Circadian Rhythms in Septic Shock Patients

Abstract

Background: Although intensive efforts to improve diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether the rhythmicity of clock gene expression is altered in patients with septic shock.Methods: This prospective pilot study was performed at the university hospital Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK). We included 20 patients with septic shock between May 2014 and January 2018, from whom blood was drawn every 4 hours over a 24-hour period to isolate CD14-positive monocytes and to measure expression of 17 clock and clock-associated genes. Of these patients, 3 whose samples expressed fewer than 8 clock genes were excluded from the final analysis. Expression data were compared to data of a healthy study population and a rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic). Results: Overall, the rhythmicity scores for septic shock patients were significantly (p < 0.0001) lower (0.23 ± 0.26) compared to the control group (12 healthy young men, 0.70 ± 0.18). 77% of the measured clock genes were classified as having inconclusive rhythms, i.e. neither rhythmic nor arrhythmic. The clock genes NR1D1, NR1D2 and CRY2 were the most rhythmic, while CLOCK and ARNTL were the least rhythmic. In addition, the expression of clock genes CRY1, NR1D1, NR1D2, DBP, and PER2 was suppressed in septic shock patients and CRY2 was significantly upregulated compared to controls.Conclusion: Compared to young healthy men, molecular rhythms in immune cells of septic shock patients were substantially decreased. The decrease in rhythmicity was clock gene-dependent. The loss of rhythmicity and downregulation of clock gene expression might be caused by sepsis and might further deteriorate immune responses and organ injury, but further studies are necessary to understand underlying pathophysiological mechanisms.Clinical trial registered with www.ClinicalTrials.gov (NCT02044575) on 24 January 2014.

The Role of Circadian Clock Genes in Critical Illness: The Potential Role of Translational Clock Gene Therapies for Targeting Inflammation, Mitochondrial Function, and Muscle Mass in Intensive Care

“…However, there are many ways to modulate immunity and the body uses them in vivo—one such pathway is regulation, and especially suppression, of cellular circadian clock proteins (Coiffard et al, 2019). It has been shown in human patients in the intensive care unit that initial inflammatory insults—for example, bacterial infection—cause an initial loss in the expression of clock-related genes (Lachmann et al, 2021) in circulating immune cells. One mechanism for this is described below.…”

“…However, it seems that human and murine BMAL1 transcripts both have binding sites for miRNA-155 and are inhibited by it (Curtis et al, 2015). Thus, it seems an evolutionary adaptation to suppress BMAL1, and thereby other clock genes such as CRY and PER in the setting of cell stress—as it is seen in immune cells of septic (Lachmann et al, 2021) as well as heavily injured trauma patients (Coiffard et al, 2019). In mice, experimental BMAL1 knockout provides a survival advantage in streptococcal pneumonia infection (Kitchen et al, 2020), mediated by improved phagocytic activity and immune cell recruitment (Kitchen et al, 2020), providing experimental evidence that the regulation of clock components has an effect on sepsis responses.…”

“…What is less clear, as there are no longitudinal studies of circadian biomarkers or gene transcripts throughout human intensive care stays, is when the cell clock resumes normality, and whether this affects disease trajectory. So far there is just evidence that on admission to intensive care, clock gene transcripts are much reduced in expression, and disordered in rhythm (Coiffard et al, 2019; Lachmann et al, 2021; Lazreg et al, 2013) at least in sepsis and trauma. One study shows that in neurologically injured patients (who may therefore have damage to the suprachiasmatic nucleus and other parts of the circadian system), clock genes are impaired for at least 1 week after admission (Diaz et al, 2020).…”

Sleep in the intensive care unit

“…In critically ill patients, there is evidence that the circadian rhythmicity of both clock genes and components of the immune system are disrupted in parallel. Disruptions in the expression of key clock genes have been seen in patients with severe sepsis [15 ▪ ,16 ▪ ,17], trauma [18], and critical neurological illness [19 ▪ ]. Lachmann et al [16 ▪ ] studied 20 patients with septic shock by measuring 17 clock and clock-associated genes isolated from their monocytes.…”

“…Disruptions in the expression of key clock genes have been seen in patients with severe sepsis [15 ▪ ,16 ▪ ,17], trauma [18], and critical neurological illness [19 ▪ ]. Lachmann et al [16 ▪ ] studied 20 patients with septic shock by measuring 17 clock and clock-associated genes isolated from their monocytes. Overall rhythmicity scores of these clock genes for septic shock patients were significantly lower as compared to healthy adults.…”