Decrease of α-defensin impairs intestinal metabolite homeostasis via dysbiosis in mouse chronic social defeat stress model

Abstract

Psychological stress has been reported to relate to dysbiosis, imbalance of the intestinal microbiota composition, and contribute to the onset and exacerbation of depression, though, underlying mechanisms of psychological stress-related dysbiosis have been unknown. It has been previously established that α-defensins, which are effector peptides of innate enteric immunity produced by Paneth cells in the small intestine, play an important role in regulation of the intestinal microbiota. However, the relationship between disruption of intestinal ecosystem and α-defensin under psychological stress is yet to be determined. Here we show using chronic social defeat stress (CSDS), a mouse depression model that (1) the exposure to CSDS significantly reduces α-defensin secretion by Paneth cells and (2) induces dysbiosis and significant composition changes in the intestinal metabolites. Furthermore, (3) they are recovered by administration of α-defensin. These results indicate that α-defensin plays an important role in maintaining homeostasis of the intestinal ecosystem under psychological stress, providing novel insights into the onset mechanism of stress-induced depression, and may further contribute to discovery of treatment targets for depression.

The Effects of Stress and Diet on the “Brain–Gut” and “Gut–Brain” Pathways in Animal Models of Stress and Depression

“…Enterochromaffin cells release serotonin both luminally and basally, thus, the decreased levels of Turicibacter reported in the reviewed studies may be associated with decreased colonic serotonin levels that arise from stress-induced alterations in enterochromaffin cell function, which may also have negative implications for vagal nerve signalling [124]. Regarding Allobaculum, Suzuki et al [76] reported that CSDS reduced faecal α-defensin levels, and this was positively correlated with Allobaculum abundance, indicating that CSDS disturbed Allobaculum abundance via perturbations in intestinal function of Paneth cells and likely also decreased the mucus layer of the intestinal barrier due to the close association of Paneth cells and the regulation of this important component. CUMS-induced alterations in Allobaculum abundance have been reported in female C57BL6 mice, however these were inconsistent across studies likely due to differing durations in the CUMS protocol [43,93].…”

“…Paneth cells have also been demonstrated to have a close association with MUC2 in that its presence around Paneth cells facilitates the secretion of antimicrobial peptides into the mucus layer [81]. Suzuki et al [76] showed that CSDS had deleterious effects on the number of Paneth cells and their secretory granules in the small intestine.…”

“…Chronic exposure to stress results in dysregulation of the HPA axis and ANS control over gut function[2,6]. As a result, Paneth cell number and function is reduced, contributing to microbial dysbiosis through a reduction in the mucus layer of the gut[29,76]. This reduction of the mucus layer also allows bacteria and their associated products to reach the gut epithelium[49].…”

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

“…This review has mainly focused on the mechanisms underlying the effect of microbes on depression, but it is also important to understand how microbes are affected by changes in the host's psychological and physiological state. A very recent study showed that exposure to chronic stress reduced the secretion of α-defensins, effector peptides of innate enteric immunity produced by Paneth cells in the small intestine, which resulted in gut dysbiosis and an impairment of intestinal metabolite homeostasis [159]. To extrapolate the mechanisms revealed in animal studies to therapeutic effects in humans, it would be necessary to gain a deeper understanding of the bidirectional communication between the gut microbiota and brain.…”

Current knowledge on the multiform reconstitution of intestinal stem cell niche

“…It was also observed that ISCs cluster which failed to produce Paneth cells turned into ISC-absent enterocysts with a limited life-span, which contain only enterocytes[ 33 ]. In addition to Dll1-induced inhibition against secretory differentiation, Paneth cells generate endogenous growth factors including Wnt-3, EGF and TGF-α, facilitating niche environment reconstitution and budding organoid maturation[ 30 , 39 ]. Accordingly, Paneth cells are regarded as essential niche cells for the ISC niche.…”