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Persistence and Sexual Dimorphism of the Pathobiome after Sepsis and Trauma
*Jennifer A. Munley1, *Gwoncheol Park2, *Lauren Kelly1, *Kolenkode B. Kannan1, *Robert T. Mankowski3, *Gemma Casadesus5, *Paramita Chakrabarty4, *Shannon M. Wallet6, *Robert Maile1, *Letitia E. Bible1, *Bo Wang7, *Lyle L. Moldawer1, Alicia M. Mohr1, *Ravinder Nagpal2, Philip Efron1
1Surgery, University of Florida, Gainesville, FL; 2Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, FL; 3Physiology and Aging, University of Florida, Gainesville, FL; 4Neuroscience, University of Florida, Gainesville, FL; 5Pharmacology and Therapeutics, University of Florida, Gainesville, FL; 6Oral Biology, University of Florida, Gainesville, FL; 7Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL

Objectives: Sepsis and trauma have each been shown to induce an intestinal “pathobiome� phenotype characterized by depleted diversity and dominance of opportunistic pathogens. However, the persistence, magnitude and perturbations of this ‘gut dysbiosis’ and its related plasma metabolome after severe injury versus severe infection remain unknown. We hypothesized that patients experiencing chronic critical illness (CCI) after sepsis or trauma would have persistent dysbiosis in their gut microbiome and gut-plasma metabolome and that these alterations would also be influenced by host sex.
Methods: A prospective observational cohort study of patients who suffered severe trauma or sepsis was conducted between 2019-2023. Stool and plasma were collected from patients 2-3 weeks after initial insult and compared to samples from healthy subjects. A high-throughput multi-omics approach was undertaken to evaluate gut microbiome diversity and composition along with gut-plasma metabolite responses. Significance was defined as p<0.05.
Results: Two weeks after insult, patients in the sepsis and trauma cohorts demonstrated strikingly depleted gut microbiome diversity, with a loss of commensal bacteria and blooms of pathogenic bacteria compared to healthy subjects. Notably, sepsis patients exhibited the lowest alpha-diversity between all cohorts. Subgroup analyses based on sex revealed resistance to changes in microbiome diversity among female trauma patients compared to healthy counterparts (Fig. 1). Furthermore, sex-specific changes in microbiome diversity among female trauma patients were observed (Fig. 1), along with sex-specific changes in fecal metabolites after trauma or sepsis. Plasma metabolites also changed after trauma and sepsis and unique correlations between intestinal microbes and gut-plasma metabolites were identified in both sepsis and trauma cohorts.
Conclusions: Dysbiosis induced by trauma and sepsis persists weeks after onset and is both sex- and insult-specific. This pathobiome and entero-septic microbial-metabolite perturbations are potentially modifiable elements. Sexual dimorphism in the resilience of the host microbiome in females highlights the need for including sex as a variable in the treatment of sepsis and trauma patients.

Figure 1. Intestinal microbiome A) beta-diversity changes after trauma or sepsis compared to healthy controls by sex, B) Observed amplicon sequence variants (ASV) by cohort and sex, and C) genus-level composition. M – male, F – female.
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