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Therapeutic Evaluation of Fecal Microbiota Transplantation in an Interleukin 10-Deficient Mouse Model

With the development of microecology in recent years, the relationship between intestinal bacteria and inflammatory bowel disease (IBD) has attracted ...

Xiangya Hospital of Central South University

Colorectal cancer (CRC) is one of the most common cancers worldwide, and the identification of new biomarkers for CRC is valuable for its diagnosis and treatment. We aimed to screen differentially expressed glycoproteins (especially O-glycoproteins) and to identify diagnostic or therapeutic candidates for colorectal cancer (CRC) based on different Tn antigen expression levels. Fresh cancer tissues and adjacent healthy tissues were obtained from CRC patients and classified into three groups based on their Tn antigen expression: CRC with negative Tn expression (CRC Tn‑), CRC with positive Tn expression (CRC Tn+) and normal control without Tn expression (NC). Protein extractions were separated and identified by iTRAQ technology. Glycoproteins and O-glycoproteins were selected using UniProt and DAVID. Deep bioinformatic analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KO), was used to annotate this O-glycoprotein interaction network. Subsequently, two O‑glycoproteins were verified by western blotting and immunohistochemistry in either LS174T cells or CRC tissues. We found that 330 differentially expressed proteins were identified by iTRAQ between CRC Tn‑ and NC tissues, 317 between CRC Tn+ and NC tissues, and 316 between CRC Tn‑ and Tn+ tissues. Of the 316 proteins, 55 glycoproteins and 19 O‑glycoproteins were identified and analyzed via deep informatics. Namely, different Tn antigen expression levels in CRC led to differential protein expression patterns, especially for glycoproteins and O‑glycoproteins. Decorin and SORBS1, two representative functional O-glycoproteins, were significantly downregulated in the CRC Tn+ tissues compared with the level in the CRC Tn‑ or NC tissues. Based on this deep bioinformatic analysis, Decorin and SORBS1 are hypothesized to be involved in the TGF‑β and PPAR‑γ signaling pathways, respectively. 

Glycoprotein screening in colorectal cancer based on differentially expressed Tn antigen.

Gastroenteropancreatic neuroendocrine tumors (GEP‑NETs) are relatively uncommon. Unfortunately, epidemiological studies on the incidence of GEP‑NETs worldwide have reported a marked increase in the detection of these tumors. Although they often exhibit relatively indolent clinical courses, GEP‑NETs have the potential for lethal progression, especially in patients who present with advanced disease. Early detection and surgical removal is currently the only reliable curative treatment for GEP‑NET patients. The objective of this study was to analyze the clinicopathological characteristics of GEP‑NETs and explore the metastasis‑related risk factors of patients with GEP‑NETs. One hundred and forty‑six patients diagnosed pathologically with GEP‑NETs from January 2001 to January 2015 at the Second Xiangya Hospital of Central South University were retrospectively evaluated. We retrieved and analyzed information concerning clinical characteristics and metastasis‑related risk factors, and used Chi‑square test and logistic regression analysis to analyze the clinicopathological characteristics of GEP‑NETs and explore the association between tumor metastasis and possible related risk factors. The results revealed that the most common clinical manifestations were abdominal pain (n=88), alteration in the character of stool (n=58) and melaena (n=33). Rectum (91/146, 62.3%) and stomach (19/146, 13.0%) were the main sites of metastasis. Both Chi‑square test and logistic regression analysis showed that tumor size (P<0.05), tumor type (P=0.008) and peritumoral lymphatic vessel density (LVD) (P=0.004) were significantly correlated with tumor metastasis. Neither Chi‑square test nor logistic regression analysis indicated that gender (P>0.05), age (P>0.05), tumor location (P>0.05), tumor number (P>0.05), chromaffin granule protein A [chromogranin A (CgA), P>0.05], synaptophysin (Syn, P>0.05) or intratumoral LVD (P>0.05) had a significant correlation with tumor metastasis. Chi‑square test revealed that tumor grade was significantly correlated with tumor metastasis. In conclusion, GEP‑NETs may occur in multiple sites of the digestive system and lack specific clinical manifestations. Tumor size, tumor type, peritumoral LVD, total LVD and tumor grade are metastasis‑related risk factors for GEP‑NET patients.

Multivariate analysis of metastasis‑related risk factors for patients with gastroenteropancreatic neuroendocrine tumors based on clinicopathological and endoscopic features.

SGSM2, a putative Rab2a GAP, regulates lysozyme sorting in Paneth cells.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by defective intestinal barrier integrity toward the microbiota and epithelial damage. Double cortin-like kinase 1 (Dclk1), a marker of intestinal tuft cells, can regulate tissue regenerative responses, but its role in epithelial repair during bacterial-dependent chronic colitis is unclear. We addressed this question using our recently developed mouse model of spontaneous microbiota-dependent colitis induced by mucin-type O-glycan deficiency (DKO), which recapitulates most features of human UC. We generated DKO mice lacking intestinal epithelial Dclk1 (DKO;Dclk1) and analyzed colitis onset and severity using clinical and histologic indices, immune responses by qPCR and immunostaining, and epithelial responses using proliferation markers and organoid culture. We found 3-4-week-old DKO;Dclk1 mice developed worsened spontaneous colitis characterized by reduced body weight, loose stool, severe colon thickening, epithelial lesions, and inflammatory cell infiltrates compared with DKO mice. The primary defect was an impaired epithelial proliferative response during inflammation. Dclk1 deficiency also reduced inflammation-induced proliferation and growth of colon organoids ex vivo. Mechanistically, Dclk1 expression was important for inflammation-induced Cox2 expression and prostaglandin E2 (PGE2) production in vivo, and PGE2 rescued proliferative defects in Dclk1-deficient colonic organoids. Although tuft cells were expanded in both DKO and DKO;Dclk1 relative to WT mice, loss of Dclk1 was associated with reduced tuft cell activation (i.e., proliferation) during inflammation. Similar results were found in DKO vs. DKO;Dclk1 mice at 3-6 months of age. Our results support that tuft cells, via Dclk1, are important responders to bacterial-induced colitis by enhancing epithelial repair responses, which in turn limits bacterial infiltration into the mucosa.

Dclk1 in tuft cells promotes inflammation-driven epithelial restitution and mitigates chronic colitis.

Imprinted genes are often identified as key players in the etiology and prognosis of many tumors; however, the role they play in colon cancer remains unclear. Along with the development of big data analysis came the discovery of a wealth of genetic prognostic factors, like microsatellite instability for colon cancer, which need to be taken into consideration when evaluating new biomarkers for the disease.

The role of PEG3 in the occurrence and prognosis of colon cancer.

A certain number of epithelial cells in intestinal crypts are DNA damage resistant and contribute to regeneration. However, the cellular mechanism underlying intestinal regeneration remains unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1) are right above Lgr5 cells in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1 cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1 cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5 radiosensitive crypt base columnar stem cells (CBCs). This enables an efficient repopulation of the intestinal epithelium at early stage when Lgr5 cells are not emerging. Furthermore, relative to CBCs, Msi1 cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1 cells are cycling ISCs that maintain and regenerate the intestinal epithelium.

Cycling Stem Cells Are Radioresistant and Regenerate the Intestine.

Crohn's disease (CD) is a chronic idiopathic inflammatory disease. Studies show that multiple risk factors during disease progression can lead to a prothrombotic state (PTS), which predisposes the patient to thrombosis. Therefore, predicting PTS can help identify patients at risk of thrombosis. The aim of our study was to classify CD patients through D-dimer levels, and construct a prediction model for PTS.

Development and validation of predictive models for Crohn's disease patients with prothrombotic state: a 6-year clinical analysis.

Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is an enteropathy characterized by multiple small intestinal ulcers of nonspecific histology, also known as chronic nonspecific multiple ulcers of the small intestine. The SLCO2A1 gene encodes a prostaglandin transporter (PGT).

Four Variants of SLCO2A1 Identified in Three Chinese Patients with Chronic Enteropathy Associated with the SLCO2A1 Gene.

The clinical features of upper gastrointestinal (L4) Crohn's disease (CD) and its subtypes, along with the associated and nutritional status, remain poorly described. Our aim was to evaluate the clinical characteristics of L4 CD phenotype and its subtypes at diagnosis, and their relationship with the nutritional status.

Body weight, serum albumin and food intolerance were linked to upper gastrointestinal Crohn's disease: a 7-year retrospective analysis.

Esophageal high-resolution manometry (HRM) is widely performed to evaluate the representation of manometric features in patients for diagnosing normal esophageal motility and motility disorders. Clinicians commonly assess esophageal motility function using a scheme termed the Chicago classification, which is difficult, time-consuming and inefficient with large amounts of data.

Deep learning for tracing esophageal motility function over time.

Diet can impact on gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown if and how the ISC niche responds to diet and influences ISC function. Here, we demonstrate that Lepr mesenchymal cells (MCs) surrounding intestinal crypts sense diet change and provide a novel niche signal to maintain ISC and progenitor cell proliferation. The abundance of these MCs increases upon administration of a high-fat diet (HFD) but dramatically decreases upon fasting. Depletion of Lepr MCs resulted in fewer intestinal stem/progenitor cells, compromised the architecture of crypt-villus axis and impaired intestinal regeneration. Furthermore, we showed that IGF1 secreted by Lepr MCs is an important effector that promotes proliferation of ISCs and progenitor cells in the intestinal crypt. We conclude that Lepr MCs sense diet alterations and, in turn, modulate intestinal stem/progenitor cell function via a stromal IGF1-epithelial IGF1R axis. These findings reveal that Lepr MCs are important mediators linking systemic diet changes to local ISC function and might serve as a novel therapeutic target for gut diseases.

Xiaowei Liu

Department of Gastroenterology

Xiangya Hospital of Central South University

Therapeutic Evaluation of Fecal Microbiota Transplantation in an Interleukin 10-Deficient Mouse Model

Xiaowei Liu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Gastroenterology

Xiangya Hospital of Central South University

Therapeutic Evaluation of Fecal Microbiota Transplantation in an Interleukin 10-Deficient Mouse Model

Department of Gastroenterology