Pub Date : 2024-08-20DOI: 10.1101/2024.08.18.24312061
Najam Gohar, Zoya Ejaz, Faizan Ahmed, Abdul Rafay, Abdullah Humayun, Momna Nisar, Ali Mushtaq, Aanusha Ghouri, Fatima Zafar, Hira Khalid, Sania Afzal, Muhammad Hammad Khan, Huzaifa Ahmad Cheema, Muhammad Shahzil, Essam Rashad, Rehmat Ullah Awan, Prasun K Jalal
Background Nearly half of the world population is infected by Helicobacter pylori (H. pylori). Bismuth-containing quadruple therapy (BQT) has shown favorable outcomes. This study compares 10-day and 14-day BQT regimens to evaluate their efficacy, safety, and compliance rates. Methods We searched electronic databases from their inception until May 2024 to retrieve all randomized controlled trials (RCTs) that compared 10-day and 14-day BQT regimens for H. pylori eradication. Meta-analysis was performed using Review Manager 5.4. Dichotomous outcomes were compared using risk ratio (RR). Results Seven RCTs and a total of 2,424 patients were included in the meta-analysis. There was no significant difference in the intention-to-treat eradication rate (RR 0.97; 95% CI 0.94, 1.01) and the per-protocol eradication rate (RR 0.96; 95% CI 0.93, 1.00) between the 10-day BQT and 14-day BQT groups. Commonly reported adverse events in both groups were epigastric pain and discomfort, nausea, and vomiting. There was no significant difference in the risk of adverse events between the two groups (RR 0.80; 95% CI 0.63, 1.02). There was no significant difference in the compliance rate between the two groups (RR 1.02; 95% CI 1.00, 1.04). Conclusion The eradication rates, risk of adverse events, and compliance rates were comparable between the two groups. Future research comparing similar drug doses with larger sample sizes and longer patient follow-ups can improve the quality of results.
{"title":"Efficacy and safety of 10-day versus 14-day bismuth-containing quadruple therapy for H. pylori eradication: A systematic review and meta-analysis","authors":"Najam Gohar, Zoya Ejaz, Faizan Ahmed, Abdul Rafay, Abdullah Humayun, Momna Nisar, Ali Mushtaq, Aanusha Ghouri, Fatima Zafar, Hira Khalid, Sania Afzal, Muhammad Hammad Khan, Huzaifa Ahmad Cheema, Muhammad Shahzil, Essam Rashad, Rehmat Ullah Awan, Prasun K Jalal","doi":"10.1101/2024.08.18.24312061","DOIUrl":"https://doi.org/10.1101/2024.08.18.24312061","url":null,"abstract":"Background\u0000Nearly half of the world population is infected by Helicobacter pylori (H. pylori). Bismuth-containing quadruple therapy (BQT) has shown favorable outcomes. This study compares 10-day and 14-day BQT regimens to evaluate their efficacy, safety, and compliance rates. Methods\u0000We searched electronic databases from their inception until May 2024 to retrieve all randomized controlled trials (RCTs) that compared 10-day and 14-day BQT regimens for H. pylori eradication. Meta-analysis was performed using Review Manager 5.4. Dichotomous outcomes were compared using risk ratio (RR). Results\u0000Seven RCTs and a total of 2,424 patients were included in the meta-analysis. There was no significant difference in the intention-to-treat eradication rate (RR 0.97; 95% CI 0.94, 1.01) and the per-protocol eradication rate (RR 0.96; 95% CI 0.93, 1.00) between the 10-day BQT and 14-day BQT groups. Commonly reported adverse events in both groups were epigastric pain and discomfort, nausea, and vomiting. There was no significant difference in the risk of adverse events between the two groups (RR 0.80; 95% CI 0.63, 1.02). There was no significant difference in the compliance rate between the two groups (RR 1.02; 95% CI 1.00, 1.04).\u0000Conclusion The eradication rates, risk of adverse events, and compliance rates were comparable between the two groups. Future research comparing similar drug doses with larger sample sizes and longer patient follow-ups can improve the quality of results.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Gut microbiota alteration is implicated in the pathogenesis of alcoholic liver disease (ALD) and HCC. No study has characterized the dysbiosis associated with ALD by microbial culturomics, an approach that certifies viability and allows the characterization of pathobiont strain candidates. Methods: A case-control study was conducted on patients with ALD without HCC (ALD-NoHCC) (n=16), ALD with HCC (ALD-HCC) (n=19), and controls (n=24). 16S rRNA amplicon sequencing and microbial culturomics were used as complementary methods for gut microbiome profiling. Results: By microbial culturomics, Thomasclavelia ramosa was the most enriched and detected in all ALD samples (100%), while it was cultivated in only a small proportion of controls (20%, p < 0.001). By 16S rRNA amplicon sequencing and 3-groups linear discriminant analysis, T. ramosa was increased explicitly in the ALD-HCC group (LDA-score > 5, p < 0.05). Conclusions: T. ramosa, identified by culturomics and 16 rRNA sequencing, is associated with ALD and ALD-HCC. Alongside the recently reported in vitro genotoxicity of this species in colorectal cancer, this species has been identified as a candidate oncobiont in ALD-HCC.
{"title":"Thomasclavelia ramosa is a Signature of Gut Dysbiosis associated with Alcohol-Related Hepatocellular Carcinoma: A First Microbial Culturomics Study","authors":"Reham Magdy Wasfy, Anissa ABDOULAYE, Patrick BORENTAIN, Babacar MBAYE, Maryam TIDJANI ALOU, Aurelia CAPUTO, Claudia ANDRIEU, Giovanna MOTTOLA, Anthony LEVASSEUR, Matthieu Million, Rene GEROLAMI","doi":"10.1101/2024.08.19.24312231","DOIUrl":"https://doi.org/10.1101/2024.08.19.24312231","url":null,"abstract":"Background: Gut microbiota alteration is implicated in the pathogenesis of alcoholic liver disease (ALD) and HCC. No study has characterized the dysbiosis associated with ALD by microbial culturomics, an approach that certifies viability and allows the characterization of pathobiont strain candidates. Methods: A case-control study was conducted on patients with ALD without HCC (ALD-NoHCC) (n=16), ALD with HCC (ALD-HCC) (n=19), and controls (n=24). 16S rRNA amplicon sequencing and microbial culturomics were used as complementary methods for gut microbiome profiling. Results: By microbial culturomics, Thomasclavelia ramosa was the most enriched and detected in all ALD samples (100%), while it was cultivated in only a small proportion of controls (20%, p < 0.001). By 16S rRNA amplicon sequencing and 3-groups linear discriminant analysis, T. ramosa was increased explicitly in the ALD-HCC group (LDA-score > 5, p < 0.05). Conclusions: T. ramosa, identified by culturomics and 16 rRNA sequencing, is associated with ALD and ALD-HCC. Alongside the recently reported in vitro genotoxicity of this species in colorectal cancer, this species has been identified as a candidate oncobiont in ALD-HCC.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1101/2024.08.08.24311598
Lina Welz, Danielle Harris, Na-Mi Kim, Abrar Alsaadi, Qcong Wu, Mhmd Oumari, Jan Taubenheim, Valery Volk, Graziella Credido, Eric Koncina, Pranab Mukherjee, Florian Tran, Laura Katharina Sievers, Polychronis Pavlidis, Nicholas Powell, Florian Rieder, Elisabeth Letellier, Silvio Waschina, Christoph Kaleta, Friedrich Feuerhake, Bram Verstockt, Melanie McReynolds, Philip Rosenstiel, Stefan Schreiber, Konrad Aden
Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal inflammation or acts as a compensatory attempt to restore cellular energy levels via de-novo nicotinamide adenine dinucleotide (NAD+) synthesis is not understood. Employing a systems medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in preclinical IBD models, we discover that steady increases in Trp levels upon therapy success coincide with a rewiring of metabolic processes within the kynurenine pathway (KP). In detail, we identify that Trp catabolism in IBD is metabolically constrained at the level of quinolinate phosphorybosyltransferase (QPRT), leading to accumulation of quinolinic acid (Quin) and a decrease of NAD+. We further demonstrate that Trp degradation along the KP occurs locally in the inflamed intestinal mucosa and critically depends on janus kinase / signal transducers and activators of transcription (JAK/STAT) signalling. Subsequently, knockdown of QPRT invitro induces NAD+ depletion and a pro-inflammatory state, which can largely be rescued by bypassing QPRT via other NAD+ precursors. We hence propose a model of impaired de-novo NAD+ synthesis from Trp in IBD. These findings point towards the replenishment of NAD+ precursors as a novel therapeutic pathway in IBD.
{"title":"A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD","authors":"Lina Welz, Danielle Harris, Na-Mi Kim, Abrar Alsaadi, Qcong Wu, Mhmd Oumari, Jan Taubenheim, Valery Volk, Graziella Credido, Eric Koncina, Pranab Mukherjee, Florian Tran, Laura Katharina Sievers, Polychronis Pavlidis, Nicholas Powell, Florian Rieder, Elisabeth Letellier, Silvio Waschina, Christoph Kaleta, Friedrich Feuerhake, Bram Verstockt, Melanie McReynolds, Philip Rosenstiel, Stefan Schreiber, Konrad Aden","doi":"10.1101/2024.08.08.24311598","DOIUrl":"https://doi.org/10.1101/2024.08.08.24311598","url":null,"abstract":"Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential\u0000amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal\u0000inflammation or acts as a compensatory attempt to restore cellular energy levels via de-novo\u0000nicotinamide adenine dinucleotide (NAD+) synthesis is not understood. Employing a systems\u0000medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in\u0000preclinical IBD models, we discover that steady increases in Trp levels upon therapy success\u0000coincide with a rewiring of metabolic processes within the kynurenine pathway (KP). In detail,\u0000we identify that Trp catabolism in IBD is metabolically constrained at the level of quinolinate\u0000phosphorybosyltransferase (QPRT), leading to accumulation of quinolinic acid (Quin) and a\u0000decrease of NAD+. We further demonstrate that Trp degradation along the KP occurs locally\u0000in the inflamed intestinal mucosa and critically depends on janus kinase / signal transducers\u0000and activators of transcription (JAK/STAT) signalling. Subsequently, knockdown of QPRT invitro\u0000induces NAD+ depletion and a pro-inflammatory state, which can largely be rescued by\u0000bypassing QPRT via other NAD+ precursors. We hence propose a model of impaired de-novo\u0000NAD+ synthesis from Trp in IBD. These findings point towards the replenishment of NAD+\u0000precursors as a novel therapeutic pathway in IBD.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"91 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.1101/2024.08.07.24311369
Jennifer Labus, Desiree Delgadillo, Steve Cole, Chencai Wang, Bruce Naliboff, Lin Chang, Benjamin Ellingson, Emeran Mayer
Background & Aims: Clinical evidence suggests significant interindividual differences in stress reactivity (SR), but biological mechanisms and therapeutic implications of these differences are poorly understood. We aimed to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of increased sympathetic nervous system (SNS) activation and brain imaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs). Methods: A cross-sectional observational study design, transcriptomics profiling, multimodal brain imaging, and psychosocial assessments were obtained in 291 female and male IBS participants and HCs. Prior to analyses, unsupervised clustering was applied to derive high and low SR subgroups across participants based on two measures of SR. General linear models tested for SR group differences in clinical and biological parameters. Exploratory analyses examined associations between SR group-specific brain alterations and gene expression. Results: The high, compared to low SR group showed greater cyclic AMP response element-binding protein (CREB) gene expression consistent with tonic SNS activity and proinflammatory changes in whole blood. Brain imaging showed neuroplastic changes in the high SR group consistent with an upregulation of ascending arousal systems and sensory processing and integration regions, and functional connectivity changes in the central autonomic network. SR moderated the sex difference in extraintestinal symptoms. Conclusions: The findings support a model of tonically increased SNS activity as a plausible risk factor for increased autonomic reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater prevalence in IBS. These findings may have important implications for personalized treatment interventions in IBS.
我们的目的是通过研究肠易激综合征（IBS）患者和健康对照组（HCs）中基于心理测量的表型与交感神经系统（SNS）激活增加的血液转录组学图谱和脑成像表型之间的关联，确定SR增加的生物学基础。研究方法采用横断面观察研究设计，对291名女性和男性肠易激综合征参与者和健康对照者进行了转录组学分析、多模态脑成像和社会心理评估。在进行分析之前，根据两种SR测量方法，对参与者进行了无监督聚类，以得出高SR亚组和低SR亚组。通用线性模型检验了临床和生物参数中的SR组差异。探索性分析检验了SR组特异性大脑改变与基因表达之间的关联。结果显示与低 SR 组相比，高 SR 组的环磷酸腺苷反应元件结合蛋白（CREB）基因表达量更高，这与强直性 SNS 活动和全血中的促炎性变化一致。脑成像显示，高SR组的神经可塑性变化与上升唤醒系统、感觉处理和整合区域的上调以及中枢自律神经网络的功能连接变化一致。SR调节了肠外症状的性别差异。结论这些研究结果支持了SNS活动增强的模型，它是导致肠易激综合征和高血压患者对社会心理压力和低水平免疫激活的自律神经反应性增强的一个合理的风险因素，在肠易激综合征中的发病率更高。这些发现可能会对肠易激综合征的个性化治疗干预产生重要影响。
{"title":"IBS stress reactivity phenotype is associated with blood transcriptome profiles and microstructural and functional brain changes","authors":"Jennifer Labus, Desiree Delgadillo, Steve Cole, Chencai Wang, Bruce Naliboff, Lin Chang, Benjamin Ellingson, Emeran Mayer","doi":"10.1101/2024.08.07.24311369","DOIUrl":"https://doi.org/10.1101/2024.08.07.24311369","url":null,"abstract":"Background & Aims: Clinical evidence suggests significant interindividual differences in stress reactivity (SR), but biological mechanisms and therapeutic implications of these differences are poorly understood.\u0000We aimed to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of increased sympathetic nervous system (SNS) activation and brain imaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs). Methods: A cross-sectional observational study design, transcriptomics profiling, multimodal brain imaging, and psychosocial assessments were obtained in 291 female and male IBS participants and HCs. Prior to analyses, unsupervised clustering was applied to derive high and low SR subgroups across participants based on two measures of SR. General linear models tested for SR group differences in clinical and biological parameters. Exploratory analyses examined associations between SR group-specific brain alterations and gene expression. Results: The high, compared to low SR group showed greater cyclic AMP response element-binding protein (CREB) gene expression consistent with tonic SNS activity and proinflammatory changes in whole blood. Brain imaging showed neuroplastic changes in the high SR group consistent with an upregulation of ascending arousal systems and sensory processing and integration regions, and functional connectivity changes in the central autonomic network. SR moderated the sex difference in extraintestinal symptoms. Conclusions: The findings support a model of tonically increased SNS activity as a plausible risk factor for increased autonomic reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater prevalence in IBS. These findings may have important implications for personalized treatment interventions in IBS.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.06.24311497
Myvizhi Esai Selvan, Daniel I Nathan, Daniela Guisado, Giulia Collatuzzo, Sushruta Iruvanti, Paolo Boffetta, John Mascarenhas, Ronald Hoffman, Louis J Cohen, Bridget K Marcellino, Zeynep H Gümüş
Background Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of somatic mutations in myeloid and lymphoid malignancy genes in the blood cells of individuals without a hematologic malignancy. Inflammation is hypothesized to be a key mediator in the progression of CHIP to hematologic malignancy and patients with CHIP have a high prevalence of inflammatory diseases. This study aimed to identify the prevalence and characteristics of CHIP in patients with inflammatory bowel disease (IBD). Methods We analyzed whole exome sequencing data from 587 Crohn′s disease (CD), 441 ulcerative colitis (UC), and 293 non-IBD controls to assess CHIP prevalence and used logistic regression to study associations with clinical outcomes. Results Older UC patients (age>45) harbored increased myeloid-CHIP mutations compared to younger patients (age≤45) (p=0.01). Lymphoid-CHIP was more prevalent in older IBD patients (p=0.007). Young CD patients were found to have myeloid-CHIP with high-risk features. IBD patients with CHIP exhibited unique mutational profiles compared to controls. Steroid use was associated with increased CHIP (p=0.05), while anti-TNF therapy was associated with decreased myeloid-CHIP (p=0.03). Pathway enrichment analyses indicated overlap between CHIP genes, IBD phenotypes, and inflammatory pathways. Conclusions Our findings underscore a connection between IBD and CHIP pathophysiology. Patients with IBD and CHIP had unique risk profiles especially among older UC patients and younger CD patients. These findings suggest distinct evolutionary pathways for CHIP in IBD and necessitate awareness among IBD providers and hematologists to identify patients potentially at risk for CHIP-related complications including malignancy, cardiovascular disease and acceleration of their inflammatory disease.
{"title":"Clonal Hematopoiesis of Indeterminate Potential in Crohn′s Disease and Ulcerative Colitis","authors":"Myvizhi Esai Selvan, Daniel I Nathan, Daniela Guisado, Giulia Collatuzzo, Sushruta Iruvanti, Paolo Boffetta, John Mascarenhas, Ronald Hoffman, Louis J Cohen, Bridget K Marcellino, Zeynep H Gümüş","doi":"10.1101/2024.08.06.24311497","DOIUrl":"https://doi.org/10.1101/2024.08.06.24311497","url":null,"abstract":"Background\u0000Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of somatic mutations in myeloid and lymphoid malignancy genes in the blood cells of individuals without a hematologic malignancy. Inflammation is hypothesized to be a key mediator in the progression of CHIP to hematologic malignancy and patients with CHIP have a high prevalence of inflammatory diseases. This study aimed to identify the prevalence and characteristics of CHIP in patients with inflammatory bowel disease (IBD). Methods\u0000We analyzed whole exome sequencing data from 587 Crohn′s disease (CD), 441 ulcerative colitis (UC), and 293 non-IBD controls to assess CHIP prevalence and used logistic regression to study associations with clinical outcomes. Results\u0000Older UC patients (age>45) harbored increased myeloid-CHIP mutations compared to younger patients (age≤45) (p=0.01). Lymphoid-CHIP was more prevalent in older IBD patients (p=0.007). Young CD patients were found to have myeloid-CHIP with high-risk features. IBD patients with CHIP exhibited unique mutational profiles compared to controls. Steroid use was associated with increased CHIP (p=0.05), while anti-TNF therapy was associated with decreased myeloid-CHIP (p=0.03). Pathway enrichment analyses indicated overlap between CHIP genes, IBD phenotypes, and inflammatory pathways. Conclusions\u0000Our findings underscore a connection between IBD and CHIP pathophysiology. Patients with IBD and CHIP had unique risk profiles especially among older UC patients and younger CD patients. These findings suggest distinct evolutionary pathways for CHIP in IBD and necessitate awareness among IBD providers and hematologists to identify patients potentially at risk for CHIP-related complications including malignancy, cardiovascular disease and acceleration of their inflammatory disease.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.06.24311443
Qiuyi Tang, Yue-Peng Hu, Qi Yang, Jing Zhou, Jing-Zhu Zhang, Jie Yang, Haibin Hao, Gang Li, Bai-Qiang Li, Lu Ke, Zhi-Hui Tong, Yu-Xiu Liu, Evan Yi-Wen Yu, Wei-Qin Li
This study sought to identify genetic cause of spontaneous intraabdominal hemorrhage (SIH) in severe acute pancreatitis (SAP) to develop more effective treatment for this life-threatening complication. A four-phase study was conducted, leveraging a large-scale acute pancreatitis (AP) patients (n=600); the first phase involved whole-exome sequencing analyses, and identified specific exonic variant located in FCGBP (i.e., rs1326680184) that was consistently associated with SIH; the second phase performed serum ELISA tests, and revealed that FCGBP variant altered FCGBP level and further led to predisposition of SIH; the third phase conducted an i) in-vivo experiment with a Fcgbp-knockdown mouse model, and demonstrated lower expression of Fcgbp led to more severe AP morphology and higher risk of hemorrhage; ii) in-vitro experiment with FCGBP-knockdown human vascular fibroblasts demonstrated that down-regulated FCGBP expression could destabilize the vascular wall, and lead to vascular injury in SAP; the fourth phase compared FCGBP variant carriers to non-carriers with clinical characteristics, and found FCGBP variant associated with higher risks of poor complications and AP prognosis and enhanced the diagnostic capability as an indicator. These findings provide important insights into the underlying mechanism of SIH in SAP, and facilitate therapeutic development for AP prognosis and critical care in an early phase.
这项研究旨在确定重症急性胰腺炎（SAP）患者自发性腹腔内出血（SIH）的遗传学原因，从而针对这种危及生命的并发症开发出更有效的治疗方法。研究利用大规模急性胰腺炎（AP）患者（n=600）进行了四个阶段的研究；第一阶段涉及全外显子组测序分析，确定了位于 FCGBP 的特定外显子变异（即：rs1326680184）、rs1326680184）与 SIH 存在一致性关联；第二阶段进行了血清 ELISA 检测，发现 FCGBP 变异改变了 FCGBP 水平，并进一步导致了 SIH 的易感性；第三阶段进行了 i) Fcgbp 敲除小鼠模型的体内实验，结果表明 Fcgbp 的低表达会导致更严重的 AP 形态和更高的出血风险；第四阶段比较了FCGBP变异携带者和非携带者的临床特征，发现FCGBP变异与较高的不良并发症风险和AP预后相关，并增强了作为指标的诊断能力。这些研究结果为了解 SAP 中 SIH 的内在机制提供了重要依据，有助于早期开发针对 AP 预后和危重症护理的治疗方法。
{"title":"Whole Exome Sequencing Reveals FCGBP Variant Associated with Spontaneous Intraabdominal Hemorrhage in Severe Acute Pancreatitis","authors":"Qiuyi Tang, Yue-Peng Hu, Qi Yang, Jing Zhou, Jing-Zhu Zhang, Jie Yang, Haibin Hao, Gang Li, Bai-Qiang Li, Lu Ke, Zhi-Hui Tong, Yu-Xiu Liu, Evan Yi-Wen Yu, Wei-Qin Li","doi":"10.1101/2024.08.06.24311443","DOIUrl":"https://doi.org/10.1101/2024.08.06.24311443","url":null,"abstract":"This study sought to identify genetic cause of spontaneous intraabdominal hemorrhage (SIH) in severe acute pancreatitis (SAP) to develop more effective treatment for this life-threatening complication. A four-phase study was conducted, leveraging a large-scale acute pancreatitis (AP) patients (n=600); the first phase involved whole-exome sequencing analyses, and identified specific exonic variant located in <em>FCGBP</em> (i.e., rs1326680184) that was consistently associated with SIH; the second phase performed serum ELISA tests, and revealed that <em>FCGBP</em> variant altered FCGBP level and further led to predisposition of SIH; the third phase conducted an i) <em>in-vivo</em> experiment with a <em>Fcgbp</em>-knockdown mouse model, and demonstrated lower expression of <em>Fcgbp</em> led to more severe AP morphology and higher risk of hemorrhage; ii) <em>in-vitro</em> experiment with <em>FCGBP</em>-knockdown human vascular fibroblasts demonstrated that down-regulated <em>FCGBP</em> expression could destabilize the vascular wall, and lead to vascular injury in SAP; the fourth phase compared <em>FCGBP</em> variant carriers to non-carriers with clinical characteristics, and found <em>FCGBP</em> variant associated with higher risks of poor complications and AP prognosis and enhanced the diagnostic capability as an indicator. These findings provide important insights into the underlying mechanism of SIH in SAP, and facilitate therapeutic development for AP prognosis and critical care in an early phase.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1101/2024.08.05.24311406
Sara Gomez-Aguililla, Sergio Farrais, Natalia Lopez-Palacios, Beatriz Arau, Carla Senosiain, Maria Corzo, Nora Fernandez-Jimenez, Angela Ruiz-Carnicer, Fernando Fernandez-Bañares, Barbara P Gonzalez-Garcia, Eva Tristan, Ana Montero-Calle, Maria Garranzo-Asensio, Isabel Casado, Mar Pujals, Juana Maria Hernandez, Jorge Infante-Menendez, Garbiñe Roy, Carolina Sousa, Concepcion Nuñez
Background Diagnosing celiac disease (CD) in individuals adhering to a gluten-free diet (GFD) presents significant challenges. Current guidelines recommend a gluten challenge (GC) lasting at least 6-8 weeks, which has several limitations. Objectives This study compares four approaches previously proposed for diagnosing CD on a GFD: IL-2 serum levels, gut-homing CD8+ T cells, %TCRγδ+ intraepithelial lymphocytes (IELs), and UBE2L3 gene expression. Additionally, we evaluated the CD8+ T-cell based method with a 3-day GC against the standard GC protocol. Methods We conducted a multicenter prospective quasi-experimental clinical study. Two subsets of individuals were considered: 1) 20 patients with CD and 15 non-CD controls previously diagnosed, to evaluate the first aim; 2) 45 individuals with uncertain diagnosis who were on a GFD and required GC following current clinical guidelines, to assess the second aim. All participants underwent a 3-day GC (10 g gluten/day). Results Among CD patients and non-CD controls, the sensitivity and specificity of IL-2, gut-homing CD8+ T cells, and UBE2L3 were 82.4% and 83.3%, 88.2% and 100%, and 52.9% and 100%, respectively. The percentage of TCRγδ+ IELs showed 88.2% sensitivity. In the uncertain diagnosis group, a CD8+ T-cell positive response was observed in 8 of the 45 subjects. Conclusion The percentage of TCRγδ+ IELs and the gut-homing CD8+ T-cell assay are promising diagnostic methods for CD on a GFD. Notably, the CD8+ T-cell assay provides a consistent and reliable alternative to the extended GC, eliminating the need for the invasive procedures to obtain duodenal samples and the prolonged gluten ingestion.
背景对坚持无麸质饮食（GFD）的人诊断乳糜泻（CD）是一项重大挑战。本研究比较了之前提出的四种诊断无麸质饮食 CD 的方法：IL-2 血清水平、肠道归巢 CD8+ T 细胞、%TCRγδ+ 上皮内淋巴细胞（IELs）和 UBE2L3 基因表达。此外，我们还对基于 CD8+ T 细胞的 3 天 GC 方法与标准 GC 方案进行了评估。方法我们进行了一项多中心前瞻性准实验临床研究。研究考虑了两组个体：1）20 名先前确诊的 CD 患者和 15 名非 CD 对照组，以评估第一个目的；2）45 名诊断不明确的个体，他们正在服用 GFD，并需要按照现行临床指南进行 GC，以评估第二个目的。结果在CD患者和非CD对照组中，IL-2、肠道归巢CD8+ T细胞和UBE2L3的敏感性和特异性分别为82.4%和83.3%、88.2%和100%、52.9%和100%。TCRγδ+ IELs 的敏感性为 88.2%。在不确定诊断组中，45 名受试者中有 8 人出现了 CD8+ T 细胞阳性反应。结论TCRγδ+ IELs的百分比和肠道归巢CD8+ T细胞检测是GFD上CD的有前途的诊断方法。值得注意的是，CD8+ T 细胞检测为扩展 GC 提供了一个稳定可靠的替代方法，无需通过侵入性程序获取十二指肠样本，也无需长时间摄入麸质。
{"title":"Diagnosis of celiac disease on a gluten-free diet: a multicenter prospective quasi-experimental clinical study","authors":"Sara Gomez-Aguililla, Sergio Farrais, Natalia Lopez-Palacios, Beatriz Arau, Carla Senosiain, Maria Corzo, Nora Fernandez-Jimenez, Angela Ruiz-Carnicer, Fernando Fernandez-Bañares, Barbara P Gonzalez-Garcia, Eva Tristan, Ana Montero-Calle, Maria Garranzo-Asensio, Isabel Casado, Mar Pujals, Juana Maria Hernandez, Jorge Infante-Menendez, Garbiñe Roy, Carolina Sousa, Concepcion Nuñez","doi":"10.1101/2024.08.05.24311406","DOIUrl":"https://doi.org/10.1101/2024.08.05.24311406","url":null,"abstract":"Background\u0000Diagnosing celiac disease (CD) in individuals adhering to a gluten-free diet (GFD) presents significant challenges. Current guidelines recommend a gluten challenge (GC) lasting at least 6-8 weeks, which has several limitations.\u0000Objectives\u0000This study compares four approaches previously proposed for diagnosing CD on a GFD: IL-2 serum levels, gut-homing CD8<sup>+</sup> T cells, %TCRγδ<sup>+</sup> intraepithelial lymphocytes (IELs), and UBE2L3 gene expression. Additionally, we evaluated the CD8<sup>+</sup> T-cell based method with a 3-day GC against the standard GC protocol. Methods\u0000We conducted a multicenter prospective quasi-experimental clinical study. Two subsets of individuals were considered: 1) 20 patients with CD and 15 non-CD controls previously diagnosed, to evaluate the first aim; 2) 45 individuals with uncertain diagnosis who were on a GFD and required GC following current clinical guidelines, to assess the second aim. All participants underwent a 3-day GC (10 g gluten/day).\u0000Results\u0000Among CD patients and non-CD controls, the sensitivity and specificity of IL-2, gut-homing CD8<sup>+</sup> T cells, and UBE2L3 were 82.4% and 83.3%, 88.2% and 100%, and 52.9% and 100%, respectively. The percentage of TCRγδ<sup>+</sup> IELs showed 88.2% sensitivity. In the uncertain diagnosis group, a CD8+ T-cell positive response was observed in 8 of the 45 subjects. Conclusion\u0000The percentage of TCRγδ<sup>+</sup> IELs and the gut-homing CD8<sup>+</sup> T-cell assay are promising diagnostic methods for CD on a GFD. Notably, the CD8+ T-cell assay provides a consistent and reliable alternative to the extended GC, eliminating the need for the invasive procedures to obtain duodenal samples and the prolonged gluten ingestion.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1101/2024.08.03.24311458
Abdullah Khalid, Sara Qureshi, Imran Ali Syed, Hassan Nadeem, Ahmad Karim Malik, Usman Aujla
ABSTRACT Introduction: The accurate diagnosis of biliary strictures or narrowing of the bile duct is challenging in clinical practice. Differentiating malignant from benign strictures is critical, because these treatments differ considerably. Although noninvasive imaging techniques help identify these strictures, they do not provide definitive tissue diagnosis, making techniques such as brush cytology and forceps biopsy essential. This study aimed to address the dearth of comparative research on the diagnostic efficacy of brush cytology and forceps biopsy in Pakistan. Methods: This single-center observational study was conducted at the Pakistan Kidney and Liver Institute & Research Center (PKLI&RC), Lahore, from March 2019 to January 2023. Patients with clinically and radiologically suspected biliary strictures were included in the study. Both brush cytology and forceps biopsy samples were subjected to cytopathological analysis by blinded pathologists. Sensitivity, specificity, and predictive values were among the key metrics analyzed. Results: The study included 54 patients in the biopsy group and 89 in the brushing group. In terms of diagnostic metrics, the biopsy technique displayed a sensitivity of 65.8%, specificity of 92.3%, positive predictive value (PPV) of 96.4%, and accuracy rate of 72.2%. For the brushing technique, the sensitivity, specificity, PPV, and accuracy were 56.7 %, 93.3%, 83.1%, and 62.9%, respectively. Although both methods showed high specificity, the biopsy technique exhibited a slightly better sensitivity and overall accuracy. Conclusion: Our findings underscore the importance of the biopsy method in the accurate diagnosis of malignant biliary strictures, showing marginally superior sensitivity and overall accuracy compared to brush cytology. This knowledge can guide clinicians in Pakistan and similar settings in making informed diagnostic choices to improve patient outcomes.
{"title":"Comparative Efficacy of Brush Cytology and Forceps Biopsy in the Diagnosis of Malignant Biliary Strictures: A Single-Center Study in Pakistan","authors":"Abdullah Khalid, Sara Qureshi, Imran Ali Syed, Hassan Nadeem, Ahmad Karim Malik, Usman Aujla","doi":"10.1101/2024.08.03.24311458","DOIUrl":"https://doi.org/10.1101/2024.08.03.24311458","url":null,"abstract":"ABSTRACT Introduction: The accurate diagnosis of biliary strictures or narrowing of the bile duct is challenging in clinical practice. Differentiating malignant from benign strictures is critical, because these treatments differ considerably. Although noninvasive imaging techniques help identify these strictures, they do not provide definitive tissue diagnosis, making techniques such as brush cytology and forceps biopsy essential. This study aimed to address the dearth of comparative research on the diagnostic efficacy of brush cytology and forceps biopsy in Pakistan. Methods: This single-center observational study was conducted at the Pakistan Kidney and Liver Institute & Research Center (PKLI&RC), Lahore, from March 2019 to January 2023. Patients with clinically and radiologically suspected biliary strictures were included in the study. Both brush cytology and forceps biopsy samples were subjected to cytopathological analysis by blinded pathologists. Sensitivity, specificity, and predictive values were among the key metrics analyzed. Results: The study included 54 patients in the biopsy group and 89 in the brushing group. In terms of diagnostic metrics, the biopsy technique displayed a sensitivity of 65.8%, specificity of 92.3%, positive predictive value (PPV) of 96.4%, and accuracy rate of 72.2%. For the brushing technique, the sensitivity, specificity, PPV, and accuracy were 56.7 %, 93.3%, 83.1%, and 62.9%, respectively. Although both methods showed high specificity, the biopsy technique exhibited a slightly better sensitivity and overall accuracy. Conclusion: Our findings underscore the importance of the biopsy method in the accurate diagnosis of malignant biliary strictures, showing marginally superior sensitivity and overall accuracy compared to brush cytology. This knowledge can guide clinicians in Pakistan and similar settings in making informed diagnostic choices to improve patient outcomes.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Screening for colorectal cancer (CRC) using plasma cell-free DNA (cfDNA) methylation is more challenging than stool testing due to the low abundance of cfDNA. Therefore, the development of signal amplification assays based on appropriate markers is essential to increase sensitivity. Methods: A total of 17 existing 450K microarray datasets including tissue, healthy white blood cell (WBC) and plasma cfDNA data from public databases were used to identify differentially methylated CpGs (DMCs) common to CRC and adenoma. The methylation status of candidate DMCs was confirmed by Sanger sequencing with CRC and normal tissues. A sense-antisense and dual MGB probe (SADMP) assay was then developed. Subsequently, the biomarkers were validated in 712 plasma samples using the SADMP method. Results: A total of 2237 DMCs showed overlap between the cancer vs. normal and adenoma vs. normal groups. Of these, 75 were hypomethylated in 30 other non-CRC cancers. After LASSO regression, this number was reduced to eight. Two of these, NTMT1 and MAP3K14-AS1, were identified as promising candidate markers following WBC validation and primer/probe design evaluation. The SADMP technology demonstrated the ability to amplify the detection signal to approximately twice the original level. Overall, the dual-target SADMP assay demonstrated a sensitivity of 84.8% for CRC (stage I: 75.0%), a sensitivity of 32.0% for advanced adenomas (AA), and a specificity of 91.5% in controls. Conclusions: The dual-target assay demonstrated high performance for CRC and AA detection in plasma-based tests, suggesting that it may serve as a promising noninvasive tool for CRC detection.
{"title":"Discovering methylation markers and development of a sense-antisense and dual-MGB probe PCR assay in plasma for colorectal cancer early detection","authors":"Yanteng Zhao, Zhijie Wang, Qiuning Yu, Xin Liu, Xue Liu, Shuling Dong, Xianping Lv, Tiao Zhang, Dihan Zhou, Qiankun Yang","doi":"10.1101/2024.07.31.24311206","DOIUrl":"https://doi.org/10.1101/2024.07.31.24311206","url":null,"abstract":"Background: Screening for colorectal cancer (CRC) using plasma cell-free DNA (cfDNA) methylation is more challenging than stool testing due to the low abundance of cfDNA. Therefore, the development of signal amplification assays based on appropriate markers is essential to increase sensitivity.\u0000Methods: A total of 17 existing 450K microarray datasets including tissue, healthy white blood cell (WBC) and plasma cfDNA data from public databases were used to identify differentially methylated CpGs (DMCs) common to CRC and adenoma. The methylation status of candidate DMCs was confirmed by Sanger sequencing with CRC and normal tissues. A sense-antisense and dual MGB probe (SADMP) assay was then developed. Subsequently, the biomarkers were validated in 712 plasma samples using the SADMP method.\u0000Results: A total of 2237 DMCs showed overlap between the cancer vs. normal and adenoma vs. normal groups. Of these, 75 were hypomethylated in 30 other non-CRC cancers. After LASSO regression, this number was reduced to eight. Two of these, NTMT1 and MAP3K14-AS1, were identified as promising candidate markers following WBC validation and primer/probe design evaluation. The SADMP technology demonstrated the ability to amplify the detection signal to approximately twice the original level. Overall, the dual-target SADMP assay demonstrated a sensitivity of 84.8% for CRC (stage I: 75.0%), a sensitivity of 32.0% for advanced adenomas (AA), and a specificity of 91.5% in controls.\u0000Conclusions: The dual-target assay demonstrated high performance for CRC and AA detection in plasma-based tests, suggesting that it may serve as a promising noninvasive tool for CRC detection.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02DOI: 10.1101/2024.07.31.24311317
Swapna Mahurkar-Joshi, Simer Shera, Jennifer Labus, Tien S Dong, Jonathan P Jacobs, Lin Chang
Background: Irritable bowel syndrome (IBS) is a female-predominant disorder of brain-gut interactions. Our previous study on colonic mucosal microbiota demonstrated significant differences between IBS bowel habit subtypes and showed that gut microbiota is associated with abdominal pain in IBS patients. However, there is no consensus on sex-related differences in mucosal microbiota in IBS compared to healthy controls (HC). We aimed to identify sex-related differences in the mucosal microbes associated with IBS. Methods: Sigmoid mucosal biopsies were obtained from 97 Rome+ IBS patients and 54 healthy controls (HC). Mucosal microbiome was characterized using 16S rRNA sequencing and analyzed and general linear models were used to test group differences between IBS diagnosis and sex. Sex-specific relationships between mucosal microbiome and IBS symptoms were assessed using sparse partial least squares (sPLS) regression. Results: Beta diversity was significantly different between men and women overall (p=.03) but not within IBS or HC. IBS women showed lower abundance of Catenibacterium and Ruminoclstridium_9 and increased abundance of Bacteroides, Escherichia/Shigella, Lachnoclostridium and Ruminococcaceae compared to men with IBS (p<0.05). However, healthy women had a lower abundance of six distinct genera compared to healthy men. In women, higher IBS symptoms were associated with an increased abundance of bacteria including prevotella_9, and paraprevotella, however, in men, IBS symptoms were associated with increased abundances of genera such as Dialister. Interestingly, increased abundance of Desulfovibrio was associated with higher symptoms in women but lower symptoms in men. Conclusion: There are distinct sex-related differences in the mucosal microbiome between IBS and healthy participants supporting the importance of studying sex-specific mechanisms in IBS pathophysiology.
{"title":"Sex Differences in Colonic Mucosal Microbiome of Irritable Bowel Syndrome Patients Compared to Healthy Controls","authors":"Swapna Mahurkar-Joshi, Simer Shera, Jennifer Labus, Tien S Dong, Jonathan P Jacobs, Lin Chang","doi":"10.1101/2024.07.31.24311317","DOIUrl":"https://doi.org/10.1101/2024.07.31.24311317","url":null,"abstract":"Background: Irritable bowel syndrome (IBS) is a female-predominant disorder of brain-gut\u0000interactions. Our previous study on colonic mucosal microbiota demonstrated significant differences between IBS bowel habit subtypes and showed that gut microbiota is associated with abdominal pain in IBS patients. However, there is no consensus on sex-related differences in mucosal microbiota in IBS compared to healthy controls (HC). We aimed to identify sex-related differences in the mucosal microbes associated with IBS. Methods: Sigmoid mucosal biopsies were obtained from 97 Rome+ IBS patients and 54 healthy controls (HC). Mucosal microbiome was characterized using 16S rRNA sequencing and analyzed and general linear models were used to test group differences between IBS diagnosis and sex. Sex-specific relationships between mucosal microbiome and IBS symptoms were assessed using sparse partial least squares (sPLS) regression. Results: Beta diversity was significantly different between men and women overall (p=.03) but not within IBS or HC. IBS women showed lower abundance of Catenibacterium and Ruminoclstridium_9 and increased abundance of Bacteroides, Escherichia/Shigella, Lachnoclostridium and Ruminococcaceae compared to men with IBS (p<0.05). However, healthy women had a lower abundance of six distinct genera compared to healthy men. In women, higher IBS symptoms were associated with an increased abundance of bacteria including prevotella_9, and paraprevotella, however, in men, IBS symptoms were associated with increased abundances of genera such as Dialister. Interestingly, increased abundance of Desulfovibrio was associated with higher symptoms in women but lower symptoms in men. Conclusion: There are distinct sex-related differences in the mucosal microbiome between IBS and healthy participants supporting the importance of studying sex-specific mechanisms in IBS pathophysiology.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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