Pub Date : 2024-07-27DOI: 10.1101/2024.07.26.24311013
Jayde E Kurland, Sheena B Patel, Richard Englehardt, Seper Dezfoli, Daniel M Tseng, Michael W Foutz, Paul S Bradley, Badi Eghterafi, Victoria T Lee, Suman Verma, Brian J deGuzman, Lishan Aklog
Background: Guidelines support Barrett's esophagus (BE) screening, but most eligible patients do not undergo endoscopic evaluation; non-endoscopic strategies are now supported as a reasonable alternative by U.S gastroenterology societies. EsoGuard (EG) is a DNA assay used with EsoCheck, a non-endoscopic cell collection device for detection of BE, which can be utilized as a triage to esophagogastroduodenoscopy (EGD) in patients meeting screening criteria. In doing so, EG may serve to enrich the population undergoing EGD, resulting in more BE diagnoses while potentially reducing utilization of already-limited endoscopy resources. Aim: To test the hypothesis that BE detection in EGDs performed on EG positive patients will be significantly higher than the positive predictive value (PPV) of screening EGD alone. Methods: Real-world data was retrospectively collected from EG positive patients for whom EGD diagnoses were available. Baseline patient characteristics, risk factors, and EGD results were obtained from the treating physicians. PPV of screening EGDs was the comparator and estimated by literature-established disease prevalence of BE, which in the U.S gastroesophageal reflux disease population is ~10.6%. The hypothesis was tested using t-tests for single proportions at a one-sided 5% significance level. Results: Data from 209 patients found 60 (28.7%) subjects with salmon-colored mucosa on EGD and specialized intestinal metaplasia on histopathology. However, 10 (4.8%) had < 1cm of disease on visual inspection, therefore, did not meet the American College of Gastroenterology definition of BE so was excluded from the analysis. Of the remaining 199 patients, 50 (25.1%) had BE on EGD. In the cohort of patients meeting ACG screening criteria, 28.9% (33/114) had BE. Overall, a 2.4-fold increase in BE detection was observed compared to the PPV of screening EGD, and in the ACG cohort this increase was 2.7-fold. Among ACG patients ≥65 years old, the increase was nearly 2.5-fold (25.9% detection rate). Conclusions: Our data suggests EG and EC used as a triage test enriches the population undergoing EGD for BE, and compared to screening EGD alone, can help direct more efficient use of endoscopy resources to unburden the system without reducing the number of eligible patients screened and diagnosed.
{"title":"Enhancing the Positive Predictive Value of EGD for Diagnosis of Barrett's Esophagus Through EsoGuard® Triage","authors":"Jayde E Kurland, Sheena B Patel, Richard Englehardt, Seper Dezfoli, Daniel M Tseng, Michael W Foutz, Paul S Bradley, Badi Eghterafi, Victoria T Lee, Suman Verma, Brian J deGuzman, Lishan Aklog","doi":"10.1101/2024.07.26.24311013","DOIUrl":"https://doi.org/10.1101/2024.07.26.24311013","url":null,"abstract":"Background: Guidelines support Barrett's esophagus (BE) screening, but most eligible patients do not undergo endoscopic evaluation; non-endoscopic strategies are now supported as a reasonable alternative by U.S gastroenterology societies. EsoGuard (EG) is a DNA assay used with EsoCheck, a non-endoscopic cell collection device for detection of BE, which can be utilized as a triage to esophagogastroduodenoscopy (EGD) in patients meeting screening criteria. In doing so, EG may serve to enrich the population undergoing EGD, resulting in more BE diagnoses while potentially reducing utilization of already-limited endoscopy resources.\u0000Aim: To test the hypothesis that BE detection in EGDs performed on EG positive patients will be significantly higher than the positive predictive value (PPV) of screening EGD alone. Methods: Real-world data was retrospectively collected from EG positive patients for whom EGD diagnoses were available. Baseline patient characteristics, risk factors, and EGD results were obtained from the treating physicians. PPV of screening EGDs was the comparator and estimated by literature-established disease prevalence of BE, which in the U.S gastroesophageal reflux disease population is ~10.6%. The hypothesis was tested using t-tests for single proportions at a one-sided 5% significance level. Results: Data from 209 patients found 60 (28.7%) subjects with salmon-colored mucosa on EGD and specialized intestinal metaplasia on histopathology. However, 10 (4.8%) had < 1cm of disease on visual inspection, therefore, did not meet the American College of Gastroenterology definition of BE so was excluded from the analysis. Of the remaining 199 patients, 50 (25.1%) had BE on EGD. In the cohort of patients meeting ACG screening criteria, 28.9% (33/114) had BE. Overall, a 2.4-fold increase in BE detection was observed compared to the PPV of screening EGD, and in the ACG cohort this increase was 2.7-fold. Among ACG patients ≥65 years old, the increase was nearly 2.5-fold (25.9% detection rate).\u0000Conclusions: Our data suggests EG and EC used as a triage test enriches the population undergoing EGD for BE, and compared to screening EGD alone, can help direct more efficient use of endoscopy resources to unburden the system without reducing the number of eligible patients screened and diagnosed.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777556","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 : 2024-07-27DOI: 10.1101/2024.07.27.24311099
Laura Buttler, David A. Velazquez Ramirez, Anja Tiede, Anna M. Conradi, Sabrina Woltemade, Robert Geffers, Birgit Bremer, Vera Spielmann, Julia Kahlhoefer, Anke Kraft, Dirk Schlueter, Markus Cornberg, Heiner Wedemeyer, Christine S. Falk, Marius Vital, Benjamin Maasoumy
Background: Decompensated liver cirrhosis (dLC) is associated with a dysbalanced microbiome, however, reasons for those observations and resulting consequences for patients are largely unexplored. We aimed to characterize bacterial and fungal components of gut microbiota applying quantitative genome-resolved metagenomics and investigate their relation with gut barrier integrity, inflammation and how this impacts the clinical outcome of dLC patients. Methods: Samples were collected prospectively from 95 consecutive hospitalized dLC patients between 2017 and 2022. Metagenomic shot-gun sequencing coupled to flow-cytometric analyses were performed for qualitative and quantitative insights into gut microbiota on a compositional and functional level. Plasma, CRP, Zonulin and CD163 were measured to investigate host functions. Competing risk analyses were performed to compare cirrhosis-related complications within 90 days. Results: Median baseline MELD was 16 and median age 57.6 years. Patients were clustered into three groups (G1-G3) showing greatly distinct microbial patterns. G1 displayed lowest diversity and highest Enterococcus relative abundance (77.97 %), whereas G2 was dominated by Bifidobacteria (52.31 %). G3 was most diverse and clustered most closely with HC. Bacterial concentrations in patients were lower compared with HC (median 2.65 x 109 cells/gram stool), especially for G1 (median of 2.65 x 109 cells/gram stool); G2 and G3 were in-between the two. Fungi were primarily detected in patient samples and an overgrowth in G1 that was dominated by Candida spp (51.63 %) was observed. Moreover, G1-patients most frequently received antibiotics (n=33; 86.8 %) at baseline and had higher plasma levels of Zonulin (p=0.044), CD163 (p=0.019) and a numerically higher incidence of infections (p=0.09). Conclusion: Different bacterial clusters were observed at qualitative and quantitative levels and correlated with fungal abundance. Antibiotic treatment contributed to dysbiosis in patients with dLC, which translated into impairment of the intestinal barrier, translocation and systemic inflammation.
{"title":"Distinct patterns of microbiota and its function in end-stage liver cirrhosis correlate with antibiotic treatment, intestinal barrier impairment and systemic inflammation","authors":"Laura Buttler, David A. Velazquez Ramirez, Anja Tiede, Anna M. Conradi, Sabrina Woltemade, Robert Geffers, Birgit Bremer, Vera Spielmann, Julia Kahlhoefer, Anke Kraft, Dirk Schlueter, Markus Cornberg, Heiner Wedemeyer, Christine S. Falk, Marius Vital, Benjamin Maasoumy","doi":"10.1101/2024.07.27.24311099","DOIUrl":"https://doi.org/10.1101/2024.07.27.24311099","url":null,"abstract":"Background: Decompensated liver cirrhosis (dLC) is associated with a dysbalanced microbiome, however, reasons for those observations and resulting consequences for patients are largely unexplored. We aimed to characterize bacterial and fungal components of gut microbiota applying quantitative genome-resolved metagenomics and investigate their relation with gut barrier integrity, inflammation and how this impacts the clinical outcome of dLC patients.\u0000Methods: Samples were collected prospectively from 95 consecutive hospitalized dLC patients between 2017 and 2022. Metagenomic shot-gun sequencing coupled to flow-cytometric analyses were performed for qualitative and quantitative insights into gut microbiota on a compositional and functional level. Plasma, CRP, Zonulin and CD163 were measured to investigate host functions. Competing risk analyses were performed to compare cirrhosis-related complications within 90 days.\u0000Results: Median baseline MELD was 16 and median age 57.6 years. Patients were clustered into three groups (G1-G3) showing greatly distinct microbial patterns. G1 displayed lowest diversity and highest Enterococcus relative abundance (77.97 %), whereas G2 was dominated by Bifidobacteria (52.31 %). G3 was most diverse and clustered most closely with HC. Bacterial concentrations in patients were lower compared with HC (median 2.65 x 109 cells/gram stool), especially for G1 (median of 2.65 x 109 cells/gram stool); G2 and G3 were in-between the two. Fungi were primarily detected in patient samples and an overgrowth in G1 that was dominated by Candida spp (51.63 %) was observed. Moreover, G1-patients most frequently received antibiotics (n=33; 86.8 %) at baseline and had higher plasma levels of Zonulin (p=0.044), CD163 (p=0.019) and a numerically higher incidence of infections (p=0.09). Conclusion: Different bacterial clusters were observed at qualitative and quantitative levels and correlated with fungal abundance. Antibiotic treatment contributed to dysbiosis in patients with dLC, which translated into impairment of the intestinal barrier, translocation and systemic inflammation.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777557","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 : 2024-07-26DOI: 10.1101/2024.07.25.24310942
Jamie M Newton, William JS Edwards, Gary Thompson, Eleni Gentekaki, Anastasios D. Tsaousis
Background: Blastocystis, the most prevalent eukaryotic gut microbe in humans, has a global distribution. Studies have linked its presence with distinct gut microbiome and metabolome profiles compared to those where the organism is absent. However, the in vivo effect of antibiotics on Blastocystis and the surrounding gut microbiome remains understudied. This case study aimed to explore how antibiotic consumption influences the presence of Blastocystis and the subsequent changes in the gut microbiome and metabolome of an individual with irritable bowel syndrome (IBS). Methods: Stool samples from an IBS patient, collected at various time points, were tested for Blastocystis presence using RT-PCR targeting the SSUrRNA gene, followed by sequencing of positive samples. Illumina sequencing determined the gut microbiome composition, while one-dimensional proton NMR spectroscopy analysed the metabolome composition. Statistical analyses were conducted to identify relationships between antibiotic consumption, bacterial diversity, metabolome composition, and Blastocystis presence. Results: Antibiotics significantly impacted the gut microbiome, with diversity declining early in the antibiotic course, then recovering later and post-course. Blastocystis was detected early, late, and post-course but not mid-course, coinciding with the decline in bacterial diversity. No significant differences were observed between Blastocystis-positive and Blastocystis-negative samples. However, bacterial composition significantly differed between samples collected before, early, and after the antibiotic course compared to those collected mid-course. Metabolite groups, including short-chain fatty acids, amino acids, and succinate, exhibited changes throughout the antibiotic course, indicating that gut metabolite composition is affected by antibiotic consumption. Discussion/Conclusion: While antibiotics did not significantly impact Blastocystis colonisation, they did cause a mid-course decline in microbial diversity and Blastocystis presence. The study also revealed significant alterations in important metabolites such as SCFAs and amino acids throughout the antibiotic course, with an altered metabolome observed post-course. This case study underscores the complex interactions between antibiotics, gut microbiota, and metabolites, highlighting the resilience of Blastocystis in the gut ecosystem.
{"title":"The impact of antibiotics on the presence of the protozoan anaerobe Blastocystis and the surrounding microbiome: a case study","authors":"Jamie M Newton, William JS Edwards, Gary Thompson, Eleni Gentekaki, Anastasios D. Tsaousis","doi":"10.1101/2024.07.25.24310942","DOIUrl":"https://doi.org/10.1101/2024.07.25.24310942","url":null,"abstract":"Background: Blastocystis, the most prevalent eukaryotic gut microbe in humans, has a global distribution. Studies have linked its presence with distinct gut microbiome and metabolome profiles compared to those where the organism is absent. However, the in vivo effect of antibiotics on Blastocystis and the surrounding gut microbiome remains understudied. This case study aimed to explore how antibiotic consumption influences the presence of Blastocystis and the subsequent changes in the gut microbiome and metabolome of an individual with irritable bowel syndrome (IBS).\u0000Methods: Stool samples from an IBS patient, collected at various time points, were tested for Blastocystis presence using RT-PCR targeting the SSUrRNA gene, followed by sequencing of positive samples. Illumina sequencing determined the gut microbiome composition, while one-dimensional proton NMR spectroscopy analysed the metabolome composition. Statistical analyses were conducted to identify relationships between antibiotic consumption, bacterial diversity, metabolome composition, and Blastocystis presence.\u0000Results: Antibiotics significantly impacted the gut microbiome, with diversity declining early in the antibiotic course, then recovering later and post-course. Blastocystis was detected early, late, and post-course but not mid-course, coinciding with the decline in bacterial diversity. No significant differences were observed between Blastocystis-positive and Blastocystis-negative samples. However, bacterial composition significantly differed between samples collected before, early, and after the antibiotic course compared to those collected mid-course. Metabolite groups, including short-chain fatty acids, amino acids, and succinate, exhibited changes throughout the antibiotic course, indicating that gut metabolite composition is affected by antibiotic consumption. Discussion/Conclusion: While antibiotics did not significantly impact Blastocystis colonisation, they did cause a mid-course decline in microbial diversity and Blastocystis presence. The study also revealed significant alterations in important metabolites such as SCFAs and amino acids throughout the antibiotic course, with an altered metabolome observed post-course. This case study underscores the complex interactions between antibiotics, gut microbiota, and metabolites, highlighting the resilience of Blastocystis in the gut ecosystem.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777558","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}
Abstract Background: Cirrhosis is a major global health problem and a leading cause of liver-related mortality. In Ethiopia specifically, cirrhosis is the 6th leading cause of death and is responsible for high hospitalization and mortality rates. However, until now, factors affecting in–hospital mortality in patients admitted due to complications of liver cirrhosis are poorly understood. This study assessed the predictors of in–hospital mortality among cirrhotic patients in Ethiopia. Methods: A retrospective cross–sectional study using data collected from the electronic medical records of patients who were admitted for complications of liver cirrhosis between January 1, 2023, and March 31, 2024, in the medical wards of Adera Medical Center, St. Pauls Hospital Millennium Medical College, and Tikur Anbessa Specialized Hospital. Frequency and cross-tabulation were used for descriptive statistics. Predictor variables with a p-value <0.25 in bivariate analyses were included in the logistic regression. The adjusted odds ratio (AOR) with the corresponding 95% confidence interval (CI) was calculated to show the strength of the association. A p-value <0.05 was considered statistically significant. Results: Of the 299 patients included in the final analysis, the majority (79.6%) were males, and the median age of the study participants was 45 (IQR, 36–56) years. Hepatitis B virus (32.1%) was the most common etiology, followed by alcohol (30.1%) and hepatitis C virus (13.4%). More than half (52.9%) of the patients were in Child-Pugh class C, and around a quarter (26.1%) of the patients had comorbidities. Ascites (69.2%), Upper gastrointestinal bleeding (50.5%), and hepatic encephalopathy (44.8%) were the most common forms of presentation. The in–hospital mortality rate was 25.4%. West Haven Grade III or IV hepatic encephalopathy (AOR: 12.0; 95% CI 2.33 – 61.63; P <0.01), Hepatocellular Carcinoma (AOR: 9.05; 95% CI 2.18 – 37.14; P: 0.01), History of previous admission within one year period (AOR: 6.80; 95% CI 2.18 – 21.18; P <0.01), Acute Kidney Injury (AOR: 6.47; 95% CI 1.77 – 23.64; P <0.01), and Model for End–Stage Liver Disease– Sodium (MELD–Na) Score (AOR: 1.17; 95% CI 1.05 – 1.30; P: 0.02), were found to be predictors of in–hospital mortality. Conclusion: In–hospital mortality of cirrhotic patients is high in Ethiopia. West Haven grade III or IV hepatic encephalopathy is the leading cause of mortality. Hence, Prompt identification and management of hepatic encephalopathy and its precipitant at an earlier stage is crucial for better treatment outcomes and survival. Keywords: Cirrhosis, In–hospital mortality, Ethiopia
摘要背景：肝硬化是一个重大的全球性健康问题，也是导致肝脏相关疾病死亡的主要原因。然而，到目前为止，人们对影响肝硬化并发症住院患者院内死亡率的因素还知之甚少。本研究评估了埃塞俄比亚肝硬化患者院内死亡率的预测因素：这是一项回顾性横断面研究，使用的数据来自 2023 年 1 月 1 日至 2024 年 3 月 31 日期间阿德拉医疗中心、圣保罗医院千禧医学院和提库尔安贝萨专科医院内科病房因肝硬化并发症住院患者的电子病历。使用频率和交叉表进行描述性统计。双变量分析中 p 值为 0.25 的预测变量被纳入逻辑回归。计算调整后的几率比（AOR）及相应的 95% 置信区间（CI），以显示相关性的强度。P值为0.05即为具有统计学意义：在纳入最终分析的 299 名患者中，大多数（79.6%）为男性，研究参与者的平均年龄为 45（IQR，36-56）岁。乙型肝炎病毒（32.1%）是最常见的病因，其次是酒精（30.1%）和丙型肝炎病毒（13.4%）。半数以上（52.9%）的患者属于 Child-Pugh C 级，约四分之一（26.1%）的患者有并发症。腹水（69.2%）、上消化道出血（50.5%）和肝性脑病（44.8%）是最常见的表现形式。院内死亡率为 25.4%。WestHaven III 级或 IV 级肝性脑病（AOR：12.0；95% CI 2.33 - 61.63；P <0.01）、肝细胞癌（AOR：9.05；95% CI 2.18 - 37.14；P：0.01）、一年内有入院史（AOR：6.80；95% CI 2.18 - 21.18；P <0.01）、急性肾损伤（AOR：6.47；95% CI 1.77 - 23.64；P <0.01）和终末期肝病模型-钠（MELD-Na）评分（AOR：1.17；95% CI 1.05 - 1.30；P：0.02）被认为是院内死亡率的预测因素：结论：在埃塞俄比亚，肝硬化患者的院内死亡率很高。西黑文 III 级或 IV 级肝性脑病是死亡的主要原因。因此，在早期阶段及时发现和处理肝性脑病及其诱发因素对于改善治疗效果和提高存活率至关重要：肝硬化 院内死亡率 埃塞俄比亚
{"title":"Predictors of In-hospital Mortality among Cirrhotic Patients in Ethiopia: A Multicenter Retrospective Study","authors":"Tamrat Petros Elias, Abate Bane Shewaye, Henok Fisseha Chichaybelu, Abdulsemed Mohammed Nur, Kaleb Assefa Berhane, Asteray Tsige Minyilshewa, Kibrab Bulto Kumsa, Biruck Mohammed Seid","doi":"10.1101/2024.07.25.24311017","DOIUrl":"https://doi.org/10.1101/2024.07.25.24311017","url":null,"abstract":"Abstract\u0000Background: Cirrhosis is a major global health problem and a leading cause of liver-related mortality.\u0000In Ethiopia specifically, cirrhosis is the 6th leading cause of death and is responsible for high\u0000hospitalization and mortality rates. However, until now, factors affecting in–hospital mortality in\u0000patients admitted due to complications of liver cirrhosis are poorly understood. This study assessed the\u0000predictors of in–hospital mortality among cirrhotic patients in Ethiopia.\u0000Methods: A retrospective cross–sectional study using data collected from the electronic medical\u0000records of patients who were admitted for complications of liver cirrhosis between January 1, 2023,\u0000and March 31, 2024, in the medical wards of Adera Medical Center, St. Pauls Hospital Millennium\u0000Medical College, and Tikur Anbessa Specialized Hospital. Frequency and cross-tabulation were used\u0000for descriptive statistics. Predictor variables with a p-value <0.25 in bivariate analyses were included\u0000in the logistic regression. The adjusted odds ratio (AOR) with the corresponding 95% confidence\u0000interval (CI) was calculated to show the strength of the association. A p-value <0.05 was considered\u0000statistically significant.\u0000Results: Of the 299 patients included in the final analysis, the majority (79.6%) were males, and the\u0000median age of the study participants was 45 (IQR, 36–56) years. Hepatitis B virus (32.1%) was the\u0000most common etiology, followed by alcohol (30.1%) and hepatitis C virus (13.4%). More than half\u0000(52.9%) of the patients were in Child-Pugh class C, and around a quarter (26.1%) of the patients had\u0000comorbidities. Ascites (69.2%), Upper gastrointestinal bleeding (50.5%), and hepatic encephalopathy\u0000(44.8%) were the most common forms of presentation. The in–hospital mortality rate was 25.4%. West\u0000Haven Grade III or IV hepatic encephalopathy (AOR: 12.0; 95% CI 2.33 – 61.63; P <0.01),\u0000Hepatocellular Carcinoma (AOR: 9.05; 95% CI 2.18 – 37.14; P: 0.01), History of previous admission\u0000within one year period (AOR: 6.80; 95% CI 2.18 – 21.18; P <0.01), Acute Kidney Injury (AOR: 6.47;\u000095% CI 1.77 – 23.64; P <0.01), and Model for End–Stage Liver Disease– Sodium (MELD–Na) Score\u0000(AOR: 1.17; 95% CI 1.05 – 1.30; P: 0.02), were found to be predictors of in–hospital mortality.\u0000Conclusion: In–hospital mortality of cirrhotic patients is high in Ethiopia. West Haven grade III or IV\u0000hepatic encephalopathy is the leading cause of mortality. Hence, Prompt identification and\u0000management of hepatic encephalopathy and its precipitant at an earlier stage is crucial for better\u0000treatment outcomes and survival.\u0000Keywords: Cirrhosis, In–hospital mortality, Ethiopia","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777559","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 : 2024-07-25DOI: 10.1101/2024.07.18.24310647
Thomas Wallach, Ahmed Soliman, John Agboola, Shagun Sharma, Lais Araujo Coelho, Meredith Pittman, Christos Chatzinakos, Sergios-Orestis Kolokotronis
Abstract Long COVID (LC) remains an ongoing issue and one which has created a substantial burden of disease. Gastrointestinal LC is relatively poorly understood. In this study we characterize a syndrome of persistent SARS-CoV2 viral material via clinical and histologic data, and RNA sequencing Methods We reviewed patients aged 5-22 years with an esophagogastroduodenoscopy (EGD) for gastrointestinal (GI) symptoms from 6/2020-6/2023, excluding patients with known histologic disease. Biopsies were sent for immunohistochemical staining. Clinical data was collected. Duodenal, ileal, cecal, and sigmoid colon samples were stained for SARS-CoV-2 using a SARS-CoV-2 nucleocapsid antibody. Slides were reviewed by a blinded pathologist. 8 patients with known duodenal SARS-CoV-2 nucleocapsid antigen (SC-NA) positivity and 8 demographically matched IBS matched patients from prior to 2020 were identified for RNA sequencing comparison. Results were compared with public data from the Gene Expression Omnibus (GEO) data repository for intestinal tissue with IBS and epithelial tissues with active SARS-CoV2 infection. Results Of 30 patients, fifteen (50%) were identified to have positive SC-NA . 3 (20%) had received at least a single SARS-CoV2 vaccine in the + cohort, and 8 (53.3%) in the - (P=0.05). Primary symptoms were pain (86%, nausea (66.6%), and weight loss (60%). 37.5% of patients with colonic SC-NA displayed hematochezia. 33% of + patients showed elevated ESR/CRP. Mean + calprotectin was 317.3 vs. 156.4 (p=0.2). 11/15 (73.3%) +SC-NA had large lymphoid aggregates (LLA) (p = 0.00338). RNA expression was consistent with known acute SARS-CoV2 infection. Hub network analysis showed a tight shift in RNA expression centered around HSPE-1p26, with involvement of known SARS-CoV2 immune mediators like NEAT1. DGE comparative analysis with IBS and acute SARS-CoV2 infection showed higher overlap with acute infection vs. IBS. FGSEA analysis with the same source data demonstrated the same. Conclusions Our findings establish a syndrome mediated by persistent viral infection (SARS-CoV2 Persistent Intestinal Epithelial Syndrome (SPIES)). We hypothesize that persistent sparse infection drives ongoing immune signaling altering movement and function, creating epithelial and movement effects overlapping with DGBI and IBD
{"title":"Identification of SARS-CoV-2 Persistent Intestinal Epithelial Syndrome (SPIES) as a Novel Disease Entity using Clinical, Histologic, and RNA Programmatic Data","authors":"Thomas Wallach, Ahmed Soliman, John Agboola, Shagun Sharma, Lais Araujo Coelho, Meredith Pittman, Christos Chatzinakos, Sergios-Orestis Kolokotronis","doi":"10.1101/2024.07.18.24310647","DOIUrl":"https://doi.org/10.1101/2024.07.18.24310647","url":null,"abstract":"Abstract Long COVID (LC) remains an ongoing issue and one which has created a substantial burden of disease. Gastrointestinal LC is relatively poorly understood. In this study we characterize a syndrome of persistent SARS-CoV2 viral material via clinical and histologic data, and RNA sequencing\u0000Methods\u0000We reviewed patients aged 5-22 years with an esophagogastroduodenoscopy (EGD) for gastrointestinal (GI) symptoms from 6/2020-6/2023, excluding patients with known histologic disease. Biopsies were sent for immunohistochemical staining. Clinical data was collected. Duodenal, ileal, cecal, and sigmoid colon samples were stained for SARS-CoV-2 using a SARS-CoV-2 nucleocapsid antibody. Slides were reviewed by a blinded pathologist. 8 patients with known duodenal SARS-CoV-2 nucleocapsid antigen (SC-NA) positivity and 8 demographically matched IBS matched patients from prior to 2020 were identified for RNA sequencing comparison. Results were compared with public data from the Gene Expression Omnibus (GEO) data repository for intestinal tissue with IBS and epithelial tissues with active SARS-CoV2 infection.\u0000Results\u0000Of 30 patients, fifteen (50%) were identified to have positive SC-NA . 3 (20%) had received at least a single SARS-CoV2 vaccine in the + cohort, and 8 (53.3%) in the - (P=0.05). Primary symptoms were pain (86%, nausea (66.6%), and weight loss (60%). 37.5% of patients with colonic SC-NA displayed hematochezia. 33% of + patients showed elevated ESR/CRP. Mean + calprotectin was 317.3 vs. 156.4 (p=0.2). 11/15 (73.3%) +SC-NA had large lymphoid aggregates (LLA) (p = 0.00338). RNA expression was consistent with known acute SARS-CoV2 infection. Hub network analysis showed a tight shift in RNA expression centered around HSPE-1p26, with involvement of known SARS-CoV2 immune mediators like NEAT1. DGE comparative analysis with IBS and acute SARS-CoV2 infection showed higher overlap with acute infection vs. IBS. FGSEA analysis with the same source data demonstrated the same.\u0000Conclusions\u0000Our findings establish a syndrome mediated by persistent viral infection (SARS-CoV2 Persistent Intestinal Epithelial Syndrome (SPIES)). We hypothesize that persistent sparse infection drives ongoing immune signaling altering movement and function, creating epithelial and movement effects overlapping with DGBI and IBD","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777560","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 : 2024-07-25DOI: 10.1101/2024.07.25.24310949
Vincent W Joustra, Andrew Yung Fong Li Yim, Peter Henneman, Ishtu L Hageman, Tristan de Waard, Evgeni Levin, Alexandra Noble, Thomas P Chapman, Femke Mol, Sarah van Zon, Donghyeok Lee, Colleen GC McGregor, Alex T Adams, Jack J Satsangi, Wouter J de Jonge, Geert R D'Haens, EPIC-CD Consortium
Biological therapeutics are now widely used in Crohn′s disease (CD), with evidence of efficacy from randomized trials and real-world experience. Primary non-response is a common, poorly understood problem. We assessed blood methylation as a predictor of response to vedolizumab (VDZ, anti-a4b7 integrin) or ustekinumab (USTE, anti-IL-12/23p40). We report a two-center, prospective cohort study in which we profiled the peripheral blood DNA methylome of 184 adult male and female CD patients prior to and during treatment with VDZ or USTE in a discovery (n=126) and an external validation cohort (n=58). We defined epigenetic biomarkers that were stable over time and associated with combined clinical and endoscopic response to VDZ or USTE with an area under curve (AUC) of 0.87 and 0.89, respectively. We validated these models in an external cohort yielding an AUC of 0.75 for both VDZ and USTE. These data will now be prospectively tested in a multicenter randomized clinical trial.
目前，生物疗法已广泛应用于克罗恩病（CD）的治疗，随机试验和实际经验都证明了其疗效。原发性无应答是一个常见的问题，却鲜为人知。我们评估了血液甲基化作为对维妥珠单抗（VDZ，抗a4b7整合素）或乌斯特库单抗（USTE，抗IL-12/23p40）反应的预测因素。我们报告了一项双中心前瞻性队列研究，在发现队列（n=126）和外部验证队列（n=58）中，我们分析了184名成年男性和女性CD患者在接受VDZ或USTE治疗前和治疗期间的外周血DNA甲基组。我们定义了表观遗传生物标志物，这些标志物随时间变化稳定，并与 VDZ 或 USTE 的临床和内镜综合反应相关，其曲线下面积 (AUC) 分别为 0.87 和 0.89。我们在外部队列中验证了这些模型，结果显示 VDZ 和 USTE 的曲线下面积均为 0.75。现在，我们将在一项多中心随机临床试验中对这些数据进行前瞻性测试。
{"title":"Peripheral blood DNA methylation signatures predict response to vedolizumab and ustekinumab in adult patients with Crohn's disease: The EPIC-CD study","authors":"Vincent W Joustra, Andrew Yung Fong Li Yim, Peter Henneman, Ishtu L Hageman, Tristan de Waard, Evgeni Levin, Alexandra Noble, Thomas P Chapman, Femke Mol, Sarah van Zon, Donghyeok Lee, Colleen GC McGregor, Alex T Adams, Jack J Satsangi, Wouter J de Jonge, Geert R D'Haens, EPIC-CD Consortium","doi":"10.1101/2024.07.25.24310949","DOIUrl":"https://doi.org/10.1101/2024.07.25.24310949","url":null,"abstract":"Biological therapeutics are now widely used in Crohn′s disease (CD), with evidence of efficacy from randomized trials and real-world experience. Primary non-response is a common, poorly understood problem. We assessed blood methylation as a predictor of response to vedolizumab (VDZ, anti-a4b7 integrin) or ustekinumab (USTE, anti-IL-12/23p40). We report a two-center, prospective cohort study in which we profiled the peripheral blood DNA methylome of 184 adult male and female CD patients prior to and during treatment with VDZ or USTE in a discovery (n=126) and an external validation cohort (n=58). We defined epigenetic biomarkers that were stable over time and associated with combined clinical and endoscopic response to VDZ or USTE with an area under curve (AUC) of 0.87 and 0.89, respectively. We validated these models in an external cohort yielding an AUC of 0.75 for both VDZ and USTE. These data will now be prospectively tested in a multicenter randomized clinical trial.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777561","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 : 2024-07-24DOI: 10.1101/2024.07.23.24310327
Philipp Rausch, Ilka Ratjen, Lukas Tittmann, Janna Enderle, Eike Matthias Wacker, Kathrin Jaeger, Malte Christoph Ruehlemann, Pierre Ellul, Robert Kruse, Jonas Halfvarsson, Dirk Roggenbuck, David Ellinghaus, Gunnar Jacobs, Michael Krawczak, Stefan Schreiber, Corinna Bang, Wolfgang Lieb, Andre Franke
Background: The prospective Kiel Inflammatory Bowel Disease (IBD) Family Cohort Study (KINDRED cohort) was initiated in 2013 to systematically and extensively collect data and biosamples from index IBD patients and their relatives (e.g., blood, stool), a population at high risk for IBD development. Regular follow-ups were conducted to collect updated health and lifestyle information, to obtain new biosamples, and to capture the incidence of IBD during development. By combining taxonomic and imputed functional microbial data collected at successive time points with extensive anthropometric, medical, nutritional, and social information, this study aimed to characterize the factors influencing the microbiota in health and disease via detailed ecological analyses. Results: Using two dysbiosis metrics (MD-index, GMHI) trained on the German KINDRED cohort, we identified strong and generalizable gradients within and across different IBD cohorts, which correspond strongly with IBD pathologies, physiological manifestations of inflammation (e.g., Bristol stool score, ASCA IgA/IgG), genetic risk for IBD, and general risk of disease onset. Anthropometric and medical factors influencing transit time strongly modify bacterial communities. Various Enterobacteriaceae (e.g., Klebsiella sp.) and opportunistic Clostridia pathogens (e.g., C. XIVa clostridioforme), characterize in combination with ectopic oral taxa (e.g. Veillonella sp., Cand. Saccharibacteria sp., Fusobacterium nucleatum) the distinct and chaotic IBD-specific communities. Functionally, amino acid metabolism and flagellar assembly are beneficial, while mucolytic functions are associated with IBD. Conclusions: Our findings demonstrate broad-scale ecological patterns which indicate drastic state transitions of communities into characteristically chaotic communities in IBD patients. These patterns appear to be universal across cohorts and influence physiological signs of inflammation, display high resilience, but show only little heritability/intrafamily transmission.
{"title":"First Insights into microbial changes within an Inflammatory Bowel Disease Family Cohort study","authors":"Philipp Rausch, Ilka Ratjen, Lukas Tittmann, Janna Enderle, Eike Matthias Wacker, Kathrin Jaeger, Malte Christoph Ruehlemann, Pierre Ellul, Robert Kruse, Jonas Halfvarsson, Dirk Roggenbuck, David Ellinghaus, Gunnar Jacobs, Michael Krawczak, Stefan Schreiber, Corinna Bang, Wolfgang Lieb, Andre Franke","doi":"10.1101/2024.07.23.24310327","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310327","url":null,"abstract":"Background: The prospective Kiel Inflammatory Bowel Disease (IBD) Family Cohort Study (KINDRED cohort) was initiated in 2013 to systematically and extensively collect data and biosamples from index IBD patients and their relatives (e.g., blood, stool), a population at high risk for IBD development. Regular follow-ups were conducted to collect updated health and lifestyle information, to obtain new biosamples, and to capture the incidence of IBD during development. By combining taxonomic and imputed functional microbial data collected at successive time points with extensive anthropometric, medical, nutritional, and social information, this study aimed to characterize the factors influencing the microbiota in health and disease via detailed ecological analyses.\u0000Results: Using two dysbiosis metrics (MD-index, GMHI) trained on the German KINDRED cohort, we identified strong and generalizable gradients within and across different IBD cohorts, which correspond strongly with IBD pathologies, physiological manifestations of inflammation (e.g., Bristol stool score, ASCA IgA/IgG), genetic risk for IBD, and general risk of disease onset. Anthropometric and medical factors influencing transit time strongly modify bacterial communities. Various Enterobacteriaceae (e.g., Klebsiella sp.) and opportunistic Clostridia pathogens (e.g., C. XIVa clostridioforme), characterize in combination with ectopic oral taxa (e.g. Veillonella sp., Cand. Saccharibacteria sp., Fusobacterium nucleatum) the distinct and chaotic IBD-specific communities. Functionally, amino acid metabolism and flagellar assembly are beneficial, while mucolytic functions are associated with IBD. Conclusions: Our findings demonstrate broad-scale ecological patterns which indicate drastic state transitions of communities into characteristically chaotic communities in IBD patients. These patterns appear to be universal across cohorts and influence physiological signs of inflammation, display high resilience, but show only little heritability/intrafamily transmission.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"132 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777563","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 : 2024-07-24DOI: 10.1101/2024.07.23.24310846
António José Preto, Shaurya Chanana, Daniel Ence, Matt D Healy, Daniel Domingo-Fernández, Kiana A West
Objective: In this work, we explored one of the largest multi-omics cohorts in Inflammatory Bowel Disease (IBD), the Study of a Prospective Adult Research Cohort (SPARC IBD), with the goal of identifying predictive biomarkers for Crohn's Disease (CD) and Ulcerative Colitis (UC) and elucidating patient subtypes. Design: We analyzed genomics, transcriptomics (gut biopsy samples), and proteomics (blood plasma) from hundreds of patients from SPARC IBD. We trained a machine learning model that classifies UC vs. CD samples. In parallel, we leveraged multi-omics data integration to unveil patient subgroups in each of the two indications independently and analyzed the molecular phenotypes of these patient subpopulations. Results: The high performance of the model showed that multi-omics signatures are able to discriminate between the two indications. The most predictive features of the model, both known and novel omics signatures for IBD, can potentially be used as diagnostic biomarkers. Patient subgroups analysis in each indication uncovered omics features associated with disease severity in UC patients, and with tissue inflammation in CD patients. This culminates with the observation of two CD subpopulations characterized by distinct inflammation profiles. Conclusion: Our work unveiled potential biomarkers to discriminate between CD and UC and to stratify each population into well-defined subgroups, offering promising avenues for the application of precision medicine strategies.
研究目的在这项研究中，我们探索了炎症性肠病（IBD）领域最大的多组学队列之一--前瞻性成人研究队列（SPARC IBD），目的是确定克罗恩病（CD）和溃疡性结肠炎（UC）的预测性生物标记物，并阐明患者亚型。设计：我们分析了数百名 SPARC IBD 患者的基因组学、转录组学（肠道活检样本）和蛋白质组学（血浆）。我们训练了一个机器学习模型来对 UC 与 CD 样本进行分类。与此同时，我们利用多组学数据整合技术揭示了这两种适应症各自独立的患者亚群，并分析了这些患者亚群的分子表型：该模型的高性能表明，多组学特征能够区分两种适应症。该模型最具预测性的特征，包括已知的和新的IBD组学特征，都有可能被用作诊断生物标志物。每个适应症的患者亚组分析发现了与 UC 患者疾病严重程度和 CD 患者组织炎症相关的全局组学特征。最终，我们观察到了两个以不同炎症特征为特征的 CD 亚群：我们的研究揭示了区分 CD 和 UC 的潜在生物标志物，并将两种人群划分为定义明确的亚组，为精准医疗策略的应用提供了前景广阔的途径。
{"title":"Multi-omics data integration identifies novel biomarkers and patient subgroups in inflammatory bowel disease","authors":"António José Preto, Shaurya Chanana, Daniel Ence, Matt D Healy, Daniel Domingo-Fernández, Kiana A West","doi":"10.1101/2024.07.23.24310846","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310846","url":null,"abstract":"Objective: In this work, we explored one of the largest multi-omics cohorts in Inflammatory Bowel Disease (IBD), the Study of a Prospective Adult Research Cohort (SPARC IBD), with the goal of identifying predictive biomarkers for Crohn's Disease (CD) and Ulcerative Colitis (UC) and elucidating patient subtypes. Design: We analyzed genomics, transcriptomics (gut biopsy samples), and proteomics (blood plasma) from hundreds of patients from SPARC IBD. We trained a machine learning model that classifies UC vs. CD samples. In parallel, we leveraged multi-omics data integration to unveil patient subgroups in each of the two indications independently and analyzed the molecular phenotypes of these patient subpopulations.\u0000Results: The high performance of the model showed that multi-omics signatures are able to discriminate between the two indications. The most predictive features of the model, both known and novel omics signatures for IBD, can potentially be used as diagnostic biomarkers. Patient subgroups analysis in each indication uncovered omics features associated with disease severity in UC patients, and with tissue inflammation in CD patients. This culminates with the observation of two CD subpopulations characterized by distinct inflammation profiles.\u0000Conclusion: Our work unveiled potential biomarkers to discriminate between CD and UC and to stratify each population into well-defined subgroups, offering promising avenues for the application of precision medicine strategies.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777562","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 : 2024-07-23DOI: 10.1101/2024.07.22.24310788
Ashley G Pereira, Lily Fu, William Xu, Armen Gharibans, Gregory O'Grady
Functional Gastrointestinal Disorders (FGID) are a group of symptom-based disorders that occur across the alimentary tract and have a high prevalence globally in both adults and children. These symptoms are chronic and/or recurrent and often have substantial effects on quality of life. Their incidence is tied to multiple factors, including gut-brain axis imbalance, which includes autonomic dysregulation related to a relative withdrawal of vagal activity. Heart rate variability biofeedback (HRVB) is a non-invasive intervention that can influence autonomic activity and has shown benefit for diverse conditions including depression and anxiety, however the evidence of its effect has not yet been systematically assessed in FGIDs. This scoping review aimed to collate and evaluate the available literature regarding HRVB and FGIDs. We systematically searched four medical databases. Four articles met inclusion criteria for being interventional studies using HRVB in FGIDs. These were heterogeneous, including both paediatric and adult as well different subtypes of FGID. Two of the four studies demonstrated significant improvements from HRVB interventions in FGID symptoms while the other two found no significant difference. Scoping evaluation indicated this inconsistency likely reflects heterogeneous populations and study designs. Further scoping review of the broader HRVB literature also discovered that at least six weeks of HRVB is required to observe an impact on FGID symptoms and defined recommended guidance for performing future evaluations of HRVB in FGIDs. Evidence on HRVB for FGID is emergent, however HRVB appears a promising intervention when administered optimally. Further studies using best-practice techniques are required.
{"title":"The Effects of Heart Rate Variability Biofeedback on Functional Gastrointestinal Disorders: A Scoping Review","authors":"Ashley G Pereira, Lily Fu, William Xu, Armen Gharibans, Gregory O'Grady","doi":"10.1101/2024.07.22.24310788","DOIUrl":"https://doi.org/10.1101/2024.07.22.24310788","url":null,"abstract":"Functional Gastrointestinal Disorders (FGID) are a group of symptom-based disorders that occur across the alimentary tract and have a high prevalence globally in both adults and children. These symptoms are chronic and/or recurrent and often have substantial effects on quality of life. Their incidence is tied to multiple factors, including gut-brain axis imbalance, which includes autonomic dysregulation related to a relative withdrawal of vagal activity. Heart rate variability biofeedback (HRVB) is a non-invasive intervention that can influence autonomic activity and has shown benefit for diverse conditions including depression and anxiety, however the evidence of its effect has not yet been systematically assessed in FGIDs. This scoping review aimed to collate and evaluate the available literature regarding HRVB and FGIDs. We systematically searched four medical databases. Four articles met inclusion criteria for being interventional studies using HRVB in FGIDs. These were heterogeneous, including both paediatric and adult as well different subtypes of FGID. Two of the four studies demonstrated significant improvements from HRVB interventions in FGID symptoms while the other two found no significant difference. Scoping evaluation indicated this inconsistency likely reflects heterogeneous populations and study designs. Further scoping review of the broader HRVB literature also discovered that at least six weeks of HRVB is required to observe an impact on FGID symptoms and defined recommended guidance for performing future evaluations of HRVB in FGIDs. Evidence on HRVB for FGID is emergent, however HRVB appears a promising intervention when administered optimally. Further studies using best-practice techniques are required.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777564","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 : 2024-07-23DOI: 10.1101/2024.07.23.24310848
Amber Bangma, Paola Pibiri, Sofie de Jong, Emilia V. Bigaeva, Gwenny M.P.J. Verstappen, Gursah Kats-Urgulu, Marcela A. Hermoso, Monique G.P. van der Wijst, Johannes R. Bjork, Shiqiang Sun, Naomi Karmi, Frans G.M. Kroese, Arnau Vich Vila, Klaas Nico Faber, Rinse K. Weersma, Werna T.C. Uniken Venema, Eleonora A.M. Festen
Background and aims Primary sclerosing cholangitis (PSC) is an inflammatory disorder of the bile ducts, often accompanied by inflammatory bowel disease (PSC-IBD). Substantial differences in clinical presentation are observed between PSC-IBD and ulcerative colitis (UC). In this study we aim to find distinct pathomechanisms for PSC-IBD using single-cell mRNA sequencing. Methods Forty-seven colonic mucosal biopsies of PSC-IBD (n=24), UC (n=18) (where possible matched inflamed (I) non-inflamed (NI)), and non-IBD subjects (n=5) were collected and dissociated. Library preparation and processing for sequencing was followed by differential abundance, differential expression, and cell-cell-interaction analyses. Stainings for DUOX2 and HLA-DR were applied on tissue sections. Results In total, 71,798 cells comprised 54 distinct cell types, including a new cell type: the DUOX2+ enterocyte, mainly present in inflamed colon and acting as antigen presenting cells (HLA-DR+). Stem cells exhibited increased abundances in PSC-NI but not in UC-NI. Additionally, we found distinct gene expression profiles in PSC and UC which were related to inflammation: while mainly inflammatory monocytes were activated in PSC inflammation, and inflammatory fibroblasts were activated in UC inflammation. Conclusion Our study found a new cell type, the DUOX2+ enterocyte that is primarily present in inflamed conditions, and based on their expression profile, potentially perform antigen presentation. Moreover, we highlight that PSC-IBD, but not UC, is characterized by the activation of inflammatory HLA-DRB1+ monocytes, which are likely involved in the activation of CD4+ T cells. Notably, we observed an increased abundance of stem cells in non-inflamed PSC-IBD, possibly linked to the elevated risk of colorectal cancer in PSC-IBD.
{"title":"Inflammatory Bowel Disease in patients with Primary Sclerosing Cholangitis: a distinct form of colitis","authors":"Amber Bangma, Paola Pibiri, Sofie de Jong, Emilia V. Bigaeva, Gwenny M.P.J. Verstappen, Gursah Kats-Urgulu, Marcela A. Hermoso, Monique G.P. van der Wijst, Johannes R. Bjork, Shiqiang Sun, Naomi Karmi, Frans G.M. Kroese, Arnau Vich Vila, Klaas Nico Faber, Rinse K. Weersma, Werna T.C. Uniken Venema, Eleonora A.M. Festen","doi":"10.1101/2024.07.23.24310848","DOIUrl":"https://doi.org/10.1101/2024.07.23.24310848","url":null,"abstract":"Background and aims\u0000Primary sclerosing cholangitis (PSC) is an inflammatory disorder of the bile ducts, often accompanied by inflammatory bowel disease (PSC-IBD). Substantial differences in clinical presentation are observed between PSC-IBD and ulcerative colitis (UC). In this study we aim to find distinct pathomechanisms for PSC-IBD using single-cell mRNA sequencing. Methods\u0000Forty-seven colonic mucosal biopsies of PSC-IBD (n=24), UC (n=18) (where possible matched inflamed (I) non-inflamed (NI)), and non-IBD subjects (n=5) were collected and dissociated. Library preparation and processing for sequencing was followed by differential abundance, differential expression, and cell-cell-interaction analyses. Stainings for DUOX2 and HLA-DR were applied on tissue sections. Results\u0000In total, 71,798 cells comprised 54 distinct cell types, including a new cell type: the DUOX2+ enterocyte, mainly present in inflamed colon and acting as antigen presenting cells (HLA-DR+). Stem cells exhibited increased abundances in PSC-NI but not in UC-NI. Additionally, we found distinct gene expression profiles in PSC and UC which were related to inflammation: while mainly inflammatory monocytes were activated in PSC inflammation, and inflammatory fibroblasts were activated in UC inflammation. Conclusion\u0000Our study found a new cell type, the DUOX2+ enterocyte that is primarily present in inflamed conditions, and based on their expression profile, potentially perform antigen presentation. Moreover, we highlight that PSC-IBD, but not UC, is characterized by the activation of inflammatory HLA-DRB1+ monocytes, which are likely involved in the activation of CD4+ T cells. Notably, we observed an increased abundance of stem cells in non-inflamed PSC-IBD, possibly linked to the elevated risk of colorectal cancer in PSC-IBD.","PeriodicalId":501258,"journal":{"name":"medRxiv - Gastroenterology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777426","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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