Journal of Gastroenterology最新文献

{"title":"Clinical factors to predict changes of esophagogastric varices after sustained viral response with direct-acting antiviral therapy.","authors":"Takao Watanabe, Yoshio Tokumoto, Hironori Ochi, Toshie Mashiba, Fujimasa Tada, Atsushi Hiraoka, Yoshiyasu Kisaka, Yoshinori Tanaka, Sen Yagi, Seiji Nakanishi, Kotaro Sunago, Kazuhiko Yamauchi, Makoto Higashino, Kana Hirooka, Masaaki Tange, Atsushi Yukimoto, Makoto Morita, Yuki Okazaki, Masashi Hirooka, Masanori Abe, Yoichi Hiasa","doi":"10.1007/s00535-024-02174-z","DOIUrl":"https://doi.org/10.1007/s00535-024-02174-z","url":null,"abstract":"<p><strong>Background: </strong>The clinical course of esophagogastric varices (EGV) after sustained virological response (SVR) with direct-acting antiviral (DAA) therapy has not been clearly elucidated. The predictors for the worsening/improvement of EGV after SVR with DAA therapy were investigated.</p><p><strong>Methods: </strong>Of the cirrhosis patients who achieved SVR with DAA therapy, 328 patients who underwent endoscopic examinations both before and after DAA therapy were enrolled. The predictors of EGV worsening or improvement were investigated.</p><p><strong>Results: </strong>Multivariate analysis identified a history of ascites retention, albumin at baseline, and MELD score at baseline as independent factors that contributed to EGV exacerbation. On multivariate analysis, two factors, BMI and platelet count, were related to EGV improvement. An integrated scoring system was created using these risk factors with or without weighting according to each hazard ratio, and the patients were divided into three groups. A scoring system with weighting of each factor appeared to be more useful, with fewer intermediate patients and more cases classified into the low-risk and high-risk groups.</p><p><strong>Conclusion: </strong>Esophagogastric varices after SVR have a varied clinical course. Using this scoring system that can accurately predict EGV outcomes in clinical settings, it may be feasible to establish a risk-based EGV surveillance plan following SVR.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver transplantation for gastroenteropancreatic neuroendocrine liver metastasis: optimal patient selection and perioperative management in the era of multimodal treatments.","authors":"Yosuke Kasai, Takashi Ito, Toshihiko Masui, Kazuyuki Nagai, Takayuki Anazawa, Yoichiro Uchida, Takamichi Ishii, Koji Umeshita, Susumu Eguchi, Yuji Soejima, Hideki Ohdan, Etsuro Hatano","doi":"10.1007/s00535-024-02166-z","DOIUrl":"https://doi.org/10.1007/s00535-024-02166-z","url":null,"abstract":"<p><p>Gastroenteropancreatic neuroendocrine tumors (NET) often metastasize to the liver. Although curative liver resection provides a favorable prognosis for patients with neuroendocrine liver metastasis (NELM), with a 5-year survival rate of 70-80%, recurrence is almost inevitable, mainly in the remnant liver. In Western countries, liver transplantation (LT) has been performed in patients with NELM, with the objective of complete removal of macro- and micro-NELMs. However, prognosis had been unsatisfactory, with 5-year overall survival and recurrence-free survival rates of approximately 50 and 30%, respectively. In 2007, the Milan criteria were proposed as indications for LT for NELM. The criteria included: (1) confirmed histology of NET-G1 or G2; (2) a primary tumor drained by the portal system and all extrahepatic diseases removed with curative resection before LT; (3) liver involvement ≤50%; (4) good response or stable disease for at least 6 months before LT; (5) age ≤ 55 years. A subsequent report demonstrated outstanding LT outcomes for NELM within the Milan criteria, with 5-year overall survival and recurrence rates of 97 and 13%, respectively. In Japan, living donor LT (LDLT) for NELM has been performed sporadically in only 16 patients by 2021 in Japan; however, no consensus has been reached on the indications or perioperative management of LDLT. This article presents the outcomes of these 16 patients who underwent LDLT in Japan and reviews the literature to clarify optimal indications and perioperative management of LDLT for NELM in the era of novel multimodal treatments.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FGFR2 fusions assessed by NGS, FISH, and immunohistochemistry in intrahepatic cholangiocarcinoma.","authors":"Zi Cao, Yichen Yang, Shasha Liu, Lin Sun, Yanxue Liu, Ye Luo, Jian Wang, Yan Sun","doi":"10.1007/s00535-024-02175-y","DOIUrl":"https://doi.org/10.1007/s00535-024-02175-y","url":null,"abstract":"<p><strong>Background: </strong>FGFR2 fusion has become a promising therapeutic target in iCCAs; however, the procedure for screening FGFR2 fusion has not been conventionally developed.</p><p><strong>Methods: </strong>FGFR2 fusion was identified using DNA + RNA-based NGS and FISH, and the concordance between DNA + RNA-based NGS, FISH, and IHC was compared.</p><p><strong>Results: </strong>FGFR2 fusions were detected in 9 out of 76 iCCAs (11.8%). The consistency of FISH and DNA + RNA-based NGS for FGFR2 fusions was high (κ value = 0.867, P = 0.001), while the consistency of IHC and DNA + RNA-based NGS was lower (κ value = 0.464, P = 0.072). All nine FGFR2 fusion-positive iCCAs were MSS with a median TMB of 2.1 mut/Mb, and only one had a CPS (PD-L1) above 5. Two FGFR2 fusion-positive iCCA patients were treated with and benefited from FGFR inhibitor therapy.</p><p><strong>Conclusions: </strong>FGFR2 fusion should be assessed for advanced iCCA patients. We recommend DNA + RNA-based NGS as the preferred option to supply all possible therapeutic targets. FISH should be preferred if the tumor sample is insufficient for NGS or if the patient is inclined to receive FGFR inhibitors promptly. Although IHC is not the preferred method to identify FGFR2 fusion, it might be used as preliminary screening for FGFR2 alterations if the hospital cannot offer NGS or FISH, and the results need to be validated before FGFR2 inhibitors treatment.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determination of optimal cutoff value of ulcerative colitis intestinal ultrasound index to estimate endoscopic improvement in ulcerative colitis.","authors":"Haruka Komatsu, Hiromu Morikubo, Yoko Kimura, Chihiro Moue, Hiromi Yonezawa, Minoru Matsuura, Jun Miyoshi, Tadakazu Hisamatsu","doi":"10.1007/s00535-024-02172-1","DOIUrl":"https://doi.org/10.1007/s00535-024-02172-1","url":null,"abstract":"<p><strong>Background: </strong>The ulcerative colitis intestinal ultrasound (UC-IUS) index (UII) has been reported as a sonographic scoring system correlating with the Mayo endoscopic subscore (MES). Endoscopic improvement (EI) of UC (MES ≤ 1) is a crucial therapeutic target in clinical practice. However, the cutoff value for estimating EI using the UII has not been established.</p><p><strong>Methods: </strong>We established test and validation cohorts comprising patients with UC undergoing IUS and endoscopy within a 15-day interval at our institution. IUS findings (bowel wall thickness, bowel blood flow, bowel wall structure, haustrations, and inflammatory fat) and endoscopic activity (MES) of each colon segment (ascending, transverse, descending, and sigmoid colon) were assessed.</p><p><strong>Results: </strong>In the test cohort (74 segments), UII was correlated with MES (r = 0.645, p < 0.0001). The median UII was 1.0 and 6.0 among participants with MES ≤ 1 and MES ≥ 2, respectively. A UII of 2 was identified as the threshold for estimating MES ≤ 1 with receiver operating characteristic analysis. In the validation cohort (122 segments), UII was correlated with MES (r = 0.675, p < 0.0001) and the estimation ability of UII ≤ 2 for EI had a positive predictive value of 85.4% and negative predictive value of 79.0%. This estimation ability of UII for EI was numerically lower but not statistically different from the previously reported Milan Ultrasound Criteria and Kyorin Ultrasound Criterion for UC.</p><p><strong>Conclusion: </strong>UII ≤ 2 can be a simple, feasible criterion for estimating EI. Correlation with MES is an advantage of the UII compared with other criteria. Proper use of various sonographic criteria is important.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic factors of second-line nivolumab monotherapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study for 184 cases.","authors":"Sho Sato, Takashi Suzuki, Takashi Chinen, Hironori Yamaguchi, Yusuke Suzuki, Nobukazu Hokamura, Zenichiro Saze, Koji Kono, Keita Takahashi, Fumiaki Yano, Tsutomu Sato, Takashi Kosaka, Itaru Endo, Yasushi Ichikawa, Yutaka Miyawaki, Hiroshi Sato, Hideaki Shimada","doi":"10.1007/s00535-024-02141-8","DOIUrl":"10.1007/s00535-024-02141-8","url":null,"abstract":"<p><strong>Background: </strong>The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated.</p><p><strong>Methods: </strong>This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors.</p><p><strong>Results: </strong>Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1 months and overall survival was 14 months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4 months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7 months.</p><p><strong>Conclusions: </strong>Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"979-985"},"PeriodicalIF":6.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The risk stratification and predictive performance of a new combined polygenic risk score for hepatocellular carcinoma.","authors":"Chengxiao Yu, Yuchen Tang, Maojie Liu, Xin Xu, Xinyuan Ge, Hongxia Ma, Guangfu Jin, Hongbing Shen, Ci Song, Zhibin Hu","doi":"10.1007/s00535-024-02144-5","DOIUrl":"10.1007/s00535-024-02144-5","url":null,"abstract":"<p><strong>Background: </strong>Recent genome-wide association studies (GWASs) in liver diseases have generated some polygenic risk scores (PRSs), but their predictive effectiveness on hepatocellular carcinoma (HCC) risk assessment remains unclear.</p><p><strong>Methods: </strong>Here, we constructed a novel combined polygenic risk score and evaluated its increment to the well-established risk model. We used 15 HCC-associated genetic loci from two PRSs and FinnGen GWAS data to calculate a PRS-combined score and to fit the related PRS model in the UK Biobank cohort (N = 436,162). The PRS-combined score was further assessed for risk stratification for HCC integrating with the recommended clinical risk scores.</p><p><strong>Results: </strong>The PRS-combined model achieved a better AUC (0.657) than that of PRS-HFC (0.637) and PRS-cirrhosis (0.645). The top 20% of the PRS-combined distribution had a 3.25 increased risk of HCC vs. the middle decile (45-55%). At the population level, the addition of PRS-combined to the CLivD score significantly increased the C-statistic (from 0.716 to 0.746) and provided a remarkable improvement in reclassification (NRI = 0.088) at the 10-year risk threshold of 0.2%. In clinic, additional assessment of PRS-combined would reclassify 34,647 intermediate-risk participants as high genetic risk, corresponding to an increase of 63.92% (62/97) of the HCC events classified at high risk using the Fibrosis-4 alone.</p><p><strong>Conclusions: </strong>The PRS may enhance HCC risk prediction effectiveness in the general population and refine risk stratification of the conventional clinical indicator.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1011-1020"},"PeriodicalIF":6.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a novel oncolytic adenovirus controlled by CDX2 promoter for esophageal adenocarcinoma therapy.","authors":"Naohiko Nakamura, Shuhei Shinoda, Mizuho Sato-Dahlman, Brett Roach, Kari Jacobsen, Masato Yamamoto","doi":"10.1007/s00535-024-02147-2","DOIUrl":"10.1007/s00535-024-02147-2","url":null,"abstract":"<p><strong>Background: </strong>Prognosis of esophageal adenocarcinoma (EAC) is still poor. Therefore, the development of novel therapeutic modalities is necessary to improve therapeutic outcomes in EAC. Here, we report a novel promoter-controlled oncolytic adenovirus targeting CDX2 (Ad5/3-pCDX2) and its specific anticancer effect for EAC.</p><p><strong>Methods: </strong>We used OE19, OE33, HT29, MKN28, RH30, and HEL299 cell lines. To establish CDX2 overexpressing OE19 cells, pCMV-GLI1 plasmid was transfected to OE19 (OE19 + GLI1). The virus replication and cytocidal effect of replication competent Ad5/3-pCDX2 were analyzed in vitro. Antitumor effect of Ad5/3-pCDX2 was assessed in xenograft mouse models by intratumoral injection of the viruses. Finally, efficacy of combination therapy with Ad5/3-pCDX2 and 5FU was evaluated.</p><p><strong>Results: </strong>EAC cells and HT29 showed high mRNA levels of CDX2, but not MKN28, RH30, and HEL299. We confirmed that deoxycholic acid (DCA) exposure enhanced CDX2 expression in EAC cells and OE19 + GLI1 had persistent CDX2 overexpression without DCA. Ad5/3-pCDX2 showed stronger cytocidal effect in OE19 + GLI1 than OE19, whereas Ad5/3-pCDX2 did not kill CDX2-negative cells. Ad5/3-pCDX2 was significantly replicated in EAC cells and the virus replication was higher in OE19 + GLI1 and OE19 with DCA compared to OE19 without DCA exposure. In vivo, Ad5/3-pCDX2 significantly suppressed OE19 tumor growth and the antitumor effect was enhanced in OE19 + GLI1 tumor. In contrast, Ad5/3-pCDX2 did not show significant antitumor effect in MKN28 tumor. Moreover, Ad5/3-pCDX2 significantly increased the efficacy of 5FU in vitro and in vivo.</p><p><strong>Conclusions: </strong>Ad5/3-pCDX2 showed specific anticancer effect for EAC, which was enhanced by bile acid exposure. Ad5/3-pCDX2 has promising potential for EAC therapy in the clinical setting.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"986-999"},"PeriodicalIF":6.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corynoline protects chronic pancreatitis via binding to PSMA2 and alleviating pancreatic fibrosis.","authors":"Pengyuan Wang, Bangwei Huang, Yu Liu, Xin Tan, Libo Liu, Baoru Zhang, Zhaoshen Li, Le Kang, Lianghao Hu","doi":"10.1007/s00535-024-02145-4","DOIUrl":"10.1007/s00535-024-02145-4","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic fibrosis is the main pathological feature of chronic pancreatitis. There is a lack of medications that effectively alleviate or reverse pancreatic fibrosis and thus cure chronic pancreatitis.</p><p><strong>Methods: </strong>We screened drugs that could alleviate pancreatic fibrosis from 80 traditional Chinese medicine monomers and verified their efficacy and mechanisms.</p><p><strong>Results: </strong>We preliminarily identified corynoline as an antifibrotic candidate by drug screening among 80 compounds. In vitro, corynoline dose-dependently reduces collagen I synthesis in pancreatic stellate cells induced by TGF-β1 and inhibits its activation. Furthermore, we found that corynoline could alleviate the morphological disruption, such as acinar cell atrophy, collagen deposition etc., as well as reduced pancreatic weight in mice with chronic pancreatitis. We further validated the antifibrotic effect of corynoline in mRNA and protein levels. We also found that corynoline could inhibit NF-κB signaling pathway in vitro and in vivo. Next, we identified PSMA2 as the binding protein of corynoline by Lip-SMap and validated it using DARTS. Moreover, the siRNA of PSMA2 disrupts the anti-fibrotic effect of corynoline.</p><p><strong>Conclusion: </strong>In conclusion, corynoline is a promising agent for the treatment of pancreatic fibrosis and chronic pancreatitis.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1037-1051"},"PeriodicalIF":6.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-molecule sequencing of the whole HCV genome revealed envelope deletions in decompensated cirrhosis associated with NS2 and NS5A mutations.","authors":"Kozue Yamauchi, Shinya Maekawa, Leona Osawa, Yasuyuki Komiyama, Natsuko Nakakuki, Hitomi Takada, Masaru Muraoka, Yuichiro Suzuki, Mitsuaki Sato, Shinichi Takano, Nobuyuki Enomoto","doi":"10.1007/s00535-024-02146-3","DOIUrl":"10.1007/s00535-024-02146-3","url":null,"abstract":"<p><strong>Background: </strong>Defective hepatitis C virus (HCV) genomes with deletion of the envelope region have been occasionally reported by short-read sequencing analyses. However, the clinical and virological details of such deletion HCV have not been fully elucidated.</p><p><strong>Methods: </strong>We developed a highly accurate single-molecule sequencing system for full-length HCV genes by combining the third-generation nanopore sequencing with rolling circle amplification (RCA) and investigated the characteristics of deletion HCV through the analysis of 21 patients chronically infected with genotype-1b HCV.</p><p><strong>Result: </strong>In 5 of the 21 patients, a defective HCV genome with approximately 2000 bp deletion from the E1 to NS2 region was detected, with the read frequencies of 34-77%, suggesting the trans-complementation of the co-infecting complete HCV. Deletion HCV was found exclusively in decompensated cirrhosis (5/12 patients), and no deletion HCV was observed in nine compensated patients. Comparing the amino acid substitutions between the deletion and complete HCV (DAS, deletion-associated substitutions), the deletion HCV showed higher amino acid mutations in the ISDR (interferon sensitivity-determining region) in NS5A, and also in the TMS (transmembrane segment) 3 to H (helix) 2 region of NS2.</p><p><strong>Conclusions: </strong>Defective HCV genome with deletion of envelope genes is associated with decompensated cirrhosis. The deletion HCV seems susceptible to innate immunity, such as endogenous interferon with NS5A mutations, escaping from acquired immunity with deletion of envelope proteins with potential modulation of replication capabilities with NS2 mutations. The relationship between these mutations and liver damage caused by HCV deletion is worth investigating.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1021-1036"},"PeriodicalIF":6.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conditional deletion of IP₃R1 by Islet1-Cre in mice reveals a critical role of IP₃R1 in interstitial cells of Cajal in regulating GI motility.","authors":"Hong Wang, Beili Zhao, Lei Huang, Xiangbin Zhu, Na Li, Can Huang, Zhen Han, Kunfu Ouyang","doi":"10.1007/s00535-024-02164-1","DOIUrl":"https://doi.org/10.1007/s00535-024-02164-1","url":null,"abstract":"<p><strong>Background and aims: </strong>Inositol 1,4,5-trisphosphate receptor type 1 (IP₃R1) has been proposed to play a physiological role in regulating gastrointestinal (GI) motility, but the underlying cell-dependent mechanism remains unclear. Here, we utilized cell-specific IP₃R1 deletion strategies to address this question in mice.</p><p><strong>Methods: </strong>Conditional IP₃R1 knockout mice using Wnt1-Cre, Islet1-Cre mice, and smMHC-Cre^EGFP were generated. Cell lineage tracing was performed to determine where gene deletion occurred in the GI tract. Whole-gut transit assay and isometric tension recording were used to assess GI function in vivo and in vitro.</p><p><strong>Results: </strong>In the mouse GI tract, Islet1-Cre targeted smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs), but not enteric neurons. IP₃R1 deletion by Islet1-Cre (isR1KO) caused a phenotype of intestinal pseudo-obstruction (IPO), evidenced by prolonged whole-gut transit time, enlarged GI tract, abdominal distention, and early lethality. IP₃R1 deletion by Islet1-Cre not only reduced the frequency of spontaneous contractions but also decreased the contractile responses to the muscarinic agonist carbachol (CCh) and electrical field stimulation (EFS) in colonic circular muscles. By contrast, smMHC-Cre^EGFP only targeted SMCs in the mouse GI tract. Although IP₃R1 deletion by smMHC-Cre^EGFP (smR1KO) also reduced the contractile responses to CCh and EFS in colonic circular muscles, the frequency of spontaneous contractions was less affected, and neither global GI abnormalities nor early lethality was found in smR1KO mice.</p><p><strong>Conclusions: </strong>IP₃R1 deletion in both ICCs and SMCs but not in SMCs alone causes an IPO phenotype, suggesting that IP₃R1 in ICCs plays an essential role in regulating GI motility in vivo.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}