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Abstract Aims The endoscopic treatment of esophagogastric varices is challenging, and the nationwide application of endoscopic therapies for various types of esophagogastric varices and different clinical scenarios remains unclear. This study investigated the use of endoscopic therapy for portal hypertension in China. Methods This study used a questionnaire survey initiated by the Liver Health Consortium in China to investigate the use of endoscopic therapies for portal hypertension. Questionnaires were released online from January 30, 2023 to February 28, 2023 and filled out by chief physicians or senior instructors responsible for endoscopic therapies in participating hospitals across 31 provinces (autonomous regions and municipalities) in China. Comparisons of guideline adherence between primary and referral medical centers were performed using the chi‐square test or Fisher's exact test. Results In total, 836 hospitals participated in the survey. For primary and secondary prophylaxis of esophagogastric variceal bleeding (EGVB), adherence to the national guidelines was 72.5% (606/836) and 39.2% (328/836), respectively. Significant differences were observed in the rate of adherence between the primary and referral centers for primary (79.9% [111/139] vs. 71.0% [495/697], p = 0.033) and secondary prophylaxis (27.3% [38/139] vs. 41.6% [290/697], p = 0.002). Of the hospitals, 78.2% (654/836) preferred endoscopic therapies for acute EGVB, and the timing of endoscopy was usually within 12 h (48.5%, 317/654) and 12–24 h (36.9%, 241/654) after bleeding. Endoscopic therapy was more likely to be the first choice of treatment for acute EGVB in referral centers than in primary centers (82.6% [576/697] vs. 56.1% [78/139], p

Abstract Ulcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract. Various programmed cell death pathways in the intestinal mucosa are crucial to the pathogenesis of UC. Disulfidptosis, a recently identified form of programmed cell death, has not been extensively reported in the context of UC. This study evaluated the expression of disulfidptosis-related genes (DRGs) in UC through public databases and assessed disulfide accumulation in the intestinal mucosal tissues of UC patients and dextran sulfate sodium (DSS)-induced colitis mice via targeted metabolomics. We utilized various bioinformatics techniques to identify UC-specific disulfidptosis signature genes, analyze their potential functions, and investigate their association with immune cell infiltration in UC. The mRNA and protein expression levels of these signature genes were confirmed in the intestinal mucosa of DSS-induced colitis mice and UC patients. A total of 24 DRGs showed differential expression in UC. Our findings underscore the role of disulfide stress in UC. Four UC-related disulfidptosis signature genes—SLC7A11, LRPPRC, NDUFS1, and CD2AP—were identified. Their relationships with immune infiltration in UC were analyzed using CIBERSORT, and their expression levels were validated by quantitative real-time PCR and western blotting. This study provides further insights into their potential functions and explores their links to immune infiltration in UC. In summary, disulfidptosis, as a type of programmed cell death, may significantly influence the pathogenesis of UC by modulating the homeostasis of the intestinal mucosal barrier.

Abstract Gut bacteriome dysbiosis is known to be implicated in the pathogenesis of inflammatory bowel disease (IBD). Crohn’s disease (CD) is an IBD subtype with extensive mucosal inflammation, yet the mucosal virome, an empirical modulator of the bacteriome and mucosal immunity, remains largely unclear regarding its composition and role. Here, we exploited trans-cohort CD patients and healthy individuals to compositionally and functionally investigate the small bowel (terminal ileum) virome and bacteriome. The CD ileal virome was characterised by an under-representation of both lytic and temperate bacteriophages (especially those targeting bacterial pathogens), particularly in patients with flare-up. Meanwhile, the virome-bacteriome ecology in CD ileal mucosa was featured by a lack of Bifidobacterium- and Lachnospiraceae-led mutualistic interactions between bacteria and bacteriophages; surprisingly it was more pronounced in CD remission than flare-up, underlining the refractory and recurrent nature of mucosal inflammation in CD. Lastly, we substantiated that ileal virions from CD patients causally exacerbated intestinal inflammation in IBD mouse models, by reshaping a gut virome-bacteriome ecology preceding intestinal inflammation (microbial trigger) and augmenting microbial sensing/defence pathways in the intestine cells (host response). Altogether, our results highlight the significance of mucosal virome in CD pathogenesis and importance of mucosal virome restoration in CD therapeutics.

Abstract Background Hepatocellular carcinoma (HCC) is characterized by aggressive progression and elevated mortality rates. This study aimed to investigate the regulatory effects of RBBP7 on HCC pathogenesis and the underlying mechanisms. Methods The expression and clinical feature of RBBP7 were evaluated using bioinformatics analysis and the assessment of clinical HCC samples. CCK8 and colony formation were employed to estimate cell proliferation function of RBBP7. Aerobic glycolysis levels of RBBP7 were evaluated by measuring ATP levels, lactic acid production, glucose uptake capacity, and the expression of relevant enzymes (PFKM, PKM2, and LDHA). The phosphorylation levels in PI3K/AKT signaling were measured by western blotting. The regulatory effect of transcription factors of specificity protein 1 (SP1) on RBBP7 mRNA expression was confirmed in dual-luciferase reporter assays and chromatin immunoprecipitation experiments. The proliferation- and glycolysis-associated proteins were assessed using immunofluorescence staining in vivo. Results We found that RBBP7 is expressed at high levels in HCC and predicts poor survival. Functional assays showed that RBBP7 promoted HCC proliferation and glycolysis. Mechanistically, it was demonstrated that RBBP7 activates the PI3K/AKT pathway, a crucial pathway in glycolysis, contributing to the progression of HCC. The outcomes of the dual-luciferase assay further confirmed that SP1 is capable of activating the promoter of RBBP7. Conclusions RBBP7, which is up-regulated by SP1, promotes HCC cell proliferation and glycolysis through the PI3K/AKT pathway. The findings of this study suggest that RBBP7 is a potential biomarker for HCC.

The gut fungi play important roles in human health and are involved in energy metabolism. This study aimed to examine gut mycobiome composition in obese subjects in two geographically different regions in China and to identify specific gut fungi associated with obesity. A total of 217 subjects from two regions with different urbanization levels [Hong Kong (HK): obese, n = 59; lean, n = 59; Kunming (KM): obese, n = 50; lean, n = 49. Mean body mass index (BMI) for obesity = 33.7] were recruited. We performed deep shotgun metagenomic sequencing on fecal samples to compare gut mycobiome composition and trophic functions in lean and obese subjects across these two regions. The gut mycobiome of obese subjects in both HK and KM were altered compared to those of lean subjects, characterized by a decrease in the relative abundance of Nakaseomyces, Schizosaccharomyces pombe, Candida dubliniensis and an increase in the abundance of Lanchanceathermotolerans, Saccharomyces paradox, Parastagonospora nodorum and Myceliophthorathermophila. Reduced fungal – bacterial and fungal – fungal correlations as well as increased negative fungal-bacterial correlations were observed in the gut of obese subjects. Furthermore, the anti-obesity effect of fungus S. pombe was further validated using a mouse model. Supplementing high-fat diet-induced obese mice with the fungus for 12 weeks led to a significant reduction in body weight gain (p

BackgroundYunnan, a southwest highland and newly industrialized region of China, has an unknown hospitalization burden of inflammatory bowel disease (IBD). The study was conducted to explore territorial hospitalization burden of IBD.MethodsThe formatted medical records of patients with IBD were collected from a territory-wide database in Yunnan Province, China, from 2015 to 2020. General characteristics of the study population were reported using descriptive statistics. To evaluate the length of stay, hospitalization costs, surgery, complications, and trends in patients with inflammatory bowel disease. The logistic regression analysis was established to explore the factors affecting the hospitalization costs.ResultsA total of 12,174 records from 8192 patients were included. The annual hospitalization cost of IBD in Yunnan Province increased significantly from 2015 to 2020. From 2015 to 2020, the regional hospitalization burden of IBD increased, but it represented a decline in cost per hospitalization (r = −0.024, P = 0.008) and the length of stay (r = −0.098, P < 0.001). Surgery rates for hospitalized patients with Crohn’s disease (CD) did not decrease (r = −0.002, P = 0.932), and even increased for patients with ulcerative colitis (UC) (r = 0.03, P = 0.002). The costs per hospitalization were $ 827.49 (540.11–1295.50) for UC and $ 1057.03 (644.26–1888.78) for CD. Among the identifiable cost items during the period, drug costs accounted for the highest proportion, accounting for 33% and 37.30% in patients with UC and CD, respectively. Surgical intervention [OR 4.87 (3.75–6.31), P < 0.001], comorbidities [OR 1.72 (1.52–1.94), P < 0.001], complications [OR 1.53 (1.32–1.78), P < 0.001], and endoscopy [OR 2.06 (1.86–2.28), P < 0.001] were predictor of high hospitalization costs.ConclusionThe increasing burden of IBD is noteworthy a newly industrialized region of China. Interventions targeting surgery, complications, and comorbidities may be effective means of controlling the increasing hospitalization costs of IBD in the regions.

Abstract The human genome encodes more than 350 kinds of Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), KRAB-type ZNF transcription factor family (KZNF) plays a vital role in gene regulatory networks. The KZNF family members include a large number of highly homologous genes, gene subtypes and pseudogenes, and their expression has a high degree of tissue specificity and precision. Due to the high complexity of its regulatory network, the KZNF gene family has not been researched in sufficient, and the role of its members in the occurrence of cancer is mostly unexplored. In this study, ZNF880 was significantly associated with overall survival (OS) and disease-free survival (DFS) in colorectal carcinoma (CRC) patients. Low ZNF880 expression resulted in shorter OS and DFS. Combined with Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) data collection in the TCGA database, we found that ZNF880 was significantly down-regulated in CRC. Further analysis of the sequence variation of ZNF880 in CRC showed that ZNF880 accumulated a large number of SNV in the C2H2 domain and KRAB domain, while promoter region of ZNF880 also showed high methylation in COAD and READ. Combined with the Cbioportal and TIMER databases, the expression of mutant ZNF880 was significantly lower in COAD compared to the wild type. Simultaneously, the lncRNA-miRNA-ZNF880 ceRNA regulatory network was constructed through co-expression and miRNAs target gene prediction, demonstrating the precision of the ZNF880 regulatory network. In addition, the decreased expression of ZNF880 caused the significant immune infiltration decreases of CD8 + cells in COAD. In contrast, the immune infiltration of CD4 + cells and macrophages in COAD is positively correlated with ZNF880. Finally, through protein–protein interaction (PPI) network analysis and transcription factor target gene prediction, we screened out the genes most likely to be related to the function of ZNF880. CENPK, IFNGR2, REC8 and ZBTB17 were identified as the most closely functioning genes with ZNF880, which may indicate that ZNF880 has important links with the formation of cell centromere, tumor immunity, cell cycle and other pathways closely related to the occurrence of CRC. These studies show that the down-regulation of ZNF880 gene is closely related to CRC, and the targeted change of the expression of its regulatory molecules (miRNA and lncRNA) may be a new perspective for CRC treatment.

Cross-talks (e.g., host-driven iron withdrawal and microbial iron uptake between host gastrointestinal tract and commensal microbes) regulate immunotolerance and intestinal homeostasis. However, underlying mechanisms that regulate the cross-talks remain poorly understood. Here, we show that bacterial products up-regulate iron-transporter transferrin and transferrin acts as an immunosuppressor by interacting with cluster of differentiation 14 (CD14) to inhibit pattern recognition receptor (PRR) signaling and induce host immunotolerance. Decreased intestinal transferrin is found in germ-free mice and human patients with ulcerative colitis, which are characterized by impaired intestinal immunotolerance. Intestinal transferrin and host immunotolerance are returned to normal when germ-free mice get normal microbial commensalism, suggesting an association between microbial commensalism, transferrin, and host immunotolerance. Mouse colitis models show that transferrin shortage impairs host’s tolerogenic responses, while its supplementation promotes immunotolerance. Designed peptide blocking transferrin–CD14 interaction inhibits immunosuppressive effects of transferrin. In monkeys with idiopathic chronic diarrhea, transferrin shows comparable or even better therapeutic effects than hydrocortisone. Our findings reveal that by up-regulating host transferrin to silence PRR signaling, commensal bacteria counteract immune activation induced by themselves to shape host immunity and contribute for intestinal tolerance.

Ulcerative colitis (UC) is a refractory inflammatory disease with imbalances in intestinal mucosal homeostasis. Cuproptosis serves as newly identified programmed cell death (PCD) form involved in UC. In the study, UC-related datasets were extracted from the Gene Expression Omnibus (GEO) database. A comparison of UC patients and healthy controls identified 11 differentially expressed cuproptosis-related genes (DE-CRGs), where FDX1, LIAS, and DLAT were differentially expressed in UC groups from the mouse models and clinical samples, with their expression correlating with disease severity. By comprehending weighted gene co-expression network analysis (WGCNA) and differential expression analysis, the key genes common to the module genes relevant to different cuproptosis-related clusters and differentially expressed genes (DEGs) both in different clusters and patients with and without UC were identified using several bioinformatic analysis. Furthermore, the mRNA levels of four characteristic genes with diagnostic potential demonstrated significant decrease in both mouse models and clinical UC samples. Our discoveries offer a theoretical foundation for cuproptosis effect in UC.

Background: Achieving endoscopic and histological remission is a critical treatment objective in ulcerative colitis (UC). Nevertheless, interobserver variability can significantly impact overall assessment performance. Objectives: We aimed to develop a deep learning algorithm for the real-time and objective evaluation of endoscopic disease activity and prediction of histological remission in UC. Design: This is a retrospective diagnostic study. Methods: Two convolutional neural network (CNN) models were constructed and trained using 12,257 endoscopic images and biopsy results sourced from 1124 UC patients who underwent colonoscopy at a single center from January 2018 to December 2022. Mayo Endoscopy Subscore (MES) and UC Endoscopic Index of Severity Score (UCEIS) assessments were conducted by two experienced and independent reviewers. Model performance was evaluated in terms of accuracy, sensitivity, and positive predictive value. The output of the CNN models was also compared with the corresponding histological results to assess histological remission prediction performance. Results: The MES-CNN model achieved 97.04% accuracy in diagnosing endoscopic remission of UC, while the MES-CNN and UCEIS-CNN models achieved 90.15% and 85.29% accuracy, respectively, in evaluating endoscopic severity of UC. For predicting histological remission, the CNN models achieved accuracy and kappa values of 91.28% and 0.826, respectively, attaining higher accuracy than human endoscopists (87.69%). Conclusion: The proposed artificial intelligence model, based on MES and UCEIS evaluations from expert gastroenterologists, offered precise assessment of inflammation in UC endoscopic images and reliably predicted histological remission.

Background: The incidence of inflammatory bowel disease (IBD) is rapidly increasing in China, a vast country with significant geographical differences. The socioeconomic status of Eastern China is significantly higher than that of Western China. Objectives: This study aimed to describe the geographical heterogeneity in the characteristics and management of patients with IBD in both Eastern and Western China. Design: This was a multicenter, cross-sectional study. Methods: Patients with IBD with ages ⩾18 years up to 18 January 2023 were included in the analysis from the Chinese database for IBD. Logistic regression was used to identify risk factors associated with surgeries among patients with IBD. Results: Among 8305 patients with IBD, the ratio of ulcerative colitis (UC) to Crohn’s disease (CD) was 4.13 and 0.33 in Western and Eastern China, respectively. The median age at diagnosis of UC and CD was 40.69 and 28.58 years, respectively. There was a male predominance among patients with UC (54.3%) and CD (68.0%). The two regions exhibited a similar distribution of disease locations in UC. However, Western China had a higher proportion of L2 involvement (30.0% versus 19.1%) and more advanced disease behavior (B2 and B3) (48.8% versus 39.8%) than Eastern China. Patients with IBD in Western China received more 5-aminosalicylic acid and corticosteroids and fewer immunomodulators and biologicals. In terms of surgical risk, Eastern China [ versus Western China, odds ratios (OR): 5.36, 95% confidence intervals (CI): 2.96–9.68] was associated with a higher risk of surgery in UC, while Western China ( versus Eastern China, OR: 3.39, 95% CI: 2.37–4.86) was associated with a higher risk of surgery in CD. Conclusion: Geographical heterogeneity exists in the disease characteristics and management of IBD in Eastern and Western China. These findings have the potential to guide the formulation of location-specific strategies aimed at enhancing the long-term outcomes of patients with IBD.

Abstract Background Liver transplantation (LT) offers a good survival chance for both the patient in short or long term, but still faces many challenges in the treatment of LT, such as the side effects associated with long‐term immunosuppression, which is one of the side effects that occurs in most patients. However, the dynamics of the cellular immune system composition over time during immune tolerance to LT after immunosuppressive therapy are not known. Methods Using single‐cell transcriptome sequencing, we analyzed five peripheral blood samples (one normal individual and four patients who underwent LT and received immunosuppressive therapy for 2 months, 1 year, 3 years, and 7 years, respectively) for immune cell composition and gene expression. Results A total of 17,462 peripheral blood mononuclear cells were acquired from a normal individual without LT and patients who underwent LT and received immunosuppressive therapy for 2 months, 1 year, 3 years, and 7 years, respectively. A total of 24 cell clusters were obtained and categorized into four different cell types based on gene expression characteristics as follows: eight clusters of T cells, two clusters of B cells, two clusters of neutrophils, two clusters of monocytes, natural killer cells, and natural killer T (NKT) cells (n = 4), and six other cell clusters. Cell subset analysis, pseudotime analysis, and intercellular communication analysis revealed that the CD8+ NKT cells specifically expressed NKG2A (KLRC1, CD159A), which may be an important cell group for CD8+ NKG2A+ NKT cells in LT, thereby highlighting the heterogeneity and functional diversity in patients who undergo LT. Conclusions We comprehensively analyzed single‐cell RNA sequencing data from a normal individual and patients who underwent LT and elucidated the mechanism underlying the development of immune tolerance in LT. CD8+ NKT cells specifically expressing KLRC1 play a crucial role in LT, and dynamic monitoring of these cells may provide novel avenues for the diagnosis and treatment of LT‐related immune rejection.

Abstract Background and aims The human gut is home to a largely underexplored microbiome component, the archaeome. Little is known of the impact of geography, urbanization, ethnicity, and diet on the gut archaeome in association with host health. We aim to delineate the variation of the human gut archaeome in healthy individuals and its association with environmental factors and host homeostasis. Methods Using metagenomic sequencing, we characterized the fecal archaeomes of 792 healthy adult subjects from 5 regions in China, spanning 6 ethnicities (Han, Zang, Miao, Bai, Dai, and Hani), consisting of both urban and rural residents for each ethnicity. In addition, we sampled 119 host variables (including lifestyle, diet, and blood parameters) and interrogated the influences of those factors, individually and combined, on gut archaeome variations. Results Population geography had the strongest impact on the gut archaeome composition, followed by urbanization, dietary habit, and ethnicity. Overall, the metadata had a cumulative effect size of 11.0% on gut archaeome variation. Urbanization decreased both the α-diversity (intrinsic microbial diversity) and the β-diversity (inter-individual dissimilarities) of the gut archaeome, and the archaea-to-bacteria ratios in feces, whereas rural residents were enriched for Methanobrevibacter smithii in feces. Consumption of buttered milk tea (a characteristic diet of the rural Zang population) was associated with increased abundance of M. smithii. M. smithii was at the central hub of archaeal-bacterial interactions in the gut microecology, where it was positively correlated with the abundances of a multitude of short chain fatty acid (SCFA)-producing bacteria (including Roseburia faecis, Collinsella aerofaciens, and Prevotella copri). Moreover, a decreased abundance of M. smithii was associated with increased human blood levels of cholinesterase in the urban population, coinciding with the increasing prevalence of noncommunicable diseases (such as dementia) during urbanization. Conclusions Our data highlight marked contributions of environmental and host factors (geography, urbanization, ethnicity, and habitual diets) to gut archaeome variations across healthy individuals, and underscore the impact of urbanization on the gut archaeome in association with host health in modern society. Video Abstract

Abstract Background Upregulation of Stathmin 1 (STMN1), a cytoplasmic phosphoprotein that controls the dynamics of cellular microtubules, is linked to malignant behavior and poor prognosis in a range of malignancies. However, little research has been done on STMN1’s potential role in HCC as a single factor in DNA methylation, m6A, or immunological modulation. Results STMN1 is overexpressed in hepatocellular carcinoma, where it is related to clinicopathological parameters and affects the prognosis of HCC patients. STMN1 overexpression plays an important role in the diagnosis and prognosis of hepatocellular carcinoma. Meanwhile, methylation of 7 CpG sites of STMN1 in HCC was correlated with prognosis, and STMN1 expression was closely related to m6A modification. In addition, STMN1 expression is associated with immune cell infiltration, immune molecules, and immune checkpoints in HCC. Conclusion STMN1 has a significant role in hepatocellular carcinoma diagnosis and prediction. STMN1 is implicated not just in the onset and course but also in the immunological modulation of the disease. DNA methylation and m6A are both linked to STMN1. Therefore, STMN1 could be used as a diagnostic and prognostic biomarker for HCC, as well as a target for immunotherapy.

Abstract Prevotella species in the human gut microbiome are primarily comprised of Prevotella copri, and its diversity and function were recently investigated in detail. Much less is known about other Prevotella species in the human gut. Here, we examined the composition of Prevotella species in human guts by mapping publicly available gut metagenomes to a dereplicated set of metagenome-assembled genomes (MAGs) representing Prevotella lineages found in human guts. In most human cohorts, P. copri is the most relatively abundant species (e.g. up to 14.3% relative abundance in Tangshan, China). However, more than half of the metagenome reads in several cohorts mapped to Prevotella MAGs representing P. stercorea and several other species sister to P. stercorea and P. copri. Analyses of genes encoded in these genomes indicated that P. stercorea and related lineages lacked many hemicellulose degrading enzymes and were thus less likely to metabolise hemicelluloses compared with P. copri and copri-related lineages. Instead, P. stercorea genomes possess several carbohydrate esterases that may be involved in releasing ester modifications from carbohydrates to facilitate their degradation. These findings reveal unexplored Prevotella diversity in the human gut and indicate possible niche partitions among these related species.

AimThis study aimed to determine the factors affecting the quality of life of patients with inflammatory bowel disease (IBD) and to construct a disease recurrence prediction model based on these influencing factors.MethodsA prospective, single-center study in China was conducted between October 2020 and March 2021. The quality of life of patients was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). Multiple stepwise regression analysis was used to analyze the factors influencing the quality of life of patients with IBD. The chi-square test and the point-biserial correlation analysis were performed to identify factors associated with clinical recurrence. A binary logistic regression model was constructed to predict the recurrence. The receiver operating characteristic curve was used to evaluate the prediction model. Patients with IBD from April 2021 to June 2021 were randomly included for model verification to evaluate the disease recurrence prediction model.ResultsThe average IBDQ score of patients with IBD was 172.2 ± 35.0 (decreased by 23.2%). The scores of all dimensions of the IBDQ were decreased, especially emotional function and systemic symptoms. Disease activity, age, extraintestinal manifestations (EIMs), and annual household income were important factors influencing the IBDQ scores of patients with ulcerative colitis, and these accounted for ~57.0% of the factors affecting the quality of life. Disease activity, EIMs, and occupational stress were important factors influencing the IBDQ scores of patients with Crohn's disease, and they accounted for approximately 75.1% of the factors affecting the quality of life. Annual household income, occupational stress, and IBDQ scores were independent risk factors for recurrence. The area under the curve of the recurrence prediction model was 81.1%. The sensitivity and specificity were 81.7 and 71.7%, respectively. The Youden index of the model was 0.534. The established recurrence prediction model has good discriminant validity in the validation cohort.ConclusionThe quality of life of patients with IBD was generally poor. The use of factors affecting the quality of life to predict disease recurrence has high predictive value and can support the management of IBD by selecting patients at a higher risk for relapse.

IntroductionUlcerative colitis (UC) is an inflammatory disease of the intestinal tract with unknown etiology. Both genetic and environmental factors are involved in the occurrence and development of UC. Understanding changes in the microbiome and metabolome of the intestinal tract is crucial for the clinical management and treatment of UC.MethodsHere, we performed metabolomic and metagenomic profiling of fecal samples from healthy control mice (HC group), DSS (Dextran Sulfate Sodium Salt) -induced UC mice (DSS group), and KT2-treated UC mice (KT2 group).Results and DiscussionIn total, 51 metabolites were identified after UC induction, enriched in phenylalanine metabolism, while 27 metabolites were identified after KT2 treatment, enriched in histidine metabolism and bile acid biosynthesis. Fecal microbiome analysis revealed significant differences in nine bacterial species associated with the course of UC, including Bacteroides, Odoribacter, and Burkholderiales, which were correlated with aggravated UC, and Anaerotruncus, Lachnospiraceae, which were correlated with alleviated UC. We also identified a disease-associated network connecting the above bacterial species with UC-associated metabolites, including palmitoyl sphingomyelin, deoxycholic acid, biliverdin, and palmitoleic acid. In conclusion, our results indicated that Anaerotruncus, Lachnospiraceae, and Mucispirillum were protective species against DSS-induced UC in mice. The fecal microbiomes and metabolomes differed significantly among the UC mice and KT2-treated and healthy-control mice, providing potential evidence for the discovery of biomarkers of UC.

Objective: Heme oxygenase-1 (HO-1) is a protein involved in the inflammatory response following ischemia-reperfusion injury (IRI). Evidence suggests that pyroptosis plays an important role in IRI. However, the underlying mechanism between HO-1 and pyroptosis in IRI requires further investigation. Methods: Using the “two-cuff” method, a Sprague Dawley rat model of liver transplantation (LT) was established using livers from donors after circulatory death. An automatic biochemical analyzer was used to detect serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels and evaluate liver function. Paraffin sections of the rat liver were stained with hematoxylin-eosin (HE) to observe the degree of pathological damage. An enzyme-linked immunosorbent assay was used to detect serum levels of interleukin (IL)-1β and IL-18. Moreover, western blotting was used to analyze the expression of HO-1, pro-caspase-1, p22, full-gasdermin D (GSDMD), and cleaved-N-GSDMD in the liver. Immunohistochemistry was used to detect NLRP3 expression. Results: HO-1 expression was time-dependent with IRI. HE staining and Suzuki score showed that necrosis was more severe at 6 h after IRI than in controls. Reactive oxygen species (ROS), ALT, and AST levels in the reperfusion were significantly higher at 6 h after IRI. Similar to HO-1 expression, pro-caspase-1, p22, and GSDMD expression in the reperfusion was time-dependent and was significantly higher at 6 h. Compared with the HO-1-shRNA (short hairpin RNA) group, the HO-1 overexpression group significantly inhibited ROS, p22, GSDMD, IL-1β, IL-18, ALT, and AST. Immunohistochemistry revealed that NLRP3 levels were the highest in the HO-1 overexpression group. Conclusions: HO-1 improved the survival rate and IRI recovery after LT in rats. This study demonstrates that HO-1 inhibits hepatocyte pyroptosis, thereby reducing IRI after LT.

The incidence rate of ulcerative colitis (UC) is increasing annually, and glucocorticoid (GC) resistance (GCR) is a common cause of UC-induced remission failure. Our previous studies have shown that the expression of miR-642a-5p is downregulated in UC with GCR, suggesting that miR-642a-5p may be related to the GC response. Therefore, we investigated the mechanism by which miR-642a-5p regulates the GC response in THP-1 cells.We found that after treatment with miR-642a-5p mimics and DEX, the expression levels of glucocorticoid receptor (GR) in the nucleus and NF-κB p65 and p50 in the cytoplasm were increased (P

Abstract Background Ulcerative colitis (UC) is one of the primary types of inflammatory bowel disease (IBD), the occurrence of which has been increasing worldwide. Although IBD is an intensively studied human microbiome-associated disease, research on Chinese populations remains relatively limited, particularly on the mucosal microbiome. The present study aimed to analyze the changes in the mucosal microbiome associated with UC from the perspectives of medical ecology and complex network analysis. Results In total, 56 mucosal microbiome samples were collected from 28 Chinese UC patients and their healthy family partners, followed by amplicon sequencing. Based on sequencing data, we analyzed species diversity, shared species, and inter-species interactions at the whole community, main phyla, and core/periphery species levels. We identified four opportunistic “pathogens” (i.e., Clostridium tertium, Odoribacter splanchnicus, Ruminococcus gnavus, and Flavonifractor plautii) with potential significance for the diagnosis and treatment of UC, which were inhibited in healthy individuals, but unrestricted in the UC patients. In addition, we also discovered in this study: (i) The positive-to-negative links (P/N) ratio, which measures the balance of species interactions or inhibition effects in microbiome networks, was significantly higher in UC patients, indicating loss of inhibition against potentially opportunistic “pathogens” associated with dysbiosis. (ii) Previous studies have reported conflicting evidence regarding species diversity and composition between UC patients and healthy controls. Here, significant differences were found at the major phylum and core/periphery scales, but not at the whole community level. Thus, we argue that the paradoxical results found in existing studies are due to the scale effect. Conclusions Our results reveal changes in the ecology and network structure of the gut mucosal microbiome that might be associated with UC, and these changes might provide potential therapeutic mechanisms of UC. The four opportunistic pathogens that were identified in the present study deserve further investigation in future studies.

Ulcerative colitis (UC) is a serious chronic intestinal inflammatory disease, with an increased incidence in recent years. The intestinal microbiota plays a key role in the pathogenesis of UC. However, there is no unified conclusion on how the intestinal microbiota changes. Most studies focus on the change between UC patients and healthy individuals, rather than the active and remission stage of the same patient. To minimize the influences of genetic differences, environmental and dietary factors, we studied the intestinal microbiota of paired fecal samples from 42 UC patients at the active and remission stages. We identified 175 species of microbes from 11 phyla and found no difference of the alpha and beta diversities between the active and remission stages. Paired t-test analysis revealed differential microbiota at levels of the phyla, class, order, family, genus, and species, including 13 species with differential abundance. For example, CAG-269 sp001916005, Eubacterium F sp003491505, Lachnospira sp000436475, et al. were downregulated in the remission, while the species of Parabacteroides distasonis, Prevotellamassilia sp900540885, CAG-495 sp001917125, et al. were upregulated in the remission. The 13 species can effectively distinguish the active and remission stages. Functional analysis showed that the sporulation and biosynthesis were downregulated, and the hydrogen peroxide catabolic process was upregulated in remission of UC. Our study suggests that the 13 species together may serve as a biomarker panel contributing to identify the active and remission stages of UC, which provides a valuable reference for the treatment of UC patients by FMT or other therapeutic methods.

Ulcerative Colitis (UC) is a non-specific and chronic inflammatory disease of colonic mucosa whose exact etiology and mechanisms remain unclear. The incidence rate of UC is increasing year by year worldwide. What followed is that the medical costs are also rising rapidly. Therefore, it is urgent to understand the pathogenesis and find promising therapeutic targets for UC. Intestinal mucosal homeostasis is essential for normal bowel function, and its imbalance may be an important pathogenesis of UC. Endogenous homeostatic regulators play roles in repairing intestinal mucosa injury after stress. Heat shock family proteins are essential endogenous homeostasis factors. They can inhibit inflammation, regulate intestinal epithelial cells’ survival and death, and promote mucosal healing. Thus, they play important roles in sustaining intestinal mucosal homeostasis and protecting against UC progression. However, the heat shock family may promote UC carcinogenesis. Here, we summarize the advances in the research of the functions of the heat shock family in UC. And this review is an attempt to light on the etiopathogenesis of UC, highlighting the endogenous protective mechanisms, hoping to provide a novel therapeutic target for UC treatment.

Background: The abnormal differentiation of Th17 cells aggravates ulcerative colitis (UC). Antimicrobial peptides (AMPs) exert pivotal protection functions against UC. KT2 is a cationic AMP that mediates colon cancer development. However, KT2′s function in UC remains unclear. Methods: The UC mouse model was induced by administering 2.5% dextran sulfate sodium, and the mice were given an enema of KT2. KT2′s function in UC and Th17 cell differentiation in vivo was evaluated through various molecular experiments. The KT2′s function in Th17 cell differentiation in vitro was evaluated by the proportion of CD4+ IL-17+ T cells, IL-17 levels, and RORγt expression levels. Meanwhile, the mechanism was assessed through quantitative real-time PCR, various loss-of-function assays, and dual-luciferase reporter gene assay. Results: KT2 restrained Th17 cell differentiation in both in vivo and in vitro UC models and slowed the UC process. KT2 elevated miR-302c-5p expression, as well as restrained Th17 cell differentiation by increasing miR-302c-5p. Meanwhile, miR-302c-5p interacted with the signal transducer and activator of transcription 3 (STAT3) and negatively regulated its expression. Furthermore, our data revealed that KT2 restrained the activation of STAT3 by elevating miR-302c-5p, thereby inhibiting Th17 cell differentiation. Conclusion: KT2 alleviates UC by repressing Th17 cell differentiation through the miR-302c-5p/STAT3 axis.

Abstract Background Cytomegalovirus (CMV) infection can significantly complicate and worsen the condition of acute severe ulcerative colitis (UC) patients. We aimed to explore the predictive risk factors to prevent and identify CMV infection at an early stage in acute UC patients. Methods A total of 115 moderate-to-severe active UC patients from 17 hospitals throughout China were enrolled. Active CMV infection was diagnosed by one of the following: CMV pp65 antigens, CMV IgM antibodies or CMV DNA. We identified the independent risk factors by multivariate analyses. Results A total of 64 of 115 active UC patients had active CMV infection. Compared to the non-CMV-infected patients, the CMV-infected patients had a tendency to be male and to exhibit abdominal pain; fever; oral ulcers; eosinopenia; low albumin, immunoglobulin (Ig) A, IgM, and IgG levels; increased high-sensitivity C-reactive protein (hsCRP) levels; hyponatremia; pancolonic lesions; initial onset type; severe activity; and glucocorticoid (high-dose) and immunosuppressive agent use (P

(1) Background: Developing countries have experienced a rapid recent rise in Inflammatory Bowel Disease (IBD) incidence and emerging evidence suggests processed foods and food additives may predispose one to the development and perpetuation of Crohn’s disease (CD). The aim of this study was to evaluate processed food and food additive intake in CD patients and controls, in Australia (high CD incidence), Hong Kong (intermediate incidence) and mainland China (emerging incidence). (2) Methods: In 274 CD patients (CD), 82 first-degree relatives (FDR), 83 household members (HM) and 92 healthy unrelated controls (HC) from Australia (n = 180), Hong Kong (HK) (n = 160) and mainland China (n = 191) we estimated early life (0–18 years), recent (12 months), and current processed and food additive intake, using validated questionnaires and a 3-day-food diary. (3) Results: Early life processed food intake: Combining all regions, CD were more likely to have consumed soft drinks and fast foods than HM, more likely to have consumed processed fruit and snacks than their FDR, and more likely to have consumed a range of processed foods than HC. HK and China CD patients were more likely to have consumed a range of processed foods than HC. Recent food-additive intake (12-months): Combining all regions, CD patients had significantly higher intakes of aspartame and sucralose, and polysorbate-80, than HC, and more total emulsifiers, artificial sweeteners, and titanium dioxide than FDR and HC. HK and China CD patients had a higher intake of almost all food additives than all controls. Current additive intake (3-days): Australian and HK CD patients had higher total food-additive intake than FDR, and HK CD patients had a higher intake of total food-additives and emulsifiers than HM. (4) Conclusions: CD patients have been exposed to more processed food and food additives than control groups, which may predispose them to CD development and ongoing inflammation.

Nonalcoholic fatty liver disease (NAFLD) results from an abnormal accumulation of lipids within hepatocytes, and is commonly associated with obesity, insulin resistance, and hyperlipidemia. Metformin is commonly used to treat type 2 diabetes mellitus and, in recent years, it was found to play a potential role in the amelioration of NAFLD. However, the mechanisms underlying the protective effect of metformin against NAFLD remain largely unknown. Transcription factor EB (TFEB) is a master transcriptional regulator of lysosomal biogenesis and autophagy and, when activated, is effective against disorders of lipid metabolism. However, the role of TFEB in hepatic steatosis is not well understood. In this report, we demonstrate that the activity of TFEB is reduced in the liver of mice fed a high-fat diet. Metformin treatment significantly reverses the activity of TFEB, and the protective effect of metformin against hepatic steatosis and insulin resistance is dependent on TFEB. We show that metformin-induced autophagy is regulated by TFEB, and our findings reveal that TFEB acts as a mediator, linking metformin with autophagy to reverse NAFLD, and highlight that TFEB may be a promising molecular target for the treatment of NAFLD.

Background & Aims: Regenerating islet-derived protein (REG3γ), an antimicrobial peptide, typically expressed by intestinal epithelial cells (IEC), plays crucial roles in intestinal homeostasis and controlling gut microbiota. However, the mechanisms that regulate IEC expression of REG3γ are still largely unclear. In this study, we investigated whether and how interleukin (IL) 33, an alarmin produced by IEC in response to injury, regulates REG3γ expression in IEC, thus contributing to intestinal homeostasis. Methods: IEC were isolated from wild-type and IL33-/- mice to determine expression of REG3γ and other antimicrobial peptides by quantitative real-time polymerase chain reaction and Western blot. IEC cell lines were used for mechanistic studies. 16S rRNA pyrosequencing analysis was used for measuring gut microbiota. Citrobacter rodentium was used for enteric infections. Results: The expression of REG3γ, but not β-defensins, in IECs of IL33-/- mice was significantly lower than wild-type mice. IL33 treatment induced IEC expression of REG3γ in both mice and human cell lines. Mechanistically, IL33 activated STAT3, mTOR, and ERK1/2 in IEC. Inhibition of these pathways abrogated IL33-induction of REG3γ. IL33-/- mice demonstrated higher bacteria loads and altered microbiota composition. IL33 did not directly inhibit bacterial growth, but promoted wild-type, not REG3γKO, IECs to kill bacteria in vitro. Consistently, C rodentium infection induced IEC IL33 expression, and IL33-/- mice demonstrated an impaired bacterial clearance with C rodentium infection. Conclusions: Our study demonstrated that IL33, which is produced by IEC in response to injury and inflammatory stimulation, in turn promotes IEC expression of REG3γ, and controls the gut microbiota of the host. Keywords: IEC, IL33, REG3γ, Microbiota

Adherent invasive Escherichia Coli (AIEC) has been implicated in the pathogenesis of Crohn’s disease (CD) in Western populations. Whether the presence of AIEC is also seen in CD populations of different genetic susceptibility and has negative impact on host microbiota ecology and therapeutics are unclear. AIEC presence was assessed in ileal tissues of 60 Hong Kong Chinese patients with CD and 56 healthy subjects. Mucosa microbiota was analyzed by 16s rRNA sequencing. Impact of AIEC on the gut microbiota was determined in a mouse model. AIEC was significantly more prevalent in ileal tissues of patients with CD than controls (30% vs 7.1%). Presence of AIEC in ileal tissues was associated with more severe mucosa microbiota dysbiosis in CD with decreased diversity and lower abundance of Firmicutes including butyrate producing Roseburia and probiotic Bacillus. A random forest model predicted the presence of AIEC with area under the curve of 0.89. AIEC exacerbated dysbiosis in dextran sodium sulfate (DSS)-induced colitis mice and led to resistance to restoration of normal gut microbiota by fecal microbiota transplantation (FMT). Proportion of donor-derived bacteria in AIEC-colonized mice was significantly lower than that in uninfected mice. AIEC was prevalent and associated with severe mucosa microbiota dysbiosis in CD in Hong Kong Chinese population. The presence of AIEC impeded restoration of normal gut microbiota. AIEC may serve as a keystone bacterium in CD and impact the efficacy of FMT.

The dysbiosis of the gut microbiome associated with ulcerative colitis (UC) has been extensively studied in recent years. However, the question of whether UC influences the spatial heterogeneity of the human gut mucosal microbiome has not been addressed. Spatial heterogeneity (specifically, the inter-individual heterogeneity in microbial species abundances) is one of the most important characterizations at both population and community scales, and can be assessed and interpreted by Taylor’s power law (TPL) and its community-scale extensions (TPLEs). Due to the high mobility of microbes, it is difficult to investigate their spatial heterogeneity explicitly; however, TPLE offers an effective approach to implicitly analyze the microbial communities. Here, we investigated the influence of UC on the spatial heterogeneity of the gut microbiome with intestinal mucosal microbiome samples collected from 28 UC patients and healthy controls. Specifically, we applied Type-I TPLE for measuring community spatial heterogeneity and Type-III TPLE for measuring mixed-species population heterogeneity to evaluate the heterogeneity changes of the mucosal microbiome induced by UC at both the community and species scales. We further used permutation test to determine the possible differences between UC patients and healthy controls in heterogeneity scaling parameters. Results showed that UC did not significantly influence gut mucosal microbiome heterogeneity at either the community or mixed-species levels. These findings demonstrated significant resilience of the human gut microbiome and confirmed a prediction of TPLE: that the inter-subject heterogeneity scaling parameter of the gut microbiome is an intrinsic property to humans, invariant with UC disease.

Background: The implications of gut microbiome to obesity have been extensively investigated in recent years although the exact mechanism is still unclear. The question whether or not obesity influences gut microbiome assembly has not been addressed. The question is significant because it is fundamental for investigating the diversity maintenance and stability of gut microbiome, and the latter should hold a key for understanding the etiological implications of gut microbiome to obesity.Methods: In this study, we adopt a dual neutral theory modeling strategy to address this question from both species and community perspectives, with both discrete and continuous neutral theory models. The first neutral theory model we apply is Hubbell's neutral theory of biodiversity that has been extensively tested in macro-ecology of plants and animals, and the second we apply is Sloan's neutral theory model that was developed particularly for microbial communities based on metagenomic sequencing data. Both the neutral models are complementary to each other and integrated together offering a comprehensive approach to more accurately revealing the possible influence of obesity on gut microbiome assembly. This is not only because the focus of both neutral theory models is different (community vs. species), but also because they adopted two different modeling strategies (discrete vs. continuous).Results: We test both the neutral theory models with datasets from Turnbaugh et al. (2009). Our tests showed that the species abundance distributions of more than ½ species (59–69%) in gut microbiome satisfied the prediction of Sloan's neutral theory, although at the community level, the number of communities satisfied the Hubbell's neutral theory was negligible (2 out of 278).Conclusion: The apparently contradictory findings above suggest that both stochastic neutral effects and deterministic environmental (host) factors play important roles in shaping the assembly and diversity of gut microbiome. Furthermore, obesity may just be one of the host factors, but its influence may not be strong enough to tip the balance between stochastic and deterministic forces that shape the community assembly. Finally, the apparent contradiction from both the neutral theories should not be surprising given that there are still near 30–40% species that do not obey the neutral law.

BACKGROUND:The aim of this study was to examine environmental factors associated with inflammatory bowel disease (IBD) in Yunnan Province, a southwestern highland region of China. METHODS:In this nested case-control study, newly diagnosed ulcerative colitis (UC) cases in 2 cities in Yunnan Province and Crohn's disease (CD) cases in 16 cities in Yunnan Province were recruited between 2008 and 2013. Controls were matched by geography, sex and age at a ratio of 1:4. Data were collected using the designed questionnaire. Conditional logistic regression models were used to estimate adjusted odds ratios (ORs). RESULTS:A total of 678 UC and 102 CD cases were recruited. For UC, various factors were associated with an increased risk of developing UC: dietary habits, including frequent irregular meal times; consumption of fried foods, salty foods and frozen dinners; childhood factors, including intestinal infectious diseases and frequent use of antibiotics; and other factors, such as mental labor, high work stress, use of non-aspirin non-steroidal anti-inflammatory drugs and allergies (OR > 1, p < 0.05). Other factors showed a protective effect: such as consumption of fruits, current smoking, physical activity, and drinking tea (OR < 1, p < 0.05). For CD, appendectomy and irregular meal times increased the disease risk (OR >1, p < 0.05), whereas physical activity may have reduced this risk (OR < 1, p < 0.05). CONCLUSIONS:This study is the first nested case-control study to analyze the association between environmental factors and IBD onset in a southwestern highland region of China. Certain dietary habits, lifestyles, allergies and childhood factors may play important roles in IBD, particularly UC.

BACKGROUND AND AIMS: The morbidity of ulcerative colitis (UC) is increasing in China every year. In addition, there is a lack of accurate diagnostic indices with which to evaluate the activity of the disease. The aim of this study was to identify UC-associated proteins as biomarkers for the diagnosis, and objective assessment of disease activity. METHODS: Differential expression of serum proteins from UC patients compared to normal controls was analyzed by two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). The expression of heat shock factor 2(HSF2)in colonic mucosa in Crohn's disease, Behcet's disease, ulcerative colitis, intestinal tuberculosis, infective enteritis, intestinal lymphoma, and normal controls was investigated by immunohistochemistry (IHC). The expression of the HSF2 in colonic mucosa of UC subjects with varying severity of disease was measured by real time-PCR and Western Blots. The expression of HSF2 was inhibited by HSF2 small interfering RNA (siRNA) transfection in Caco-2 cells. The concentrations of HSF2, IL-1β, and TNF-α in serum and IL-1β, and TNF-α in the supernatants of transfected Caco-2 cells were determined by ELISA. RESULTS: HSF2 was differentially expressed in UC patients compared to normal controls. HSF2 expression was significantly higher in the intestinal mucosa of UC patients compared to other six groups. The results of immunohistochemistry, real time-PCR, Western Blots, and ELISA showed that the expression of HSF2 increased in parallel with the severity of UC. The serum concentration of HSF2 also positively correlated with levels of IL-1β and TNF-α. After down-regulation expression of HSF2 in Caco-2 cells by RNA interference, the productions of IL-1β and TNF-α stimulated by lipopolysaccharide (LPS) increased dramatically. CONCLUSIONS: HSF2 appears to be a potential novel molecular marker for UC activity, and may provide a basis for studies on the pathogenesis and novel therapeutic targets for UC.