{"doi":"10.1016/j.jcmgh.2020.02.008","title":"Targeted Intestinal Tight Junction Hyperpermeability Alters the Microbiome, Behavior, and Visceromotor Responses","abstract":"Markedly increases in intestinal permeability occur in inflammatory bowel disease, graft-versus-host disease, celiac disease, and multiple organ dysfunction. In these diseases, effectors of increased permeability include immune signaling,1Su L. et al.Gastroenterology. 2009; 136: 551-563Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar microbiome,2Edelblum K.L. et al.Cell Mol Gastroenterol Hepatol. 2017; 4: 285-297Abstract Full Text Full Text PDF PubMed Google Scholar and corticosteroids3Meddings J.B. et al.Gastroenterology. 2000; 119: 1019-1028Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar that, in part, signal through epithelial myosin light chain kinase (MLCK). More modest permeability increases occur in other disorders, including irritable bowel syndrome (IBS), autism spectrum disorder, depression, and stress-related disorders. However, data directly linking barrier loss to phenotypes of these diseases are lacking. To define the impact of modestly increased intestinal permeability, we studied transgenic mice with intestinal epithelial-specific constitutively-active myosin light chain kinase (CAMLCK) expression. This MLCK-dependent tight junction regulation increased intestinal permeability (Supplementary Figure S1A and B).1Su L. et al.Gastroenterology. 2009; 136: 551-563Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Nevertheless, postnatal growth (Supplementary Figure S1C), reproduction, intestinal transit (Supplementary Figure S1D), intestinal histology, epithelial proliferation (a sensitive indicator of epithelial damage), and epithelial turnover are unaffected in CAMLCK transgenic (CAMLCKTg) mice.1Su L. et al.Gastroenterology. 2009; 136: 551-563Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar In contrast, mucosal tumor necrosis factor-α, interferon-γ, interleukin (IL)-10, and IL-13 transcripts as well as numbers of lamina propria neutrophils, CD4+ T cells, and IgA+ plasma cells are modestly increased by CAMLCK expression.1Su L. et al.Gastroenterology. 2009; 136: 551-563Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar,2Edelblum K.L. et al.Cell Mol Gastroenterol Hepatol. 2017; 4: 285-297Abstract Full Text Full Text PDF PubMed Google Scholar Subclinical inflammation is, therefore, present and, by microbiome-dependent, IL-17–mediated processes, affords partial protection from acute pathogen invasion.2Edelblum K.L. et al.Cell Mol Gastroenterol Hepatol. 2017; 4: 285-297Abstract Full Text Full Text PDF PubMed Google Scholar Immune activation is nevertheless unlikely to amplify CAMLCK-driven permeability increases, as barrier function and ZO-1 anchoring are both acutely normalized by enzymatic MLCK inhibition.1Su L. et al.Gastroenterology. 2009; 136: 551-563Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar,4Yu D. et al.Proc Natl Acad Sci U S A. 2010; 107: 8237-8241Crossref PubMed Scopus (135) Google Scholar We initially analyzed the gut microbiome of 31 wild-type (WT) and CAMLCKTg pups born to 8 WT dams. The microbiomes segregated by pup genotype but not dam (Supplementary Figure S1E) and included increased Clostridium and decreased Bacteroidetes, Enterococcus spp, and Prevotella in CAMLCKTg mice (Supplementary Figure S1F). Increased intestinal permeability can therefore cause dysbiosis-like microbiome shifts. Interestingly, maternal separation, which increases intestinal permeability, causes similar alterations and can be partially corrected by MLCK inhibitor–induced barrier restoration.5Rincel M. et al.Psychopharmacology (Berl). 2019; 236: 1583-1596Crossref PubMed Scopus (16) Google Scholar Microbiome alterations overlapping with the above have been reported in IBS and autism spectrum disorder. We therefore asked if CAMLCKTg mice displayed anxiety-like behavior, as occurs in those disorders, using the open field test (Figure 1A). Both the percentage of distance traveled in the center and the fraction of time spen","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2020,"id":64803,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9637,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":343445,"name":"Valérie Bacquie","orcid":null,"position":1,"is_corresponding":false},{"id":342368,"name":"Maı̈wenn Olier","orcid":"0000-0001-7214-1134","position":2,"is_corresponding":false},{"id":342369,"name":"Marion Rincel","orcid":"0000-0001-5622-9670","position":3,"is_corresponding":false},{"id":343446,"name":"B. Ringot-Destrez","orcid":null,"position":4,"is_corresponding":false},{"id":342370,"name":"Sandrine Ellero‐Simatos","orcid":"0000-0002-9282-1804","position":5,"is_corresponding":false},{"id":343447,"name":"Hélène Eutamène","orcid":null,"position":6,"is_corresponding":false},{"id":343448,"name":"Colette Bétoulières","orcid":null,"position":7,"is_corresponding":false},{"id":342371,"name":"J. Thomas","orcid":"0000-0002-1959-2427","position":8,"is_corresponding":false},{"id":342372,"name":"Jean Lainé","orcid":"0000-0002-7305-7556","position":9,"is_corresponding":false},{"id":342373,"name":"Leo Gros","orcid":"0009-0009-6946-1618","position":10,"is_corresponding":false},{"id":342374,"name":"Mathilde Lévêque","orcid":"0000-0003-1253-3798","position":11,"is_corresponding":false},{"id":342375,"name":"Renaud Léonard","orcid":"0000-0001-5023-1032","position":12,"is_corresponding":false},{"id":343449,"name":"Cherryl Harkat","orcid":null,"position":13,"is_corresponding":false},{"id":342376,"name":"Catherine Robbe‐Masselot","orcid":"0000-0001-6266-6033","position":14,"is_corresponding":false},{"id":342377,"name":"R Róka","orcid":"0000-0003-2373-2194","position":15,"is_corresponding":false},{"id":342378,"name":"Muriel Mercier‐Bonin","orcid":"0000-0001-8398-2529","position":16,"is_corresponding":false},{"id":342379,"name":"Vassilia Théodorou","orcid":"0000-0003-0801-264X","position":17,"is_corresponding":false},{"id":342380,"name":"Muriel Darnaudéry","orcid":"0000-0003-0209-3880","position":18,"is_corresponding":false},{"id":250828,"name":"Jerrold R. Turner","orcid":"0000-0003-0627-9455","position":19,"is_corresponding":false},{"id":342381,"name":"Laurent Ferrier","orcid":"0000-0003-2981-7375","position":20,"is_corresponding":false},{"id":342367,"name":"Orsolya Inczefi","orcid":"0000-0001-7974-1263","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-18T21:12:58.081635Z","pmid":"32147490","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}