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The review aims to discuss emerging evidence in the field of microbiome-dependent roles in host defense during critical illness with a focus on lung, kidney, and brain inflammation.The gut microbiota of critical ill patients is characterized by lower diversity, lower abundances of key commensal genera, and in some cases overgrowth by one bacterial genera, a state otherwise known as dysbiosis. Increasing evidence suggests that microbiota-derived components can reach the circulatory system from the gut and modulate immune homeostasis. Dysbiosis might have greater consequences for the critically ill than previously imagined and could contribute to poor outcome. Preclinical studies suggest that impaired communication across the gut – organ axes is associated with brain, lung – and kidney failure.In health, a diverse microbiome might enhance host defense, while during critical illness, the dysbiotic microbiome might contribute to comorbidity and organ dysfunction. Future research should be aimed at further establishing the causes and consequences of dysbiosis seen in the critically ill, which will provide perspective for developing new strategies of intervention.