Circadian rhythms in septic shock patients

Abstract

Background Despite the intensive efforts to improve the 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 h over a 24-h period to isolate CD14-positive monocytes and to measure the 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. A rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic), and expression data were compared to data of a healthy study population additionally. Results 77% of the measured clock genes showed 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. 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). 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 Molecular rhythms in immune cells of septic shock patients were substantially altered and decreased compared to healthy young men. The decrease in rhythmicity was clock gene-dependent. The loss of rhythmicity and down-regulation 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. Trail registration Clinical trial registered with www.ClinicalTrials.gov (NCT02044575) on 24 January 2014.

Synergies of Multiple Zeitgebers Tune Entrainment

“…In natural and clinical environments, there are usually multiple zeitgeber rhythms, such as light (Comas et al, 2006;Lachmann et al, 2021), food availability (Woller et al, 2016;Manella et al, 2021) or drug schedules (Bernard et al, 2010;Innominato et al, 2014;Battaglin et al, 2021), acting simultaneously on the circadian clock. Additionally, on the single cell level intercellular coupling (Tokuda et al, 2018) and also cell intrinsic rhythms can interact rhythmically with components of the circadian clock.…”

“…Thus, with this multitude of zeitgebers that can act on the organismic and molecular clock network, it is an important goal to understand the optimal timing relationships between the different Zeitgebers. This goal becomes specially relevant in patients with disturbed clocks [including ICU patients, septic shock patients and cancer patients (Broadberry et al, 2018;Lachmann et al, 2021)], since optimal timing schedules might improve their clock function and overall their well-being. Experimentally, robust circadian rhythms via scheduled feeding improved the prognosis of mice with pancreatic adenocarcinoma (Li et al, 2010).…”

“…Under natural conditions (Oda and Friesen, 2011) and also in clinical environments (Innominato et al, 2014;Lachmann et al, 2021), the co-occurrence of multiple zeitgeber inputs to the circadian clock is very common. We simulate the co-occurring zeitgeber inputs of light cycles on Period and drug cycles on Rev-Erb.…”

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.…”

Circadian Rhythms in Bacterial Sepsis Pathology: What We Know and What We Should Know

“…In addition, a day-night difference in the acute phase response to endotoxemia exists in healthy volunteers with a more pronounced inflammatory response during the resting phase [the night ( Alamili et al., 2014 )]. Moreover, septic patients had higher levels of cytokines than other intensive care unit (ICU) patients ( Acuna-Fernandez et al., 2020 ) and exhibited several alterations in clock gene rhythms ( Coiffard et al., 2019 ; Acuna-Fernandez et al., 2020 ; Lachmann et al., 2021 ). These alterations were accompanied by an increase in urinary 6-sulfatoxymelatonin (aMT6s) excretion, which is related to chronodisruption ( Acuna-Fernandez et al., 2020 ).…”