Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles
The balanced interplay between epithelial barrier, immune system, and microbiota maintains gut homeostasis, while disruption of this interplay may lead to inflammation. Paracellular permeability is governed by intercellular tight-junctions (TJs). Zonulin is, to date, the only known physiological reg...
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Frontiers Media S.A.
2019-09-01
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Series: | Frontiers in Immunology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02233/full |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Alba Miranda-Ribera Alba Miranda-Ribera Maria Ennamorati Gloria Serena Gloria Serena Murat Cetinbas Murat Cetinbas Jinggang Lan Ruslan I. Sadreyev Ruslan I. Sadreyev Nitya Jain Nitya Jain Alessio Fasano Alessio Fasano Maria Fiorentino Maria Fiorentino |
spellingShingle |
Alba Miranda-Ribera Alba Miranda-Ribera Maria Ennamorati Gloria Serena Gloria Serena Murat Cetinbas Murat Cetinbas Jinggang Lan Ruslan I. Sadreyev Ruslan I. Sadreyev Nitya Jain Nitya Jain Alessio Fasano Alessio Fasano Maria Fiorentino Maria Fiorentino Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles Frontiers in Immunology gut permeability microbial products trafficking tight-junctions zonulin transgenic mouse microbiota dysbiosis |
author_facet |
Alba Miranda-Ribera Alba Miranda-Ribera Maria Ennamorati Gloria Serena Gloria Serena Murat Cetinbas Murat Cetinbas Jinggang Lan Ruslan I. Sadreyev Ruslan I. Sadreyev Nitya Jain Nitya Jain Alessio Fasano Alessio Fasano Maria Fiorentino Maria Fiorentino |
author_sort |
Alba Miranda-Ribera |
title |
Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles |
title_short |
Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles |
title_full |
Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles |
title_fullStr |
Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles |
title_full_unstemmed |
Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles |
title_sort |
exploiting the zonulin mouse model to establish the role of primary impaired gut barrier function on microbiota composition and immune profiles |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2019-09-01 |
description |
The balanced interplay between epithelial barrier, immune system, and microbiota maintains gut homeostasis, while disruption of this interplay may lead to inflammation. Paracellular permeability is governed by intercellular tight-junctions (TJs). Zonulin is, to date, the only known physiological regulator of intestinal TJs. We used a zonulin transgenic mouse (Ztm) model characterized by increased small intestinal permeability to elucidate the role of a primary impaired gut barrier on microbiome composition and/or immune profile. Ztm exhibit an altered gene expression profile of TJs in the gut compared to wild-type mice (WT): Claudin-15, Claudin-5, Jam-3, and Myosin-1C are decreased in the male duodenum whereas Claudin-15, Claudin-7, and ZO-2 are reduced in the female colon. These results are compatible with loss of gut barrier function and are paralleled by an altered microbiota composition with reduced abundance of the genus Akkermansia, known to have positive effects on gut barrier integrity and strengthening, and an increased abundance of the Rikenella genus, associated to low-grade inflammatory conditions. Immune profile analysis shows a subtly skewed distribution of immune cell subsets toward a pro-inflammatory phenotype with more IL-17 producing adaptive and innate-like T cells in Ztm. Interestingly, microbiota “normalization” involving the transfer of WT microbiota into Ztm, did not rescue the altered immune profile. Our data suggest that a primary impaired gut barrier causing an uncontrolled trafficking of microbial products leads to a latent pro-inflammatory status, with a skewed microbiota composition and immune profile that, in the presence of an environmental trigger, as we have previously described (1), might promote the onset of overt inflammation and an increased risk of chronic disease. |
topic |
gut permeability microbial products trafficking tight-junctions zonulin transgenic mouse microbiota dysbiosis |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.02233/full |
work_keys_str_mv |
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doaj-da36ae80191545a981441f6cc3ddd8e02020-11-24T21:58:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-09-011010.3389/fimmu.2019.02233461209Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune ProfilesAlba Miranda-Ribera0Alba Miranda-Ribera1Maria Ennamorati2Gloria Serena3Gloria Serena4Murat Cetinbas5Murat Cetinbas6Jinggang Lan7Ruslan I. Sadreyev8Ruslan I. Sadreyev9Nitya Jain10Nitya Jain11Alessio Fasano12Alessio Fasano13Maria Fiorentino14Maria Fiorentino15Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, United StatesDepartment of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, United StatesDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Genetics, Harvard Medical School, Boston, MA, United StatesDepartment of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, United StatesDepartment of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, United StatesDepartment of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United StatesDepartment of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, United StatesThe balanced interplay between epithelial barrier, immune system, and microbiota maintains gut homeostasis, while disruption of this interplay may lead to inflammation. Paracellular permeability is governed by intercellular tight-junctions (TJs). Zonulin is, to date, the only known physiological regulator of intestinal TJs. We used a zonulin transgenic mouse (Ztm) model characterized by increased small intestinal permeability to elucidate the role of a primary impaired gut barrier on microbiome composition and/or immune profile. Ztm exhibit an altered gene expression profile of TJs in the gut compared to wild-type mice (WT): Claudin-15, Claudin-5, Jam-3, and Myosin-1C are decreased in the male duodenum whereas Claudin-15, Claudin-7, and ZO-2 are reduced in the female colon. These results are compatible with loss of gut barrier function and are paralleled by an altered microbiota composition with reduced abundance of the genus Akkermansia, known to have positive effects on gut barrier integrity and strengthening, and an increased abundance of the Rikenella genus, associated to low-grade inflammatory conditions. Immune profile analysis shows a subtly skewed distribution of immune cell subsets toward a pro-inflammatory phenotype with more IL-17 producing adaptive and innate-like T cells in Ztm. Interestingly, microbiota “normalization” involving the transfer of WT microbiota into Ztm, did not rescue the altered immune profile. Our data suggest that a primary impaired gut barrier causing an uncontrolled trafficking of microbial products leads to a latent pro-inflammatory status, with a skewed microbiota composition and immune profile that, in the presence of an environmental trigger, as we have previously described (1), might promote the onset of overt inflammation and an increased risk of chronic disease.https://www.frontiersin.org/article/10.3389/fimmu.2019.02233/fullgut permeabilitymicrobial products traffickingtight-junctionszonulin transgenic mousemicrobiotadysbiosis |