Endotoxin-Induced Physiological and Psychological Sickness Responses in Healthy Humans: Insights into the Post-Acute Phase

Abstract

Introduction: Experimental endotoxemia is a translational model of systemic inflammation that has contributed significantly to our current understanding of sickness behavior and inflammation-associated depression. Previous studies using this model revealed a strong association between cytokine levels, endocrine changes, and psychological sickness symptoms during the acute phase of inflammation. The objective of this randomized, double-blind, placebo-controlled crossover study was to gain insight into potential post-acute physiological and psychological consequences of endotoxin administration that may either persist or newly emerge between 24 to 72 h after injection. The main focus was on associations between serum levels of C-reactive protein (CRP) and affective symptoms as well as alterations in diurnal cortisol profile, two key features of inflammation-associated depression. Methods: Healthy male volunteers (N=18) received an injection of either endotoxin (0.8 ng/kg) or placebo on two separate but otherwise identical study days, 7 days apart. Blood and saliva samples were collected during acute and post-acute phases after injection to measure blood inflammatory markers (interleukin [IL]-6, IL-1 receptor antagonist [ra], CRP) and salivary cortisol levels. In addition, participants completed a comprehensive battery of questionnaires to assess physical and psychological sickness symptoms. Results: Endotoxin treatment induced a short-time rise in plasma IL-6 and a longer increase in IL-1ra. The increase in serum CRP was delayed compared to cytokines, peaking at 24 h and gradually decreasing until 72 h after injection. The inflammatory response was accompanied by bodily and psychological sickness symptoms which occurred only in the acute phase, whereas none of the symptoms persisted or recurred in the post-acute phase. Salivary cortisol levels were significantly increased during acute phase and exhibited pronounced circadian changes. However, no significant differences in diurnal cortisol profiles were observed between placebo and endotoxin conditions on the days after treatment. Conclusion: Our findings suggest that CRP, which is elevated in patients with inflammation-associated depression, does not appear to be responsible for depressive symptomatology. Moreover, a single inflammatory episode is not sufficient to alter diurnal cortisol profiles, as observed in inflammation-associated depression. In addition, the absence of persistent LPS-induced psychological and physiological changes beyond the acute phase further supports the safety of endotoxin administration in humans.

How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review

“…C-reactive protein (CRP) rises about 6 h p.i., with a peak at about 24 h p.i. (see also Engler and colleagues [ 23 ] in this article collection). In contrast to animal studies (for review, see [ 24 ]), human experimental endotoxemia utilizes comparatively low doses of LPS due to a higher responsiveness of the human immune system to endotoxin.…”

“…Due to the acute response, the similarity to a natural infection, and no known long-term complications (see Engler et al [ 23 ] in this article collection), the model of experimental endotoxemia should be safe for individuals with some vulnerability as well. To the best of our knowledge, only one study has used the model in a chronic pain population so far.…”