Antibiotic Exposure and Risk of New-Onset Ulcerative Colitis: a Systematic Review and Meta-Analysis.

BACKGROUND: Antibiotic exposure has been reported as a risk factor for the development of ulcerative colitis; however, the clinical results were controversial. Therefore, we performed a meta-analysis to evaluate the association of antibiotic exposure with the new onset of UC. METHODS: A comprehensive literature search for relevant studies published up to February 2024, exploring the association between antibiotic exposure and new-onset UC, was performed by using Medline and Embase, and the statistical analysis was conducted by using the Stata software. RESULTS: A total of 16 articles were included in the study, including 12 case-control studies and 4 cohort studies. The pooled analysis revealed that antibiotic exposure was associated with an increased risk of new-onset UC (summary OR = 1.28, 95% CI = 1.26 - 1.31). Subgroup analyses showed that both case-control studies and cohort studies have yielded consistent conclusions. CONCLUSIONS: This meta-analysis suggests that antibiotic exposure is a risk factor for the development of UC. It is, therefore, necessary to avoid unnecessary and excessive use of antibiotics.

Metformin abrogates Fusobacterium nucleatum-induced chemoresistance in colorectal cancer by inhibiting miR-361-5p/sonic hedgehog signaling-regulated stemness.

BACKGROUND: Chemotherapy resistance is the major cause of recurrence in patients with colorectal cancer (CRC). A previous study found that Fusobacterium (F.) nucleatum promoted CRC chemoresistance. Additionally, metformin rescued F. nucleatum-induced tumorigenicity of CRC. Here, we aimed to investigate whether metformin could revert F. nucleatum-induced chemoresistance and explore the mechanism. METHODS: The role of metformin in F. nucleatum-infected CRC cells was confirmed using cell counting kit 8 assays and CRC xenograft mice. Stemness was identified by tumorsphere formation. Bioinformatic analyses were used to explore the regulatory molecules involved in metformin and F. nucleatum-mediated regulation of the sonic hedgehog pathway. RESULTS: We found that metformin abrogated F. nucleatum-promoted CRC resistance to chemotherapy. Furthermore, metformin attenuated F. nucleatum-stimulated stemness by inhibiting sonic hedgehog signaling. Mechanistically, metformin diminished sonic hedgehog signaling proteins by targeting the MYC/miR-361-5p cascade to reverse F. nucleatum-induced stemness, thereby rescuing F. nucleatum-triggered chemoresistance in CRC. CONCLUSIONS: Metformin acts on F. nucleatum-infected CRC via the MYC/miR-361-5p/sonic hedgehog pathway cascade, subsequently reversing stemness and abolishing F. nucleatum-triggered chemoresistance. Our results identified metformin intervention as a potential clinical treatment for patients with chemoresistant CRC with high amounts of F. nucleatum.

Noninvasive predictive models based on lifestyle analysis and risk factors for early-onset colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.

SRSF3 functions as an oncogene in colorectal cancer by regulating the expression of ArhGAP30.

BACKGROUND: Splicing factor SRSF3 is an oncogene and overexpressed in various kinds of cancers, however, the function and mechanism involved in colorectal cancer (CRC) remained unclear. The aim of this study was to explore the relationship between SRSF3 and carcinogenesis and progression of CRC. METHODS: The expression of SRSF3 in CRC tissues was detected by immunohistochemistry. The proliferation and invasion rate was analyzed by CCK-8 assay, colony formation assay, transwell invasion assay and xenograft experiment. The expression of selected genes was detected by western blot or real time PCR. RESULTS: SRSF3 is overexpressed in CRC tissues and its high expression was associated with CRC differentiation, lymph node invasion and AJCC stage. Upregulation of SRSF3 was also associated with shorter overall survival. Knockdown of SRSF3 in CRC cells activated ArhGAP30/Ace-p53 and decreased cell proliferation, migration and survival; while ectopic expression of SRSF3 attenuated ArhGAP30/Ace-p53 and increases cell proliferation, migration and survival. Targeting SRSF3 in xenograft tumors suppressed tumor progression in vivo. CONCLUSIONS: Taken together, our data identify SRSF3 as a regulator for ArhGAP30/Ace-p53 in CRC, and highlight potential prognostic and therapeutic significance of SRSF3 in CRC.

PD-L1 Overexpression on Tumor-Infiltrating Lymphocytes Related to Better Prognosis of Colorectal Cancer.

BACKGROUND: PD-L1 expression on tumor-infiltrating lymphocytes (TILs) has recently been reported as a biomarker for colorectal cancer (CRC). However, the prognostic and clinical significance of PD-L1 on TILs in CRC remains controversial. We performed this meta-analysis to evaluate the association between the PD-L1 expression on TILs and clinicopathological features and prognosis of CRC patients. METHODS: A comprehensive literature search for relevant studies published up to Feb 2020 was performed using Medline, Embase, and Web of Science. Odds ratio (OR) with 95% CI was selected to appraise the correlation between PD-L1 expression on TILs with prognostic and clinicopathological characteristics of CRC patients. Begg's and Egger's test were used to assess publication bias. The statistical analysis was conducted using Stata software. RESULTS: A total of 19 studies including 5,213 CRC cases were included in this meta-analysis. The pooled results showed that PD-L1 overexpression on TILs was relevant to longer OS (OR = 1.36, 95% CI = 1.19 - 1.55, p < 0.01) and longer DFS/RFS (OR = 1.22, 95% CI = 1.03 - 1.44, p = 0.02). Moreover, CRC patients with high expression of PD-L1 on TILS was associated with lower T stage (OR = 2.30, 95% CI = 1.85 - 2.87, p < 0.01), less lymph node in-vasion (OR = 1.48, 95% CI = 1.03 - 2.13, p = 0.03), less distant metastasis (OR = 2.56, 95% CI = 1.81 - 3.64, p < 0.01), earlier TNM stage (OR = 1.93, 95% CI = 1.34 - 2.66, p < 0.01), later tumor grade (OR = 0.38, 95% CI = 0.23 - 0.62, p < 0.01) and high MSI status (OR = 0.36, 95% CI = 0.25 - 0.52, p < 0.01). But it is not related to tumor size, tumor differentiation, MMR status, BRAF mutant, and KRAS mutant. CONCLUSIONS: This meta-analysis revealed that PD-L1 expression on TILs can serve as a significant biomarker for positive prognosis and clinicopathological features of CRC. Our results may provide some useful information when using PD-L1 expression to predict the survival of CRC patients and to select the beneficial CRC patients from PD-1/PD-L1 antibody treatment.

Helicobacter Pylori Infection Increases the Risk of Colorectal Adenomas: an Updated Meta-Analysis.

BACKGROUND: H. pylori infection has been reported as a risk factor for colorectal adenoma (CRA); however, the clinical results were controversial. Therefore, we performed a meta-analysis to evaluate the association of H. pylori infection and CRA risk. METHODS: A comprehensive literature search for relevant studies published up to November 2017 was performed using Medline and Embase, and the statistical analysis was conducted using Stata software. RESULTS: A total of twenty-five studies including 8,675 cases and 15,275 controls were included in the analysis. The pooled analysis showed that H. pylori infection was associated with an increased risk of CRA (OR = 1.86, 95% CI = 1.55 - 2.23). Subgroup analyses according to the ethnicity, study type, and H. pylori detection method were further conducted. The results showed that H. pylori infection was associated with an increased risk of CRA both in Caucasian (OR = 2.23, 95% CI = 1.36 - 3.66) and Asian population (OR = 1.58, 95% CI = 1.36 - 1.82). Both the case-control studies and cross sectional studies suggested the H. pylori infection could promote the risk of CRA (case control: OR was 2.00, 95% CI = 1.22 - 3.28; cross-sectional: OR was 1.68, 95% CI = 1.43 - 1.99). For H. pylori infection detection methods, there is significant association between H. pylori infection and CRA risk using the serum IgG method and RUT, but not with the UBT and IHC method. CONCLUSIONS: This analysis suggests that H. pylori infection may be a risk factor for CRA.

CD24 Overexpression Related to Lymph Node Invasion and Poor Prognosis of Colorectal Cancer.

BACKGROUND: Cluster of differentiation 24 (CD24) has recently been reported as a biomarker for colorectal cancer. However, the clinical and prognostic significance of CD24 in colorectal cancer remains controversial. Therefore, we performed a meta-analysis to clarify this issue. METHODS: A comprehensive literature search was performed using Medline, Embase, Web of Science, and CNKI, and the statistical analysis was conducted using Stata software. RESULTS: A total of thirteen studies including 2,180 cases were included in this meta-analysis. The pooled analysis indicated that CD24 expression was associated with lymph node invasion (RR = 0.71 (negative versus positive), 95% CI = 0.52 - 0.96, p = 0.02, Figure 3), differentiation (RR = 0.81 (well versus poor), 95% CI = 0.67 - 0.99, p = 0.04), and T stage (RR = 0.74 (T1 + T2 versus T3 + T4), 95% CI = 0.65 - 0.85, p = 0.00). The prognosis analysis also suggested CD24 overexpression indicating poorer 5-year OS rate (RR = 0.74, 95% CI = 0.58 - 0.93, p = 0.01) However, CD24 was not associated with other clinicopathological features such as tumor size, tumor grade, distant metastasis, TNM stage and Dukes stage. CONCLUSIONS: Taken together, this meta-analysis suggested that CD24 is an efficient prognostic factor in colorectal cancer.

A positive feedback loop between STAT3 and cyclooxygenase-2 gene may contribute to Helicobacter pylori-associated human gastric tumorigenesis.

Persistent infection with Helicobacter pylori (H. pylori) contributes to gastric diseases including chronic gastritis and gastric cancer. However, the pathogenesis of this carcinogenic bacterium has not been completely elucidated. Here, we report that H. pylori rapidly triggers STAT3 signaling and induces STAT3-dependent COX-2 expression both in vitro and in vivo. STAT3 upregulates COX-2 by binding to and increasing the activity of COX-2 promoter. COX-2 in turn regulates IL-6/STAT3 signaling under basal conditions and during H. pylori infection. These findings suggest that a positive feedback loop between STAT3 and COX-2 exists in the basal condition and H. pylori infectious condition. Immunohistochemical staining revealed that H. pylori-positive gastritis tissues exhibited markedly higher levels of pSTAT3(Tyr705) than H. pylori-negative ones. High pSTAT3(Tyr705) levels are correlated with intestinal metaplasia and dysplasia, suggesting pSTAT3(Tyr705) may be useful in the early detection of gastric tumorigenesis. Additionally, a strong positive correlation between STAT3/pSTAT3(Tyr705) levels and COX-2 expression was identified in gastritis and gastric cancer tissues. Together, these findings provide new evidence for a positive feedback loop between STAT3 signaling and COX-2 in H. pylori pathogenesis and may lead to new approaches for early detection and effective therapy of gastric cancer

CD24 mediates gastric carcinogenesis and promotes gastric cancer progression via STAT3 activation.

The development of gastric cancer (GC) is a complex multistep process, including numerous genetic and epigenetic changes. CD24 is associated with enhanced invasiveness of GC and a poor prognosis. However, the mechanism by which CD24 induces GC progression remains poorly characterized. Here, we found that the expression of CD24 gradually increased in samples of normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis (CAG), CAG with intestinal metaplasia, dysplasia and GC. Moreover, the knockdown of CD24 induced significant levels of apoptosis in GC cells via the mitochondrial apoptotic pathway. CD24 may also promote cellular invasion and regulate the expression of E-cadherin, fibronectin and vitamin D receptor in GC cells. The activation of signal transducer and activator of transcription 3 (STAT3) may mediate CD24-induced GC survival and invasion in vitro. Furthermore, CD24-induced GC progression and STAT3 activation could also be detected in vivo and in clinical GC tissues samples. Taken together, our results indicate that CD24 mediates gastric carcinogenesis and may promote GC progression by suppressing apoptosis and promoting invasion, with the activation of STAT3 playing a critical role.

Role of STAT3 and vitamin D receptor in EZH2-mediated invasion of human colorectal cancer.

The polycomb group protein enhancer of zeste homologue 2 (EZH2), which has histone methyltransferase (HMT) activity, is overexpressed in malignant tumours. However, the role of EZH2 in colorectal cancer (CRC) invasion is little known. Here we investigated the clinical significance, biological effects, and mechanisms of EZH2 signalling. Knockdown of EZH2 significantly reduced cell invasion and secretion of matrix metalloproteinases 2/9 (MMP2/9) in in vitro studies. Knockdown of EZH2 dramatically increased overall survival and decreased metastasis of lung in in vivo studies. Conversely, overexpression of EZH2 significantly increased lung metastasis and shortened overall survival when compared with control tumours. EZH2-induced CRC cell invasion may depend on down-regulation of vitamin D receptor (VDR), which is considered to be a marker of CRC invasion. EZH2 regulates the histone trimethylation of lysine 27 (H3K27me3) in the VDR promoter. Moreover, we found that STAT3 directly binds to the EZH2 promoter and regulates VDR down-regulation in CRC cells. Significant inverse correlations were observed between the expression of EZH2 and pSTAT3 and that of VDR in CRC tissues compared with normal tissue in patients. We show the role of EZH2 in CRC metastasis and identify VDR as a target gene of EZH2. EZH2 expression may be directly regulated by STAT3, and STAT3 may play an important role in EZH2-mediated VDR down-regulation in CRC. This pathway may provide potential targets in aggressive CRC.

Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition.

The progression of colorectal carcinoma (CRC) to invasive and metastatic disease may involve localized occurrences of epithelial-mesenchymal transition (EMT). However, mechanisms of the EMT process in CRC progression are not fully understood. We previously showed that knockdown of signal transducer and activator of transcription 3 (STAT3) up-regulated E-cadherin (a key component in EMT progression) in CRC. In this study, we examined the roles of STAT3 in CRC EMT and ZEB1, an EMT inducer, in STAT3-induced down-regulation of E-cadherin. Knockdown of STAT3 significantly increased E-cadherin and decreased N-cadherin and vimentin expressions in highly invasive LoVo CRC cells. Meanwhile, overexpression of STAT3 significantly reduced E-cadherin and enhanced N-cadherin and vimentin expressions in weakly invasive SW1116 CRC cells. Activation of STAT3 significantly increased CRC cell invasiveness and resistance to apoptosis. Knockdown of STAT3 dramatically enhanced chemosensitivity of CRC cells to fluorouracil. STAT3 regulated ZEB1 expression in CRC cells, and the STAT3-induced decrease in E-cadherin and cell invasion depended on activation of ZEB1 in CRC cells. Additionally, pSTAT3(Tyr-705) and ZEB1 expressions were significantly correlated with TNM (tumor, lymph node, and metastasis stages) (p < 0.01). In conclusion, STAT3 may directly mediate EMT progression and regulate ZEB1 expression in CRC. ZEB1 may participate in STAT3-induced cell invasion and E-cadherin down-regulation in CRC cells. The expressions of pSTAT3(Tyr-705) and ZEB1 may be positively associated with CRC metastasis. Our data may provide potential targets to prevent and/or treat CRC invasion and metastasis.

Identification of potential target genes of butyrate in dimethylhydrazine-induced colorectal cancer in mice.

The mechanism by which butyrate prevents colorectal cancer (CRC) is unclear. The objective of this study was to identify potential target genes of butyrate in 1,2-dimethylhydrazine (DMH)-induced CRC in mice. Nontumor colorectal tissues of mice from DMH + butyrate, DMH, and control groups were hybridized on Agilent Mouse Whole Genome 44K Oligo Microarrays. Selected genes were validated by qRT-PCR. Data was further analyzed by KEGG, gene ontology (GO), and pathway studio software. The tumor incidence in the DMH + butyrate and DMH groups was 30% and 90%, respectively (P < 0.05). There were 355 genes downregulated due to DMH treatment while upregulated by butyrate, and 475 genes upregulated by DMH while downregulated by butyrate. The results revealed that most of the tumor-related signaling pathways (e.g., MAPK pathway, Wnt pathway, insulin pathway, and VEGF pathway) were downregulated by butyrate. The GO terms related to cell differentiation, cell cycle, cell proliferation, cell death, cell adhesion, and cell migration were significantly affected. The chemopreventive effects of butyrate were confirmed in the DMH-induced CRC mice model. And mechanisms encompassing multiple pathways and GO terms are involved in the regulation of gene expression.

Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer.

Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.

Comparison of the clinicopathological characteristics of young and elderly patients with gastric carcinoma: a meta analysis.

To evaluate the relationship between age and clinicopathological characteristics in gastric carcinoma patients, we performed the meta-analysis based on nine retrospective clinical trials. Comparing elderly patients with young patients it showed lower male/female ratio, more diffuse GC, more Borrmann type IV, more poorly differentiated carcinoma, more peritoneal metastasis, less vascular invasion, fewer partial resections, and better 5-year survival rate. These particular age-related characteristics need to be further investigated.

MicroRNA 345, a methylation-sensitive microRNA is involved in cell proliferation and invasion in human colorectal cancer.

Aberrant methylation has been shown to trigger the inactivation of tumor suppressor genes during tumorigenesis. MicroRNAs (miRNAs) have been found deregulated in human colorectal cancer (CRC), and some of them may function as tumor suppressor genes. Here, we investigated CpG island promoter hypermethylation as a potential mechanism underlying miRNA disruption and identifed methylation-sensitive miRNAs that might repress CRC development. We compared differential expression of miRNAs after 5-aza-2'-deoxycitidine (5-aza-dC) treatment using microarrays. DNA methylation status of the candidate miRNA was analyzed. The candidate miRNA was transfected into CRC cells and growth-suppressive mechanisms were explored. Luciferase reporter assay and western blot were used to identify the target genes of the candidate miRNA. The expression of mir-345 was significantly increased after 5-aza-dC treatment. DNA methylation analyses of mir-345 showed high methylation levels in tumor versus normal tissues. Expression of mir-345 was significantly down-regulated in 51.6% of CRC tissues compared with corresponding non-cancerous tissues. Low expression of mir-345 was associated with lymph node metastasis and worse histological type. Increased mir-345 function was sufficient to suppress colon cancer cell proliferation and invasiveness in vitro. Furthermore, we identified BCL2-associated athanogene 3 (BAG3), an anti-apoptosis protein, to be a target of mir-345. These results suggested as a methylation-sensitive miRNA in CRC, mir-345 may play an important role of antineoplastic as a growth inhibitor in the development of CRC.

Methodological reporting of randomized controlled trials in major hepato-gastroenterology journals in 2008 and 1998: a comparative study.

BACKGROUND: It was still unclear whether the methodological reporting quality of randomized controlled trials (RCTs) in major hepato-gastroenterology journals improved after the Consolidated Standards of Reporting Trials (CONSORT) Statement was revised in 2001. METHODS: RCTs in five major hepato-gastroenterology journals published in 1998 or 2008 were retrieved from MEDLINE using a high sensitivity search method and their reporting quality of methodological details were evaluated based on the CONSORT Statement and Cochrane Handbook for Systematic Reviews of interventions. Changes of the methodological reporting quality between 2008 and 1998 were calculated by risk ratios with 95% confidence intervals. RESULTS: A total of 107 RCTs published in 2008 and 99 RCTs published in 1998 were found. Compared to those in 1998, the proportion of RCTs that reported sequence generation (RR, 5.70; 95%CI 3.11-10.42), allocation concealment (RR, 4.08; 95%CI 2.25-7.39), sample size calculation (RR, 3.83; 95%CI 2.10-6.98), incomplete outecome data addressed (RR, 1.81; 95%CI, 1.03-3.17), intention-to-treat analyses (RR, 3.04; 95%CI 1.72-5.39) increased in 2008. Blinding and intent-to-treat analysis were reported better in multi-center trials than in single-center trials. The reporting of allocation concealment and blinding were better in industry-sponsored trials than in public-funded trials. Compared with historical studies, the methodological reporting quality improved with time. CONCLUSION: Although the reporting of several important methodological aspects improved in 2008 compared with those published in 1998, which may indicate the researchers had increased awareness of and compliance with the revised CONSORT statement, some items were still reported badly. There is much room for future improvement.

ADRM1 as a therapeutic target in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a primary liver tumor, is the third leading cause of cancer-related mortality worldwide. The proteasome system is overactivated in the majority of tumors, including HCC. However, targeting the proteasome system in HCC is not as effective as in other types of cancer. Therefore, a new target of HCC therapy needs to be identified, and the potential mechanism must be studied. Using the The Cancer Gene Genome Atlas and GEO datasets, the present investigation demonstrated for the first time that ADRM1 is overexpressed in HCC, and the high level of its expression predicts poor overall survival in HCC patients. The high expression of ADRM1 in HCC was verified using tumor tissue arrays. By comparing paired tumor and nontumor tissues, it was shown that the majority of HCC patients (76.25%) exhibited higher ADRM1 expression in the tumor than in normal tissues. in vitro experiments demonstrated that targeting ADRM1 with shRNAs significantly suppressed the proliferation of HCC cells. RA190, a specific inhibitor of ADRM1, suppressed cell proliferation and colony formation by HCC cells in a concentration-dependent manner. The study of the mechanism of the effects of RA190 revealed that targeting ADRM1 blocked the G2/M transition in the cell cycle and induced apoptosis of HCC cells. Together, the obtained results indicate that ADRM1 is a promising target for HCC therapy and suggest that ADRM1 inhibitors, such as RA190, have the potential for clinical application in the treatment of HCC.

Fusobacterium nucleatum exacerbates colitis by damaging epithelial barriers and inducing aberrant inflammation.

OBJECTIVE: Fusobacterium nucleatum (F. nucleatum) has been reported to be enriched in patients with inflammatory bowel disease (IBD). This study aimed to explore the role of F. nucleatum in IBD and its pathogenic mechanism. METHODS: Several bacteria that have been reported to be associated with IBD or colorectal cancer were measured in the fecal samples of 91 patients with IBD and 43 healthy individuals. Mice with dextran sulfate sodium (DSS)-induced colitis and a Caco-2 cell line were used to explore the pathogenicity of F. nucleatum. Barrier damage was evaluated by a transmission electron microscope, the permeability of fluorescein isothiocyanate-dextran, transepithelial electrical resistance and immunofluorescence. Protein levels of the cell-cell junction and activation of the STAT3 signaling pathway were detected by immunohistochemistry and immunoblot. Cytokine secretion and T-cell differentiation were measured by quantitative real-time polymerase chain reaction and flow cytometry. RESULTS: F. nucleatum was significantly enriched in the feces of patients with IBD and its abundance correlated with disease activity. Administration of F. nucleatum markedly exacerbated colitis in a DSS mouse model. Mechanistically, F. nucleatum damaged epithelial integrity and increased permeability by regulating the expression and distribution of tight junction proteins zonula occludens-1 and occludin. Moreover, F. nucleatum promoted the secretion of cytokines (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1ß, IL-6, and IL-17), activated the STAT3 signaling pathway, and induced CD4+ T cell proliferation and Th1 and Th17 subset differentiations. CONCLUSION: F. nucleatum can damage the intestinal barrier and induce aberrant inflammation, which exacerbates colitis.

Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner.

Reversible post-translational modifications represent a mechanism to control tumor metabolism. Here we show that mitochondrial Sirtuin5 (SIRT5), which mediates lysine desuccinylation, deglutarylation, and demalonylation, plays a role in colorectal cancer (CRC) glutamine metabolic rewiring. Metabolic profiling identifies that deletion of SIRT5 causes a marked decrease in 13C-glutamine incorporation into tricarboxylic-acid (TCA) cycle intermediates and glutamine-derived non-essential amino acids. This reduces the building blocks required for rapid growth. Mechanistically, the direct interaction between SIRT5 and glutamate dehydrogenase 1 (GLUD1) causes deglutarylation and functional activation of GLUD1, a critical regulator of cellular glutaminolysis. Consistently, GLUD1 knockdown diminishes SIRT5-induced proliferation, both in vivo and in vitro. Clinically, overexpression of SIRT5 is significantly correlated with poor prognosis in CRC. Thus, SIRT5 supports the anaplerotic entry of glutamine into the TCA cycle in malignant phenotypes of CRC via activating GLUD1.