134 Chapter 6 Effects of the disease state of sepsis on the gut microbiome Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [20]. Several studies have shown a loss of diversity of the microbiome – the collection of all genomes of microbes in an ecosystem - in critically ill patients [1, 2, 21-23]. The loss of diversity, called dysbiosis, has been described to potentially be associated with poor outcome, although the underlying mechanism still needs to be elucidated [21, 24]. Ojima et al. found that extremes in the ratio of Bacteroidetes relative to Firmicutes in stool samples was predictive for death compared with survivors [2, 25]. Furthermore, the relative abundance of Pseudomonas aeruginosa was predictive of survival in microbiota of endotracheal tubes, with survivors favouring the phylum Actinobacteria which includes Bifidobacteria, usually found in probiotic therapies [26]. The microbiome of patients in the intensive care unit (ICU) is characterized by a loss of diversity, site specificity, and microbial richness, as well as overgrowth of opportunistic pathogens, usually tending towards a single taxon [2, 21,27, 28]. Depletions in Faecalibacterium which produces short chain fatty acids vital for a healthy gut were also seen [29]. There are large interpersonal differences in microbiome dysregulation, which can be expected as critically ill patients are continuously exposed to a wide range of endogenous alterations that have been shown to modulate the composition of the gut microbiota (e.g. an increased production of catecholamines, altered glucose metabolism and gastrointestinal dysmotility)[18, 21, 30]. It is difficult to disentangle the effect of the septic response sepsis itself has on the microbiota and the effect of the treatment given for sepsis. A mice study of pneumonia-derived sepsis in which mice were inoculated intranasally with the gramnegative bacillus Burkholderia pseudomallei showed a marked shift in faecal bacterial composition in all septic mice with a strong increase in Proteobacteria and decrease in Actinobacteria [31]. These results are in line with recent reports on intestinal dysbiosis in mice inoculated via the airways with influenza as well as Mycobacterium tuberculosis [32, 33]. In these studies, no B. pseudomallei, influenza or M. tuberculosis was detected in faeces. These studies demonstrate that the systemic inflammatory response itself can lead to marked alterations in the gut microbiota during sepsis. Neonatal sepsis and microbiome Premature or low birth weight neonates and infants often receive multiple courses of antibiotics, which together with their low diversity microbiome may lead to profound long-term health consequences (e.g. asthma, psoriasis, other autoimmune disease, and obesity/metabolic imbalance), as well as susceptibility to development of infectious diseases [34-38]. Additionally, through antibiotic pressure, putatively beneficial commensal bacteria may be replaced by multidrug-resistant (MDR) pathogens. These factors pose a threat to the otherwise quasi-stable microbiome that develops by around age three [39]. Regardless of class, overall increased antibiotic selective pressure is associated with reduced bacterial diversity and colonization with MDR organisms. Studies report a 2-9 fold increased risk of MDR bacterial acquisition among patients treated with antibiotics, which also leads to enhanced shedding and hence contagiousness [40]. However, some antibiotics affect species richness more than others [41]. In addition
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