Pub Date : 2024-09-18DOI: 10.1093/ecco-jcc/jjae146
Liesbeth Jozefien Munster, Aagje Johanna Martina Pronk, Marco William Mundt, Roel Hompes, Willem Adrianus Bemelman, Jarmila Dagmara Wendelien van der Bilt, Christianne Johanna Buskens
Background and aim This study aims to evaluate the effect of time to Crohn’s disease (CD) diagnosis on perianal fistula (PAF) outcomes in patients with a fistula as first manifesting sign. Methods In this multicenter, retrospective study, CD patients with a PAF preceding CD diagnosis between November 2015 and June 2022 were included. The primary outcome parameter was the time to CD diagnosis and its correlation with long-term outcomes. Results In total, 126 patients with a PAF prior to CD diagnosis were identified. Median time to CD diagnosis was 15.0 months (IQR 3.8-47.3). A total of 49 patients (38.9%) had a clinically closed fistula of which 21 patients (42.9%) achieved radiological healing. 25 patients (19.8%) underwent defunctioning, of which 9 patients (36.0%) needed proctectomy. Median time to CD diagnosis was shortest in patients with radiological healing (4.0 months, IQR 2.0-16.5) or clinical closure without radiological healing (11.0 months, IQR 3.0-47.8). In patients without fistula closure (n=51), median time to CD diagnosis was significantly longer compared to patients with fistula closure, 18.0 months vs 8.0 months (p=0.031). In patients who needed defunctioning, median time to diagnosis was more than twice as long compared to patients without defunctioning, 30.0 months vs 12.0 months (p=0.054). Conclusion A prolonged time to CD diagnosis in patients with a PAF as a manifesting sign is associated with worse long-term outcomes. Patients in whom radiological healing could be achieved had the shortest time to CD diagnosis, emphasizing the relevance of increased clinical awareness of underlying CD in fistula patients.
背景和目的 本研究旨在评估克罗恩病（CD）确诊时间对以肛瘘为首发表现的患者肛周瘘管（PAF）预后的影响。方法 在这项多中心回顾性研究中，纳入了在2015年11月至2022年6月期间确诊克罗恩病之前出现PAF的克罗恩病患者。主要结果参数是 CD 诊断时间及其与长期预后的相关性。结果 共发现 126 名患者在确诊 CD 之前出现过 PAF。确诊 CD 的中位时间为 15.0 个月（IQR 3.8-47.3）。共有 49 名患者（38.9%）的瘘管在临床上已经闭合，其中 21 名患者（42.9%）的瘘管在放射学上已经愈合。25名患者（19.8%）进行了功能障碍切除术，其中9名患者（36.0%）需要进行直肠切除术。在放射学愈合（4.0 个月，IQR 2.0-16.5）或临床闭合但放射学未愈合的患者中，CD 诊断的中位时间最短（11.0 个月，IQR 3.0-47.8）。在未关闭瘘管的患者中（n=51），CD 诊断的中位时间明显长于关闭瘘管的患者，前者为 18.0 个月，后者为 8.0 个月（p=0.031）。在需要关闭瘘管的患者中，诊断时间的中位数是未关闭瘘管患者的两倍多，分别为 30.0 个月对 12.0 个月（P=0.054）。结论 以 PAF 为表现体征的患者确诊 CD 的时间过长与较差的长期预后有关。能通过放射学检查获得愈合的患者确诊 CD 的时间最短，这强调了临床上提高对瘘管患者潜在 CD 的认识的重要性。
{"title":"Prolonged time to diagnosis of Crohn’s disease in patients with perianal fistulas negatively affects long-term outcomes","authors":"Liesbeth Jozefien Munster, Aagje Johanna Martina Pronk, Marco William Mundt, Roel Hompes, Willem Adrianus Bemelman, Jarmila Dagmara Wendelien van der Bilt, Christianne Johanna Buskens","doi":"10.1093/ecco-jcc/jjae146","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae146","url":null,"abstract":"Background and aim This study aims to evaluate the effect of time to Crohn’s disease (CD) diagnosis on perianal fistula (PAF) outcomes in patients with a fistula as first manifesting sign. Methods In this multicenter, retrospective study, CD patients with a PAF preceding CD diagnosis between November 2015 and June 2022 were included. The primary outcome parameter was the time to CD diagnosis and its correlation with long-term outcomes. Results In total, 126 patients with a PAF prior to CD diagnosis were identified. Median time to CD diagnosis was 15.0 months (IQR 3.8-47.3). A total of 49 patients (38.9%) had a clinically closed fistula of which 21 patients (42.9%) achieved radiological healing. 25 patients (19.8%) underwent defunctioning, of which 9 patients (36.0%) needed proctectomy. Median time to CD diagnosis was shortest in patients with radiological healing (4.0 months, IQR 2.0-16.5) or clinical closure without radiological healing (11.0 months, IQR 3.0-47.8). In patients without fistula closure (n=51), median time to CD diagnosis was significantly longer compared to patients with fistula closure, 18.0 months vs 8.0 months (p=0.031). In patients who needed defunctioning, median time to diagnosis was more than twice as long compared to patients without defunctioning, 30.0 months vs 12.0 months (p=0.054). Conclusion A prolonged time to CD diagnosis in patients with a PAF as a manifesting sign is associated with worse long-term outcomes. Patients in whom radiological healing could be achieved had the shortest time to CD diagnosis, emphasizing the relevance of increased clinical awareness of underlying CD in fistula patients.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259346","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 : 2024-09-14DOI: 10.1093/ecco-jcc/jjae148
Weicang Wang, Yuxin Wang, Katherine Z Sanidad, Yige Wang, Jianan Zhang, Wenqi Yang, Quancai Sun, Ipek Bayram, Renhua Song, Haixia Yang, David Johnson, Heather L Sherman, Daeyoung Kim, Lisa M Minter, Justin J-L Wong, Melody Y Zeng, Eric A Decker, Guodong Zhang
Background and Aims Human studies suggest that a high intake of polyunsaturated fatty acid (PUFA) is associated with an increased risk of inflammatory bowel disease (IBD). PUFA is highly prone to oxidation. To date, it is unclear whether unoxidized or oxidized PUFA is involved in the development of IBD. Here, we aim to compare the effects of unoxidized PUFA vs. oxidized PUFA on the development of IBD and associated colorectal cancer. Methods We evaluated the effects of unoxidized and oxidized PUFA on dextran sodium sulfate (DSS)- and IL-10 knockout-induced colitis, and azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice. Additionally, we studied the roles of gut microbiota and Toll-like receptor 4 (TLR4) signaling involved. Results Administration of a diet containing oxidized PUFA, at human consumption-relevant levels, increases the severity of colitis and exacerbates the development of colitis-associated colon tumorigenesis in mice. Conversely, a diet rich in unoxidized PUFA doesn’t promote colitis. Furthermore, oxidized PUFA worsens colitis-associated intestinal barrier dysfunction and leads to increased bacterial translocation, and it fails to promote colitis in Toll-like receptor 4 (TLR4) knockout mice. Finally, oxidized PUFA alters the diversity and composition of gut microbiota, and it fails to promote colitis in mice lacking the microbiota. Conclusions These results support that oxidized PUFA promotes the development of colitis and associated tumorigenesis in mouse models via TLR4- and gut microbiota-dependent mechanisms. Our findings highlight the potential need to update regulation policies and industrial standards for oxidized PUFA levels in food.
{"title":"Oxidized polyunsaturated fatty acid promotes colitis and colitis-associated tumorigenesis in mice","authors":"Weicang Wang, Yuxin Wang, Katherine Z Sanidad, Yige Wang, Jianan Zhang, Wenqi Yang, Quancai Sun, Ipek Bayram, Renhua Song, Haixia Yang, David Johnson, Heather L Sherman, Daeyoung Kim, Lisa M Minter, Justin J-L Wong, Melody Y Zeng, Eric A Decker, Guodong Zhang","doi":"10.1093/ecco-jcc/jjae148","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae148","url":null,"abstract":"Background and Aims Human studies suggest that a high intake of polyunsaturated fatty acid (PUFA) is associated with an increased risk of inflammatory bowel disease (IBD). PUFA is highly prone to oxidation. To date, it is unclear whether unoxidized or oxidized PUFA is involved in the development of IBD. Here, we aim to compare the effects of unoxidized PUFA vs. oxidized PUFA on the development of IBD and associated colorectal cancer. Methods We evaluated the effects of unoxidized and oxidized PUFA on dextran sodium sulfate (DSS)- and IL-10 knockout-induced colitis, and azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice. Additionally, we studied the roles of gut microbiota and Toll-like receptor 4 (TLR4) signaling involved. Results Administration of a diet containing oxidized PUFA, at human consumption-relevant levels, increases the severity of colitis and exacerbates the development of colitis-associated colon tumorigenesis in mice. Conversely, a diet rich in unoxidized PUFA doesn’t promote colitis. Furthermore, oxidized PUFA worsens colitis-associated intestinal barrier dysfunction and leads to increased bacterial translocation, and it fails to promote colitis in Toll-like receptor 4 (TLR4) knockout mice. Finally, oxidized PUFA alters the diversity and composition of gut microbiota, and it fails to promote colitis in mice lacking the microbiota. Conclusions These results support that oxidized PUFA promotes the development of colitis and associated tumorigenesis in mouse models via TLR4- and gut microbiota-dependent mechanisms. Our findings highlight the potential need to update regulation policies and industrial standards for oxidized PUFA levels in food.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259345","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 : 2024-09-11DOI: 10.1093/ecco-jcc/jjae145
Tommaso Lorenzo Parigi, Luca Massimino, Alfredo Carini, Roberto Gabbiadini, Peter Bertoli, Mariangela Allocca, Cristina Bezzio, Arianna Dal Buono, Ferdinando D’Amico, Federica Furfaro, Laura Loy, Alessandra Zilli, Federica Ungaro, Vipul Jairath, Laurent Peyrin-Biroulet, Alessandro Armuzzi, Silvio Danese
Background and Aim Criteria for "difficult-to-treat" Inflammatory Bowel Disease (IBD) (DTT-IBD) have recently been proposed to standardize terminology. We aimed to evaluate the prevalence, characteristics, management, and outcomes of DTT-IBD. Methods We conducted a retrospective study in two tertiary centers in Italy. Results Among 1736 IBD patients treated with biologics/advanced small molecules, 430 (24.8%) met at least one DTT-IBD criterion, of which 331 (77%) failed at least 2 mechanisms of action. In ulcerative colitis (UC), left-sided and extended colitis were risk factors for DTT compared to proctitis (OR 6.55, 1.93-40.98, p=0.011; and OR 10.12, 3.01-63.14, p=0.002, respectively). In Crohn’s disease (CD), multiple localizations (L3+L4) (OR 3.04, 1.09-8.34, p=0.03), stricturing (OR 2.24, 1.52-3.34, p<0.001) and penetrating (OR 2.33, 1.55-3.53, p<0.001) behaviors, and perianal disease (OR 2.49, 1.75-3.53, p<0.001) were the main risk factors for DTT. Delay in advanced treatment initiation was positively associated with DTT-CD (OR 1.74, 1.27–2.41 p=0.001) but protective in UC (OR 0.65, 0.45-0.93 p=0.019). The rates of symptomatic, biochemical, and endoscopic remission were lower in DTT-IBD compared to non-DTT-IBD. The difference was most evident for endoscopic remission (25% vs 62%). Drug persistency in each following line of treatment progressively decreased in CD and UC. All advanced drugs used in DTT-IBD had similar persistence. Conclusions DTT-IBD was prevalent in approximately one-quarter of patients with IBD in a tertiary care setting. Certain IBD phenotypes and the delay in initiating treatment in CD were risk factors for DTT. Drug persistency decreased progressively with every subsequent line of therapy.
{"title":"Prevalence, characteristics, management, and outcomes of difficult-to-treat inflammatory bowel disease","authors":"Tommaso Lorenzo Parigi, Luca Massimino, Alfredo Carini, Roberto Gabbiadini, Peter Bertoli, Mariangela Allocca, Cristina Bezzio, Arianna Dal Buono, Ferdinando D’Amico, Federica Furfaro, Laura Loy, Alessandra Zilli, Federica Ungaro, Vipul Jairath, Laurent Peyrin-Biroulet, Alessandro Armuzzi, Silvio Danese","doi":"10.1093/ecco-jcc/jjae145","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae145","url":null,"abstract":"Background and Aim Criteria for \"difficult-to-treat\" Inflammatory Bowel Disease (IBD) (DTT-IBD) have recently been proposed to standardize terminology. We aimed to evaluate the prevalence, characteristics, management, and outcomes of DTT-IBD. Methods We conducted a retrospective study in two tertiary centers in Italy. Results Among 1736 IBD patients treated with biologics/advanced small molecules, 430 (24.8%) met at least one DTT-IBD criterion, of which 331 (77%) failed at least 2 mechanisms of action. In ulcerative colitis (UC), left-sided and extended colitis were risk factors for DTT compared to proctitis (OR 6.55, 1.93-40.98, p=0.011; and OR 10.12, 3.01-63.14, p=0.002, respectively). In Crohn’s disease (CD), multiple localizations (L3+L4) (OR 3.04, 1.09-8.34, p=0.03), stricturing (OR 2.24, 1.52-3.34, p&lt;0.001) and penetrating (OR 2.33, 1.55-3.53, p&lt;0.001) behaviors, and perianal disease (OR 2.49, 1.75-3.53, p&lt;0.001) were the main risk factors for DTT. Delay in advanced treatment initiation was positively associated with DTT-CD (OR 1.74, 1.27–2.41 p=0.001) but protective in UC (OR 0.65, 0.45-0.93 p=0.019). The rates of symptomatic, biochemical, and endoscopic remission were lower in DTT-IBD compared to non-DTT-IBD. The difference was most evident for endoscopic remission (25% vs 62%). Drug persistency in each following line of treatment progressively decreased in CD and UC. All advanced drugs used in DTT-IBD had similar persistence. Conclusions DTT-IBD was prevalent in approximately one-quarter of patients with IBD in a tertiary care setting. Certain IBD phenotypes and the delay in initiating treatment in CD were risk factors for DTT. Drug persistency decreased progressively with every subsequent line of therapy.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259372","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 : 2024-09-10DOI: 10.1093/ecco-jcc/jjae135
Yue Cui, Marion David, Laura Bouchareychas, Sandrine Rouquier, Satria Sajuthi, Marion Ayrault, Candice Navarin, Gregory Lara, Audrey Lafon, Gaëlle Saviane, Sonia Boulakirba, Alexandra Menardi, Alexandra Demory, Jihane Frikeche, Stephanie de la Forest Divonne Beghelli, Hsiaomei Heidi Lu, Celine Dumont, Tobias Abel, David Fenard, Maurus de la Rosa, Julie Gertner-Dardenne
Background and Aims Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn’s disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. CAR (Chimeric Antigen Receptor) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, Interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD. Methods Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients. Results Our study showed that IL23R-CAR displayed negligible tonic signalling and strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation. Conclusions Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.
背景和目的 调节性 T 细胞（Tregs）是维持组织稳态的关键调节因子。免疫平衡的破坏与克罗恩病（CD）的发病机制有关。因此，Treg疗法是恢复病变肠道免疫平衡的一种前景广阔的长效疗法。CAR（嵌合抗原受体）T细胞疗法为癌症治疗带来了革命性的变化。这种创新方法也为改善 CD 的治疗提供了机会。通过靶向疾病相关蛋白--白细胞介素-23受体（IL23R），我们设计了表达IL23R-CAR的Tregs，用于治疗活动性CD。方法 通过免疫组化分析验证了活动性 CD 肠道 IL23R 的表达。通过体外实验评估了IL23R-CAR Tregs的表型和功能特征，并在异种移植肿瘤模型中监测了它们的迁移能力。针对活动性 CD 患者的结肠活检细胞，进行了转录组学和蛋白质组学分析，以将分子特征与 IL23R-CAR Treg 激活联系起来。结果 我们的研究表明，IL23R-CAR 的强直性信号可忽略不计，信噪比很高。即使长期暴露于促炎细胞因子和靶抗原，IL23R-CAR Tregs 在体外扩增过程中仍能保持调节表型。IL23R-CAR Tregs 上的 IL23R 可触发 CAR 特异性活化，并显著增强其抑制活性。此外，IL23R-CAR Tregs 还能迁移到人源化小鼠的 IL23R 表达组织中。最后，IL23R-CAR Tregs 对活动性 CD 的结肠活检衍生细胞产生了特异性激活，这表明 CAR 能有效参与活动性 CD。CD 患者活检组织的分子剖析也揭示了与 IL23R-CAR 激活相关的转录组和蛋白质组模式。结论 总体而言，我们的研究结果表明，IL23R-CAR Tregs 是一种治疗活动性 CD 的有前途的疗法。
{"title":"IL23R-specific CAR Tregs for the treatment of Crohn’s disease","authors":"Yue Cui, Marion David, Laura Bouchareychas, Sandrine Rouquier, Satria Sajuthi, Marion Ayrault, Candice Navarin, Gregory Lara, Audrey Lafon, Gaëlle Saviane, Sonia Boulakirba, Alexandra Menardi, Alexandra Demory, Jihane Frikeche, Stephanie de la Forest Divonne Beghelli, Hsiaomei Heidi Lu, Celine Dumont, Tobias Abel, David Fenard, Maurus de la Rosa, Julie Gertner-Dardenne","doi":"10.1093/ecco-jcc/jjae135","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae135","url":null,"abstract":"Background and Aims Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn’s disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. CAR (Chimeric Antigen Receptor) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, Interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD. Methods Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients. Results Our study showed that IL23R-CAR displayed negligible tonic signalling and strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation. Conclusions Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142213026","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 : 2024-05-04DOI: 10.1093/ecco-jcc/jjae061
David A Muñiz Pedrogo, Cynthia L Sears, Joanna M P Melia
The risk of colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD), particularly in extensive ulcerative colitis (UC) and Crohn’s colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and pro-inflammatory properties by organizing into biofilms, potentially making them more resistant to the host’s immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumor-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histologic inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. 5-aminosalicylates, commonly used in the treatment of UC, have antimicrobial and anti-carcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC via mechanisms independent of inflammation is still unknown. Further research is warranted to identify potential new microbial targets of therapy for chemoprevention of dysplasia and CRC in IBD.
{"title":"Colorectal cancer in inflammatory bowel disease: a review of the role of gut microbiota and bacterial biofilms in disease pathogenesis","authors":"David A Muñiz Pedrogo, Cynthia L Sears, Joanna M P Melia","doi":"10.1093/ecco-jcc/jjae061","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae061","url":null,"abstract":"The risk of colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD), particularly in extensive ulcerative colitis (UC) and Crohn’s colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and pro-inflammatory properties by organizing into biofilms, potentially making them more resistant to the host’s immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumor-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histologic inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. 5-aminosalicylates, commonly used in the treatment of UC, have antimicrobial and anti-carcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC via mechanisms independent of inflammation is still unknown. Further research is warranted to identify potential new microbial targets of therapy for chemoprevention of dysplasia and CRC in IBD.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832116","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 : 2024-05-02DOI: 10.1093/ecco-jcc/jjae060
Miguel Regueiro, Britta Siegmund, Andres J Yarur, Flavio Steinwurz, Krisztina B Gecse, Martina Goetsch, Abhishek Bhattacharjee, Joseph Wu, Jesse Green, Aoibhinn McDonnell, Catherine Crosby, Krisztina Lazin, Diogo Branquinho, Irene Modesto, Maria T Abreu
Background and Aims Infections are a safety concern in patients with ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration, and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE program. Methods Proportions, incidence rates (IRs; per 100 patient-years) and descriptive analyses of all, serious, severe, herpes zoster, and opportunistic infections are reported in the Pivotal UC cohort (ELEVATE UC 52 and ELEVATE UC 12). Cox regression models evaluated potential baseline risk factors. Results In this analysis (n=787), proportions (IRs) of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three (0.6%) and five (1.9%) patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group (etrasimod: 0.4%; placebo: 0.8%); all localized and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count (ALC) <0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. Conclusions Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC <0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterize the etrasimod safety profile.
{"title":"Etrasimod for the Treatment of Ulcerative Colitis: Analysis of Infection Events From the ELEVATE UC Clinical Program","authors":"Miguel Regueiro, Britta Siegmund, Andres J Yarur, Flavio Steinwurz, Krisztina B Gecse, Martina Goetsch, Abhishek Bhattacharjee, Joseph Wu, Jesse Green, Aoibhinn McDonnell, Catherine Crosby, Krisztina Lazin, Diogo Branquinho, Irene Modesto, Maria T Abreu","doi":"10.1093/ecco-jcc/jjae060","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae060","url":null,"abstract":"Background and Aims Infections are a safety concern in patients with ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration, and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE program. Methods Proportions, incidence rates (IRs; per 100 patient-years) and descriptive analyses of all, serious, severe, herpes zoster, and opportunistic infections are reported in the Pivotal UC cohort (ELEVATE UC 52 and ELEVATE UC 12). Cox regression models evaluated potential baseline risk factors. Results In this analysis (n=787), proportions (IRs) of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three (0.6%) and five (1.9%) patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group (etrasimod: 0.4%; placebo: 0.8%); all localized and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count (ALC) &lt;0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. Conclusions Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC &lt;0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterize the etrasimod safety profile.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831720","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 : 2024-05-01DOI: 10.1093/ecco-jcc/jjae064
Helena Tavares de Sousa, Marta Ferreira, Irene Gullo, Ana Mafalda Rocha, Ana Pedro, Dina Leitão, Carla Oliveira, Fátima Carneiro, Fernando Magro
Background and aims Stricturing (B2) and penetrating (B3) ileal Crohn’s disease have been reported to present similar levels of histopathological transmural fibrosis. This study aimed to compare the fibrosis-related transcriptomic profiles of penetrating and stricturing ileal Crohn’s disease. Methods Using Nanostring technology and comparative bioinformatics, we analyzed the expression of 787 fibrosis-related genes in 36 ileal surgical specimens, 12 B2 and 24 B3, the latter including 12 cases with associated stricture(s) (B3s) and 12 without (B3o). Quality control of extracted RNA was performed according to Nanostring parameters and principal component analysis for the distribution analysis. For the selection of the differentially expressed genes a p-adjusted <0.05 and Fold Change ≤-1.5 or ≥ 1.5 was adopted. qPCR and immunohistochemistry analyses were used to validate selected differentially expressed genes. Results We included 34 patients with B2 and B3 phenotypes, balanced for age at diagnosis, age at surgery, gender, Crohn’s disease localization, perianal disease and therapy. Inflammation and fibrosis histopathological scoring were similar in all cases. B2 and B3 groups showed a very good clustering regarding 30 significantly differentially expressed genes, all being remarkably upregulated in B3. More than half of these genes were involved in Crohn’s disease fibrogenesis, while eight differentially expressed genes were so in other organs. The most significantly active biologic processes and pathways in penetrating disease were response to TGFβand matrix organization and degradation, as validated by immunohistochemistry. Conclusions Despite the histopathological similarities in fibrosis between stricturing and penetrating ileal Crohn’s disease, their fibrosis-related transcriptomic profiles are distinct. Penetrating disease exhibits a distinctive transcriptomic landscape related to enhanced matrix remodeling.
{"title":"Fibrosis-related transcriptome unveils a distinctive remodeling matrix pattern in penetrating ileal Crohn's disease","authors":"Helena Tavares de Sousa, Marta Ferreira, Irene Gullo, Ana Mafalda Rocha, Ana Pedro, Dina Leitão, Carla Oliveira, Fátima Carneiro, Fernando Magro","doi":"10.1093/ecco-jcc/jjae064","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae064","url":null,"abstract":"Background and aims Stricturing (B2) and penetrating (B3) ileal Crohn’s disease have been reported to present similar levels of histopathological transmural fibrosis. This study aimed to compare the fibrosis-related transcriptomic profiles of penetrating and stricturing ileal Crohn’s disease. Methods Using Nanostring technology and comparative bioinformatics, we analyzed the expression of 787 fibrosis-related genes in 36 ileal surgical specimens, 12 B2 and 24 B3, the latter including 12 cases with associated stricture(s) (B3s) and 12 without (B3o). Quality control of extracted RNA was performed according to Nanostring parameters and principal component analysis for the distribution analysis. For the selection of the differentially expressed genes a p-adjusted &lt;0.05 and Fold Change ≤-1.5 or ≥ 1.5 was adopted. qPCR and immunohistochemistry analyses were used to validate selected differentially expressed genes. Results We included 34 patients with B2 and B3 phenotypes, balanced for age at diagnosis, age at surgery, gender, Crohn’s disease localization, perianal disease and therapy. Inflammation and fibrosis histopathological scoring were similar in all cases. B2 and B3 groups showed a very good clustering regarding 30 significantly differentially expressed genes, all being remarkably upregulated in B3. More than half of these genes were involved in Crohn’s disease fibrogenesis, while eight differentially expressed genes were so in other organs. The most significantly active biologic processes and pathways in penetrating disease were response to TGFβand matrix organization and degradation, as validated by immunohistochemistry. Conclusions Despite the histopathological similarities in fibrosis between stricturing and penetrating ileal Crohn’s disease, their fibrosis-related transcriptomic profiles are distinct. Penetrating disease exhibits a distinctive transcriptomic landscape related to enhanced matrix remodeling.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831793","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 : 2024-04-20DOI: 10.1093/ecco-jcc/jjae056
Matthew K Schroeder, Suha Abushamma, Alvin T George, Balakrishna Ravella, John Hickman, Anusha Elumalai, Paul Wise, Maria Zulfiqar, Daniel R Ludwig, Anup Shetty, Satish E Viswanath, Chongliang Luo, Shaji Sebastian, David H Ballard, Parakkal Deepak
Background and Aims Perianal fistulizing Crohn’s disease (PFCD) is an aggressive phenotype of Crohn’s disease defined by frequent relapses and disabling symptoms. A novel consensus classification system was recently outlined by the TOpCLASS consortium that seeks to unify disease severity with patient-centered goals but has not yet been validated. We aimed to apply this to a real-world cohort and identify factors that predict transition between classes over time. Methods We identified all patients with PFCD and at least one baseline and one follow-up pelvic (pMRI). TOpCLASS classification, disease characteristics, and imaging indices were collected retrospectively at time periods corresponding with respective MRIs. Results We identified 100 patients with PFCD of which 96 were assigned TOpCLASS Classes 1 – 2c at baseline. Most patients (78.1%) started in Class 2b, but changes in classification were observed in 52.1% of all patients. Male sex (72.0%, 46.6%, 40.0%, p = 0.03) and prior perianal surgery (52.0% vs 44.6% vs 40.0%, p = 0.02) were more frequently observed in those with improved class. Baseline pMRI indices were not associated with changes in classification, however, greater improvements in mVAI, MODIFI-CD, and PEMPAC were seen among those who improved. Linear mixed effect modeling identified only male sex (-0.31, 95% CI -0.60 to -0.02) with improvement in class. Conclusion The TOpCLASS classification highlights the dynamic nature of PFCD over time, however, our ability to predict transitions between classes remains limited and requires prospective assessment. Improvement in MRI index scores over time was associated with a transition to lower TOpCLASS classification.
{"title":"TOpCLASS Expert Consensus Classification of Perianal Fistulizing Crohn’s Disease: A Real-World Application in a Serial Fistula MRI Cohort","authors":"Matthew K Schroeder, Suha Abushamma, Alvin T George, Balakrishna Ravella, John Hickman, Anusha Elumalai, Paul Wise, Maria Zulfiqar, Daniel R Ludwig, Anup Shetty, Satish E Viswanath, Chongliang Luo, Shaji Sebastian, David H Ballard, Parakkal Deepak","doi":"10.1093/ecco-jcc/jjae056","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae056","url":null,"abstract":"Background and Aims Perianal fistulizing Crohn’s disease (PFCD) is an aggressive phenotype of Crohn’s disease defined by frequent relapses and disabling symptoms. A novel consensus classification system was recently outlined by the TOpCLASS consortium that seeks to unify disease severity with patient-centered goals but has not yet been validated. We aimed to apply this to a real-world cohort and identify factors that predict transition between classes over time. Methods We identified all patients with PFCD and at least one baseline and one follow-up pelvic (pMRI). TOpCLASS classification, disease characteristics, and imaging indices were collected retrospectively at time periods corresponding with respective MRIs. Results We identified 100 patients with PFCD of which 96 were assigned TOpCLASS Classes 1 – 2c at baseline. Most patients (78.1%) started in Class 2b, but changes in classification were observed in 52.1% of all patients. Male sex (72.0%, 46.6%, 40.0%, p = 0.03) and prior perianal surgery (52.0% vs 44.6% vs 40.0%, p = 0.02) were more frequently observed in those with improved class. Baseline pMRI indices were not associated with changes in classification, however, greater improvements in mVAI, MODIFI-CD, and PEMPAC were seen among those who improved. Linear mixed effect modeling identified only male sex (-0.31, 95% CI -0.60 to -0.02) with improvement in class. Conclusion The TOpCLASS classification highlights the dynamic nature of PFCD over time, however, our ability to predict transitions between classes remains limited and requires prospective assessment. Improvement in MRI index scores over time was associated with a transition to lower TOpCLASS classification.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629821","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 : 2024-04-18DOI: 10.1093/ecco-jcc/jjae052
Helen Burton-Murray, Katheryn Kiser, Jenny Gurung, Katherine Williams, Jennifer J Thomas, Hamed Khalili
Background and Aim Recent studies have shown that up to 53% of patients with inflammatory bowel disease (IBD) screen positive for avoidant/restrictive food intake disorder (ARFID). There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen (NIAS), and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 (EDE-Q8), to rule-out/characterize other eating disorder cognitive and behavioral symptoms. Methods Participants included adults with UC who are enrolled in an in an ongoing cohort study with quiescent UC (SCCAI ≤2 or fecal calprotectin <150 µg/g with corticosteroid-free clinical remission for ≥ 3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and other eating disorder symptom scores (8-item Eating Disorder Examination-Questionnaire; EDE-Q-8). Results We included 101 participants who completed the NIAS at their baseline cohort assessment (age 49.9±16.5 years; 55% female). Eleven participants (11%) screened positively for ARFID on at least one NIAS subscale (n=8 male). Up to thirty participants (30%) screened positive for other eating disorder symptoms (EDE-Q-8 Global ≥2.3). Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. Conclusions Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.
{"title":"Avoidant/restrictive food intake disorder symptoms are not as frequent as other eating disorder symptoms when ulcerative colitis is in remission","authors":"Helen Burton-Murray, Katheryn Kiser, Jenny Gurung, Katherine Williams, Jennifer J Thomas, Hamed Khalili","doi":"10.1093/ecco-jcc/jjae052","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae052","url":null,"abstract":"Background and Aim Recent studies have shown that up to 53% of patients with inflammatory bowel disease (IBD) screen positive for avoidant/restrictive food intake disorder (ARFID). There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen (NIAS), and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 (EDE-Q8), to rule-out/characterize other eating disorder cognitive and behavioral symptoms. Methods Participants included adults with UC who are enrolled in an in an ongoing cohort study with quiescent UC (SCCAI ≤2 or fecal calprotectin &lt;150 µg/g with corticosteroid-free clinical remission for ≥ 3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and other eating disorder symptom scores (8-item Eating Disorder Examination-Questionnaire; EDE-Q-8). Results We included 101 participants who completed the NIAS at their baseline cohort assessment (age 49.9±16.5 years; 55% female). Eleven participants (11%) screened positively for ARFID on at least one NIAS subscale (n=8 male). Up to thirty participants (30%) screened positive for other eating disorder symptoms (EDE-Q-8 Global ≥2.3). Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. Conclusions Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624258","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 : 2024-04-13DOI: 10.1093/ecco-jcc/jjae055
Margaret Brown, Anne Dodd, Fang Shi, Emily Greenwood, Sini Nagpal, Vasantha L Kolachala, Subra Kugathasan, Greg Gibson
Background and Aims Crohn’s disease is characterized by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn’s disease patients have revealed valuable insights into pathology, however have not been conducted jointly on less invasive peripheral blood mononuclear cells (PBMCs). Furthermore, the heterogeneous responses to treatments among individuals with Crohn’s disease imply hidden diversity of pathological mechanisms. Methods We employed single nucleus multiomic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source bioinformatics applications. Results Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signaling in two individuals with Crohn’s disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalized approach to understanding disease pathology. Conclusions This study highlights how multiomic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.
背景和目的 克罗恩病的特征是由遗传、免疫和环境因素共同导致的胃肠道炎症。克罗恩病患者肠道组织的转录组学和表观基因组学分析揭示了有价值的病理学观点，但尚未对侵入性较小的外周血单核细胞（PBMCs）进行联合分析。此外，克罗恩病患者对治疗的不同反应意味着病理机制隐藏的多样性。方法 我们采用了单核多组学分析方法，将外周血单核细胞的 snRNA-seq 和 snATAC-seq 与多种开源生物信息学应用结合起来。结果 我们的研究结果揭示了个体间多种多样的转录特征，突显了 PBMC 特征的异质性。然而，在 B 细胞和 T 细胞中观察到了三个异质性群体之间惊人的一致性。不同的基因调控机制部分解释了这些特征，特别是在两个患有克罗恩病的个体中发现了涉及 TGFß 信号转导的特征。一个突变映射到了一个转录因子结合位点上，该位点位于一个与该通路表达相关的可访问差异峰上，这对以个性化方法了解疾病病理具有重要意义。结论 本研究强调了多组学分析如何揭示导致 PBMC 特征异质性的共同调控机制，其中一种机制可能是炎症性疾病所特有的。
{"title":"Concordant B and T Cell Heterogeneity Inferred from the Multiomic Landscape of Peripheral Blood Mononuclear Cells in a Crohn’s Disease Cohort","authors":"Margaret Brown, Anne Dodd, Fang Shi, Emily Greenwood, Sini Nagpal, Vasantha L Kolachala, Subra Kugathasan, Greg Gibson","doi":"10.1093/ecco-jcc/jjae055","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae055","url":null,"abstract":"Background and Aims Crohn’s disease is characterized by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn’s disease patients have revealed valuable insights into pathology, however have not been conducted jointly on less invasive peripheral blood mononuclear cells (PBMCs). Furthermore, the heterogeneous responses to treatments among individuals with Crohn’s disease imply hidden diversity of pathological mechanisms. Methods We employed single nucleus multiomic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source bioinformatics applications. Results Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signaling in two individuals with Crohn’s disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalized approach to understanding disease pathology. Conclusions This study highlights how multiomic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596405","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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