A phase 2 randomized, placebo-controlled trial of inulin for the prevention of gut pathogen colonization and infection among patients admitted to the intensive care unit for sepsis

Abstract

Patients admitted to the intensive care unit (ICU) often have gut colonization with pathogenic bacteria and such colonization is associated with increased risk for death and infection. We conducted a trial to determine whether a prebiotic would improve the gut microbiome to decrease gut pathogen colonization and decrease downstream risk for infection among newly admitted medical ICU patients with sepsis. This was a randomized, double-blind, placebo-controlled trial of adults who were admitted to the medical ICU for sepsis and were receiving broad-spectrum antibiotics. Participants were randomized 1:1:1 to placebo, inulin 16 g/day, or inulin 32 g/day which were given for seven days. The trial primary outcome was a surrogate measure for gut colonization resistance, namely the within-individual change from ICU admission to Day 3 in the relative abundance of short chain fatty acid (SCFA)-producing bacteria based on rectal swabs. Additional outcomes sought to evaluate the impact of inulin on the gut microbiome and downstream clinical effects. Ninety participants were analyzed including 30 in each study group. There was no difference between study groups in the within-individual change in the relative abundance of SCFA-producing bacteria from ICU admission to ICU Day 3 (placebo: 0.0% change, IQR − 8·0% to + 7·4% vs. combined inulin: 0·0% change, IQR − 10·1% to + 4·8%; p = 0·91). At end-of-treatment on ICU Day 7, inulin did not affect SCFA-producer levels, microbiome diversity, or rates of gut colonization with pathogenic bacteria. After 30 days of clinical follow-up, inulin did not affect rates of death or clinical, culture-proven infection. Patients who died or developed culture-proven infections had lower relative abundance of SCFA-producing bacteria at ICU admission compared to those who did not (p = 0·03). Prebiotic fiber had minimal impact on the gut microbiome in the ICU and did not improve clinical outcomes. Clinicaltrials.gov: NCT03865706. Does prebiotic fiber alter the gut microbiome in the medical ICU to decrease gut pathogen colonization and decrease downstream risk for infection? This randomized controlled trial found that prebiotic inulin at doses up to 32 grams/day did not alter the gut microbiome among adults admitted to the ICU with sepsis. Even at these high doses, inulin was well tolerated. The taxonomic composition of the gut microbiome, assessed using longitudinal rectal swabs and stool samples for up to thirty days of follow-up, was not substantively altered by inulin; also unchanged by inulin were fecal levels of short chain fatty acids, gut colonization with pathogenic bacteria including vancomycin-resistant Enterococcus and multidrug-resistant Gram-negative bacteria, and clinical outcomes including culture-proven infection or death. Pre- and probiotics may face significant challenges in the ICU. Improved understanding of the dynamic changes within the gut microbiome in the ICU may lead to more targeted therapies.