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'INFLAMMAGEING' IN THE INTESTINE: IS IT A CAUSE OF DECLINE
IN MUCUS BARRIER FUNCTION?
Bruno Sovran1,4, Adriaan A. van Beek2,4, Marlies Elderman4,5, Jasper Kamphuis1, Floor Hugenholtz4,6,
Clara Belzer4,6, Jan J.H. Hoeijmakers3, Paul de Vos4,5, Huub F.J. Savelkoul2, Jan Dekker4 and Jerry M.
Wells1,5.
1
Host-Microbe Interactomics Group, Wageningen University and Research Center, Wageningen, The
Netherlands; 2Cell Biology and Immunology Group, Wageningen University and Research Center,
Wageningen, The Netherlands; 3Department of Genetics, Erasmus MC, Rotterdam, the Netherlands;
4
Top Institute Food and Nutrition, Wageningen, The Netherlands; 5University Medical Center of
Groningen, Groningen, The Netherlands; 6Laboratory of Microbiology, Wageningen University and
Research Center, The Netherlands
Corresponding author: [email protected]
Introduction and objectives
Our knowledge of the age-related changes of the systemic immune system has improved over the
past few years. However, there is a major lack of knowledge on how ageing affects very basic aspects
pertaining to intestinal innate immunity and homeostasis. Understanding age-related changes in the
intestine and the impact on the microbiota is a goal of clear medical relevance as it may provide us
with models and new insights to prevent degeneration of physiological and immune functions. The aim
of this study was to investigate, the effects of ageing on intestinal morphology, including mucus
properties, host responses and microbiota changes in naturally aged (18 month-old) and fast-ageing
ERCC1-/Δ7 mice. The fast-ageing ERCC1-/Δ7 mice have a mutation for ERCC1, a protein involved in
DNA repair and develop the typical ageing phenotypes including ataxia, neurodegeneration and liver
pathology. Moreover, the lifespan of ERCC1-/Δ7 mice is decreased from 118 weeks to around 20
weeks, compared to wild-type mice.
Materials and Methods
Wild-type (WT) and ERCC1-/Δ7 mice were reared under SPF conditions and sacrificed respectively at
18 months and 16 weeks of age. Total RNA from ileum and colon was purified, and analysed for full
genome transcriptome analysis. Microbiota composition of faecal samples was determined using a
mouse intestinal chip (MITChip). Tissue morphology (H&E), mucus barrier function (PAS/AB) and
bacterial compartmentalization (FISH) were addressed by staining segments of ileum and proximal
colon fixed in Carnoy’s fixative.
Results and Discussion
Both naturally aged mice and 16-week-old ERCC1-/Δ7 mice showed marked changes in intestinal
morphology compared to young adult mice. The colonic mucosa of naturally and fast-aged ERCC1-/Δ7
mice was thicker with more immune cell infiltration than in younger mice. Furthermore, in aged mice
the mucus layer was thinner than in young WT mice, and more easily penetrable by luminal bacteria.
The small intestine did not show inflammation, but the mucus morphology was unattached and more
easily penetrable by luminal bacteria. These observations in the colon were confirmed at the level of
gene expression, where inflammatory genes were strongly increased and innate immunity strongly
down-regulated compared to younger mice. In the ileum, both inflammatory and immune gene sets
were relatively increased compared to WT. The microbiota is dramatically affected by ageing in fast
ageing mice model. We conclude that ageing has marked effects on the intestinal barrier, including
mucosal thickening, immune cell infiltration, mucus depletion, and the intestinal microbiota. Given the
importance of inflammation in the intestine and microbiota in several chronic diseases and disorders
we speculate that 'inflammageing' in the intestine may even be a trigger for the decline in mucus
barrier function in old age.