Sepsis-induced morbidity in mice: Effects on body temperature, body weight, cage activity, social behavior and cytokines in brain

Abstract

Infection negatively impacts mental health, as evidenced by the lethargy, malaise, and cognitive deficits experienced during illness. These changes in central nervous system processes, collectively termed sickness behavior, have been shown in animal models to be mediated primarily by the actions of cytokines in brain. Most studies of sickness behavior to date have used bolus injection of bacterial lipopolysaccharide (LPS) or selective administration of the proinflammatory cytokines interleukin-1β (IL-1β) or IL-6 as the immune challenge. Such models, although useful for determining mechanisms responsible for acute changes in physiology and behavior, do not adequately represent the more complex effects on central nervous system (CNS) processes of a true infection with replicating pathogens. In the present study, we used the cecal ligation and puncture (CLP) model to quantify sepsis-induced alterations in several facets of physiology and behavior of mice. We determined the impact of sepsis on cage activity, body temperature, food and water consumption and body weights of mice. Because cytokines are critical mediators of changes in behavior and temperature regulation during immune challenge, we also quantified sepsis-induced alterations in cytokine mRNA and protein in brain during the acute period of sepsis onset. We now report that cage activity and temperature regulation in mice that survive are altered for up to 23 days after sepsis induction. Food and water consumption are transiently reduced, and body weight is lost during sepsis. Furthermore, sepsis decreases social interactions for 24 – 48 hours. Finally, mRNA and protein for IL-1β, IL-6, and tumor necrosis factor-α (TNFα) are upregulated in the hypothalamus, hippocampus, and brain stem during sepsis onset, from 6–72 hour post sepsis induction. Collectively, these data indicate that sepsis not only acutely alters physiology, behavior and cytokine profiles in brain, but that some brain functions are impaired for long periods in animals that survive.

Physical fitness and physical activity in fatigued and non-fatigued inflammatory bowel disease patients

“…This finding is consistent with literature on cancer patients and liver transplant recipients, which demonstrated a relationship between impaired cardiorespiratory fitness and severity of fatigue [17,22]. The origin of the impaired cardiorespiratory fitness is possibly a less active behavior, as part of sickness behavior [53][54][55][56]. Since we know that disease activity is an important determinant of fatigue complaints, this sickness behavior may be induced by circulating cytokines (IL-1, IL-6, and TNF-a) during active disease [3,5,7,[57][58][59][60].…”

Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity

“…Of interest, effects of sepsis on body temperature and activity rhythms persist long after the animal has recovered and is no longer at risk of dying (Granger et al, 2013). These observations suggest that sepsis alters brain function, and are in agreement with observations that patients surviving sepsis often suffer severe and debilitating cognitive impairment.…”

“…These changes in sleep coincide with increased cytokine mRNA and protein in brain (Granger et al, 2013). Of interest, effects of sepsis on body temperature and activity rhythms persist long after the animal has recovered and is no longer at risk of dying (Granger et al, 2013).…”

Glucocorticoid resistance as a major drive in sepsis pathology

“…For example, anti-TNF has proven somewhat protective in the most severe cases of sepsis [73,74] and treatment with recombinant interleukin-1 receptor was associated with significant improvement in sepsis patients with features of macrophage activation syndrome [75]. Third, sepsis may be much more than an inflammatory disease and issues such as clotting [76], complement activation [77,78] but also thermoregulation [79,80], metabolism [81][82][83][84], microbiome changes [85,86] and even circadian rhythm [87] disturbances may be equally important as inflammation. Fourth, many of the failed clinical trials have been based on pre-clinical work with small model organisms, such as mice.…”