Effects of acute stress provocation on cortisol levels, zonulin and inflammatory markers in low- and high-stressed men
Introduction
Previous studies have reported that individuals scoring high on scales associated with long-term stress, such as vital exhaustion (Kudielka et al., 2006), allostatic load index (Juster et al., 2011), and exhaustion disorder (Jönsson et al., 2015), respond with reduced hypothalamic-pituitary-adrenal (HPA) axis reactivity (as measured by cortisol) to acute psychosocial stress, induced by the Trier Social Stress Test (TSST) (Kirschbaum, Pirke, & Hellhammer, 1993). Chronic stress has also been related to reduced blood pressure and norepinephrine reactivity to acute stress (Matthews, Gump, & Owens, 2001). In individuals suffering from work-related stress and vital exhaustion, a generally decreased functioning of the parasympathetic nervous system (PNS), quantified by high frequency heart rate variability (HF-HRV), has been observed (Thayer, Yamamoto, & Brosschot, 2010; Watanabe et al., 2002). A dysfunctional reactivity, or general activity, of the stress system has been suggested as a possible link to a number of cardiovascular, endocrine, autoimmune, metabolic, and behavioral disorders (Chrousos, 2009).
The steroid hormone cortisol is released by the adrenals in response to stress and is normally regulated by negative feedback (Brzozowski et al., 2016; Miller and O’Callaghan, 2002). Increased cortisol levels have been related to suppression of the immune system (Tomfohr, Edwards, & Dimsdale, 2012). The amount of cortisol seems to be an objective biological marker of stress (Wosu, Valdimarsdóttir, Shields, Williams, & Williams, 2013), and increased concentrations are related to diseases like coronary heart disease, type 2 diabetes and allergy (Miller and O’Callaghan, 2002; Stenius et al., 2011; Wosu et al., 2013).
Intestinal integrity is an essential barrier and defense mechanism to avoid translocation of luminal antigens. However, situations like stress can weaken the integrity and increase paracellular permeability (Brzozowski et al., 2016) that normally is regulated in a dynamic interplay between the mucosa and luminal content to prevent harmful substances from entering the body. It was recently shown that people exposed to stress by giving a speech in front of an audience experienced increased small-intestinal permeability and increased salivary cortisol (Vanuytsel et al., 2014). This was also observed in participants exposed to cold pain stress (Alonso et al., 2012). The importance of gut health can be exemplified by children having increased risk of developing atopic eczema before the age of two if it proceeds by low gut bacterial diversity (Wang et al., 2008) and high levels of salivary cortisol (Stenius et al., 2011).
Zonulin has been identified as a precursor for haptoglobin-2, and circulating zonulin protein is known to reversibly regulate intestinal permeability by modulating intercellular tight junctions (Tripathi et al., 2009) and is therefore a suitable marker of intestinal permeability (Fasano, 2011). Increased zonulin concentration has been reported in various diseases (Fasano, 2011), and it has been suggested that increased circulating zonulin might be mediated through increased circulating IL-6 (Moreno-Navarrete et al., 2012). Increased permeability, as well as psychosocial stress, has been shown to activate the inflammatory cascade, with increased concentrations of circulating pro-inflammatory cytokines, of which IL-6 is one of the most consistently documented (Rohleder, Aringer, & Boentert, 2012).
In the present study we aimed to examine intestinal permeability and physiological and inflammatory markers of reactivity to acute psychosocial stress in high-stressed and low-stressed individuals using a virtual version of the TSST (Jönsson et al., 2010).
Section snippets
Participants
Forty-five healthy men aged 19–35 years were recruited through advertisements at Lund University, in student magazines, and via the web from June 2015 to February 2016. The study was conducted in the same time period. It was explicitly stated that we were interested in persons that during the last six months felt either non-stressed or stressed. Only men were included because the menstrual cycle may affect the magnitude of cortisol response to psychosocial stressors (Kudielka, Hellhammer, &
Results
On the day of V-TSST, 17 of the participants had SMBQ ≥ 3.75 and were therefore classified as high-stressed (HIGHS), 23 participants had SMBQ ≤ 2.75 and were classified as low-stressed (LOWS), according to Grossi et al. (2003). Characteristics of participants are presented in Table 1.
Discussion
In line with previous studies (Fich et al., 2014; Jönsson et al., 2010; Jönsson et al., 2015) heart rate, self-reported anxiety and cortisol were increased during V-TSST, indicating that stress induction was successful. Self-reported anxiety was significantly more pronounced in HIGHS than LOWS during the V-TSST. Furthermore, the positive correlations between cortisol in saliva compared to serum confirm the ability to use either body fluid for measurement of this common biological marker of
Funding
This work was supported by Dr. Håkansson’s Foundation, Eslöv, and Probi AB, Lund, Sweden. The funding sources had no role in performing the study; in the collection, analysis and interpretation of data; in writing of the report; and in the decision to submit the article for publication.
Author contribution paragraph
C.L. designed and performed the study, analyzed the biochemical data, interpreted the data, and wrote the manuscript. P.J. designed the study, performed the physiological and statistical analyzes, interpreted data, and wrote the manuscript, H.B. was test leader in V-TSST and contributed to manuscript preparation, G.Ö. participated in the study design and manuscript preparation, J.E. and G.J. participated in the study design and approved the manuscript, S.A. designed the study and participated
Declaration of interest
The authors declare no conflict of interest related to this publication. G.Ö. is employed by Probi AB. C.L. has taken up a position in the public company BioGaia AB after the manuscript first was submitted.
Acknowledgements
All participants are greatly thanked for their participation and Anne-Marie Rohrstock is acknowledged for technical assistance.
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