Dose-Dependent Effects of Endotoxin on Neurobehavioral Functions in Humans

Abstract

Clinical and experimental evidence document that inflammation and increased peripheral cytokine levels are associated with depression-like symptoms and neuropsychological disturbances in humans. However, it remains unclear whether and to what extent cognitive functions like memory and attention are affected by and related to the dose of the inflammatory stimulus. Thus, in a cross-over, double-blind, experimental approach, healthy male volunteers were administered with either placebo or bacterial lipopolysaccharide (LPS) at doses of 0.4 (n = 18) or 0.8 ng/kg of body weight (n = 16). Pro- and anti-inflammatory cytokines, norephinephrine and cortisol concentrations were analyzed before and 1, 1.75, 3, 4, 6, and 24 h after injection. In addition, changes in mood and anxiety levels were determined together with working memory (n-back task) and long term memory performance (recall of emotional and neutral pictures of the International Affective Picture System). Endotoxin administration caused a profound transient physiological response with dose-related elevations in body temperature and heart rate, increases in plasma interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and IL-1 receptor antagonist (IL-1ra), salivary and plasma cortisol, and plasma norepinephrine. These changes were accompanied by dose-related decreased mood and increased anxiety levels. LPS administration did not affect accuracy in working memory performance but improved reaction time in the high-dose LPS condition compared to the control conditon. In contrast, long-term memory performance was impaired selectively for emotional stimuli after administration of the lower but not of the higher dose of LPS. These data suggest the existence of at least two counter-acting mechanisms, one promoting and one inhibiting cognitive performance during acute systemic inflammation.

Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities

“…Furthermore, disruptions in the gastrointestinal mucosa could then contribute to immune activation and O&NS in the pathophysiology of MDD [48] . The administration of LPS to humans may affect mood and elevate anxiety, while increasing peripheral levels of several cytokines [49] . Indeed, the infusion of inflammatory cytokines is arguably good evidence that cytokines contribute to depression as depressive symptoms are observed clinically with the therapeutic administration of interferon [50,51] .…”

Gut Microbiota: The Conductor in the Orchestra of Immune–Neuroendocrine Communication

“…Elevated levels of cytokines and neuropeptides were shown to be associated with disrupted sleep, depressed mood, increased anxiety levels, impaired long-term memory for emotional stimuli, and elevated visceral pain sensitivity. 116,118 Particularly in elderly patients, elevated levels of the gut microbiotadelivered LPS, and the resulting endotoxemia, are more frequent as a result of small intestinal bacterial overgrowth that is caused by disturbed gut motility and increased intestinal permeability. 119 Indeed, gut microbiota alterations have been described in several diseases with altered GI motility, raising the urgency that increased attention be given to the role of the gut microbiome in modulating GI function.…”

The Gut Microbiome and the Brain

“…These changes are accompanied by depressed mood, increased anxiety, and impaired long-term memory for emotional stimuli. 27 In addition, visceral pain sensitivity thresholds are reduced and visceral pain (provoked by rectal distension) is rated as more unpleasant after administration of low-dose LPS. 28 Increased exposure to gut microbiome-derived LPS (endotoxemia) may occur in the elderly, in whom it is diminished by yogurt consumption, 29 as a consequence of small intestinal bacterial overgrowth (SIBO), 30,31 and secondary to increased intestinal permeability resulting from extreme physiologic stress, 32 ethanol exposure, 33 or a ''fast-food style'' Western diet, high in both carbohydrate and saturated fat.…”