{"title":"食管微生物群的改变与 Th17 免疫反应以及贲门失弛缓症 LC20 磷酸化受损之间的相互作用。","authors":"Hiroko Ikeda, Eikichi Ihara, Kosuke Takeya, Koji Mukai, Manabu Onimaru, Kenoki Ouchida, Yoshitaka Hata, Xiaopeng Bai, Yoshimasa Tanaka, Taisuke Sasaki, Fumiyo Saito, Masumi Eto, Jiro Nakayama, Yoshinao Oda, Masafumi Nakamura, Haruhiro Inoue, Yoshihiro Ogawa","doi":"10.1007/s00535-024-02088-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Achalasia is an esophageal motility disorder with an unknown etiology. We aimed to determine the pathogenesis of achalasia by studying alterations in esophageal smooth muscle contraction and the associated inflammatory response, and evaluate the role of esophageal microbiota in achalasia development.</p><p><strong>Methods: </strong>We analyzed esophageal mucosa and lower esophageal sphincter (LES) samples, obtained from patients with type II achalasia who underwent peroral endoscopic myotomy. Esophageal conditioned media obtained from patients were transferred into the mouse esophagus to determine whether the esophageal intraluminal environment is associated with achalasia.</p><p><strong>Results: </strong>Approximately 30% of 20-kDa myosin light chains (LC<sub>20</sub>) was phosphorylated in LES from the control group under resting and stimulated conditions, whereas less than 10% of LC<sub>20</sub> phosphorylation was detected in achalasia under all conditions. The hypophosphorylation of LC<sub>20</sub> in achalasia was associated with the downregulation of the myosin phosphatase-inhibitor protein CPI-17. Th17-related cytokines, including IL-17A, IL-17F, IL-22, and IL-23A, were significantly upregulated in achalasia. α-Diversity index of esophageal microbiota and the proportion of several microbes, including Actinomyces and Dialister, increased in achalasia. Actinomyces levels positively correlated with IL-23A levels, whereas Dialister levels were positively associated with IL-17A, IL-17F, and IL-22 levels. Esophageal IL-17F levels increased in mice after oral administration of the conditioned media.</p><p><strong>Conclusions: </strong>In LES of patients with achalasia, hypophosphorylation of LC<sub>20</sub>, a possible cause of impaired contractility, was associated with CPI-17 downregulation and an increased Th17-related immune response. The esophageal intraluminal environment, represented by the esophageal microbiota, could be associated with the development and exacerbation of achalasia.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"361-375"},"PeriodicalIF":6.9000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The interplay between alterations in esophageal microbiota associated with Th17 immune response and impaired LC20 phosphorylation in achalasia.\",\"authors\":\"Hiroko Ikeda, Eikichi Ihara, Kosuke Takeya, Koji Mukai, Manabu Onimaru, Kenoki Ouchida, Yoshitaka Hata, Xiaopeng Bai, Yoshimasa Tanaka, Taisuke Sasaki, Fumiyo Saito, Masumi Eto, Jiro Nakayama, Yoshinao Oda, Masafumi Nakamura, Haruhiro Inoue, Yoshihiro Ogawa\",\"doi\":\"10.1007/s00535-024-02088-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Achalasia is an esophageal motility disorder with an unknown etiology. We aimed to determine the pathogenesis of achalasia by studying alterations in esophageal smooth muscle contraction and the associated inflammatory response, and evaluate the role of esophageal microbiota in achalasia development.</p><p><strong>Methods: </strong>We analyzed esophageal mucosa and lower esophageal sphincter (LES) samples, obtained from patients with type II achalasia who underwent peroral endoscopic myotomy. Esophageal conditioned media obtained from patients were transferred into the mouse esophagus to determine whether the esophageal intraluminal environment is associated with achalasia.</p><p><strong>Results: </strong>Approximately 30% of 20-kDa myosin light chains (LC<sub>20</sub>) was phosphorylated in LES from the control group under resting and stimulated conditions, whereas less than 10% of LC<sub>20</sub> phosphorylation was detected in achalasia under all conditions. The hypophosphorylation of LC<sub>20</sub> in achalasia was associated with the downregulation of the myosin phosphatase-inhibitor protein CPI-17. Th17-related cytokines, including IL-17A, IL-17F, IL-22, and IL-23A, were significantly upregulated in achalasia. α-Diversity index of esophageal microbiota and the proportion of several microbes, including Actinomyces and Dialister, increased in achalasia. Actinomyces levels positively correlated with IL-23A levels, whereas Dialister levels were positively associated with IL-17A, IL-17F, and IL-22 levels. Esophageal IL-17F levels increased in mice after oral administration of the conditioned media.</p><p><strong>Conclusions: </strong>In LES of patients with achalasia, hypophosphorylation of LC<sub>20</sub>, a possible cause of impaired contractility, was associated with CPI-17 downregulation and an increased Th17-related immune response. The esophageal intraluminal environment, represented by the esophageal microbiota, could be associated with the development and exacerbation of achalasia.</p>\",\"PeriodicalId\":16059,\"journal\":{\"name\":\"Journal of Gastroenterology\",\"volume\":\" \",\"pages\":\"361-375\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2024-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Gastroenterology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00535-024-02088-w\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/3/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00535-024-02088-w","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/12 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景介绍贲门失弛缓症是一种病因不明的食管运动障碍。我们旨在通过研究食管平滑肌收缩和相关炎症反应的改变来确定贲门失弛缓症的发病机制，并评估食管微生物群在贲门失弛缓症发病中的作用：我们分析了食管粘膜和下食管括约肌（LES）样本，这些样本取自接受口腔内镜下肌切开术的 II 型贲门失弛缓症患者。将从患者处获得的食管条件培养基转移到小鼠食管中，以确定食管腔内环境是否与贲门失弛缓症有关：结果：在静息和刺激条件下，对照组 LES 中约有 30% 的 20-kDa 肌球蛋白轻链（LC20）被磷酸化，而在贲门失弛缓症患者中，在所有条件下检测到的 LC20 磷酸化均低于 10%。在贲门失弛缓症中，LC20的低磷酸化与肌球蛋白磷酸酶抑制蛋白CPI-17的下调有关。Th17相关细胞因子，包括IL-17A、IL-17F、IL-22和IL-23A，在贲门失弛缓症中显著上调。放线菌水平与 IL-23A 水平呈正相关，而 Dialister 水平与 IL-17A、IL-17F 和 IL-22 水平呈正相关。小鼠口服条件培养基后，食管 IL-17F 水平升高：结论：在贲门失弛缓症患者的 LES 中，LC20 的低磷酸化（可能是导致收缩力受损的原因之一）与 CPI-17 的下调和 Th17 相关免疫反应的增加有关。以食管微生物群为代表的食管腔内环境可能与贲门失弛缓症的发生和恶化有关。
The interplay between alterations in esophageal microbiota associated with Th17 immune response and impaired LC20 phosphorylation in achalasia.
Background: Achalasia is an esophageal motility disorder with an unknown etiology. We aimed to determine the pathogenesis of achalasia by studying alterations in esophageal smooth muscle contraction and the associated inflammatory response, and evaluate the role of esophageal microbiota in achalasia development.
Methods: We analyzed esophageal mucosa and lower esophageal sphincter (LES) samples, obtained from patients with type II achalasia who underwent peroral endoscopic myotomy. Esophageal conditioned media obtained from patients were transferred into the mouse esophagus to determine whether the esophageal intraluminal environment is associated with achalasia.
Results: Approximately 30% of 20-kDa myosin light chains (LC20) was phosphorylated in LES from the control group under resting and stimulated conditions, whereas less than 10% of LC20 phosphorylation was detected in achalasia under all conditions. The hypophosphorylation of LC20 in achalasia was associated with the downregulation of the myosin phosphatase-inhibitor protein CPI-17. Th17-related cytokines, including IL-17A, IL-17F, IL-22, and IL-23A, were significantly upregulated in achalasia. α-Diversity index of esophageal microbiota and the proportion of several microbes, including Actinomyces and Dialister, increased in achalasia. Actinomyces levels positively correlated with IL-23A levels, whereas Dialister levels were positively associated with IL-17A, IL-17F, and IL-22 levels. Esophageal IL-17F levels increased in mice after oral administration of the conditioned media.
Conclusions: In LES of patients with achalasia, hypophosphorylation of LC20, a possible cause of impaired contractility, was associated with CPI-17 downregulation and an increased Th17-related immune response. The esophageal intraluminal environment, represented by the esophageal microbiota, could be associated with the development and exacerbation of achalasia.
期刊介绍：
The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
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