- Letter to the Editor
- Open Access
Ileal antimicrobial peptide expression is dysregulated in old age
© The Author(s). 2017
Received: 8 May 2017
Accepted: 23 August 2017
Published: 29 August 2017
In an effort to understand the mechanisms underlying the high prevalence of gastrointestinal tract disorders in old age, we investigated the expression of intestinal antimicrobial peptides in the terminal small intestine of aged mice. Our results show that old mice have reduced transcript levels of ileal α-defensins and lysozyme, two important types of intestinal antimicrobial peptides produced by Paneth cells. In contrast, expression of the C-type lectins Reg3b and Reg3g, as well as β-defensin 1, angiogenin 4 and Relmb, which are made by several epithelial cell types, was significantly upregulated in aged animals suggesting an ongoing response to epithelial distress. Those changes in antimicrobial peptide gene expression associated with histological damage of the ileal epithelium and subtle modifications in the composition of the commensal microbiota. Our findings suggest that dysregulation of antimicrobial peptides expression is a feature of homeostasis disruption in the aged intestine and may contribute to geriatric gastrointestinal dysfunction.
Aging is associated with a higher frequency of disorders of the gastrointestinal tract (GIT), which are important causes of morbidity in the elderly population . The GIT is constantly exposed to dietary antigens and trillions of commensals and pathogenic microorganisms, which pose a tremendous immunological challenge. The intestinal epithelium deals with this challenge via the intestinal epithelial barrier, a functional entity composed by the epithelial cells, the mucus layer, the mucosal lymphoid tissue, a full repertoire of effector immune cells, and secreted immunoglobulins and antimicrobial peptides and proteins (AMPP) . Defects of the intestinal epithelial barrier integrity may lead to increased permeability and inflammation [2, 3] and have been proposed as important contributing factors to geriatric gastrointestinal dysfunction [4, 5].
It is not currently known whether alteration in the synthesis of intestinal AMPP is a distinctive feature of gastrointestinal aging. Intestinal AMPP are produced by epithelial cells of the GIT . AMPP have been associated with the control of commensal microbes [7, 8] as well as the defense from enteric infections [9–11], they can affect the composition of the intestinal microbiota and thus, its many functions in host’s metabolism and physiology . AMPP are critical for the maintenance of the intestinal barrier and the immunological homeostasis of the GIT.
Based on their recognized importance for intestinal homeostasis and defense, several AMPP from different functional classes (α-defensins, β-defensins, C-type lectins, RNAses and the cell wall-degrading enzyme lysozyme) were chosen for comparative gene expression analyses in the terminal ileum. The relative transcript levels in old animals (Fig. 1r) showed various degrees of significant differences with the younger animals (no significant differences were observed between genders). In contrast with the increased Paneth cell numbers, transcript levels for Defa20 (a member of the α-defensins group produced exclusively by Paneth cells) and those of lysozyme (Lyz, another exclusive Paneth cell product) were slightly but significantly decreased. This, together with the histological and electron microscopy data is suggestive of Paneth cell dysfunction in the aged mice. In contrast, transcription of the genes Reg3b and Reg3g (coding for the C-type lectins Reg3b and Reg3g) was significantly increased, together with the resistin-like molecule beta (Relmb, gene Retnlb), β-defensin 1 (Defb1) and the RNAse angiogenin 4 (Ang4). The upregulation of expression of these antimicrobial genes, particularly the striking induction of β-defensin 1 and Relmb, together with the changes in Paneth and goblet cell numbers has been previously associated with gastrointestinal inflammation [14–16] and is strongly suggestive of ongoing epithelial distress in the ileum of aged mice.
Beta diversity comparison between young and old mice shows no significant differences. Beta diversity was assessed using Unifrac metrics (weighted and unweighted) and a disimilarity matrix. Unifrac weighted incorporates phylogenetic distances and the relative abundance of the taxa, while Unifrac unweighted qualifies the membership community (presence or absence). Bray-Curtis metrics compute the dissimilarity in the communities structure. Metrics were tested for significance using a F-test (AMOVA)
Our findings show that the homeostatic expression of AMPP is altered in the aged ileum. Those alterations were concurrent with epithelial degeneration, a slight increase in the number of Paneth and goblet cells, and mild shifts in the commensal microbial composition. However, it is currently unclear how these alterations relate to each other, namely whether they are linked or independent events and which ones might be cause or consequence. In any case, our findings open the interesting possibility of a potential contribution of altered AMPP expression to the gastrointestinal dysfunction of old age and pose the question of why and how the observed alterations are happening in the first place. Environmental factors such as diet and polymedication are thought to influence significantly the susceptibility of elderly persons to gastrointestinal disorders . For example, certain diets can drive the microbiota towards a more pro-inflammatory composition and disturb its delicate equilibrium with the gut immune system effectively promoting dysfunction of the intestinal barrier . However, the environmental argument does not easily hold for experimental animals kept in a controlled environment (including the diet), indicating an important involvement of fundamental host-dependent factors. Based on our data, we propose that key primary disrupting events are related to age-acquired defects in the differentiation and/or function of the secretory cell lineage, particularly Paneth and goblet cells, responsible for the secretion of multiple AMPP and mucins. Such defects would have major detrimental consequences for the integrity and function of the intestinal barrier [20, 21] and might ultimately favor the development of gastrointestinal inflammatory and physiological disorders.
This work was funded by a Discovery grant (401949–2011) from the Natural Sciences and Engineering Research Council of Canada (NSERC) to AM. ST holds a PhD scholarship from the Fonds de Recherche du Québec-Nature et Technologies (FRQNT). AM was funded by awards from the Fonds de Recherche du Québec-Santé (FRQS) and the Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CRCHUS).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
ST, AM, SI, GDL and GG performed data collection. LCF and NMLC conducted the microbiota analyses. ST, NMLC and AM wrote the manuscript. All authors contributed to experimental design and analysis, and manuscript correction. AM led the study. All authors read and approved the final manuscript.
Ethics approval and consent to participate
All the animal work was approved by the Animal Care Committee of the Université de Sherbrooke, protocol # 281–15.
Consent for publication
The authors declare that they have no competing interests.
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