Title : Sepsis as a metabolic adaptation failure
Sepsis is a most deadly unmet medical need. It hits 30 million people yearly, leading to 8 million deaths, amongst which 3 million children. Usually, sepsis starts with a serious (bacterial) infection that spreads and triggers many systems of the host, including inflammation, immunity, coagulation, complement, but also thermoregulation, circadian rhythm and other systems are modulated. Of note, despite the enormous investments in sepsis, no major new therapies at the bedside have emerged, and sepsis is reputed for its high amounts of failed clinical trials. Patients are treated by antibiotics and organ support. The reasons behind these difficulties are hard to find, but we suggest that an over-emphasis on inflammation and inflammation-blockers is maybe one of the reasons. If the major probleam in sepsis, responsible for lethality, is not inflammation, then what is it?
To our opinion, the very well-known metabolic reprogramming in sepsis is the key. It has been known since many years, that sepsis patients undergo severe metabolic shifts, as they show hyperglycemia, followed by hypoglycemia, high lactate levels, and high blood concentrations of free fatty acids (FFAs) and glycerol. In a mouse model of sepsis, the cecal ligation and puncture (CLP) model, these typical metabolic changes are observed, and we interpret them as an accelerated and profound starvation response, based on lack of calorie intake and high calorie needs. The animals perform lipolysis as well as consume their glycogen stores and perform muscle degradation. A massive amount of energy-rich metabolites is released in the blood, but the major catabolic systems in the liver are failing to consume these metabolites. I will show that the receptor for Glucocorticoids (GR) quickly loses function in septic liver, and that PPARa, the major FFA sensor and driver of beta oxidations and ketogenesis is reducing in amounts in this organ. The mechanism underlying the GR problem is not known but based on a highly artificial model system in cell cultures using the cytokine TNF as a trigger, a mechanism of competition between transcription factors and GR for transcriptional co-regulators, such as p300, is one of the possibilities. The status of our work in relation to GR in sepsis will be shown, as well as the potential complications for the progression of sepsis. Equally so, I will show our findings on PPARa, and how this important transcription factor is modulated in sepsis.