Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol

There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defe...

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Published in:	Gastroenterology (New York, N.Y. 1943) Vol. 151; no. 4; p. 733
Main Authors:	Rahman, Khalidur, Desai, Chirayu, Iyer, Smita S, Thorn, Natalie E, Kumar, Pradeep, Liu, Yunshan, Smith, Tekla, Neish, Andrew S, Li, Hongliang, Tan, Shiyun, Wu, Pengbo, Liu, Xiaoxiong, Yu, Yuanjie, Farris, Alton B, Nusrat, Asma, Parkos, Charles A, Anania, Frank A
Format:	Journal Article
Language:	English
Published:	United States 01.10.2016
Subjects:	Animals Cell Adhesion Molecules - deficiency Cholesterol Diet, High-Fat - adverse effects Diet, High-Fat - methods Dietary Carbohydrates Disease Models, Animal Dysbiosis - complications Dysbiosis - genetics Fructose Gastrointestinal Microbiome - genetics Intestinal Mucosa - metabolism Intestinal Mucosa - microbiology Liver - pathology Male Mice Mice, Inbred C57BL Non-alcoholic Fatty Liver Disease - genetics Non-alcoholic Fatty Liver Disease - microbiology Non-alcoholic Fatty Liver Disease - pathology Permeability Receptors, Cell Surface - deficiency Reverse Transcriptase Polymerase Chain Reaction Bacterial Translocation Claudin-4 Occludin
ISSN:	1528-0012, 1528-0012
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Abstract	There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH. Male C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy. F11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation. Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.
AbstractList	There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH. Male C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy. F11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation. Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH. There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH.BACKGROUND & AIMSThere is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH.Male C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy.METHODSMale C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy.F11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation.RESULTSF11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation.Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.CONCLUSIONSMice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.
Author	Anania, Frank A Parkos, Charles A Kumar, Pradeep Smith, Tekla Nusrat, Asma Neish, Andrew S Desai, Chirayu Iyer, Smita S Wu, Pengbo Liu, Yunshan Farris, Alton B Li, Hongliang Yu, Yuanjie Liu, Xiaoxiong Tan, Shiyun Rahman, Khalidur Thorn, Natalie E
Author_xml	– sequence: 1 givenname: Khalidur surname: Rahman fullname: Rahman, Khalidur email: reben.rahman@emory.edu organization: Division of Digestive Diseases, Department of Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia; Atlanta VA Medical Center, Decatur, Georgia. Electronic address: reben.rahman@emory.edu – sequence: 2 givenname: Chirayu surname: Desai fullname: Desai, Chirayu organization: P.D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Gujarat, India – sequence: 3 givenname: Smita S surname: Iyer fullname: Iyer, Smita S organization: Microbiology and Immunology, Yerkes National Primate Center, Emory University, Atlanta, Georgia – sequence: 4 givenname: Natalie E surname: Thorn fullname: Thorn, Natalie E organization: Division of Digestive Diseases, Department of Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia – sequence: 5 givenname: Pradeep surname: Kumar fullname: Kumar, Pradeep organization: Division of Digestive Diseases, Department of Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia – sequence: 6 givenname: Yunshan surname: Liu fullname: Liu, Yunshan organization: Atlanta VA Medical Center, Decatur, Georgia – sequence: 7 givenname: Tekla surname: Smith fullname: Smith, Tekla organization: Division of Digestive Diseases, Department of Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia; Atlanta VA Medical Center, Decatur, Georgia – sequence: 8 givenname: Andrew S surname: Neish fullname: Neish, Andrew S organization: Department of Pathology and Laboratory Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia – sequence: 9 givenname: Hongliang surname: Li fullname: Li, Hongliang organization: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China – sequence: 10 givenname: Shiyun surname: Tan fullname: Tan, Shiyun organization: Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China – sequence: 11 givenname: Pengbo surname: Wu fullname: Wu, Pengbo organization: Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China – sequence: 12 givenname: Xiaoxiong surname: Liu fullname: Liu, Xiaoxiong organization: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China – sequence: 13 givenname: Yuanjie surname: Yu fullname: Yu, Yuanjie organization: Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China – sequence: 14 givenname: Alton B surname: Farris fullname: Farris, Alton B organization: Department of Pathology and Laboratory Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia – sequence: 15 givenname: Asma surname: Nusrat fullname: Nusrat, Asma organization: Department of Pathology, The University of Michigan, Ann Arbor, Michigan – sequence: 16 givenname: Charles A surname: Parkos fullname: Parkos, Charles A organization: Department of Pathology, The University of Michigan, Ann Arbor, Michigan – sequence: 17 givenname: Frank A surname: Anania fullname: Anania, Frank A email: fanania@emory.edu organization: Division of Digestive Diseases, Department of Medicine, Yerkes National Primate Center, Emory University, Atlanta, Georgia; Atlanta VA Medical Center, Decatur, Georgia. Electronic address: fanania@emory.edu
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ContentType	Journal Article
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Snippet	There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis...
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SubjectTerms	Animals Cell Adhesion Molecules - deficiency Cholesterol Diet, High-Fat - adverse effects Diet, High-Fat - methods Dietary Carbohydrates Disease Models, Animal Dysbiosis - complications Dysbiosis - genetics Fructose Gastrointestinal Microbiome - genetics Intestinal Mucosa - metabolism Intestinal Mucosa - microbiology Liver - pathology Male Mice Mice, Inbred C57BL Non-alcoholic Fatty Liver Disease - genetics Non-alcoholic Fatty Liver Disease - microbiology Non-alcoholic Fatty Liver Disease - pathology Permeability Receptors, Cell Surface - deficiency Reverse Transcriptase Polymerase Chain Reaction
Title	Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol
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