Psychosocial stress-induced intestinal permeability in healthy humans: What is the evidence?

Abstract

An impaired intestinal barrier function can be detrimental to the host as it may allow the translocation of luminal antigens and toxins into the subepithelial tissue and bloodstream. In turn, this may cause local and systemic immune responses and lead to the development of pathologies. In vitro and animal studies strongly suggest that psychosocial stress is one of the factors that can increase intestinal permeability via mast-cell dependent mechanisms. Remarkably, studies have not been able to yield unequivocal evidence that such relation between stress and intestinal permeability also exists in (healthy) humans. In the current Review, we discuss the mechanisms that are involved in stress-induced intestinal permeability changes and postulate factors that influence these alterations and that may explain the translational difficulties from in vitro and animal to human studies. As human research differs highly from animal research in the extent to which stress can be applied and intestinal permeability can be measured, it remains difficult to draw conclusions about the presence of a relation between stress and intestinal permeability in (healthy) humans. Future studies should bear in mind these difficulties, and more research into in vivo methods to assess intestinal permeability are warranted.

Keywords: CRH; Cortisol; Intestinal permeability; Mast cells; Psychosocial stress.

Fig. 1

Intestinal permeability transport routes. 1) The transcellular route for nutrients such as glucose, amino acids, and vitamins using active transport, 2) the transcellular route for small compounds, 3) endocytosis of larger peptides, proteins, and bacterial components (in follicle-associated epithelium by macropinocytosis), and 4) the paracellular route used by larger compounds, ions, and water. Created with Biorender.com. Adapted from Vanuytsel et al., 2021). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Psychosocial stress activates the two core stress systems, namely, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary (SAM) axis. Activation of the SAM axis starts with neuronal activation in the locus coeruleus (LC), which consequently stimulates sympathetic ganglia to send excitatory signals to sympathetic nerves. This stimulates the adrenal medulla to secrete adrenaline but also stimulates the eosinophils to degranulate. Consequently, eosinophils release corticotrophin releasing hormone (CRH), which stimulates mast cells to degranulate and release inflammatory cytokines that increase intestinal permeability. The HPA axis starts with the central secretion of CRH from the paraventricular nucleus (PVN) of the hypothalamus, which stimulates the secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland. In turn, the adrenal cortex secretes glucocorticoids (e.g., cortisol) which can induce negative effects on the intestinal barrier by stimulating inflammation. Created with Biorender.com. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)