.