Antibiotics are commonly used prophylactically or to treat infections in the Intensive Care Unit (ICU), however, several studies showed that the benefits of antibiotics for prevention of infection, multi-organ failure and death in the ICU are unclear. We characterized here the compositional and metabolic changes induced by critical illness and antibiotics in a cohort of 75 individuals in conjunction with 2,180 gut microbiome samples representing 16 different diseases. We revealed an “infection-vulnerable” gut microbiome environment only in critically ill treated with antibiotics (ICU+). Feeding of Caenorhabditis elegans with Bifidobacterium animalis and Lactobacillus crispatus, species that expanded in ICU+ patients revealed a significant negative impact of these microbes on host viability and developmental homeostasis. These results suggest that more the antibiotic administration rather than critical illness can dramatically impact essential functional activities in the gut related to immune responses questioning the liberal use of antibiotics in the critically ill.