Gut最新文献

{"title":"Association between appendectomy and Parkinson's disease from the UK Biobank.","authors":"Zhiyun Wang, Mengjie Li, Dongrui Ma, Mengnan Guo, Xiaoyan Hao, Zhengwei Hu, Shuangjie Li, Chunyan Zuo, Yuanyuan Liang, Chenwei Hao, Yanmei Feng, Chan Zhang, Chengyuan Mao, Jun Wu, Shilei Sun, Yu-Ming Xu, Changhe Shi","doi":"10.1136/gutjnl-2024-332353","DOIUrl":"10.1136/gutjnl-2024-332353","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"e10"},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418581","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":"Immune checkpoint inhibitors and the liver: balancing therapeutic benefit and adverse events.","authors":"Eleonora De Martin, Claudia A M Fulgenzi, Ciro Celsa, Astrid Laurent-Bellue, Aria Torkpour, Pasquale Lombardi, Antonio D'Alessio, David J Pinato","doi":"10.1136/gutjnl-2024-332125","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332125","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have led to breakthrough improvements in the management of malignancy including hepatocellular (HCC) and biliary tract cancer, improving decades-old standards of care and increasing patient survival. In both liver tumour types, which commonly arise in the context of liver inflammation and underlying functional impairment, the lack of validated predictors of response underscores the need to balance predicted gains in survival with risk of treatment-related hepatoxicity and decompensation of underlying chronic liver disease.In addition, the liver is implicated in the toxicity associated with ICI therapy for non-liver cancers, which exhibits a high degree of variability in presentation and severity. An accurate assessment is mandatory for the diagnosis and management of ICI-induced liver injury.In this Recent Advances article, we provide an overview of the mechanisms of efficacy and toxicity of anticancer immunotherapy in liver tumours and liver toxicity in extrahepatic malignancies.We compare and contrast characteristics, management strategies and outcomes from immune-related liver injury in patients with chronic hepatitis/cirrhosis or with an underlying healthy liver and discuss the latest findings on how toxicity and decompensation may impact the outlook of patients with liver tumours and extrahepatic malignancies offering insights into the future directions of clinical research and practice in the field.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806857","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":"Perturbation of mRNA splicing in liver cancer: insights, opportunities and challenges.","authors":"Qi Jia, Xiaoxiao Sun, Haoyu Li, Jianglong Guo, Kongyan Niu, Kui Ming Chan, René Bernards, Wenxin Qin, Haojie Jin","doi":"10.1136/gutjnl-2024-333127","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333127","url":null,"abstract":"<p><p>Perturbation of mRNA splicing is commonly observed in human cancers and plays a role in various aspects of cancer hallmarks. Understanding the mechanisms and functions of alternative splicing (AS) not only enables us to explore the complex regulatory network involved in tumour initiation and progression but also reveals potential for RNA-based cancer treatment strategies. This review provides a comprehensive summary of the significance of AS in liver cancer, covering the regulatory mechanisms, cancer-related AS events, abnormal splicing regulators, as well as the interplay between AS and post-transcriptional and post-translational regulations. We present the current bioinformatic approaches and databases to detect and analyse AS in cancer, and discuss the implications and perspectives of AS in the treatment of liver cancer.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806860","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":"Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma.","authors":"Suki Ha, Vincent Wai-Sun Wong, Xiang Zhang, Jun Yu","doi":"10.1136/gutjnl-2024-332398","DOIUrl":"10.1136/gutjnl-2024-332398","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver injuries, ranging from hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis to MASLD-associated hepatocellular carcinoma (MASLD-HCC). Recent studies have highlighted the bidirectional impacts between host genetics/epigenetics and the gut microbial community. Host genetics influence the composition of gut microbiome, while the gut microbiota and their derived metabolites can induce host epigenetic modifications to affect the development of MASLD. The exploration of the intricate relationship between the gut microbiome and the genetic/epigenetic makeup of the host is anticipated to yield promising avenues for therapeutic interventions targeting MASLD and its associated conditions. In this review, we summarise the effects of gut microbiome, host genetics and epigenetic alterations in MASLD and MASLD-HCC. We further discuss research findings demonstrating the bidirectional impacts between gut microbiome and host genetics/epigenetics, emphasising the significance of this interconnection in MASLD prevention and treatment.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"141-152"},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476476","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":"Impact of margin thermal ablation after endoscopic mucosal resection of large (≥20 mm) non-pedunculated colonic polyps on long-term recurrence.","authors":"Timothy O'Sullivan, Francesco Vito Mandarino, Julia L Gauci, Anthony M Whitfield, Clarence Kerrison, James Elhindi, Catarina Neto do Nascimento, Sunil Gupta, Oliver Cronin, Anthony Sakiris, Juan Francisco Prieto Aparicio, Sophie Arndtz, Gregor Brown, Spiro Raftopoulos, David Tate, Eric Y Lee, Stephen J Williams, Nicholas Burgess, Michael J Bourke","doi":"10.1136/gutjnl-2024-332907","DOIUrl":"10.1136/gutjnl-2024-332907","url":null,"abstract":"<p><strong>Background and aims: </strong>The efficacy of colorectal endoscopic mucosal resection (EMR) is limited by recurrence and the necessity for conservative surveillance. Margin thermal ablation (MTA) after EMR has reduced the incidence of recurrence at the first surveillance colonoscopy at 6 months (SC1). Whether this effect is durable to second surveillance colonoscopy (SC2) is unknown. We evaluated long-term surveillance outcomes in a cohort of LNPCPs that have undergone MTA.</p><p><strong>Methods: </strong>LNPCPs undergoing EMR and MTA from four academic endoscopy centres were prospectively recruited. EMR scars were evaluated at SC1 and in the absence of recurrence, SC2 colonoscopy was conducted in a further 12 months. A historical control arm was generated from LNPCPs that underwent EMR without MTA. The primary outcome was recurrence at SC2 in all LNPCPs with a recurrence-free scar at SC1.</p><p><strong>Results: </strong>1152 LNPCPs underwent EMR with complete MTA over 90 months until October 2022. 854 LNPCPs underwent SC1 with 29/854 (3.4%) LNPCPs demonstrating recurrence. 472 LNPCPs free of recurrence at SC1 underwent SC2. 260 LNPCPs with complete SC2 follow-up formed the control arm from January 2012 to May 2016. Recurrence at SC2 was significantly less in the MTA arm versus controls (1/472 (0.2%) vs 9/260 (3.5%); p<0.001)).</p><p><strong>Conclusion: </strong>LNPCPs that have undergone successful EMR with MTA and are free of recurrence at SC1 are unlikely to develop recurrence in subsequent surveillance out to 2 years. Provided the colon is cleared of synchronous neoplasia, the next surveillance can be potentially extended to 3-5 years. Such an approach would reduce costs and enhance patient compliance.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"67-74"},"PeriodicalIF":23.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345114","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":"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":"","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":"","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":"","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":"","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":"","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":"","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}