Pub Date : 2024-11-07DOI: 10.1136/gutjnl-2024-332602
Anna Castells-Nobau, José Maria Moreno-Navarrete, Lisset de la Vega-Correa, Irene Puig, Massimo Federici, Jiuwen Sun, Remy Burcelin, Laurence Guzylack-Piriou, Pierre Gourdy, Laurent Cazals, María Arnoriaga-Rodríguez, Gema Frühbeck, Luisa Maria Seoane, José López-Miranda, Francisco J Tinahones, Carlos Dieguez, Marc-Emmanuel Dumas, Vicente Pérez-Brocal, Andrés Moya, Nikolaos Perakakis, Geltrude Mingrone, Stefan Bornstein, Jose Ignacio Rodriguez Hermosa, Ernesto Castro, Jose Manuel Fernández-Real, Jordi Mayneris-Perxachs
Background: The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity.
Objective: To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues.
Design: Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose).
Results: Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in Drosophila melanogaster validated these human insulin sensitivity-associated changes.
Conclusion: These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now.
背景:微生物群正在成为胰岛素抵抗和肥胖症易感性的关键因素:微生物群正在成为导致胰岛素抵抗和肥胖的关键因素:了解肠道微生物群与多种组织的胰岛素敏感性之间的相互作用:设计:在六项研究中采用多组学和多组织综合方法,将优生血糖钳夹测量(六项研究中的四项采用了这种方法)与葡萄糖代谢和胰岛素抵抗的其他测量方法(糖化血红蛋白(HbA1c)和空腹血糖)相结合:结果:在四项研究(ADIPOINST,n=15;IRONMET,n=121;FLORINASH,n=67;FLOROMIDIA,n=24)中,蛋白质细菌门的几个属和种始终与胰岛素敏感性呈负相关。空肠、回肠和结肠的转录组分析显示,T 细胞相关特征与胰岛素敏感性呈正相关。回肠和结肠中的蛋白质细菌与 HbA1c 呈正相关,但与 T 细胞数量呈负相关。空肠脱氧胆酸与胰岛素敏感性呈负相关。皮下脂肪组织(ADIPOMIT,n=740)和内脏脂肪组织(VAT)(ADIPOINST,n=29)的转录组学揭示了分别与 HbA1c 和胰岛素敏感性相关的 T 细胞相关特征。VAT 蛋白细菌与胰岛素敏感性呈负相关。ADIPOINST 和 FLORINASH 研究中的多组学和多组织整合将粪便蛋白细菌与空肠和肝脏脱氧胆酸以及空肠、VAT 和肝脏转录组特征联系起来,这些特征涉及肌动蛋白细胞骨架、胰岛素和 T 细胞信号传导。空腹血糖与干扰素诱导的基因以及肠道和增值血管中的抗病毒反应密切相关。在黑腹果蝇中进行的研究验证了这些与人类胰岛素敏感性相关的变化:这些数据全面揭示了微生物组-肠道-脂肪肝轴及其对全身胰岛素作用的影响,提出了潜在的治疗目标。
{"title":"Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism.","authors":"Anna Castells-Nobau, José Maria Moreno-Navarrete, Lisset de la Vega-Correa, Irene Puig, Massimo Federici, Jiuwen Sun, Remy Burcelin, Laurence Guzylack-Piriou, Pierre Gourdy, Laurent Cazals, María Arnoriaga-Rodríguez, Gema Frühbeck, Luisa Maria Seoane, José López-Miranda, Francisco J Tinahones, Carlos Dieguez, Marc-Emmanuel Dumas, Vicente Pérez-Brocal, Andrés Moya, Nikolaos Perakakis, Geltrude Mingrone, Stefan Bornstein, Jose Ignacio Rodriguez Hermosa, Ernesto Castro, Jose Manuel Fernández-Real, Jordi Mayneris-Perxachs","doi":"10.1136/gutjnl-2024-332602","DOIUrl":"10.1136/gutjnl-2024-332602","url":null,"abstract":"<p><strong>Background: </strong>The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity.</p><p><strong>Objective: </strong>To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues.</p><p><strong>Design: </strong>Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose).</p><p><strong>Results: </strong>Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in <i>Drosophila melanogaster</i> validated these human insulin sensitivity-associated changes.</p><p><strong>Conclusion: </strong>These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":23.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365061","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}
Pub Date : 2024-11-05DOI: 10.1136/gutjnl-2024-334008
Ruize Qu, Zhipeng Zhang, Wei Fu
{"title":"Potential microbial effects on microsatellite instability possibly drive divergence in colorectal cancer immunotherapy responses among different anatomical subsites.","authors":"Ruize Qu, Zhipeng Zhang, Wei Fu","doi":"10.1136/gutjnl-2024-334008","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334008","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581875","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}
Pub Date : 2024-11-05DOI: 10.1136/gutjnl-2024-333763
Norah Terrault, Anna S Lok
{"title":"Quest for HBV functional cure: what have we learnt from silencing RNAs?","authors":"Norah Terrault, Anna S Lok","doi":"10.1136/gutjnl-2024-333763","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333763","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582097","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}
Pub Date : 2024-11-05DOI: 10.1136/gutjnl-2024-332782
Mingming Xiao, Rong Tang, Haoqi Pan, Jing Yang, Xuhui Tong, He Xu, Yanmei Guo, Yalan Lei, Di Wu, Yubin Lei, Yamei Han, Zhilong Ma, Wei Wang, Jin Xu, Xianjun Yu, Si Shi
Background: PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer.
Objective: There is a significant unmet clinical need to broaden the utility of PARPi.
Design: RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC‒MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses.
Results: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both in vitro and in vivo. Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi.
Conclusions: Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.
{"title":"TPX2 serves as a novel target for expanding the utility of PARPi in pancreatic cancer through conferring synthetic lethality.","authors":"Mingming Xiao, Rong Tang, Haoqi Pan, Jing Yang, Xuhui Tong, He Xu, Yanmei Guo, Yalan Lei, Di Wu, Yubin Lei, Yamei Han, Zhilong Ma, Wei Wang, Jin Xu, Xianjun Yu, Si Shi","doi":"10.1136/gutjnl-2024-332782","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332782","url":null,"abstract":"<p><strong>Background: </strong>PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer.</p><p><strong>Objective: </strong>There is a significant unmet clinical need to broaden the utility of PARPi.</p><p><strong>Design: </strong>RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC‒MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses.</p><p><strong>Results: </strong>Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi.</p><p><strong>Conclusions: </strong>Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582195","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}
Pub Date : 2024-11-05DOI: 10.1136/gutjnl-2024-332508
Amit G Singal, Manasa Narasimman, Darine Daher, Sruthi Yekkaluri, Yan Liu, MinJae Lee, Vanessa Cerda, Aisha Khan, Karim Seif El Dahan, Jennifer Kramer, Purva Gopal, Caitlin Murphy, Ruben Hernaez
Background: Hepatocellular carcinoma (HCC) is plagued by failures across the cancer care continuum, leading to frequent late-stage diagnoses and high mortality. We evaluated the effectiveness of mailed outreach invitations plus patient navigation to promote HCC screening process completion in patients with cirrhosis.
Methods: Between April 2018 and September 2021, we conducted a multicentre pragmatic randomised clinical trial comparing mailed outreach plus patient navigation for HCC screening (n=1436) versus usual care with visit-based screening (n=1436) among patients with cirrhosis at three US health systems. Our primary outcome was screening process completion over a 36-month period, and our secondary outcome was the proportion of time covered (PTC) by screening. All patients were included in intention-to-screen analyses.
Results: All 2872 participants (median age 61.3 years; 32.3% women) were included in intention-to-screen analyses. Screening process completion was observed in 6.6% (95% CI: 5.3% to 7.9%) of patients randomised to outreach and 3.3% (95% CI: 2.4% to 4.3%) of those randomised to usual care (OR 2.05, 95% CI: 1.44 to 2.92). The intervention increased HCC screening process completion across most subgroups including age, sex, race and ethnicity, Child-Turcotte-Pugh class and health system. PTC was also significantly higher in the outreach arm than usual care (mean 37.5% vs 28.2%; RR 1.33, 95% CI: 1.31 to 1.35). Despite screening underuse, most HCC in both arms were detected at an early stage.
Conclusion: Mailed outreach plus navigation significantly increased HCC screening process completion versus usual care in patients with cirrhosis, with a consistent effect across most examined subgroups. However, screening completion remained suboptimal in both arms, underscoring a need for more intensive interventions.
{"title":"Effectiveness of mailed outreach and patient navigation to promote HCC screening process completion: a multicentre pragmatic randomised clinical trial.","authors":"Amit G Singal, Manasa Narasimman, Darine Daher, Sruthi Yekkaluri, Yan Liu, MinJae Lee, Vanessa Cerda, Aisha Khan, Karim Seif El Dahan, Jennifer Kramer, Purva Gopal, Caitlin Murphy, Ruben Hernaez","doi":"10.1136/gutjnl-2024-332508","DOIUrl":"10.1136/gutjnl-2024-332508","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is plagued by failures across the cancer care continuum, leading to frequent late-stage diagnoses and high mortality. We evaluated the effectiveness of mailed outreach invitations plus patient navigation to promote HCC screening process completion in patients with cirrhosis.</p><p><strong>Methods: </strong>Between April 2018 and September 2021, we conducted a multicentre pragmatic randomised clinical trial comparing mailed outreach plus patient navigation for HCC screening (n=1436) versus usual care with visit-based screening (n=1436) among patients with cirrhosis at three US health systems. Our primary outcome was screening process completion over a 36-month period, and our secondary outcome was the proportion of time covered (PTC) by screening. All patients were included in intention-to-screen analyses.</p><p><strong>Results: </strong>All 2872 participants (median age 61.3 years; 32.3% women) were included in intention-to-screen analyses. Screening process completion was observed in 6.6% (95% CI: 5.3% to 7.9%) of patients randomised to outreach and 3.3% (95% CI: 2.4% to 4.3%) of those randomised to usual care (OR 2.05, 95% CI: 1.44 to 2.92). The intervention increased HCC screening process completion across most subgroups including age, sex, race and ethnicity, Child-Turcotte-Pugh class and health system. PTC was also significantly higher in the outreach arm than usual care (mean 37.5% vs 28.2%; RR 1.33, 95% CI: 1.31 to 1.35). Despite screening underuse, most HCC in both arms were detected at an early stage.</p><p><strong>Conclusion: </strong>Mailed outreach plus navigation significantly increased HCC screening process completion versus usual care in patients with cirrhosis, with a consistent effect across most examined subgroups. However, screening completion remained suboptimal in both arms, underscoring a need for more intensive interventions.</p><p><strong>Trial registration number: </strong>NCT02582918.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261651","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}
Pub Date : 2024-11-01DOI: 10.1136/gutjnl-2024-332281
Yalin Tu, Haoran Wu, Chengpeng Zhong, Yan Liu, Zhewen Xiong, Siyun Chen, Jing Wang, Patrick Pak-Chun Wong, Weiqin Yang, Zhixian Liang, Jiahuan Lu, Shufen Chen, Lingyun Zhang, Yu Feng, Willis Wai-Yiu Si-Tou, Baoyi Yin, Yingnan Lin, Jianxin Liang, Liying Liang, Joaquim S L Vong, Weida Ren, Tsz Tung Kwong, Howard Leung, Ka Fai To, Stephanie Ma, Man Tong, Hanyong Sun, Qiang Xia, Jingying Zhou, David Kerr, Nick La Thangue, Joseph J Y Sung, Stephen Lam Chan, Alfred Sze-Lok Cheng
Background Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. Objective We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). Design We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial ([NCT03419481][1]) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. Results HCC patients showing higher HDAC1 / 2 / 3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Conclusion Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance ([NCT05873244][2]). Data are available on reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom
{"title":"Pharmacological activation of STAT1-GSDME pyroptotic circuitry reinforces epigenetic immunotherapy for hepatocellular carcinoma","authors":"Yalin Tu, Haoran Wu, Chengpeng Zhong, Yan Liu, Zhewen Xiong, Siyun Chen, Jing Wang, Patrick Pak-Chun Wong, Weiqin Yang, Zhixian Liang, Jiahuan Lu, Shufen Chen, Lingyun Zhang, Yu Feng, Willis Wai-Yiu Si-Tou, Baoyi Yin, Yingnan Lin, Jianxin Liang, Liying Liang, Joaquim S L Vong, Weida Ren, Tsz Tung Kwong, Howard Leung, Ka Fai To, Stephanie Ma, Man Tong, Hanyong Sun, Qiang Xia, Jingying Zhou, David Kerr, Nick La Thangue, Joseph J Y Sung, Stephen Lam Chan, Alfred Sze-Lok Cheng","doi":"10.1136/gutjnl-2024-332281","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332281","url":null,"abstract":"Background Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood. Objective We aimed to identify ICB resistance-associated druggable histone deacetylases (HDACs) and develop a readily translatable combination approach for patients with hepatocellular carcinoma (HCC). Design We correlated the prognostic outcomes of HCC patients from a pembrolizumab trial ([NCT03419481][1]) with tumourous cell expressions of all HDAC isoforms by single-cell RNA sequencing. We investigated the therapeutic efficacy and mechanism of action of selective HDAC inhibition in 4 ICB-resistant orthotopic and spontaneous models using immune profiling, single-cell multiomics and chromatin immunoprecipitation-sequencing and verified by genetic modulations and co-culture systems. Results HCC patients showing higher HDAC1 / 2 / 3 expressions exhibited deficient IFNγ signalling and poorer survival on ICB therapy. Transient treatment of a selective class-I HDAC inhibitor CXD101 resensitised HDAC1/2/3high tumours to ICB therapies, resulting in CD8+T cell-dependent antitumour and memory T cell responses. Mechanistically, CXD101 synergised with ICB to stimulate STAT1-driven antitumour immunity through enhanced chromatin accessibility and H3K27 hyperacetylation of IFNγ-responsive genes. Intratumoural recruitment of IFNγ+GZMB+cytotoxic lymphocytes further promoted cleavage of CXD101-induced Gasdermin E (GSDME) to trigger pyroptosis in a STAT1-dependent manner. Notably, deletion of GSDME mimicked STAT1 knockout in abolishing the antitumour efficacy and survival benefit of CXD101-ICB combination therapy by thwarting both pyroptotic and IFNγ responses. Conclusion Our immunoepigenetic strategy harnesses IFNγ-mediated network to augment the cancer-immunity cycle, revealing a self-reinforcing STAT1-GSDME pyroptotic circuitry as the mechanistic basis for an ongoing phase-II trial to tackle ICB resistance ([NCT05873244][2]). Data are available on reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03419481&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05873244&atom=%2Fgutjnl%2Fearly%2F2024%2F11%2F01%2Fgutjnl-2024-332281.atom","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563069","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}
Pub Date : 2024-11-01DOI: 10.1136/gutjnl-2019-320170corr1
BMJ Publishing Group Ltd and British Society of Gastroenterology
Monteiro S, Grandt J, Uschner FE, et al . Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous …
Monteiro S, Grandt J, Uschner FE, et al .炎症小体的不同激活易导致既往有或既往无急性慢性肝衰竭的人类和实验性肝硬化...
{"title":"Correction: Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation","authors":"BMJ Publishing Group Ltd and British Society of Gastroenterology","doi":"10.1136/gutjnl-2019-320170corr1","DOIUrl":"https://doi.org/10.1136/gutjnl-2019-320170corr1","url":null,"abstract":"Monteiro S, Grandt J, Uschner FE, et al . Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383772","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}
Pub Date : 2024-10-30DOI: 10.1136/gutjnl-2024-334018
Mathieu Pioche, Guillaume Vidal, Madj Ben Rejeb, Rémi Collin, Jérémie Jacques
{"title":"Single-use scopes may reduce various environmental impacts of gastroscopy in some situations but probably not in routine practice of endoscopy units.","authors":"Mathieu Pioche, Guillaume Vidal, Madj Ben Rejeb, Rémi Collin, Jérémie Jacques","doi":"10.1136/gutjnl-2024-334018","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334018","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":23.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545119","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}
Pub Date : 2024-10-26DOI: 10.1136/gutjnl-2024-332804
Llum Olmedo, Xavier Calvet, Emili Gené, Dmitry S Bordin, Irina Voynovan, M. Castro-Fernandez, Manuel Pabón-Carrasco, Alma Keco-Huerga, Ángeles Perez-Aisa, Alfredo J Lucendo, Luís Rodrigo, Aiman S Sarsenbaeva, Igor B Khlinov, Galyna Fadieienko, Oleg Zaytsev, Ángel Lanas, Samuel J Martínez-Domínguez, Enrique Alfaro, Laimas Jonaitis, Óscar Núñez, Rinaldo Pellicano, Luis Hernández, Oleksiy Gridnyev, Juozas Kupcinskas, Antonio Gasbarrini, Doron Boltin, Yaron Niv, Gülüstan Babayeva, Ricardo Marcos-Pinto, Bojan Tepes, Marino Venerito, Veronika Papp, Frode Lerang, Mārcis Leja, Perminder S Phull, Wojciech Marlicz, Michael Doulberis, Sinead M Smith, Vladimir Milivojevic, Lumir Kunovsky, Antonio Mestrovic, Tamara Matysiak-Budnik, Halis Simsek, Anna Cano-Català, Ignasi Puig, Leticia Moreira, Pablo Parra, Olga P Nyssen, Francis Megraud, Colm O'Morain, Javier P Gisbert
Background Bismuth quadruple therapies (BQTs) including bismuth, a proton pump inhibitor (PPI) and two antibiotics have been shown to be highly effective for treating Helicobacter pylori infection even in areas of high bacterial antibiotic resistance. Objective To describe the time trends of use, effectiveness and safety of BQT in Europe using the European Registry on Helicobacter pylori Management (Hp-EuReg). Design Patients registered in the Hp-EuReg from 2013 to 2021 who had received BQT were included. The regimens prescribed, the number of eradication attempts, effectiveness, adherence and safety were analysed. The effectiveness was assessed by modified intention to treat (mITT). Time-trend and multivariate analyses were performed to determine variables that predicted treatment success. Results Of the 49 690 patients included in the Hp-EuReg, 15 582 (31%) had received BQT. BQT use increased from 8.6% of all treatments in 2013 to 39% in 2021. Single-capsule BQT—containing bismuth, metronidazole and tetracycline—plus a PPI (single-capsule BQT, ScBQT) was the most frequent treatment mode (43%). Schemes that obtained an effectiveness above 90% were the 10-day ScBQT and 14-day BQT using tetracycline plus metronidazole, or amoxicillin plus either clarithromycin or metronidazole. Only ScBQT achieved above 90% cure rates in all the geographical areas studied. Using the ScBQT scheme, adherence, the use of standard or high-dose PPIs, 14-day prescriptions and the use of BQT as first-line treatment were significantly associated with higher mITT effectiveness. Conclusion The use of BQT increased notably in Europe over the study period. A 10-day ScBQT was the scheme that most consistently achieved optimal effectiveness. Trial registration number [NCT02328131][1]. All data relevant to the study are included in the article or uploaded as online supplemental information. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02328131&atom=%2Fgutjnl%2Fearly%2F2024%2F10%2F25%2Fgutjnl-2024-332804.atom
{"title":"Evolution of the use, effectiveness and safety of bismuth-containing quadruple therapy for Helicobacter pylori infection between 2013 and 2021: results from the European registry on H. pylori management (Hp-EuReg)","authors":"Llum Olmedo, Xavier Calvet, Emili Gené, Dmitry S Bordin, Irina Voynovan, M. Castro-Fernandez, Manuel Pabón-Carrasco, Alma Keco-Huerga, Ángeles Perez-Aisa, Alfredo J Lucendo, Luís Rodrigo, Aiman S Sarsenbaeva, Igor B Khlinov, Galyna Fadieienko, Oleg Zaytsev, Ángel Lanas, Samuel J Martínez-Domínguez, Enrique Alfaro, Laimas Jonaitis, Óscar Núñez, Rinaldo Pellicano, Luis Hernández, Oleksiy Gridnyev, Juozas Kupcinskas, Antonio Gasbarrini, Doron Boltin, Yaron Niv, Gülüstan Babayeva, Ricardo Marcos-Pinto, Bojan Tepes, Marino Venerito, Veronika Papp, Frode Lerang, Mārcis Leja, Perminder S Phull, Wojciech Marlicz, Michael Doulberis, Sinead M Smith, Vladimir Milivojevic, Lumir Kunovsky, Antonio Mestrovic, Tamara Matysiak-Budnik, Halis Simsek, Anna Cano-Català, Ignasi Puig, Leticia Moreira, Pablo Parra, Olga P Nyssen, Francis Megraud, Colm O'Morain, Javier P Gisbert","doi":"10.1136/gutjnl-2024-332804","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332804","url":null,"abstract":"Background Bismuth quadruple therapies (BQTs) including bismuth, a proton pump inhibitor (PPI) and two antibiotics have been shown to be highly effective for treating Helicobacter pylori infection even in areas of high bacterial antibiotic resistance. Objective To describe the time trends of use, effectiveness and safety of BQT in Europe using the European Registry on Helicobacter pylori Management (Hp-EuReg). Design Patients registered in the Hp-EuReg from 2013 to 2021 who had received BQT were included. The regimens prescribed, the number of eradication attempts, effectiveness, adherence and safety were analysed. The effectiveness was assessed by modified intention to treat (mITT). Time-trend and multivariate analyses were performed to determine variables that predicted treatment success. Results Of the 49 690 patients included in the Hp-EuReg, 15 582 (31%) had received BQT. BQT use increased from 8.6% of all treatments in 2013 to 39% in 2021. Single-capsule BQT—containing bismuth, metronidazole and tetracycline—plus a PPI (single-capsule BQT, ScBQT) was the most frequent treatment mode (43%). Schemes that obtained an effectiveness above 90% were the 10-day ScBQT and 14-day BQT using tetracycline plus metronidazole, or amoxicillin plus either clarithromycin or metronidazole. Only ScBQT achieved above 90% cure rates in all the geographical areas studied. Using the ScBQT scheme, adherence, the use of standard or high-dose PPIs, 14-day prescriptions and the use of BQT as first-line treatment were significantly associated with higher mITT effectiveness. Conclusion The use of BQT increased notably in Europe over the study period. A 10-day ScBQT was the scheme that most consistently achieved optimal effectiveness. Trial registration number [NCT02328131][1]. All data relevant to the study are included in the article or uploaded as online supplemental information. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02328131&atom=%2Fgutjnl%2Fearly%2F2024%2F10%2F25%2Fgutjnl-2024-332804.atom","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490300","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}
Pub Date : 2024-10-26DOI: 10.1136/gutjnl-2024-332457
Schalk Willem Van der Merwe, Maite G Fernandez-Barrena
Cirrhosis marks the advanced stage of chronic liver disease characterised by sustained inflammation leading to the loss of hepatocytes and the progression of fibrosis. These structural and functional alterations profoundly impact blood flow within the hepatic microcirculation, potentially culminating in portal hypertension over time. Traditionally, the evolution of cirrhosis has been divided into two clinical phases: An initial asymptomatic stage known as compensated cirrhosis followed by decompensated cirrhosis, marked by the emergence of complications such as ascites, variceal bleeding, hepatic encephalopathy, jaundice, coagulopathy and bacterial infections. Decompensated cirrhosis typically signals a more aggressive disease course with patients susceptible to hepatic and extrahepatic organ dysfunction, complications or necessitating liver transplantation.1 It is imperative to recognise that decompensated cirrhosis transcends hepatic manifestations representing a systemic disorder. Recent observational studies in Europe, including chronic liver failure acute-on-chronic liver failure (CANONIC) and PREDICTing Acute-on-chronic liver failure (PREDICT), have further classified decompensated cirrhosis into non-acute and various forms of acute decompensation, potentially leading to acute-on-chronic liver failure (ACLF). However, the precise factors determining the trajectory towards decompensation in cirrhosis remain elusive. Accumulating evidence suggests that specific preceding events play pivotal roles in this progression. Notably, clinically significant portal hypertension, systemic inflammation and failure of the intestinal barrier leading to bacterial product translocation through the portal circulation are key events interdependently influencing each …
{"title":"Safe and successful gut-restricted adsorbent strategy against cirrhosis and acute-on-chronic liver failure","authors":"Schalk Willem Van der Merwe, Maite G Fernandez-Barrena","doi":"10.1136/gutjnl-2024-332457","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332457","url":null,"abstract":"Cirrhosis marks the advanced stage of chronic liver disease characterised by sustained inflammation leading to the loss of hepatocytes and the progression of fibrosis. These structural and functional alterations profoundly impact blood flow within the hepatic microcirculation, potentially culminating in portal hypertension over time. Traditionally, the evolution of cirrhosis has been divided into two clinical phases: An initial asymptomatic stage known as compensated cirrhosis followed by decompensated cirrhosis, marked by the emergence of complications such as ascites, variceal bleeding, hepatic encephalopathy, jaundice, coagulopathy and bacterial infections. Decompensated cirrhosis typically signals a more aggressive disease course with patients susceptible to hepatic and extrahepatic organ dysfunction, complications or necessitating liver transplantation.1 It is imperative to recognise that decompensated cirrhosis transcends hepatic manifestations representing a systemic disorder. Recent observational studies in Europe, including chronic liver failure acute-on-chronic liver failure (CANONIC) and PREDICTing Acute-on-chronic liver failure (PREDICT), have further classified decompensated cirrhosis into non-acute and various forms of acute decompensation, potentially leading to acute-on-chronic liver failure (ACLF). However, the precise factors determining the trajectory towards decompensation in cirrhosis remain elusive. Accumulating evidence suggests that specific preceding events play pivotal roles in this progression. Notably, clinically significant portal hypertension, systemic inflammation and failure of the intestinal barrier leading to bacterial product translocation through the portal circulation are key events interdependently influencing each …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490303","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}