Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis
Authors
Muñoz Zamarrón, María LeticiaIdentifiers
Permanent link (URI): http://hdl.handle.net/10017/63990DOI: 10.1002/hep.30349
PMID: 30414342
ISSN: 0270-9139
Date
2019-09-01Academic Departments
Universidad de Alcalá. Departamento de Medicina y Especialidades Médicas
Funders
Ministerio de Sanidad
Instituto de Salud Carlos III
Ministerio de Asuntos Económicos y Transformación Digital
Comunidad de Madrid
FEDER
Bibliographic citation
Muñoz, L. et al. (2019) ‘Intestinal Immune Dysregulation Driven by Dysbiosis Promotes Barrier Disruption and Bacterial Translocation in Rats With Cirrhosis’, Hepatology (Baltimore, Md.), 70(3), pp. 925–938. Available at: https://doi.org/10.1002/hep.30349.
Description / Notes
14 p.
Project
info:eu-repo/grantAgreement/ISCIII//PI14%2F00876/ES/Relevancia del daño inflamatorio intestinal en la patogenia de la traslocación bacteriana y de la disregulación inmunitaria de la cirrosis. Compromiso de la respuesta inmune adaptativa
info:eu-repo/grantAgreement/ISCIII//PI14%2F051871/ES/POTENCIAL TERAPÉUTICO DE LA INMUNOMODULACIÓN EN ENFERMEDADES PREVALENTES CON PATOGENIA POR TRASLOCACIÓN BACTERIANA, COMO EPOC Y CIRROSIS
info:eu-repo/grantAgreement/ISCIII//PI18%2F01726/ES/ Estudio del estado de senescencia del sistema inmunoinflamatorio en la lesión medular de larga duración y su relevancia clínica. Análisis de la significación patogénica de la traslocación bacteriana instestinal
info:eu-repo/grantAgreement/MINECO//SAF2017-86343-R /ES/Mecanismos etiopatogénicos de disfunción inmunitaria en la cirrosis. Análisis de la relevancia de la microbiota e inflamación intestinal y de la sistémica asociada al virus C
info:eu-repo/grantAgreement/CAM//B2017%2FBMD-3804/ES/MEDICINA INDIVIDUALIZADA TRASLACIONAL EN INFLAMACIÓN Y CÁNCER
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/acceptedVersion
Rights
© 2018 by the American Association for the Study of Liver Diseases
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
In cirrhosis, intestinal dysbiosis, intestinal barrier impairment, and systemic immune system abnormalities lead to gut bacterial translocation (GBT) and bacterial infection. However, intestinal immune system dysfunction and its contribution to barrier damage are poorly understood. This study correlates immune system dysregulation in the intestines of rats at different stages of CCl4 -induced cirrhosis with barrier function and pathogenic microbiota. The following variables were addressed in the small intestine: intraepithelial lymphocyte (IEL) and lamina propria lymphocyte (LPL) activation status and cytokine production (flow cytometry), cytokine mRNA and protein expression (quantitative real-time PCR and immunofluorescence), microbiota composition of ileum content (16S recombinant DNA massive sequencing), permeability (fecal albumin loss), and epithelial junctions (immunohistochemistry and immunofluorescence). The intestinal mucosa in rats with cirrhosis showed a proinflammatory pattern of immune dysregulation in IELs and LPLs, which featured the expansion of activated lymphocytes, switch to a T helper 1 (Th1) regulatory pattern, and Th17 reduction. In rats with cirrhosis with ascites, this state was associated with epithelial junction protein disruption, fecal albumin loss, and GBT. Direct correlations (P < 0.01) were observed between elevated interferon gamma (IFN?)-expressing T cytotoxic LPLs and fecal albumin and between inflammatory taxa abundance and IFN?-producing immune cells in the ileum. Bowel decontamination led to redistributed microbiota composition, reduced proinflammatory activation of mucosal immune cells, normalized fecal albumin levels, and diminished GBT; but there were no modifications in Th17 depletion. Conclusion: The intestinal mucosa of rats with cirrhosis acquires a proinflammatory profile of immune dysregulation that parallels the severity of cirrhosis; this impaired intestinal immune response is driven by gut dysbiosis and leads to disrupted barrier function, promoting GBT.
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