Antidepressant fluoxetine alleviates colitis by reshaping intestinal microenvironment.

BACKGROUND: The impact of antidepressants on Inflammatory bowel diseases (IBD) has been extensively studied. However, the biological effects and molecular mechanisms of antidepressants in alleviating colitis remain unclear. METHODS: We systematically assessed how antidepressants (fluoxetine, fluvoxamine and venlafaxine) affected IBD and chose fluoxetine, the most effective one, for mechanism studies. We treated the C56BL/6 mice of the IBD model with fluoxetine and their controls. We initially assessed the severity of intestinal inflammation in mice by body weight loss, disease Activity Index scores and the length of the colon. The H&E staining and immunohistochemical staining of MUC2 of colon sections were performed to observe the pathological changes. RT-qPCR and western blot were conducted to assess the expression level of the barrier and inflammation-associated genes. Then, single-cell RNA sequencing was performed on mouse intestinal mucosa. Seurat was used to visualize the data. Uniform Manifold Approximation and Projection (UMAP) was used to perform the dimensionality reduction. Cell Chat package was used to perform cell-cell communication analysis. Monocle was used to conduct developmental pseudotime analysis. Last, RT-qPCR, western blot and immunofluorescence staining were conducted to test the phenomenon discovered by single-cell RNA sequencing in vitro. RESULTS: We found that fluoxetine treatment significantly alleviated colon inflammation. Notably, single-cell RNA sequencing analysis revealed that fluoxetine affected the distribution of different cell clusters, cell-cell communication and KEGG pathway enrichment. Under the treatment of fluoxetine, enterocytes, Goblet cells and stem cells became the dominating cells. The pseudotime analysis showed that there was a trend for M1 macrophages to differentiate into M2 macrophages. Lastly, we tested this phenomenon in vitro, which exhibited anti-inflammatory effects on enterocytes. CONCLUSIONS: Fluoxetine exhibited anti-inflammatory effects on intestinal mucosa via remodeling of the intestinal cells and macrophages, which reveals that fluoxetine is a promising therapeutic drug for the treatment of IBD and psychiatric comorbidities.

Both extracellular vesicles from helicobacter pylori-infected cells and helicobacter pylori outer membrane vesicles are involved in gastric/extragastric diseases.

Bacterial-derived extracellular vesicles (EVs) have emerged as crucial mediators in the cross-talk between hosts and pathogens, playing a significant role in infectious diseases and cancers. Among these pathogens, Helicobacter pylori (H. pylori) is a particularly important bacterium implicated in various gastrointestinal disorders, gastric cancers, and systemic illnesses. H. pylori achieves these effects by stimulating host cells to secrete EVs and generating internal outer membrane vesicles (OMVs). The EVs derived from H. pylori-infected host cells modulate inflammatory signaling pathways, thereby affecting cell proliferation, apoptosis, cytokine release, immune cell modification, and endothelial dysfunction, as well as disrupting cellular junctional structures and inducing cytoskeletal reorganization. In addition, OMVs isolated from H. pylori play a pivotal role in shaping subsequent immunopathological responses. These vesicles incite both inflammatory and immunosuppressive reactions within the host environment, facilitating pathogen evasion of host defenses and invasion of host cells. Despite this growing understanding, research involving H. pylori-derived EVs remains in its early stages across different domains. In this comprehensive review, we present recent advancements elucidating the contributions of EV components, such as non-coding RNAs (ncRNAs) and proteins, to the pathogenesis of gastric and extragastric diseases. Furthermore, we highlight their potential utility as biomarkers, therapeutic targets, and vehicles for targeted delivery.

A Sedentary Lifestyle Changes the Composition and Predicted Functions of the Gut Bacterial and Fungal Microbiota of Subjects from the Same Company.

A sedentary lifestyle affects the diversity and composition of the gut microbiota, but previous studies have mainly focused on bacteria instead of fungi. Here, we compared both the fecal bacterial and fungal microbiota compositions and functions in sedentary persons and controls. Subjects from the China Railway Corporation, including 99 inspectors and 88 officials, were enrolled in our study. Fecal microbiota communities were analyzed using 16S rRNA gene sequencing for bacteria and ITS sequencing for fungi. We found that the diversity of the gut microbiota of the sedentary group was significantly lower than that of the control group (P < 0.05). The sedentary group had a higher abundance of Firmicutes, a lower abundance of Actinobacteria and Proteobacteria and a higher abundance of Ascomycota, and a lower abundance of Basidiomycota. Furthermore, functional prediction analysis of the fungal microbiota revealed more L-tryptophan degradation to 2-amino-3-carboxymuconate semialdehyde, more phospholipid remodeling (phosphatidylethanolamine, yeast), and more L-tyrosine degradation I, as well as less pentose phosphate pathway (non-oxidative branch), less adenosine nucleotide biosynthesis and less L-valine biosynthesis in the sedentary group (P < 0.05). Thus, a sedentary lifestyle changes the composition and function of the gut microbiota. It may change the pentose phosphate pathway (non-oxidative branch), nucleic acid and amino acid biosynthesis and phospholipid metabolism in fungi.

Association between new plasma inflammatory markers and risk of colorectal neoplasms in individuals over 50 years old.

OBJECTIVE(S): The prognostic value of systemic cytokine profiles and inflammatory markers in colorectal cancer were explored by several studies. We want to know more about inflammatory biomarkers in colorectal adenoma and early cancer. METHOD: The level of 38 inflammatory markers in the plasma of 112 adenoma patients, 72 Tis-T1 staging of colorectal carcinoma patients, 34 T2-T4 staging of colorectal carcinoma patients and 53 normal subjects were detected and compared. RESULT(S): Eight inflammatory biomarkers (Eotaxin, GCSF, IL-4, IL-5, IL-17E, MCP-1, TNF-α and VEGF-A) have higher plasma concentrations in colorectal adenoma and cancer patients compared with normal participants over 50 years old. CONCLUSION(S): Inflammatory markers may have the prognostic value for colorectal adenoma and early-stage carcinoma.

M2 Macrophage-Derived Exosomal Ferritin Heavy Chain Promotes Colon Cancer Cell Proliferation.

Colon cancer is a widespread life-threatening malignancy with complex and multifactorial etiology. Both epidemiological cohort studies and basic research support the substantial role of iron metabolism in colon cancer. Thus, understanding the mechanisms of how essential iron metabolic proteins are dysregulated may provide new treatment strategies for colon cancer. Ferritin is the main iron storage protein that occupies a vital position in iron metabolism. Studies reported that ferritin is differentially highly expressed in tissues from multiple malignancies. However, the source and function of highly expressed ferritin in colon cancer have not been explored. In this study, we found that the protein level but not RNA level of ferritin heavy chain (FTH1) was upregulated in colon cancer using paired clinical samples. Co-culture system was used to mimic the in vivo circumstance and study the cell-cell communication of macrophages and colon cancer cells. Results showed that M2 macrophages could substantially increase the FTH1 levels in colon cancer cells. This effect could be blocked by the exosome biogenesis/ secretion inhibitor GW4869, implying the vital role of exosomes in this biological process. Besides, we found that purified exosomes from M2 macrophages could deliver FTH1 into colon cancer cells and promote cell proliferation. Furtherly, EdU assay and live cell imaging system were performed in FTH1-OE (overexpression) colon cancer cell lines and confirmed the cell proliferation promoting effect of FTH1. Our results unveil the source and function of highly expressed FTH1 in colon cancer and provide a new potential therapeutic target for the treatment of colon cancer.

Comprehensive Analysis of Differentially Expressed Long Noncoding RNA-mRNA in the Adenoma-Carcinoma Sequence of DNA Mismatch Repair Proficient Colon Cancer.

DNA proficient mismatch repair colon cancer (pMMR CC) is the most common subtype of sporadic CC. We aimed to investigate the role of long noncoding RNAs (lncRNAs) in pMMR CC carcinogenesis. In the present study, we conducted transcriptomic analysis of lncRNAs-mRNAs in five low-grade intraepithelial neoplasia (LGIN), five high-grade intraepithelial neoplasia (HGIN), four pMMR CC, and five normal control (NC) tissues. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway, and coexpression network analyses were performed to elucidate the functions of lncRNAs and mRNAs as well as their interactions. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate five dysregulated lncRNAs in a large set of colon tissues. Receiver-operating characteristic (ROC) curves were employed to evaluate the performance of the candidate lncRNAs. A set of 5783 differentially expressed lncRNAs and 4483 differentially expressed mRNAs were detected among the LGIN, HGIN, pMMR CC, and NC samples. These differentially expressed lncRNAs and mRNAs were assigned to 275 significant GO terms and 179 significant KEGG enriched pathways. qRT-PCR confirmed that the expression of five selected lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, NR_026543, and ENST00000545920) were consistent with the microarray data. ROC analysis showed that four lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, and NR_026543) had larger area under the ROC curve (AUC) values compared to serum carcinoembryonic antigens, thereby distinguishing NC from pMMR CC. In conclusion, several lncRNAs play various roles in the adenoma-carcinoma sequence and may serve as potential biomarkers for the early diagnosis of pMMR CC.

Diagnostic performance of narrow-band imaging international colorectal endoscopic and Japanese narrow-band imaging expert team classification systems for colorectal cancer and precancerous lesions.

BACKGROUND: In recent years, two new narrow-band imaging (NBI) classifications have been proposed: The NBI international colorectal endoscopic (NICE) classification and Japanese NBI expert team (JNET) classification. Most validation studies of the two new NBI classifications were conducted in classification setting units by experienced endoscopists, and the application of use in different centers among endoscopists with different endoscopy skills remains unknown. AIM: To evaluate clinical application and possible problems of NICE and JNET classification for the differential diagnosis of colorectal cancer and precancerous lesions. METHODS: Six endoscopists with varying levels of experience participated in this study. Eighty-seven consecutive patients with a total of 125 lesions were photographed during non-magnifying conventional white-light colonoscopy, non-magnifying NBI, and magnifying NBI. The three groups of endoscopic pictures of each lesion were evaluated by the six endoscopists in randomized order using the NICE and JENT classifications separately. Then we calculated the six endoscopists' sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for each category of the two classifications. RESULTS: The sensitivity, specificity, and accuracy of JNET classification type 1 and 3 were similar to NICE classification type 1 and 3 in both the highly experienced endoscopist (HEE) and less-experienced endoscopist (LEE) groups. The specificity of JNET classification type 1 and 3 and NICE classification type 3 in both the HEE and LEE groups was > 95%, and the overall interobserver agreement was good in both groups. The sensitivity of NICE classification type 3 lesions for diagnosis of SM-d carcinoma in the HEE group was significantly superior to that in the LEE group (91.7% vs 83.3%; P = 0.042). The sensitivity of JNET classification type 2B lesions for the diagnosis of high-grade dysplasia or superficial submucosal invasive carcinoma in the HEE and LEE groups was 53.8% and 51.3%, respectively. Compared with other types of JNET classification, the diagnostic ability of type 2B was the weakest. CONCLUSION: The treatment strategy of the two classification type 1 and 3 lesions can be based on the results of endoscopic examination. JNET type 2B lesions need further examination.

Diagnostic value of novel retroflexion colonoscopy in the right colon: A randomized controlled trial.

BACKGROUND: Colonoscopy is the accepted gold standard for the detection of colorectal cancer. However, colonoscopy is less effective in preventing colon cancer in the right side compared with the left side. AIM: To investigate the feasibility of a novel type of retroflexion colonoscope, EC-3490Ti colonoscope, for detection of proximal colon lesions. METHODS: In this prospective trial, we recruited patients who underwent colonoscopy for screening or surveillance. When the endoscopists could not grasp the whole observation of the right-side colon mucosa in the forward view (FV), insertion and withdrawal were repeatedly performed in the FV group with the EC38-i10F colonoscope while retroflexion was performed in the retroflexed view (RV) group with the EC-3490Ti colonoscope. Adenoma detection rate, the total number of adenomas per positive participant, the success rate of retroflexion, and endoscope withdrawal time were recorded and compared. RESULTS: The total adenoma detection rate (39.3% vs 37.7%, P = 0.646) did not show any significant difference between the two groups. However, the polyp detection rate (59.6% vs 51.0%, P = 0.002), adenoma detection rate in the right colon (21.6% vs 14.4%, P = 0.012), and the total number of adenomas per positive participant (2.1 vs 1.7, P = 0.011) reached statistical significance. Retroflexion was achieved in 91.7% of our cohort. Compared with the FV group, the withdrawal time was significantly prolonged in the RV group (586.1 ± 124.4 s vs 508.8 ± 129.6 s, P < 0.001). In contrast, the proportion of additional ancillary pressure decreased (27.4% vs 45.7%, P < 0.001), and the visual analog scale pain scores did not increase (2.7 ± 1.4 vs 2.8 ± 1.4, P = 0.377). CONCLUSION: Retroflexion in the proximal colon could be performed successfully and safely with the EC-3490Ti colonoscope. This maneuver could detect more adenomas effectively.