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Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
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Objectives: Previous preclinical evidence indicates a protective role of quercetin against inflammatory bowel disease (IBD). However, there is no evidence from human populations, resulting in knowledge gaps regarding the role of quercetin in the IBD development. We aimed to prospectively evaluate the associations between dietary quercetin intake and IBD in humans and in vivo animal models. Methods: We included 187 709 IBD-free participants from the UK Biobank. Dietary information was collected using validated 24-hour dietary recalls and the quercetin intake was estimated based on national nutrient databases. Incident IBD was ascertained via inpatient and primary care data. Cox proportional hazard models were used to estimate the multi-variable adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Experiments were conducted in two chemical-induced (dextran sulfate sodium salt and trinitro-benzene-sulfonic acid) mouse models orally pretreated with quercetin (CAS number: 117-39-5) solution to evaluate the effects of quercetin at physiological levels. Results: After a mean follow-up of 9.7 years, we documented 863 incident IBD. Compared to participants with the lowest quintile intake of quercetin, those in the highest quintiles were associated with a lower risk of IBD (aHR 0.76, 95% CI 0.60-0.95; P-trend = 0.004) and ulcerative colitis (aHR 0.69, 95% CI 0.53-0.91; P-trend = 0.001), but not Crohn's disease (aHR 0.95, 95% CI 0.62-1.45; P-trend = 0.765). Mouse models showed that pretreatment with quercetin could attenuate the chemically induced colitis. Conclusions: Higher quercetin intake was associated with a lower risk of IBD, especially UC. The protective role of quercetin is promising in humans and warrants further investigation into downstream mechanisms.
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Colite Ulcerativa , Doença de Crohn , Quercetina , Quercetina/administração & dosagem , Quercetina/farmacologia , Humanos , Colite Ulcerativa/prevenção & controle , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/induzido quimicamente , Doença de Crohn/prevenção & controle , Doença de Crohn/epidemiologia , Estudos Prospectivos , Feminino , Masculino , Animais , Pessoa de Meia-Idade , Adulto , Camundongos , Idoso , Dieta , Fatores de Risco , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. METHODS: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. FINDINGS: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. INTERPRETATION: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. FUNDING: Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).
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Exercício Físico , Gastroenteropatias , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Comportamento Sedentário , Humanos , Gastroenteropatias/genética , Gastroenteropatias/etiologia , Gastroenteropatias/epidemiologia , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Fatores de RiscoRESUMO
BACKGROUND: Cumulative preclinical evidence reported quercetin, a major flavonoid, can attenuate the disease activity of inflammatory bowel diseases (IBD). However, there is limited evidence that supports the benefits of quercetin for patients with IBD. OBJECTIVES: To investigate whether dietary quercetin intake is associated with adverse outcomes among individuals with IBD in a prospective cohort study. METHODS: We included 2293 participants with IBD (764 Crohn's disease [CD] and 1529 ulcerative colitis [UC]) from the UK Biobank. Dietary information was collected using validated 24-h dietary assessments, and quercetin intake was estimated based on national nutrient databases. Two outcomes, enterotomy and all-cause mortality, were obtained based on the national data. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: After a mean (standard deviation) follow-up of 9.6 (1.8) y, we documented 193 enterotomy events and 176 deaths. Compared with participants with the lowest quartile intake of quercetin, those in the highest quartiles were associated with lower risk of enterotomy (HR: 0.46; 95% CI: 0.28, 0.76) and all-cause mortality (HR: 0.53; 95% CI: 0.33, 0.83) in IBD. The inverse associations between quercetin and enterotomy were consistent in CD (HR: 0.30; 95% CI: 0.12, 0.78) but not UC (HR: 0.58; 95% CI: 0.32, 1.07), while the inverse associations between quercetin and mortality were consistent both in CD (HR: 0.37; 95% CI: 0.15, 0.92) and UC (HR: 0.55; 95% CI: 0.31, 0.95). CONCLUSIONS: Higher dietary intake of quercetin was associated with lower risk of enterotomy and all-cause mortality in IBD. Our study provides novel evidence that further suggests the benefits of quercetin for patients with IBD, while also calling for further validation in other cohorts and clinical trials.
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Dieta , Doenças Inflamatórias Intestinais , Quercetina , Humanos , Quercetina/administração & dosagem , Quercetina/farmacologia , Estudos Prospectivos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Estudos de Coortes , Modelos de Riscos Proporcionais , Doença de Crohn , Fatores de RiscoRESUMO
OBJECTIVE: We aimed to evaluate whether individuals with type 2 diabetes (T2D) were at higher risk of developing a wide range of gastrointestinal diseases based on a population-based cohort study. RESEARCH DESIGN AND METHODS: This study included 374,125 participants free of gastrointestinal disorders at baseline; of them, 19,719 (5.27%) with T2D were followed-up by linking to multiple medical records to record gastrointestinal disease diagnoses. Multivariable Cox models were used to estimate the hazard ratios (HRs) and CIs. Logistic models were used to examine the associations between polygenic risk scores (PRS) and clinical gastrointestinal phenotypes. RESULTS: During a median follow-up of 12.0 years, we observed the new onset of 15 gastrointestinal diseases. Compared with nondiabetes, participants with T2D had an increased risk of gastritis and duodenitis (HR 1.58, 95% CI 1.51-1.65), peptic ulcer (HR 1.56, 95% CI 1.43-1.71), diverticular disease (HR 1.19, 95% CI 1.14-1.24), pancreatitis (HR 1.45, 95% CI 1.24-1.71), nonalcoholic fatty liver disease (HR 2.46, 95% CI 2.25-2.69), liver cirrhosis (HR 2.92, 95% CI 2.58-3.30), biliary disease (HR 1.18, 95% CI 1.10-1.26), gastrointestinal tract cancers (HR 1.28, 95% CI 1.17-1.40), and hepatobiliary and pancreatic cancer (HR 2.32, 95% CI 2.01-2.67). Positive associations of PRS of T2D with gastritis, duodenitis, and nonalcoholic fatty liver disease were also observed. CONCLUSIONS: In this large cohort study, we found that T2D was associated with increased risks of a wide range of gastrointestinal outcomes. We suggest the importance of early detection and prevention of gastrointestinal disorders among patients with T2D.
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Diabetes Mellitus Tipo 2 , Duodenite , Gastrite , Hepatopatia Gordurosa não Alcoólica , Humanos , Diabetes Mellitus Tipo 2/genética , Estudos de Coortes , Estratificação de Risco Genético , Hepatopatia Gordurosa não Alcoólica/complicações , Duodenite/complicações , Estudos Prospectivos , Medição de Risco , Gastrite/complicações , Fatores de RiscoRESUMO
BACKGROUND: Mitochondrial dysfunction has been linked to the development of inflammatory bowel disease (IBD), but the genetic pathophysiology was not fully elucidated. We employed Mendelian randomization and colocalization analyses to investigate the associations between mitochondrial-related genes and IBD via integrating multi-omics. METHODS: Summary-level data of mitochondrial gene methylation, expression and protein abundance levels were obtained from corresponding methylation, expression and protein quantitative trait loci studies, respectively. We obtained genetic associations with IBD and its two subtypes from the Inflammatory Bowel Disease Genetics Consortium (discovery), the UK Biobank (replication), and the FinnGen study (replication). We performed summary-data-based Mendelian randomization analysis to assess the associations of mitochondrial gene-related molecular features with IBD. Colocalization analysis was further conducted to assess whether the identified signal pairs shared a causal genetic variant. FINDINGS: After integrating the multi-omics data between mQTL-eQTL and eQTL-pQTL, we identified two mitochondrial genes, i.e., PARK7 and ACADM, with tier 1 evidence for their associations with IBD and ulcerative colitis (UC). PDK1 and FISI genes were associated with UC risk with tier 2 and tier 3 evidence, respectively. The methylation of cg05467918 in ACADM was associated with lower expression of ACADM, which fits with the positive effect of cg05467918 methylation on UC risk. Consistently, the inverse associations between gene methylation and gene expression were also observed in PARK7 (cg10385390) and PDK1 (cg17679246), which were corroborated with the protective role in UC. At circulating protein level, genetically predicted higher levels of PARK7 (OR 0.36, 95% CI 0.25-0.52) and HINT1 (OR 0.47, 95% CI 0.30-0.74) were inversely associated with IBD risk; genetically predicted higher level of HINT1 was associated with a decreased risk of Crohn's disease (CD) (OR 0.26, 95% CI 0.14-0.49) and a higher level of ACADM (OR 0.67, 95% CI 0.55-0.83), PDK1 (OR 0.63, 95% CI 0.49-0.81), FIS1 (OR 0.63, 95% CI 0.47-0.83) was associated with a decreased risk of UC. INTERPRETATION: We found that the mitochondrial PARK7 gene was putatively associated with IBD risk, and mitochondrial FIS1, PDK1, and ACADM genes were associated with UC risk with evidence from multi-omics levels. This study identified mitochondrial genes in relation to IBD, which may enhance the understanding of the pathogenic mechanisms of IBD development. FUNDING: XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and Healthy Zhejiang One Million People Cohort (K-20230085).
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Doenças Mitocondriais , Humanos , Multiômica , Doenças Inflamatórias Intestinais/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Proteínas do Tecido Nervoso/genéticaRESUMO
Background: Beverage consumption was found to be associated with cardiovascular disease and mortality in the general population. However, it is unclear whether this association still exists in individuals with inflammatory bowel disease (IBD). Objectives: To investigate the associations of sugar-sweetened beverages, artificially sweetened beverages, and natural juices with cardiovascular disease and all-cause mortality among individuals with IBD. Design: Prospective cohort study. Methods: We included 1981 participants with IBD in the UK Biobank. Consumption of beverages was measured using a validated 24-h diet recall. Outcomes of interest were overall cardiovascular disease and all-cause mortality. Cox proportional hazard models were used to estimate the hazard ratios and 95% confidence intervals (CIs). Results: During a mean (SD) follow-up of 10.1 (1.7) years, we documented 205 cardiovascular events and 133 deaths. Compared to non-consumers, those consuming sugar-sweetened beverages more than 1 unit/day (reported in glasses/cans/250 ml/cartons) were associated with 64% (95% CI: 5-155, p = 0.030) and 97% (95% CI: 16-233, p = 0.012) increased risk of cardiovascular disease and all-cause mortality, respectively. We also observed a 78% (95% CI: 3-205, p = 0.038) increased risk of cardiovascular disease in participants who consumed artificially sweetened beverages more than 1 unit/day when compared with non-consumers. We did not observe significant associations between natural juice consumption and the two outcomes in IBD. Conclusion: Higher sugar- and artificially sweetened beverage consumption were associated with adverse cardiovascular and mortality outcomes in IBD. These exploratory results were consistent with the evidence in the general population and highlighted the importance of diet management in individuals with IBD.
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BACKGROUND AND AIMS: The associations between gastrointestinal diseases (GIs) and cardiovascular disease (CVD) were unclear. We conducted a prospective cohort study to explore their associations. METHODS: This study included 330 751 individuals without baseline CVD from the UK Biobank cohort. Individuals with and without GIs were followed up until the ascertainment of incident CVDs, including coronary heart disease (CHD), cerebrovascular disease (CeVD), heart failure (HF) and peripheral artery disease (PAD). The diagnosis of diseases was confirmed with combination of the nationwide inpatient data, primary care data, and cancer registries. A multivariable Cox proportional hazard regression model was used to estimate the associations between GIs and the risk of incident CVD. RESULTS: During a median follow-up of 11.8 years, 31 605 incident CVD cases were diagnosed. Individuals with GIs had an elevated risk of CVD (hazard ratio 1.37; 95% confidence interval 1.34-1.41, P < 0.001). Eleven out of fifteen GIs were associated with an increased risk of CVD after Bonferroni-correction, including cirrhosis, non-alcoholic fatty liver disease, gastritis and duodenitis, irritable bowel syndrome, Barrett's esophagus, gastroesophageal reflux disease, peptic ulcer, celiac disease, diverticulum, appendicitis, and biliary disease. The associations were stronger among women, individuals aged ≤ 60 years, and those with body mass index ≥ 25 kg/m2. CONCLUSIONS: This large-scale prospective cohort study revealed the associations of GIs with an increased risk of incident CVD, in particular CHD and PAD. These findings support the reinforced secondary CVD prevention among patients with gastrointestinal disorders.
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BACKGROUND: To examine whether general and abdominal adiposity was a risk factor for the new-onset of inflammatory bowel disease (IBD) and the potential mediating effect of metabolic and inflammation status. METHODS: A total of 492,998 individuals free of IBD recruited from 2006 to 2010 in the UK Biobank were included in our study, with ongoing follow-up linking to the health-related outcome. Multivariable Cox regression models were used to evaluate the associations between general adiposity (body mass index) and abdominal adiposity (waist circumference) and the subsequent risk of IBD and its subtype. We also investigated the potential mediating effects of metabolic and inflammation status by carrying out exploratory mediation analyses. RESULTS: During a median follow-up of 12.5 years, we documented 2954 incident IBD cases (915 Crohn's disease [CD] and 2039 ulcerative colitis). After adjustment for important confounders, body mass index (hazard ratio [HR] highest quintile [Q5] vs. lowest quintile [Q1] = 1.18, 95% confidence interval [CI] 1.04-1.32; P-trend = 0.006) and waist circumference (HR Q5 vs. Q1 = 1.30, 95% CI 1.14-1.49; P-trend <0.001) showed a positive association with the risk of IBD. The associations were partially mediated by metabolic status (24%; 15%), C-reactive protein (36%; 19%) and inflammation score (82%; 46%). CONCLUSIONS: Adiposity bore a risk factor for incident IBD, whereas unhealthy metabolism, especially inflammation, seemed to be an important intermediate condition between the association. Our findings provide evidence for possible mechanisms relating adiposity to IBD from an epidemiological perspective, and experimental studies are needed for further demonstration.
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Adiposidade , Doenças Inflamatórias Intestinais , Humanos , Estudos de Coortes , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/etiologia , Fatores de Risco , Obesidade/epidemiologia , Inflamação/epidemiologiaRESUMO
Background: The incidence and severity of coronavirus disease 2019 (COVID-19) among Crohn's disease (CD) patients are unknown in China. This study aimed to clarify the clinical courses and outcomes of CD patients in the first COVID-19 wave after the end of "zero-COVID" policy in China. Methods: Clinical characteristics, including vaccination doses and medications of 880 CD patients from a prospective cohort were collected for analysis. Results: Of the enrolled patients (n = 880) who underwent nucleic acid or antigen testing for COVID-19 from Dec 7, 2022, to Jan 7, 2023, 779 (88.5%) were infected with COVID-19. Among the infected patients, 755 (96.9%) were mild, 14 (1.8%) were moderate, one patient with leukemia died of cerebral hemorrhage (mortality, 0.1%) and only 9 (1.2%) were asymptomatic. Fever, cough, headache and appetite loss were the most frequently observed symptoms in general, respiratory, neurological and gastrointestinal manifestations, respectively. The age and disease duration were significantly higher (40/32, 5.6/3.6, all p < 0.05) in moderate patients than those in mild patients. All other clinical characteristics, including CD activity and medication exposure, showed no significant differences between the above two groups. Furthermore, no significant difference in vaccination or comorbidities was observed between the two groups. Conclusion: Most CD patients contracted the Omicron infection and experienced mild disease courses in the first COVID-19 wave attack after China ended the "zero-COVID" policy irrespective of vaccination dose or comorbidities.
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COVID-19 , Doença de Crohn , Humanos , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , COVID-19/epidemiologia , Teste para COVID-19 , Estudos Prospectivos , ComorbidadeRESUMO
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.
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Neoplasias Colorretais , Inibidores de Hidroximetilglutaril-CoA Redutases , Limosilactobacillus reuteri , Microbiota , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Triptofano , Estudos Retrospectivos , Neoplasias Colorretais/prevenção & controleRESUMO
Maladaptation of host-microbiota metabolic interplay plays a critical role in colorectal cancer initiation. Here, through a combination of single-cell transcriptomics, microbiome profiling, metabonomics, and clinical analysis on colorectal adenoma and carcinoma tissues, we demonstrate that host's urea cycle metabolism is significantly activated during colorectal tumorigenesis, accompanied by the absence of beneficial bacteria with ureolytic capacity, such as Bifidobacterium, and the overabundance of pathogenic bacteria lacking ureolytic function. Urea could enter into macrophages, inhibit the binding efficiency of p-STAT1 to SAT1 promotor region, and further skew macrophages toward a pro-tumoral phenotype characterized by the accumulation of polyamines. Treating a murine model using urea cycle inhibitors or Bifidobacterium-based supplements could mitigate urea-mediated tumorigenesis. Collectively, this study highlights the utility of urea cycle inhibitors or therapeutically manipulating microbial composition using probiotics to prevent colorectal cancer.
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Neoplasias Colorretais , Microbioma Gastrointestinal , Microbiota , Camundongos , Animais , Microbioma Gastrointestinal/fisiologia , Carcinogênese , Neoplasias Colorretais/patologia , Transformação Celular NeoplásicaRESUMO
The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40-50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild-type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild-type p53 and suppresses tumor growth only in p53-wild-type (p53-WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM-induced CRC growth in mouse models with the intestinal epithelial cell-specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53-WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6 A-YTHDF2-dependent pri-miR-6769b/pri-miR-499a processing. Biosynthetic mature miR-6769b-3p and miR-499a-3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53-WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53-dependent cancer growth inhibition, which could be targeted for therapy in p53-WT CRC.
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Neoplasias Colorretais , MicroRNAs , Animais , Camundongos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Superoxide dismutase 1 (SOD1) modulates intestinal barrier integrity and intestinal homeostasis as an antioxidant enzyme. Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). However, whether and how SOD1 regulates ISCs is unknown. In this study, we established intestinal organoids from tamoxifen-inducible intestinal epithelial cell-specific Sod1 knockout (Sod1f/f; Vil-creERT2) mice. We found that loss of Sod1 in organoids suppressed the proliferation and survival of cells and Lgr5 gene expression. SOD1 is known for nearly half a century for its canonical role as an antioxidant enzyme. We identified its enzyme-independent function in ISC: inhibition of SOD1 enzymatic activity had no impact on organoid growth, and enzymatically inactive Sod1 mutants could completely rescue the growth defects of Sod1 deficient organoids, suggesting that SOD1-mediated ISC growth is independent of its enzymatic activity. Moreover, Sod1 deficiency did not affect the ROS levels of the organoid, but induced the elevated WNT signaling and excessive Paneth cell differentiation, which mediates the occurrence of growth defects in Sod1 deficient organoids. In vivo, epithelial Sod1 loss induced a higher incidence of apoptosis in the stem cell regions and increased Paneth cell numbers, accompanied by enhanced expression of EGFR ligand Epiregulin (EREG) in the stromal tissue, which may compensate for Sod1 loss and maintain intestinal structure in vivo. Totally, our results show a novel enzyme-independent function of SOD1 in ISC growth under homeostasis.
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Neoplasias Intestinais , Superóxido Dismutase , Camundongos , Animais , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Epirregulina/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Ligantes , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/metabolismo , Celulas de Paneth/metabolismo , Organoides/metabolismo , Neoplasias Intestinais/metabolismo , Receptores ErbB/metabolismo , Tamoxifeno/farmacologia , Mucosa Intestinal/metabolismo , Proliferação de CélulasRESUMO
Chronic inflammation and gut microbiota dysbiosis are risk factors for colorectal cancer. In clinical practice, patients with inflammatory bowel disease (IBD) have a greatly increased risk of developing colitis-associated colorectal cancer (CAC). However, the underlying mechanism of the initiation of CAC remains unknown. Systematic analyses using an existing genome-wide association study (GWAS) and conditional deletion of Zfp90 (encoding zinc finger protein 90 homolog) in a CAC mouse model indicated that Zfp90 is a putative oncogene in CAC development.Strikingly, depletion of the gut microbiota eliminated the tumorigenic effect of Zfp90 in the CAC mouse model. Moreover, fecal microbiota transplantation demonstrated that Zfp90 promoted CAC dependent on the gut microbiota. Analysis of 16s rDNA sequences in fecal specimens from the CAC mouse model allowed us to speculate that a Prevotella copri-defined microbiota might mediate the oncogenic role of Zfp90 in the development of CAC. Mechanistic studies revealed Zfp90 accelerated CAC development through the TLR4-PI3K-AKT-NF-κB pathway. Our findings revealed the crucial role of the Zfp90-microbiota-NF-κB axis in creating a tumor-promoting environment and suggested therapeutic targets for CAC prevention and treatment.
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Neoplasias Associadas a Colite/metabolismo , Microbioma Gastrointestinal , Proteínas Repressoras/metabolismo , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/microbiologia , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Repressoras/genéticaRESUMO
Long non-coding RNAs (lncRNAs) play key roles in colorectal carcinogenesis. Here, we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis. First, we identified rs6695584 as the causative SNP in 1q41 locus. The A>G mutation of rs6695584 created a protein-binding motif of BATF, altered the enhancer activity, and subsequently activated lncSLCC1 expression. Further validation in two independent CRC cohorts confirmed the upregulation of lncSLCC1 in CRC tissues, and revealed that increased lncSLCC1 expression was associated with poor survival in CRC patients. Mechanistically, lncRNA-SLCC1 interacted with AHR and transcriptionally activated HK2 expression, the crucial enzyme in glucose metabolism, thereby driving the glycolysis pathway and accelerating CRC tumor growth. The functional assays revealed that lncSLCC1 induced glycolysis activation and tumor growth in CRC mediated by HK2. In addition, HK2 was upregulated in colorectal cancer tissues and positively correlated with lncSLCC1 expression and patient survival. Taken together, our findings reveal a risk SNP-mediated oncogene lncRNA-SLCC1 promotes CRC through activating the glycolysis pathway.
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Carcinogênese/genética , Neoplasias Colorretais/genética , Hexoquinase/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glicólise/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais/genéticaRESUMO
OBJECTIVE: As a canonical membrane tethering factor, the function of synbindin has been expanding and indicated in immune response. Here, we investigated the role of synbindin in the regulation of toll-like receptor 4 (TLR4) signalling and macrophage response to microbiota during colitis. DESIGN: Three distinct mouse models allowing global, myeloid-specific or intestinal epithelial cell-specific synbindin heterozygous deletion were constructed and applied to reveal the function of synbindin during dextran sodium sulfate (DSS) colitis. Effects of synbindin on TLR4 signalling and macrophage activation in response to bacterial lipopolysaccharide (LPS) or Fusobacterium nucleatum were evaluated. The colocalisation and interaction between synbindin and Rab7b were determined by immunofluorescence and coimmunoprecipitation. Synbindin expression in circulating monocytes and intestinal mucosal macrophages of patients with active IBD was detected. RESULTS: Global synbindin haploinsufficiency greatly exacerbated DSS-induced intestinal inflammation. The increased susceptibility to DSS was abolished by gut microbiota depletion, while phenocopied by specific synbindin heterozygous deletion in myeloid cells rather than intestinal epithelial cells. Profoundly aberrant proinflammatory gene signatures and excessive TLR4 signalling were observed in macrophages with synbindin interference in response to bacterial LPS or Fusobacterium nucleatum. Synbindin was significantly increased in intestinal mucosal macrophages and circulating monocytes from both mice with DSS colitis and patients with active IBD. Interleukin 23 and granulocyte-macrophage colony-stimulating factor were identified to induce synbindin expression. Mechanistic characterisation indicated that synbindin colocalised and directly interacted with Rab7b, which coordinated the endosomal degradation pathway of TLR4 for signalling termination. CONCLUSION: Synbindin was a key regulator of TLR4 signalling and restrained the proinflammatory macrophage activation against microbiota during colitis.
Assuntos
Colite/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Receptor 4 Toll-Like/efeitos dos fármacos , Proteínas de Transporte Vesicular/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Transdução de Sinais , proteínas de unión al GTP Rab7/efeitos dos fármacosRESUMO
OBJECTIVE: Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC. DESIGN: 18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1. RESULTS: We have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function. CONCLUSION: F. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.
Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Infecções por Fusobacterium/genética , Glicólise/genética , RNA Longo não Codificante/genética , Animais , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico por imagem , Proteínas de Ligação a DNA , Fluordesoxiglucose F18/farmacocinética , Fusobacterium nucleatum , Microbioma Gastrointestinal , Regulação Neoplásica da Expressão Gênica , Histona Acetiltransferases , Humanos , Camundongos , Fosfopiruvato Hidratase , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Transdução de Sinais , Células Tumorais Cultivadas , Proteínas Supressoras de TumorRESUMO
The molecular mechanisms that control the development of colorectal cancer (CRC) remain poorly defined. Here we show Synbindin promoted CRC oncogenesis by activating Wnt signaling and altering gut microbiome. Synbindin upregulation in human CRCs was associated with poor patient prognosis. Intestine-specific disruption of Synbindin balanced the disturbed gut microbiota and protected mice against tumor formation in the colitis-associated cancer (CAC) model. The protective role was compromised after gut microbiota depletion. In host, increased goblet cells and mucin2 expression, together with increased intestinal epithelial cells (IECs) apoptosis and decreased epithelial proliferation were observed. Further transcriptomic sequencing identified Wnt signaling a major regulatory node downstream of Synbindin. Combined molecular and cellular characterizations revealed that Synbindin confers Disheveled-3 (DVL3)-based signalosome assembly and acts as a modular scaffold for DVL3 and Axin2 complex, orchestrating the intensity of Wnt signaling. These findings identify a critical role of Synbindin in gut microbiome composition and Wnt signaling activation in colorectal carcinogenesis, and highlight Synbindin as an adaptor protein with multifaceted roles.