Dongchao Xu’s research while affiliated with National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and other places

Acute pancreatitis (AP) is characterized by autodigestion of the pancreas, and some patients may rapidly progress to systemic inflammation, pancreatic necrosis, and multi-organ failure. Numerous studies have detailed the bidirectional communication networks between the pancreas and the intestinal microbiota, as well as its metabolites. Such crosstalk affects the progression of AP and recovery through intestinal barrier disruption. Furthermore, advances in experimental research and clinical studies have indicated that gut microorganisms exhibit distinct alterations in response to different levels of severity and etiologies of AP. This information has greatly expanded our knowledge of the role of the gut microflora and microbial metabolites in the pathology of disease and has reinforced the basis of therapeutic approaches that target candidate intestinal microbiota. In this review, we aim to provide an overview of the composition and diversity of the gut microbial community, to highlight the candidate bacteria and microbiota-derived metabolites responsible for AP, and to elucidate their interactions with and regulation of immune-relevant receptors in intestinal epithelial cells (IECs) in the host. Future research should focus on identifying and characterizing AP-associated bacterial strains, elucidating their distinct pathogenic mechanisms across different etiologies and stages of AP, and leveraging these insights to develop preventive and therapeutic strategies.

Introduction Peritoneal metastasis often predicts advanced progression and a poor prognosis in colorectal cancer (CRC). However, peritoneal metastases are extremely difficult to predict or diagnose by routine diagnostic methods. Material and methods In this study, a microarray containing 30 samples from peritoneal metastasis and their matched CRC primaries obtained during cytoreductive surgery were compared to take a long hard look at all the options on the significant differentially expressed genes. The potential interactions and mechanisms of these expressed genes in promoting peritoneal metastasis were analyzed and studied by multiple bioinformatics analysis. Results The results suggested that the functions of these genes are closely related to immune response and cytokine activity. Additionally, the top 10 core genes’ correction with the leukocyte infiltration and serum cytokine profiles were identified and may be expected to become diagnostic and therapeutic targets of peritoneal metastasis in CRC. Conclusions The expression of IL-6, IL-10 and IL-17 in plasma and their correlation with leukocyte infiltration are proven potential diagnostic, prognostic, and therapeutic biomarkers for peritoneal management of CRC.

Background Endoscopic retrograde cholangiopancreatography (ERCP) has become a routine endoscopic procedure that is essential for diagnosing and managing various conditions, including gallstone extraction and the treatment of bile duct and pancreatic tumors. Despite its efficacy, post-ERCP infections – particularly those caused by carbapenem-resistant Enterobacterales (CRE) – present significant risks. These risks highlight the need for accurate predictive models to enhance postprocedural care, reduce the mortality risk associated with post-ERCP CRE sepsis, and improve patient outcomes in the context of increasing antibiotic resistance. Objective This study aimed to examine the risk factors for 30-day mortality in patients with CRE sepsis following ERCP and to develop a nomogram for accurately predicting 30-day mortality risk. Methods Data from 195 patients who experienced post-ERCP CRE sepsis between January 2010 and December 2022 were analyzed. Variable selection was optimized via the least absolute shrinkage and selection operator (LASSO) regression model. Multivariate logistic regression analysis was then employed to develop a predictive model, which was evaluated in terms of discrimination, calibration, and clinical utility. Internal validation was achieved through bootstrapping. Results The nomogram included the following predictors: age > 80 years (hazard ratio [HR] 2.61), intensive care unit (ICU) admission within 90 days prior to ERCP (HR 2.64), hypoproteinemia (HR 4.55), quick Pitt bacteremia score ≥ 2 (HR 2.61), post-ERCP pancreatitis (HR 2.52), inappropriate empirical therapy (HR 3.48), delayed definitive therapy (HR 2.64), and short treatment duration (< 10 days) (HR 5.03). The model demonstrated strong discrimination and calibration. Conclusions This study identified significant risk factors associated with 30-day mortality in patients with post-ERCP CRE sepsis and developed a nomogram to accurately predict this risk. This tool enables healthcare practitioners to provide personalized risk assessments and promptly administer appropriate therapies against CRE, thereby reducing mortality rates.

Background Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking. Methods The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques. Results The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8 + T cells, dendritic cells, macrophages, neutrophils and CD4 + T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines. Conclusion COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD.

For a long time, myeloid-derived suppressor cells (MDSCs) dilated in circulation system of colorectal cancer (CRC) patients have been puzzling clinicians. Various evidence shows that MDSCs constitute the bulk of immunosuppression in CRC, which is related to tumor growth, adhesion, invasion, metastasis, and immune escape. However, the mechanisms underlying these cells formation remain incompletely understood. In this study, we reported that CRC cell-derived LC3-dependent extracellular vesicles (LDEVs)-mediated M-MDSCs formation via TLR2-MYD88 pathway. Furthermore Hsp60 was the LDEVs surface ligand that triggered these MDSCs induction. In clinical studies, we reported that accumulation of circulating M-MDSCs as well as IL-10 and arginase1 secretion were reliant upon the levels of tumor cell-derived LDEVs in CRC patients. These findings indicated how local tumor cell-derived extracellular vesicles influence distal hematopoiesis and provided novel justification for therapeutic targeting of LDEVs in patients with CRC.

Aims: Primary choledocholithiasis is a common digestive disease with high morbidity and relapse. However, the compositions and functions of the bile microbial ecosystem and the pathogenesis of microfloral regulation of host metabolism resulting in stone formation are poorly understood. Main methods: Biliary samples collected from patients with acute cholangitis induced by benign biliary stricture (nonlithiasis group, n = 17) and primary choledocholithiasis (lithiasis group, n = 33) were subjected to multiomics analyses. Furthermore, clinicopathological features collected over a 24-month follow-up period were examined to evaluate the predictive value of candidate microbes. Key findings: Five alpha diversity indices of the bile microbiome were significantly decreased in the lithiasis group. Furthermore, we identified 49 differential bile flora between the two groups, and the relative abundances of 6 bacteria, Actinobacteria, Actinobacteriota, Staphylococcales, Micrococcales, Altererythrobacter and Carnobacteriaceae, were associated with primary choledocholithiasis relapse conditions. Multiomics analyses showed that specific changes in disease-related bacterial taxa were closely related to metabolite variation (low-molecular weight carboxylic acids, sterol liquid and acylcarnitine), which might reflect disease prognosis. According to microbiomic and metabolomic pathway analyses, we revealed that bacterial infections, microbiota-derived amino acid metabolites and secondary bile acid-related pathways were significantly enriched in the stone-formation group, suggesting a novel host-microbial metabolic mechanism of primary choledocholithiasis. Significance: Our study first indicates bile host-microbial dysbiosis modulates the abnormal accumulation of metabolites might further disrupt calcium homeostasis and generate insoluble saponification. Additionally, we determined the predictive value of Actinomycetes phylum reduction for recurrence in primary common bile duct stone patients.

Background Cuproptosis is a novel type of mediated cell death strongly associated with the progression of several cancers and has been implicated as a potential therapeutic target. However, the role of cuproptosis in cholangiocarcinoma (CCA) for prognostic prediction, subgroup classification, and therapeutic strategies remains largely unknown. Methods A systematic analysis was conducted among 146 cuproptosis-related genes (CRGs) and clinical information based on independent mRNA and protein datasets to elucidate the potential mechanisms and prognostic prediction value of CRGs. A ten-CRG prediction model was constructed, and its effects on CCA prognosis were significantly connected to poor patient survival. Additionally, the expression patterns of our model included genes that were validated with several CCA cancer cell lines and a normal biliary epithelial cell line. Results First, a ten-CRG signature (ADAM9, ADAM17, ALB, AQP1, CDK1, MT2A, PAM, SOD3, STEAP3 and TMPRSS6) displayed excellent predictive performance for the overall survival of CCA. The low-cuproptosis group had a significantly better prognosis than the high-cuproptosis group with transcriptome and protein cohorts. Second, compared with the high-risk and low-risk groups, the two groups displayed distinct tumor microenvironments, reduced proportions of endothelial cells and increased levels of cancer-associated fibroblasts based on CIBERSORTx and EPIC analyses. Third, patients’ sensitivities to chemotherapeutic drugs and immune checkpoints revealed distinctive differences between the two groups. Finally, in replicating the expression patterns of the ten genes, these results were validated with qRT‒PCR results validating the abnormal expression pattern of the target genes in CCA. Conclusions Collectively, we established and verified an effective prognostic model that could separate CCA patients into two heterogeneous cuproptosis subtypes based on the molecular or protein characteristics of ten CRGs. These findings may provide potential benefits for unveiling molecular characteristics, and defining subgroups could improve the early diagnosis and individualized treatment of CCA patients.