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

Kim R Simpfendorfer; Nancy Wang; Dedreia L Tull; David P De Souza; Amsha Nahid; Andre Mu; Dianna M Hocking; John S Pedersen; Odilia L C Wijburg; Malcolm J McConville; Richard A Strugnell

doi:10.1186/s10020-019-0077-2

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

Mol Med. 2019 Apr 3;25(1):12. doi: 10.1186/s10020-019-0077-2.

Authors

Kim R Simpfendorfer^{1

2}, Nancy Wang³, Dedreia L Tull⁴, David P De Souza⁴, Amsha Nahid⁴, Andre Mu^{1

5

6}, Dianna M Hocking¹, John S Pedersen⁷, Odilia L C Wijburg¹, Malcolm J McConville^{4

8}, Richard A Strugnell⁹

Affiliations

¹ The Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
² Present address: The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
³ The Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. nancyw@unimelb.edu.au.
⁴ Metabolomics Australia, Bio21 Institute, The University of Melbourne, Parkville, Australia.
⁵ Doherty Applied Microbial Genomics, Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁶ Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
⁷ Alfred Hospital, Monash University, Prahran, Australia.
⁸ Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne, Parkville, Australia.
⁹ The Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. rastru@unimelb.edu.au.

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 (T_RM). 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.

Keywords: Gut; Inflammation; Permeability; SIgA; Tissue resident memory T cells; Urinary biomarker.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / genetics
Cytokines / blood
Female
Gastrointestinal Tract / immunology*
Gastrointestinal Tract / metabolism
Intraepithelial Lymphocytes / immunology*
Male
Metabolome*
Mice, Inbred C57BL
Mice, Knockout
Receptors, Polymeric Immunoglobulin / genetics*
Urine / chemistry*

Substances

Antibodies
Cytokines
Receptors, Polymeric Immunoglobulin