Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary
Background & Aims: The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR) can sense xenobiotics, dietary, microbial, and metabolic cues. Roles of Ahr in intestinal epithelial cells (IECs) have been much less elucidated compared with those in intestinal innate immune cells...
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Elsevier
2022
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oai:doaj.org-article:765f970da1ec401187be7dddfa8c4f392021-11-14T04:34:15ZAryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary2352-345X10.1016/j.jcmgh.2021.08.014https://doaj.org/article/765f970da1ec401187be7dddfa8c4f392022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001818https://doaj.org/toc/2352-345XBackground & Aims: The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR) can sense xenobiotics, dietary, microbial, and metabolic cues. Roles of Ahr in intestinal epithelial cells (IECs) have been much less elucidated compared with those in intestinal innate immune cells. Here, we explored whether the IEC intrinsic Ahr could modulate the development of alcohol-related liver disease (ALD) via the gut–liver axis. Methods: Mice with IEC specific Ahr deficiency (AhrΔIEC) were generated and fed with a control or ethanol diet. Alterations of intestinal microbiota and metabolites were investigated by 16S ribosomal RNA sequencing, metagenomics, and untargeted metabolomics. AHR agonists were used to evaluate the therapeutic potentials of intestinal Ahr activation for ALD treatment. Results: AhrΔIEC mice showed more severe liver injury after ethanol feeding than control mice. Ahr deficiency in IECs altered the intestinal metabolite composition, creating an environment that promoted the overgrowth of Helicobacter hepaticus and Helicobacter ganmani in the gut, enhancing their translocation to mesenteric lymph nodes and liver. Among the altered metabolites, isobutyric acid was increased in the cecum of ethanol-fed AhrΔIEC mice relative to control mice. Furthermore, both H. hepaticus and isobutyric acid administration aggravated ethanol-induced liver injury in vivo and in vitro. Supplementation with AHR agonists, 6-formylindolo[3,2-b]carbazole and indole-3-carbinol, protected mice from ALD development by specifically activating intestinal Ahr without affecting liver Ahr function. Alcoholic patients showed lower intestinal AHR expression and higher H. hepaticus levels compared with healthy individuals. Conclusions: Our results indicate that targeted restoration of IEC intrinsic Ahr function may present as a novel approach for ALD treatment.Minyi QianJun LiuDanyang ZhaoPengpeng CaiChuyue PanWenxin JiaYingsheng GaoYufei ZhangNan ZhangYinan ZhangQuan ZhangDalei WuChengjie ShanMeiling ZhangBernd SchnablSong YangXu ShenLirui WangElsevierarticleAryl Hydrocarbon ReceptorAlcohol-Related Liver DiseaseHelicobacter hepaticusIsobutyric AcidDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 233-256 (2022) |
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DOAJ |
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DOAJ |
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EN |
| topic |
Aryl Hydrocarbon Receptor Alcohol-Related Liver Disease Helicobacter hepaticus Isobutyric Acid Diseases of the digestive system. Gastroenterology RC799-869 |
| spellingShingle |
Aryl Hydrocarbon Receptor Alcohol-Related Liver Disease Helicobacter hepaticus Isobutyric Acid Diseases of the digestive system. Gastroenterology RC799-869 Minyi Qian Jun Liu Danyang Zhao Pengpeng Cai Chuyue Pan Wenxin Jia Yingsheng Gao Yufei Zhang Nan Zhang Yinan Zhang Quan Zhang Dalei Wu Chengjie Shan Meiling Zhang Bernd Schnabl Song Yang Xu Shen Lirui Wang Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary |
| description |
Background & Aims: The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR) can sense xenobiotics, dietary, microbial, and metabolic cues. Roles of Ahr in intestinal epithelial cells (IECs) have been much less elucidated compared with those in intestinal innate immune cells. Here, we explored whether the IEC intrinsic Ahr could modulate the development of alcohol-related liver disease (ALD) via the gut–liver axis. Methods: Mice with IEC specific Ahr deficiency (AhrΔIEC) were generated and fed with a control or ethanol diet. Alterations of intestinal microbiota and metabolites were investigated by 16S ribosomal RNA sequencing, metagenomics, and untargeted metabolomics. AHR agonists were used to evaluate the therapeutic potentials of intestinal Ahr activation for ALD treatment. Results: AhrΔIEC mice showed more severe liver injury after ethanol feeding than control mice. Ahr deficiency in IECs altered the intestinal metabolite composition, creating an environment that promoted the overgrowth of Helicobacter hepaticus and Helicobacter ganmani in the gut, enhancing their translocation to mesenteric lymph nodes and liver. Among the altered metabolites, isobutyric acid was increased in the cecum of ethanol-fed AhrΔIEC mice relative to control mice. Furthermore, both H. hepaticus and isobutyric acid administration aggravated ethanol-induced liver injury in vivo and in vitro. Supplementation with AHR agonists, 6-formylindolo[3,2-b]carbazole and indole-3-carbinol, protected mice from ALD development by specifically activating intestinal Ahr without affecting liver Ahr function. Alcoholic patients showed lower intestinal AHR expression and higher H. hepaticus levels compared with healthy individuals. Conclusions: Our results indicate that targeted restoration of IEC intrinsic Ahr function may present as a novel approach for ALD treatment. |
| format |
article |
| author |
Minyi Qian Jun Liu Danyang Zhao Pengpeng Cai Chuyue Pan Wenxin Jia Yingsheng Gao Yufei Zhang Nan Zhang Yinan Zhang Quan Zhang Dalei Wu Chengjie Shan Meiling Zhang Bernd Schnabl Song Yang Xu Shen Lirui Wang |
| author_facet |
Minyi Qian Jun Liu Danyang Zhao Pengpeng Cai Chuyue Pan Wenxin Jia Yingsheng Gao Yufei Zhang Nan Zhang Yinan Zhang Quan Zhang Dalei Wu Chengjie Shan Meiling Zhang Bernd Schnabl Song Yang Xu Shen Lirui Wang |
| author_sort |
Minyi Qian |
| title |
Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary |
| title_short |
Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary |
| title_full |
Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary |
| title_fullStr |
Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary |
| title_full_unstemmed |
Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver DiseaseSummary |
| title_sort |
aryl hydrocarbon receptor deficiency in intestinal epithelial cells aggravates alcohol-related liver diseasesummary |
| publisher |
Elsevier |
| publishDate |
2022 |
| url |
https://doaj.org/article/765f970da1ec401187be7dddfa8c4f39 |
| work_keys_str_mv |
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| _version_ |
1718429963635392512 |