Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?

Claude Libert,Jolien Vandewalle,Lise Van Wyngene

doi:10.15252/emmm.201708712

Abstract

Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems.

Highlights

Sepsis is a highly lethal and urgent unmet medical need
Because of suboptimal electron transport chain (ETC). function, mitochondrial Tricyclic acid cycle (TCA)-mediated respiration in sepsis leads to the production of dangerous reactive oxygen species (ROS; Arulkumaran et al, 2016), a process which can be prevented by switching to glycolysis, which generates ATP without ROS production and this might be a form of damage control
The increased free fatty acids (FFAs) levels activate and upregulate the expression of peroxisome proliferator-activated receptor (PPAR-a), the main transcription factor responsible for the induction of genes involved in the b-oxidation of fatty acids and the production of ketone bodies (KBs)

Summary

Introduction

Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Naïve immune cells rely on glycolysis and oxidative phosphorylation as the main metabolic pathways to generate ATP. The metabolic pathway shifts from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect, to meet the increased energy demand in activated immune cells.

Results

Conclusion