Intensive care unit (ICU) patients are exposed to many factors (antibiotics, shock, intestinal dysfunction) resulting in loss of gut microbiome diversity and overgrowth of multidrug-resistant bacteria such as Enterobacterales. In ICU patients, gut Enterobacteriaceae expansion is associated with impaired innate immunity and higher risk of secondary infection. A potential therapeutic strategy is modulating this “gut-lung axis” through dietary fibers and the resulting short-chain fatty acids (SCFA) production that can enrich microbiome diversity and related metabolome, restore immunity, and improve respiratory outcomes. In a published preclinical model, SCFA restored lung immune responses against Pseudomonas aeruginosa lung infection in mice colonized by multidrug-resistant Enterobacterales (MRE). Preliminary data suggest that fiber-rich diet has similar beneficial effects. These findings underscore the potential for dietary fibers to enhance outcomes of secondary infection by modulating the gut microbiome, metabolome, and immune responses. However, use and choice of fibers in ICU enteral nutrition are not currently informed by their microbiome/metabolome modulation potential. This proposal aims to identify dietary fibers with the highest potential to mitigate the impact of MRE gut colonization on secondary infections in ICU patients. Through a translational design, we will start by characterizing microbiome samples from MRE gut colonized ICU patients who develop secondary infections to establish clinically relevant models by patient microbiome transfer to in-vitro and gnotobiotic models. This pipeline will screen dietary fibers based on fiber-microbiome interactions. Finally, we will employ mathematical modeling to integrate clinical and experimental data, creating digital twins to simulate and predict patient outcomes according to fibers. This innovative approach will guide future clinical trials in testing fibers to improve ICU patient outcomes.