Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease
ABSTRACTIntestinal epithelial cell (IEC) regulation of barrier function and mucosal homeostasis enables the establishment of a harmonious gut microenvironment. However, host-derived regulatory networks that modulate intestinal antimicrobial defenses have not been fully defined. Herein we generated m...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Gut Microbes |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19490976.2023.2257269 |
| _version_ | 1797320578520055808 |
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| author | Gengfeng Li Jian Lin Xiang Gao Huiling Su Ritian Lin Han Gao Zhongsheng Feng Huili Wu Baisui Feng Keqiang Zuo Yingchuan Li Wei Wu Leilei Fang Zhanju Liu |
| author_facet | Gengfeng Li Jian Lin Xiang Gao Huiling Su Ritian Lin Han Gao Zhongsheng Feng Huili Wu Baisui Feng Keqiang Zuo Yingchuan Li Wei Wu Leilei Fang Zhanju Liu |
| author_sort | Gengfeng Li |
| collection | DOAJ |
| description | ABSTRACTIntestinal epithelial cell (IEC) regulation of barrier function and mucosal homeostasis enables the establishment of a harmonious gut microenvironment. However, host-derived regulatory networks that modulate intestinal antimicrobial defenses have not been fully defined. Herein we generated mice with IEC-specific deletion of Gpr65 (Gpr65ΔIEC) and investigated the role of epithelial GPR65 using DSS- and C. rodentium-induced murine colitis models. RNA sequencing analysis was conducted on colonic IECs from Gpr65fl/fl and Gpr65ΔIEC mice, and colonoids and colonic epithelial cell lines were used to evaluate the pH-sensing effect of GPR65. The expression of GPR65 was determined in IECs from patients with inflammatory bowel disease (IBD) and DSS colitis mice by qRT-PCR, Western blot, and immunohistochemistry, respectively. We observed that the absence of GPR65 in IECs abrogated homeostatic antimicrobial programs, including the production of antimicrobial peptides (AMPs) and defense response-associated proteins. Gpr65ΔIEC mice displayed dysbiosis of the gut microbiota and were prone to DSS- and C. rodentium-induced colitis, as characterized by significantly disrupted epithelial antimicrobial responses, pathogen invasion, and increased inflammatory infiltrates in the inflamed colon. RNA sequencing analysis revealed that deletion of GPR65 in IECs provoked dramatic transcriptome changes with respect to the downregulation of immune and defense responses to bacteria. Forced AMP induction assays conducted in vivo or in ex vivo colonoids revealed that IEC-intrinsic GPR65 signaling drove antimicrobial defense. Mechanistically, GPR65 signaling promoted STAT3 phosphorylation to optimize mucosal defense responses. Epithelial cell line and colonoid assays further confirmed that epithelial GPR65 sensing pH synergized with IL-22 to facilitate antimicrobial responses. Finally, the expression of GPR65 was markedly decreased in the inflamed epithelia of IBD patients and DSS colitis mice. Our findings define an important role of epithelial GPR65 in regulating intestinal homeostasis and mucosal inflammation and point toward a potential therapeutic approach by targeting GPR65 in the treatment of IBD. |
| first_indexed | 2024-03-08T04:41:13Z |
| format | Article |
| id | doaj.art-b6d071b3a3144e2b808f120118e04a6e |
| institution | Directory Open Access Journal |
| issn | 1949-0976 1949-0984 |
| language | English |
| last_indexed | 2024-03-08T04:41:13Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Gut Microbes |
| spelling | doaj.art-b6d071b3a3144e2b808f120118e04a6e2024-02-08T12:02:07ZengTaylor & Francis GroupGut Microbes1949-09761949-09842023-12-0115210.1080/19490976.2023.2257269Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel diseaseGengfeng Li0Jian Lin1Xiang Gao2Huiling Su3Ritian Lin4Han Gao5Zhongsheng Feng6Huili Wu7Baisui Feng8Keqiang Zuo9Yingchuan Li10Wei Wu11Leilei Fang12Zhanju Liu13Center for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaDepartment of Gastroenterology, Linfen Central Hospital of Shanxi Medical University, Linfen, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaDepartment of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, ChinaDepartment of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaCenter for IBD Research, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, ChinaABSTRACTIntestinal epithelial cell (IEC) regulation of barrier function and mucosal homeostasis enables the establishment of a harmonious gut microenvironment. However, host-derived regulatory networks that modulate intestinal antimicrobial defenses have not been fully defined. Herein we generated mice with IEC-specific deletion of Gpr65 (Gpr65ΔIEC) and investigated the role of epithelial GPR65 using DSS- and C. rodentium-induced murine colitis models. RNA sequencing analysis was conducted on colonic IECs from Gpr65fl/fl and Gpr65ΔIEC mice, and colonoids and colonic epithelial cell lines were used to evaluate the pH-sensing effect of GPR65. The expression of GPR65 was determined in IECs from patients with inflammatory bowel disease (IBD) and DSS colitis mice by qRT-PCR, Western blot, and immunohistochemistry, respectively. We observed that the absence of GPR65 in IECs abrogated homeostatic antimicrobial programs, including the production of antimicrobial peptides (AMPs) and defense response-associated proteins. Gpr65ΔIEC mice displayed dysbiosis of the gut microbiota and were prone to DSS- and C. rodentium-induced colitis, as characterized by significantly disrupted epithelial antimicrobial responses, pathogen invasion, and increased inflammatory infiltrates in the inflamed colon. RNA sequencing analysis revealed that deletion of GPR65 in IECs provoked dramatic transcriptome changes with respect to the downregulation of immune and defense responses to bacteria. Forced AMP induction assays conducted in vivo or in ex vivo colonoids revealed that IEC-intrinsic GPR65 signaling drove antimicrobial defense. Mechanistically, GPR65 signaling promoted STAT3 phosphorylation to optimize mucosal defense responses. Epithelial cell line and colonoid assays further confirmed that epithelial GPR65 sensing pH synergized with IL-22 to facilitate antimicrobial responses. Finally, the expression of GPR65 was markedly decreased in the inflamed epithelia of IBD patients and DSS colitis mice. Our findings define an important role of epithelial GPR65 in regulating intestinal homeostasis and mucosal inflammation and point toward a potential therapeutic approach by targeting GPR65 in the treatment of IBD.https://www.tandfonline.com/doi/10.1080/19490976.2023.2257269GPR65intestinal epithelial cellantimicrobial peptideinflammatory bowel diseaseantimicrobial defense |
| spellingShingle | Gengfeng Li Jian Lin Xiang Gao Huiling Su Ritian Lin Han Gao Zhongsheng Feng Huili Wu Baisui Feng Keqiang Zuo Yingchuan Li Wei Wu Leilei Fang Zhanju Liu Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease Gut Microbes GPR65 intestinal epithelial cell antimicrobial peptide inflammatory bowel disease antimicrobial defense |
| title | Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease |
| title_full | Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease |
| title_fullStr | Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease |
| title_full_unstemmed | Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease |
| title_short | Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease |
| title_sort | intestinal epithelial ph sensing receptor gpr65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease |
| topic | GPR65 intestinal epithelial cell antimicrobial peptide inflammatory bowel disease antimicrobial defense |
| url | https://www.tandfonline.com/doi/10.1080/19490976.2023.2257269 |
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