Disruption of the gut microbiota is a frequent occurrence among patients admitted to intensive care units. Particular shifts, including the proliferation of Enterobacteriaceae and other opportunistic pathogens (pathobionts), have been associated with worse clinical outcomes. In non-critically ill populations, administration of enteral nutrition containing prebiotic short-chain fructooligosaccharides (scFOS-EN) has been shown to help restore microbial balance. The consequences of scFOS-EN supplementation on the microbiome in the setting of critical illness, however, are uncertain and hard to forecast given the highly altered microbial ecosystem. To address this gap, we carried out a pilot randomized controlled trial (RCT) in critically ill trauma patients to investigate the influence of scFOS-EN relative to a fiber-free enteral formula (NF-EN) on the temporal evolution of the gut microbiota. This investigation was designed as a single-center, prospective, double-blind RCT. Mechanically ventilated trauma patients in the ICU were randomized to receive either scFOS-EN or an isocaloric fiber-free control formula (NF-EN). Serial stool specimens were subjected to 16S rRNA gene sequencing for detailed characterization of microbial composition. Linear mixed-effects modeling was applied to quantify changes in microbial taxa over the 10-day observation period after formula initiation. In addition, time-aware dimensionality reduction techniques were utilized to uncover individualized temporal trajectories and their links to clinical variables, while microbial interaction networks were constructed to examine interspecies relationships. Analysis included 57 stool samples obtained from 17 patients (7 assigned to NF-EN and 10 to scFOS-EN). All individuals displayed marked dysbiosis at baseline and had received broad-spectrum antibiotics. In comparison with NF-EN, scFOS-EN administration was associated with a more rapid reduction in Bifidobacterium (−0.6%/day, p = .026) and Firmicutes (3.5%/day, p < .001), accompanied by larger expansions of multiple Bacteroidaceae taxa. Notably, proliferation of the pathobiont Enterobacteriaceae (0.3%/day, p = .003) was observed only among patients receiving scFOS-EN. These unfavorable microbial shifts, particularly the increased Enterobacteriaceae load, were strongly modulated by antecedent and concurrent antibiotic exposure and coincided with heightened competitive interactions within the microbial community. The response of the dysbiotic gut microbiota to scFOS-EN in critically ill trauma patients is highly context-specific. Antecedent treatment with antibiotics targeting anaerobic bacteria appears to convert an otherwise potentially advantageous effect into a detrimental one. These results call into question the routine application of prebiotic interventions and emphasize the necessity for tailored nutritional approaches in the intensive care environment.
