The intestinal microbiome is emerging as a crucial mediator between external insults and systemic infections. New research suggests that our intestinal microorganisms contribute to critical illness and the development of non-gastrointestinal infectious diseases.Common pathways include a loss of fecal intestinal bacterial diversity and a disproportionate increase in toxogenic bacterial species. Therapeutic interventions targeting the microbiome- primarily probiotics- have yielded limited results to date. However, knowledge in this area is rapidly expanding and microbiome-based therapy such as short-chain fatty acids may eventually become a standard strategy for preventing systemic infections in the context of critical illness. The intestinal microbiome is emerging as a crucial mediator between external insults and systemic infections. New research suggests that our intestinal microorganisms contribute to critical illness and the development of non-gastrointestinal infectious diseases. Common pathways include a loss of fecal intestinal bacterial diversity and a disproportionate Therapeutic interventions targeting the microbiome- has probiotics-have yielded limited results to date. However, knowledge in this area is rapidly expanding and microbiome-based therapy such as short-chain fatty acids may eventually become a standard strategy for preventing systemic infections in the context of critical illness.