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Advanced Age Impairs Intestinal Antimicrobial Peptide Response and Worsens Fecal Microbiome Dysbiosis Following Burn Injury in Mice

Wheatley, Elizabeth G.*; Curtis, Brenda J.*; Hulsebus, Holly J.*,†; Boe, Devin M.*,†,‡; Najarro, Kevin*; Ir, Diana§; Robertson, Charles E.§; Choudhry, Mashkoor A.||; Frank, Daniel N.§,¶; Kovacs, Elizabeth J.*,†,‡,¶

doi: 10.1097/SHK.0000000000001321
Basic Science Aspects: PDF Only

ABSTRACT Maintenance of the commensal bacteria that comprise the gut microbiome is essential to both gut and systemic health. Traumatic injury, such as burn, elicits a number of changes in the gut, including a shift in the composition of the microbiome (dysbiosis), increased gut leakiness, and bacterial translocation into the lymphatic system and bloodstream. These effects are believed to contribute to devastating secondary complications following burn, including pneumonia, acute respiratory distress syndrome, multi-organ failure, and septic shock. Clinical studies demonstrate that advanced age causes a significant increase in mortality following burn, but the role of the gut in this age-dependent susceptibility has not been investigated. In this study, we combined our well-established murine model of scald burn injury with bacterial 16S-rRNA gene sequencing to investigate how burn injury affects the fecal microbiome in aged versus young mice. Of our treatment groups, the most substantial shift in gut microbial populations was observed in aged mice that underwent burn injury. We then profiled anti-microbial peptides (AMPs) in the ileum and found that burn injury stimulated a 20-fold rise in levels of regenerating islet-derived protein 3 gamma (Reg3γ), a 16-fold rise in regenerating islet-derived protein 3 beta (Reg3β), and an 8-fold rise in Cathelicidin-related antimicrobial peptide (Cramp) in young, but not aged mice. Advanced age alone elicited 5-fold higher levels of alpha defensin related sequence1 (Defa-rs1) in the ileum, but this increase was lost following burn. Comparison of bacterial genera abundance and AMP expression across treatment groups revealed distinct correlation patterns between AMPs and individual genera. Our results reveal that burn injury drives microbiome dysbiosis and altered AMP expression in an age-dependent fashion, and highlight potential mechanistic targets contributing to the increased morbidity and mortality observed in elderly burn patients.

*Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Burn Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045

Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045

Medical Scientist Training Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045

§Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045

||Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153

GI and Liver and Innate Immunity Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045

Address reprint requests to Elizabeth J. Kovacs, PhD, Director, Burn Research, Director, Alcohol Research Program, Professor, Department of Surgery, GITES, University of Colorado Denver / Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, Aurora, CO 80045. E-mail: Elizabeth.Kovacs@UCDenver.edu

Received 2 December, 2018

Revised 26 December, 2018

Accepted 16 January, 2019

Research Funding: NIH R01 AG018859 (EJK), R01 GM115257 (EJK), R21 AA026295 (EJK), R01 GM128242 (MAC).

The authors declare no conflicts of interest.

© 2019 by the Shock Society