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Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence?

ABSTRACT: BACKGROUND: A familial defect in intestinal barrier function has been found in Crohn's disease. AIM: To investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn's disease. SUBJECTS: The study included 39 patients with Crohn's disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls. METHODS: Intestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal. RESULTS: Baseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls. CONCLUSION The findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn's disease.

SUBMITTER: Soderholm JD

PROVIDER: S-EPMC1760070 | biostudies-other | 1999 Jan

REPOSITORIES: biostudies-other

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Project description:Since Crohn's disease is a transmural disease, we hypothesized that examination of deep submucosal tissues directly involved in the inflammatory disease process may provide unique insights into bacterial populations transgressing intestinal barriers and bacterial populations more representative of the causes and agents of the disease. We performed deep 16s microbiota sequencing on isolated ilea mucosal and submucosal tissues on 20 patients with Crohn's disease and 15 non-inflammatory bowel disease controls with a depth of coverage averaging 81,500 sequences in each of the 70 DNA samples yielding an overall resolution down to 0.0001% of the bacterial population. Of the 4,802,328 total sequences generated, 98.9% or 4,749,183 sequences aligned with the Kingdom Bacteria that clustered into 8545 unique sequences with <3% divergence or operational taxonomic units enabling the identification of 401 genera and 698 tentative bacterial species. There were significant differences in all taxonomic levels between the submucosal microbiota in Crohn's disease compared to controls, including organisms of the Order Desulfovibrionales that were present within the submucosal tissues of most Crohn's disease patients but absent in the control group. A variety of organisms of the Phylum Firmicutes were increased in the subjacent submucosa as compared to the parallel mucosal tissue including Ruminococcus spp., Oscillospira spp., Pseudobutyrivibrio spp., and Tumebacillus spp. In addition, Propionibacterium spp. and Cloacibacterium spp. were increased as well as large increases in Proteobacteria including Parasutterella spp. and Methylobacterium spp. This is the first study to examine the microbial populations within submucosal tissues of patients with Crohn's disease and to compare microbial communities found deep within the submucosal tissues with those present on mucosal surfaces. Our data demonstrate the existence of a distinct submucosal microbiome and ecosystem that is not well reflected in the mucosa and/or downstream fecal material.

Project description:BackgroundIntestinal barrier impairment plays an essential role in the pathogenesis of Crohn's disease (CD), and claudins (CLDNs) dysfunction contributes to intestinal mucosa injury. SOX9, an important transcription factor, is upregulated in the disease-affected colon of patients with CD; however, its precise role in CD remains largely unknown. Our aim was to explore the interaction between SOX9 and CLDNs, and further elucidate the underlying mechanisms in CD.MethodsSOX9 expression in patients with CD was evaluated using quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. The regulatory relationship between SOX9 and CLDNs was analyzed via a dual-luciferase reporter assay, chromatin immunoprecipitation, overexpression, and RNA interference methods. MicroRNAs (miRNAs) involved in the SOX9-CLDN pathway were predicted with bioinformatics analysis, and the upstream molecular mechanism was interpreted using MassARRAY methylation detection.FindingsUpregulated expression of SOX9 in the disease-affected intestine mucosa was identified in both patients with CD and mice challenged with trinitrobenzene sulfonic acid (TNBS). SOX9 negatively regulated the expression of CLDN8, accompanying reduced intestinal permeability. MiR-145-5p downregulation was found in patients with CD and TNBS-induced colitis mice owing to an aberrant miR-145 promoter hypermethylation, which subsequently interfered the SOX9-CLDN8 pathway. MiR-145-5p agomir treatment alleviated TNBS-induced colitis in wild-type mice by inhibiting Sox9 expression and restoring Cldn8 expression, whereas similar findings were not apparent in the Cldn8-/- mice.InterpretationSOX9 mediates the crosstalk between upstream miR-145-5p and downstream CLDN8, and further impairs intestinal mucosal barrier homeostasis in CD. Targeting the miR-145-5p/SOX9/CLDN8 pathway represents a promising therapeutic strategy for CD.FundingThe National Natural Science Foundation of China (#81870374, #81670498, #81630018, #82070538, #8210031148), the Guangdong Science and Technology (#2017A030306021, #2020A1515111087), the Guangzhou Science and Technology Department (#202002030041), and the Fundamental Research Funds for the Central Universities (#19ykzd11).

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Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence?

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