Septic Stability? Gut Microbiota in Young Adult Mice Maintains Overall Stability After Sepsis Compared to Old Adult Mice

Mankowski, Robert T.; Thomas, Ryan M.; Darden, Dijoia B; Gharaibeh, Raad Z.; Hawkins, Russell B.; Cox, Michael C.; Nacionales, Dina C.; Ungaro, Ricardo; Dirain, Marvin; Moore, F. A.; Leeuwenburgh, Christiaan; Brakenridge, Scott C.; Clanton, Thomas L.; Laitano, Orlando; Moldawer, Lyle L.; Mohr, Alicia M.; Efron, Philip A.

doi:10.1097/shk.0000000000001648

Cited by 13 publications

(17 citation statements)

References 51 publications

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“…This has been previously demonstrated by members of our group. 33 These findings support our hypothesis that the pathologic changes within the gut microbiome are not permanent and likely can be prevented or reversed to alter posttrauma outcomes.…”

Section: Discussionsupporting

confidence: 83%

Stress-related changes in the gut microbiome after trauma

Kelly

Gharaibeh

Pons

et al. 2021

J Trauma Acute Care Surg

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BACKGROUND:The gut microbiome protects the host from infection by promoting epithelial integrity and providing basal immunologic stimulation. Disruption of this delicate ecosystem is linked to morbidity and mortality among critically ill patients, but the impact of traumatic injury on the gut microbiome is poorly understood. This study sought to identify alterations in gut microbiota following trauma and persistent stress in rodents without confounding antibiotics. METHODS:Male Sprague-Dawley rats aged 9 weeks to 11 weeks were randomized to naive, lung contusion with hemorrhagic shock (LCHS), and LCHS plus either 7 (LCHS/CS 7/7) or 14 days (LCHS/CS 14) of restraint cylinder stress for 2 hours daily. Stool was collected on Days 0, 3, 7, and 14 for bacterial whole genome DNA isolation. Alpha diversity, or the number and relative abundance of unique bacterial species within each cohort, was assessed using Chao1 indices. Beta diversity, or the measure of differences in biodiversity across cohorts, was assessed by principle coordinate analysis. False discovery rate correction was applied to all statistical analyses and corrected for cohousing effects. RESULTS:Rodent groups subject to restraint stress demonstrated a progressive increase in alpha diversity over time. These microbiota changes resolved after cessation of stress (LCHS/CS 7/7) but continued to increase among rats subjected to ongoing stress (LCHS/CS 14). The LCHS/CS 7/7 also demonstrated reductions in class Actinobacteria and increased abundance of the genus Bacteroides by Day 7, which resolved by Day 14. Increased abundance of Bacteroides was also noted in the LCHS/CS 14 cohort, suggesting the role of chronic stress in its destabilization. CONCLUSION: This study points to persistent stress as a potential source of the destabilization of microbial diversity seen after trauma. This lack of microbiota stability could be associated with worse long-term outcomes in critically ill trauma patients. Further studies are warranted to elucidate mechanistic pathways and potential therapeutic modalities.

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Section: Discussionsupporting

confidence: 83%

Stress-related changes in the gut microbiome after trauma

Kelly

Gharaibeh

Pons

et al. 2021

J Trauma Acute Care Surg

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“…We have previously demonstrated the impact of age on the stability of the murine microbiota after CLP-DCS 29 . However, it is unknown what impact sex has in relation to microbiome changes after sepsis over the adult age range.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously demonstrated the impact of age on the stability of the murine microbiota after CLP-DCS. 29 However, it is unknown what impact sex has in relation to microbiome changes after sepsis over the adult age range. Given the clinical data demonstrating survival differences after sepsis between male and female patients, we sought to determine whether the changes in the host microbiota in a murine model of sepsis/PICS are based on the sex of the host.…”

Section: Resultsmentioning

confidence: 99%

Sex differences associate with late microbiome alterations after murine surgical sepsis

Efron

Darden

et al. 2022

J Trauma Acute Care Surg

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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.

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“…Although more research is needed to identify mechanistic links that may lead to effective therapeutic targets, it is possible to conjecture future therapeutic strategies. The first obvious approach involves prevention of microbiome dysbiosis, which would include fecal microbiota transplantation from healthy subjects given evidence in that stabilization of the microbiota in a young versus old mice in a murine model of sepsis may help to explain improved outcomes in young patients with sepsis compared to old (103). Additionally, improving the microbial environment by supplementing beneficial bacteria by fecal microbiota transplantation (FMT) that can abrogate the pro-inflammatory process and myopathy may provide clinical improvement in sepsis patients (104).…”

Section: Immunological Mediators Of Satellite Cell Dysfunction In Sepsismentioning

confidence: 99%

Sepsis-Induced Myopathy and Gut Microbiome Dysbiosis: Mechanistic Links and Therapeutic Targets

Mankowski

Laitano

Darden

et al. 2021

Shock

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Sepsis is currently defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The skeletal muscle system is among the host organ systems compromised by sepsis. The resulting neuromuscular dysfunction and impaired regenerative capacity defines sepsis-induced myopathy and manifests as atrophy, loss of strength, and hindered regeneration after injury. These outcomes delay recovery from critical illness and confer increased vulnerability to morbidity and mortality. The mechanisms underlying sepsis-induced myopathy, including the potential contribution of peripheral organs, remain largely unexplored. The gut microbiome is an immunological and homeostatic entity that interacts with and controls end-organ function, including the skeletal muscle system. Sepsis induces alterations in the gut microbiota composition, which is globally termed a state of ''dysbiosis'' for the host compared to baseline microbiota composition. In this review, we critically evaluate existing evidence and potential mechanisms linking sepsis-induced myopathy with gut microbiota dysbiosis.

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Septic Stability? Gut Microbiota in Young Adult Mice Maintains Overall Stability After Sepsis Compared to Old Adult Mice

Cited by 13 publications

References 51 publications

Stress-related changes in the gut microbiome after trauma

Stress-related changes in the gut microbiome after trauma

Sex differences associate with late microbiome alterations after murine surgical sepsis

Sepsis-Induced Myopathy and Gut Microbiome Dysbiosis: Mechanistic Links and Therapeutic Targets

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