Gut最新文献

{"title":"Beyond traditional subtyping: a multilayered genomic perspective on colorectal cancer.","authors":"Shaida Ouladan, Elias Orouji","doi":"10.1136/gutjnl-2024-332325","DOIUrl":"10.1136/gutjnl-2024-332325","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"e7"},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular immunotherapies and immune cell depleting therapies in inflammatory bowel diseases: the next magic bullet?","authors":"Markus Friedrich Neurath, Bruce Eric Sands, Florian Rieder","doi":"10.1136/gutjnl-2024-332919","DOIUrl":"10.1136/gutjnl-2024-332919","url":null,"abstract":"<p><p>Despite significant advances in biologic and small molecule treatments and the emergence of combination therapies to treat inflammatory bowel diseases (IBD) a large unmet need remains to control intestinal inflammation. New approaches targeting several pathways simultaneously with a favorable safety profile and agents that trigger anti-inflammatory pathways to drive durable resolution of inflammation are needed. This article discusses novel cellular immunotherapies and immune cell depleting therapies in IBD, including CAR-T cell approaches, Tr1 and T regulatory (Treg) cells and cell depleting antibodies such as rosnilimab. These novel approaches have the potential to overcome current therapeutic limitations in the treatment of IBD.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"9-14"},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma.","authors":"Ao Chen, Vanilla Xin Zhang, Qingyang Zhang, Karen Man-Fong Sze, Lu Tian, Hongyang Huang, Xia Wang, Eva Lee, Jingyi Lu, Xueying Lyu, Man-Fong Joyce Lee, Chun Ming Wong, Daniel Wai-Hung Ho, Irene Oi-Lin Ng","doi":"10.1136/gutjnl-2024-331903","DOIUrl":"10.1136/gutjnl-2024-331903","url":null,"abstract":"<p><strong>Objective: </strong>Fat mass and obesity-associated protein (FTO), an eraser of <i>N</i> ⁶-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown.</p><p><strong>Design: </strong>The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment.</p><p><strong>Results: </strong>FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8⁺ T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH <i>N</i> ⁶-methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8⁺ T cells, resulting in the inhibition of CD8⁺ T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment.</p><p><strong>Conclusion: </strong>Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"90-102"},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Butyrate-producing Faecalibacterium prausnitzii suppresses natural killer/T-cell lymphoma by dampening the JAK-STAT pathway","authors":"Zhuangzhuang Shi, Min Li, Chen Zhang, Hongwen Li, Yue Zhang, Lei Zhang, Xin Li, Ling Li, Xinhua Wang, Xiaorui Fu, Zhenchang Sun, Xudong Zhang, Li Tian, Mingzhi Zhang, Wei-Hua Chen, Zhaoming Li","doi":"10.1136/gutjnl-2024-333530","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333530","url":null,"abstract":"Background Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes. Objective To characterise the gut microbiota feature and identify potential probiotics that could ameliorate the development of NKTCL. Design This cross-sectional study employed shotgun metagenomic sequencing to profile the gut microbiota in two Chinese NKTCL cohorts, with validation conducted in an independent Korean cohort. Univariable and multivariable Cox proportional hazards analyses were applied to assess associations between identified marker species and patient outcomes. Tumour-suppressing effects were investigated using comprehensive in vivo and in vitro models. In addition, metabolomics, RNA sequencing, chromatin immunoprecipitation sequencing, Western blot analysis, immunohistochemistry and lentiviral-mediated gene knockdown system were used to elucidate the underlying mechanisms. Results We first unveiled significant gut microbiota dysbiosis in NKTCL patients, prominently marked by a notable reduction in Faecalibacterium prausnitzii which correlated strongly with shorter survival among patients. Subsequently, we substantiated the antitumour properties of F. prausnitzii in NKTCL mouse models. Furthermore, F. prausnitzii culture supernatant demonstrated significant efficacy in inhibiting NKTCL cell growth. Metabolomics analysis revealed butyrate as a critical metabolite underlying these tumour-suppressing effects, validated in three human NKTCL cell lines and multiple tumour-bearing mouse models. Mechanistically, butyrate suppressed the activation of Janus kinase-signal transducer and activator of transcription pathway through enhancing histone acetylation, promoting the expression of suppressor of cytokine signalling 1. Conclusion These findings uncover a distinctive gut microbiota profile in NKTCL and provide a novel perspective on leveraging the therapeutic potential of F. prausnitzii to ameliorate this malignancy. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. The metagenomic sequencing data reported in this study are available at the China National Center for Bioinformation (CNCB)— National Genomics Data Center (NGDC) under BioProject accession number PRJCA010329, and the gut metagenomic data of public Korean NKTCL cohort can be accessed in the Sequence Read Archive database with accession number of PRJNA1043252. The RNA and ChIP sequencing data are available at the National Omics Data Encyclopedia (NODE) under Project ID of OEP005390, OEP004744, and OEP004746, respectively. All other data are available in the manuscript including its supplementary files or from the corresponding authors on reasonable request.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"94 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time for arginine methylation: PRMT5 inhibition to advance cholangiocarcinoma treatment","authors":"Romain Désert, Lipika Goyal, Thomas F Baumert","doi":"10.1136/gutjnl-2024-333632","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333632","url":null,"abstract":"Cholangiocarcinoma (CCA) is a highly aggressive adenocarcinoma of the biliary tract system with unsatisfactory therapeutic options.1 Standard frontline treatment for unresectable or metastatic CCA consisting of cisplatin and gemcitabine combined with checkpoint inhibitors targeting programmed cell death ligand 1 or programmed cell death 1 offers objective response rates of less than 30% and a median survival of approximately a year.1 Targeted therapies against FGFR2 fusions and IDH1 mutations have gained regulatory approval in CCA, but these are applicable only in a minority of patients.1 Disease-agnostic approvals of therapies targeting HER2 overexpression, NTRK fusions, RET fusions and microsatellite-unstable tumours also benefit patients with CCA, but again, only a small minority. Therefore, novel strategies to treat CCA are urgently needed. Molecular heterogeneity stands as a major barrier to improving outcomes in CCA. Genetic alterations in DNA only explain a part of this heterogeneity. A rising number of studies suggest a major role for epigenetic perturbations in controlling CCA fate.2 Indeed, epigenetic vulnerabilities including histone modifications have been suggested as novel CCA targets.1 An example of a histone regulator is the protein arginine methyltransferase 5 (PRMT5). PRMT5 forms a homotetramer that associates with methylosome protein 50 (MEP50) in a highly active complex that exhibits high affinity for arginine residues. Via histone methylation, PRMT5 functions as a transcriptional co-repressor supporting gene expression of oncogenic signalling via regulation of genes such as p53, NFκB or p21.2 In addition, PRMT5 regulates splicing via its role as the enzymatic component of the methylosome, a multi-subunit complex containing MEP50, facilitating small nuclear ribonucleoprotein assembly (figure 1). PRMT5 and MEP50 functions have been shown to be important in regulating genome stability and DNA repair.3 Preclinical studies of PRMT5 inhibitors have shown antitumour activity …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"9 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoscopic papillectomy versus surgical ampullectomy for adenomas and early cancers of the papilla: a retrospective Pancreas2000/European Pancreatic Club analysis","authors":"Marcus Hollenbach, Christian Heise, Einas Abou-Ali, Aiste Gulla, Francesco Auriemma, Kevin Soares, Galen Leung, Mark A Schattner, William R Jarnagin, Tiegong Wang, Fabrice Caillol, Marc Giovannini, Yanis Dahel, Thilo Hackert, Woo Hyun Paik, Alessandro Zerbi, Gennaro Nappo, Bertrand Napoleon, Urban Arnelo, Erik Haraldsson, Asif Halimi, Alexander Waldthaler, Uwe Will, Rita Saadeh, Viliam Masaryk, Sophia E van der Wiel, Marco J Bruno, Enrique Perez-Cuadrado-Robles, Pierre Deprez, Alain Sauvanet, Louisa Bolm, Tobias Keck, Régis Souche, Jean-Michel Fabre, Nicolas Musquer, Georg Kähler, Steffen Seyfried, Maria Chiara Petrone, Alberto Mariani, Piera Zaccari, Giulio Belfiori, Stefano Crippa, Massimo Falconi, Stefano Partelli, Bengisu Yilmaz, Ihsan Ekin Demir, Güralp O Ceyhan, Sohei Satoi, Jean Marc Regimbeau, Johan Gagniére, Alessandro Repici, Andrea Anderloni, Charles Vollmer, Fabio Casciani, Marco Del Chiaro, Atsushi Oba, Richard D Schulick, Arthur Berger, Laura Maggino, Roberto Salvia, Peter Schemmer, Doerte Wichmann, Yosuke Inoue, Mario Dinis-Ribeiro, Ana Laranjo, Diogo Libanio, Tobias Kleemann, Vasile Sandru, Madaline Ilie, Reea Ahola, Johanna Laukkarinen, Brigitte Schumacher, David Albers, Tiago Cúrdia Gonçalves, Louise Barbier, Ephrem Salamé, Tobias J Weismüller, Dominik Heling, Arnaud Alves, Elias Karam, Nicolas Regenet, Ana Dugic, Steffen Muehldorfer, Stéphanie Truant, Karel Caca, Benjamin Meier, Bogdan P Miutescu, Marcel Tantau, David Birnbaum, Rainer Christoph Miksch, Edris Wedi, Katrin Salzmann, Matthieu Bruzzi, Renato M Lupinacci, Patrice David, Charles De Ponthaud, Arthur Schmidt, Sara Regnér, Sebastien Gaujoux","doi":"10.1136/gutjnl-2022-327996","DOIUrl":"https://doi.org/10.1136/gutjnl-2022-327996","url":null,"abstract":"Objective Ampullary neoplastic lesions can be resected by endoscopic papillectomy (EP) or transduodenal surgical ampullectomy (TSA) while pancreaticoduodenectomy is reserved for more advanced lesions. We present the largest retrospective comparative study analysing EP and TSA. Design Of all patients in the database, lesions with prior interventions, benign histology advanced malignancy (T2 and more), patients with hereditary syndromes and those undergoing pancreatoduodenectomy were excluded. All remaining cases as well as a subgroup of them, after propensity-score matching (nearest-neighbour-method) based on age, gender, anthropometrics, comorbidities, size and histological subtype, were analysed. The median follow-up was 21 months (IQR 10–47) after the primary intervention. Primary outcomes were rates of complete resection (R0) and complications. Groups were compared by Fisher’s exact or χ2 test, Mann-Whitney-U-test and log-rank test for survival. Results Of 1673 patients in the database, 1422 underwent EP and 251 TSA. Of them, 23.2% were excluded for missing or inconclusive data and 19.8% of patients for prior interventions or hereditary syndromes. Final histology showed in 24.2% of EP and 14.8% of TSA patients a histology other than adenoma or adenocarcinoma while advanced cancers were recorded in 10.9% of EP and 36.6% of TSA patients. Finally, 569 EP and 63 TSA were included in the overall analysis, with a higher rate of more advanced cases and higher R0 resection rates in the TSA groups (90.5% vs 73.1%; p<0.01), with additional ablation in the EP group in 14.4%. Severe adverse event rates were 3.2% (TSA) vs 1.9% (EP). Recurrence after histological R0 resection was 16% (EP) vs 3.2% (TSA; p=0.01), and additional therapy for R1 resection was applied in 67% of the 159 cases. Propensity-score-based matching identified 62 pairs of EP/TSA patients with comparable baseline patient and lesion characteristics. The initial R0-rate was 72.6% (EP) compared with 90.3% (TSA, p=0.02) with recurrences found in 8% (EP) vs 3.2% (TSA; p=0.07); reinterventions were more frequent in the EP group. Overall survival was comparable. Conclusions The rate of patients with poor indications due to non-neoplastic disease or advanced cancer is still high for both EP and TSA; multiple retreatments were necessary for EP. Although EP can be considered an appropriate primary therapy for certain ampullary adenomas, case selection for both therapies (especially with regard to the best step-up approach) should be studied further. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"18 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response letter to the editor","authors":"Jana Jarošová, Tomas Hucl","doi":"10.1136/gutjnl-2023-331758","DOIUrl":"https://doi.org/10.1136/gutjnl-2023-331758","url":null,"abstract":"We are delighted that Fritzsche et al have expressed an interest in our randomised trial investigating the effects of endoluminal radiofrequency ablation (RFA) on survival and stent patency in cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) patients.1 2 We fully agree that plastic stents are likely to exhibit shorter patency in patients with CCA. The low patency in our small subgroup of patients treated with RFA and plastic stents (n=5) was due to the development of acute cholangitis within 2 weeks of the index procedures, requiring reintervention in three of these patients. We used plastic stents only in situations where anatomical considerations did not allow for the safe and reliable use of metal stents. We believe that this decision was necessary and fully justified in this more susceptible subset of patients. Interestingly, we observed no difference in stent patency in PDAC patients, even though almost all …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"31 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The road to a world-unified approach to the management of patients with gastric intestinal metaplasia: a review of current guidelines","authors":"BMJ Publishing Group Ltd and British Society of Gastroenterology","doi":"10.1136/gutjnl-2024-333029corr1","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333029corr1","url":null,"abstract":"Dinis-Ribeiro M, Shah S, El-Serag H, et al . The road …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"37 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary prophylaxis in patients with high risk oesophageal varices to prevent oesophageal variceal bleeding (OVB)—The CAVARLY is stronger together!!","authors":"Harsh Vardhan Tevethia, Apurva Pande, Rajan Vijayaraghavan, Guresh Kumar, Shiv Kumar Sarin","doi":"10.1136/gutjnl-2024-334130","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334130","url":null,"abstract":"We would like to thank Dunne et al 1 for their interest in our work.2 Their main concerns are that the rates of liver-related events (LREs) including progression to ascites were similar in both the groups in spite of lower mortality and oesophageal variceal bleed (OVB) in the combination arm as compared with the other arms. Second, the rates of OVBs and the bleed-related mortality were higher in the carvedilol arm as compared with the other arms. We would like to emphasise that in our study, we did not find any significant difference between the carvedilol arm and the combination arm in the reduction of hepatic venous pressure gradient (HVPG). The latter has been shown to correlate with various LREs and their progression.3 The reduction by 10% or …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"25 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator <i>POU2AF2</i>.","authors":"Vidya Rajasekaran, Bradley T Harris, Ruby T Osborn, Claire Smillie, Kevin Donnelly, Marion Bacou, Edward Esiri-Bloom, Li-Yin Ooi, Morven Allan, Marion Walker, Stuart Reid, Alison Meynert, Graeme Grimes, James P Blackmur, Peter G Vaughan-Shaw, Philip J Law, Ceres Fernández-Rozadilla, Ian Tomlinson, Richard S Houlston, Kevin B Myant, Farhat Vn Din, Maria Timofeeva, Malcolm G Dunlop, Susan M Farrington","doi":"10.1136/gutjnl-2024-332121","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332121","url":null,"abstract":"<p><strong>Background: </strong>Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on <i>POU2AF2</i>, <i>COLCA1</i> and <i>POU2AF3</i> genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk.</p><p><strong>Objective: </strong>Undertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.</p><p><strong>Design: </strong>We employ analysis of RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation sequencing and single-cell ATAC sequencing data to identify, prioritise and characterise the genes that contribute to CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.</p><p><strong>Results: </strong>We establish rs3087967 as a prime eQTL variant at 11q23.1, colocalising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell-specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the <i>Apc^Min/+</i> mouse phenotype on abrogation of <i>Pou2af2</i> expression specifically.</p><p><strong>Conclusion: </strong>We demonstrate that genotype at rs3087967 controls a portfolio of genes through misregulation of <i>POU2AF2. POU2AF2</i> is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142750501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}