Sex differences associate with late microbiome alterations after murine surgical sepsis

Abstract

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.

Multicompartmental traumatic injury induces sex-specific alterations in the gut microbiome

“…This group also demonstrated that after 7 days, male microbiota were dominated by Bacteroidales, while females had high abundance of Clostridiales. 13 While this study was of a model of surgical sepsis, this suggests that critical illness induces a decline in alpha-diversity and changes in beta-diversity similar to our study within 1 week 13 . Given the findings by this group, additional studies on the longer-term effects of severe trauma on the microbiome in both sexes are warranted to elucidate microbiome resilience and recovery after insult.…”

“…Unfortunately, there is a paucity of data investigating the influence of sex on the microbiome in trauma and critical illness. Efron et al 13 found that both murine males and females subjected to cecal ligation and puncture had a decline in alpha-diversity and differences in beta-diversity compared with controls after 7 days which recovered by Day 14 only in females. This group also demonstrated that after 7 days, male microbiota were dominated by Bacteroidales, while females had high abundance of Clostridiales.…”

Multicompartmental traumatic injury and the microbiome: Shift to a pathobiome

“…In addition, we only evaluated microbiome and intestinal change in male rats; going forward, it will be important to assess sex differences between males and females. Sex has been proven to influence the microbiome, and one study had already demonstrated unique microbial composition between sexes in the setting of murine sepsis 49,50 . Finally, this study was only of rats aged 9 to 11 weeks; further studies on the potential influence of age on intestinal dysbiosis after trauma should be considered.…”

“…Sex has been proven to influence the microbiome, and one study had already demonstrated unique microbial composition between sexes in the setting of murine sepsis. 49,50 Finally, this study was only of rats aged 9 to 11 weeks; further studies on the potential influence of age on intestinal dysbiosis after trauma should be considered.…”

Interactions between Gender and Sepsis—Implications for the Future

“…However, at day 14, the microbiome of females recovers fully while that of males still differs from controls. Notably, female recovery seems age dependent; only young females are similar to controls at day 14 [ 41 ]. The authors that showed these findings have suggested that female resilience to microbiome pathogens may explain some of the sex-related differences in sepsis outcomes.…”