Mus musculus deficient for secretory antibodies show delayed growth with an altered urinary metabolome

Molecular Medicine

John S. Pedersen¹  Amsha Nahid²  David P. De Souza²  Malcolm J. McConville²  Dedreia L. Tull²  Dianna M. Hocking³  Kim R. Simpfendorfer³  Richard A. Strugnell³  Odilia L. C. Wijburg³  Nancy Wang³  Andre Mu³ 

[1] Alfred Hospital, Monash University;Metabolomics Australia, Bio21 Institute, The University of Melbourne;The Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity;

关键词: SIgA;    Inflammation;    Gut;    Permeability;    Urinary biomarker;    Tissue resident memory T cells;   

DOI  :  10.1186/s10020-019-0077-2

来源: DOAJ

【 摘 要 】

Abstract Background The polymeric immunoglobulin receptor (pIgR) maintains the integrity of epithelial barriers by transporting polymeric antibodies and antigens through the epithelial mucosa into the lumen. In this study, we examined the role of pIgR in maintaining gut barrier integrity, which is important for the normal development in mice. Methods Cohorts of pIgR −/− mice and their wildtype controls were housed under Specific Pathogen Free (SPF) conditions and monitored for weight gain as an indicator of development over time. The general physiology of the gastrointestinal tract was analysed using immunohistochemistry in young (8–12 weeks of age) and aged mice (up to 18 months of age), and the observed immunopathology in pIgR −/− mice was further characterised using flow cytometry. Urinary metabolites were analysed using gas chromatography-mass spectrometry (GC-MS), which revealed changes in metabolites that correlated with age-related increase in gut permeability in pIgR −/− mice. Results We observed that pIgR −/− mice exhibited delayed growth, and this phenomenon is associated with low-grade gut inflammation that increased with ageing. The gross intraepithelial lymphocytic (IEL) infiltration characteristic of pIgR −/− mice was redefined as CD8α+αβ+ T cells, the majority of which expressed high levels of CD103 and CD69 consistent with tissue resident memory T cells (TRM). Comparison of the urinary metabolome between pIgR −/− and wild-type mice revealed key changes in urinary biomarkers fucose, glycine and Vitamin B5, suggestive of altered mucosal permeability. A significant increase in gut permeability was confirmed by analysing the site-specific uptake of sugar probes in different parts of the intestine. Conclusion Our data show that loss of the secretory antibody system in mice results in enhanced accumulation of inflammatory IELs in the gut, which likely reflects ongoing inflammation in reaction to gut microbiota or food antigens, leading to delayed growth in pIgR −/− mice. We demonstrate that this leads to the presence of a unique urinary metabolome profile, which may provide a biomarker for altered gut permeability.

【 授权许可】

Unknown