31 Pathogenesis of sepsis Cellular metabolism Changes in cellular metabolism may contribute to immune suppression [45]. A metabolic shift from oxidative phosphorylation to glycolysis, known as the Warburg effect, is critical for cells to mount an inflammatory response when stimulated by LPS, and failure in this shift can result in reduced cellular responsiveness [2]. Consequently, an imbalance in cellular metabolism has been associated with the altered phenotype of monocytes in sepsis. However, the underlying mechanisms appear to be more complex than simple shifts between oxidative phosphorylation and glycolysis [2]. Unlike LPS, which triggers a classical Warburg effect, other bacterial stimuli have been observed to increase both glycolysis and oxidative phosphorylation in monocytes [46]. Likewise, in sepsis patients with immune suppression, monocyte metabolic dysfunction is not confined to glycolysis but extends to a broad suppression of metabolic pathways, including glycolysis, fatty acid oxidation, and oxidative phosphorylation [47]. Microbiome The microbiome consists of trillions of bacteria of which most are found in the gastrointestinal tract [48]. Dysbiosis of the microbiome (meaning a decreased microbial diversity) has been associated with altered immune responses (for instance altered cytokine production capacity of immune cells). Sepsis affects the composition of the intestinal microbiome, characterized by a loss of diversity, lower abundances of key commensal genera (such as Faecalibacterium, Blautia, Ruminococcus) and overgrowth of opportunistic pathogens [49]. Small studies show that the gut is overrun by a single bacterial genus in patients with sepsis, most notably by Clostridium difficile, Staphylococcus spp., Escherichia spp., Shigella spp., Salmonella spp., and Enterococcus spp. [50]. This overgrowth by one genus occurs in roughly one third of the septic patients, but increases with time spend on the ICU [51]. The underlying mechanism is not fully understood, but antibiotic treatment that is part of standard care in septic patients seems to have the most disruptive effect on the microbiome, possibly amplified by the use of (par)enteral feeding and gastric acid inhibitory drugs [52]. Murine studies support a role for the microbiome in regulation of granulocytosis, neutrophil homeostasis and host resistance to sepsis [53]. In pneumonia derived sepsis disruption of the gut microbiome impaired host defense; underlying mechanisms likely include a reduced responsiveness to microbial stimulation and an impaired phagocytosis capacity of alveolar macrophages [54]. In addition, neutrophils from microbiota-depleted mice demonstrated a diminished capacity to migrate into inflamed tissues [55]. The immune response can further be compromised when translocation of pathological microbes through disintegrated epithelial barriers results in systemic and lymphatic spreading of pathogens. Theories of connections between the gut microbiome and distant organ function, the so-called gut-organ axis, are rapidly developing. For instance, a recent study showed evidence of gut bacteria present in the lung microbiome in mice with experimental sepsis and humans with acute respiratory distress syndrome, supporting the existence of the gut-lung axis [56]. Research concerning the pathophysiological mechanism underlying these phenomena is growing rapidly [52, 57], as are studies regarding the microbiome as a therapeutic target in critically ill patients [58]. 2
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