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Published on: July 12, 2018
Sex differences associate with late microbiome alterations after murine surgical sepsis
Philip Alexander Efron1, Dijoia B Darden, Eric C Li
1From the Department of Surgery (P.A.E., D.B.D., J.M., L.K., B.F., D.C.N., R.F.U., M.L.D., J.R., F.A.M., S.C.B., L.L.M., A.M.M., R.M.T.), Department of Aging and Geriatric Research (P.A.E., R.T.M., C.L.), Department of Medicine (E.C.L.), and Division of Infectious Diseases and Global Medicine, Department of Neuroscience (T.C.F.), University of Florida College of Medicine, Gainesville; Department of Nutrition and Integrative Physiology (O.L.), Florida State University College of Health and Human Sciences, Tallahassee; Department of Pharmacology and Therapeutics (G.C.), College of Medicine, and Department of Molecular Genetics and Microbiology (R.M.T.), University of Florida; and Section of General Surgery (R.M.T.); North Florida/South Georgia Veterans Health System, Gainesville, Florida.
Background:
Sepsis-induced gut microbiome alterations contribute to sepsis-related morbidity and mortality. Given evidence for improved postsepsis outcomes in females compared with males, we hypothesized that female mice maintain microbiota resilience versus males.
Methods:
Mixed-sex C57BL/6 mice underwent cecal ligation and puncture (CLP) with antibiotics, saline resuscitation, and daily chronic stress and were compared with naive (nonsepsis/no antibiotics) controls. For this work, the results of young (3-5 months) and old (18-22 months) adult mice were analyzed by sex, independent and dependent of age. Mice were sacrificed at days 7 and 14, and 16S rRNA gene sequencing was performed on fecal bacterial DNA. α and β diversity were determined by Shannon index and Bray-Curtis with principal coordinate analysis, respectively. False discovery rate (FDR) correction was implemented to account for potential housing effect.
Results:
In control mice, there was no difference in α or β diversity between male and female mice (FDR, 0.76 and 0.99, respectively). However, male mice that underwent CLP with daily chronic stress had a decrease in microbiota α diversity at 7 days post-CLP (Shannon FDR, 0.005), which was sustained at 14 days post-CLP (Shannon FDR, 0.001), compared with baseline. In addition, male mice maintained differences in β diversity even at day 14 compared with controls (FDR, <0.0001). In contrast, female mice had a decreased microbiota α diversity (Shannon FDR, 0.03) and β diversity (FDR, 0.02) 7 days post-CLP but recovered their α and β diversity by post-CLP day 14 (Shannon FDR, 0.5, and FDR, 0.02, respectively). Further analysis of females revealed that only young female mice were not different (β diversity) post-CLP day 14 to controls.
Conclusion:
Although sepsis-induced perturbations of the intestinal microbiota occur initially in both male and female C57BL/6 mice, females demonstrate different microbiota by day 14. This may be seen primarily in younger females. This difference in recovery may play a role in outcome differences between sexes after sepsis.
