Tjitske van Engelen

286 Chapter 11 Supplementary Electronic Material 2 - Dysbiosis The intestinal microbiome consists of a community of microbes, that contribute to crucial processes of human homeostasis and health, such as metabolism of carbohydrates and production of vitamins and hormones [1]. In disease, the microbiome establishes protection against enteric and systemic pathogens and microbiome-dependent metabolic pathways can drive distinct immune responses to invading pathogens [2-5]. Several studies have shown extreme perturbations of the microbiome in critically ill patients [6-8]. Dysbiosis is associated with poor outcome, although the underlying mechanisms are not yet understood [9, 10]. The intestinal microbiome of the septic patient is characterized by a loss of diversity, lower abundances of key commensal genera (such as Faecalibacterium, Blautia and Ruminococcus spp.) and overgrowth of opportunistic pathogens [6]. The disease itself, as well as the interventions from clinical care, potentially have disruptive effects on the microbiome, most notably following antibiotic administration [11]. Current microbiota-targeted therapies either try to reduce the overgrowth of potentially pathogenic microorganisms (such as the use of selective decontamination of the digestive tract (SDD)) or try to resupply beneficial microbes. SDD can prevent nosocomial infections in critically ill patients and reduce mortality; however, widespread use may contribute to the rising problem of antibiotic resistance [12, 13]. To resupply the gut with beneficial microbes, probiotics (living microorganisms) may be combined with prebiotics (dietary components that enhance the growth of these microorganisms) into so-called synbiotics. A large meta-analysis studied the use of probiotics and synbiotics in the ICU and found a decrease in the incidence of ventilator-associated pneumonia [14]. Microbiota-targeted therapy also appears to prevent sepsis in specific populations. For example, a recent large randomized, double-blind, placebo-controlled trial of an oral symbiotic preparation in healthy new-borns in rural India, showed a significant reduction in sepsis and death after 60 days [15]. An interesting alternative treatment is the use of faecal microbiota transplantation (FMT), in which faeces of healthy donors in infused to recolonize the total microbiome. The success of this treatment is shown in patients with recurrent C. difficile infections, although long term safety has not been established, and case reports show a potential benefit in the treatment of sepsis [16, 17]. Since dysbiosis of the microbiome could increase the susceptibility to sepsis and is associated with a poor outcome, the microbiome itself and microbiota-targeted interventions may contribute to personalized medicine in sepsis. Current limitations that need to be addressed are the large variations in dysbiosis between and within individuals, the limited mechanistic knowledge in a field of mostly observational and associative studies, and the scarce number of interventional trials studying the use of microbes as a treatment for the critically ill.

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