Microbiota-host interactions and infection dynamics in critical illness.

Critically ill patients in the ICU experience high rates of secondary infections, largely attributed to immune dysfunction and impaired host defense. We recently reported that intestinal dysbiosis in critically ill patients is associated with expansion of hypofunctional immature neutrophils, resulting in a significant reduction in infection-free survival. To further establish the causal impact of Enterobacteriaceae enrichment on neutrophil dysfunction, we established a humanized microbiota mouse model of critical illness. Using this model of intestinal dysbiosis, we observed that mice colonized with the microbiome from critically ill patients displayed comparable microbiome composition to their donors, with significant enrichment of Enterobacteriaceae compared to mice colonized with a healthy microbiome. ICU-microbiota colonized mice had a significantly altered immune landscape in the circulation. These alterations in immune landscape were independent of systemic inflammation or intestinal barrier dysfunction. Lastly, we observed significant alterations to the neutrophil compartment mirroring those observed in our human cohort, with expansion of immature neutrophils which display an immunosuppressive phenotype. We show that these perturbations to neutrophil phenotype occur in the bone marrow though “mis-trained immunity” via metabolic and epigenetic programming. Taken together, these findings further establish intestinal dysbiosis in critical illness as a driver of neutrophil dysfunction, with metabolic and epigenetic reprogramming of neutrophils as a mediator of immune dysfunction. Therefore, precision-based microbiota modifications targeting Enterobacteriaceae enrichment may be a useful therapeutic adjunct in critical illness, where clinical interventions for immune dysfunction are severely lacking.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Medicine – Immunology

Grantor

Cumming School of Medicine

Year dc:date.issued

2025

Author dc:creator

• Schlechte, Jared

Advisor dc:contributor.advisor

• McDonald, Braedon

Committee members dc:contributor.committeemember

• Gillrie, Mark
• Geuking, Markus

• critical illness
• microbiome
• dysbiosis

Statement dc:rights

• Unless otherwise indicated, this material is protected by copyright and has been made available with authorization from the copyright owner. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/49906

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/122313