Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition.

Summary

In a mouse model of acute endotoxemia, physiologic-range systemic LPS rapidly induced 100–10,000-fold blooms of gut-luminal facultative pathogens without overt enteropathy. The effect was TLR4-dependent, mediated by increased luminal reactive oxygen species that transiently halted microbial fermentation and enabled oxidative respiration-driven pathogen expansion.

Key Findings

• Systemic LPS exposure caused 100–10,000-fold increases of K. pneumoniae, E. coli, E. faecium, and S. Typhimurium in the gut within 24 hours.
• The pathogen bloom occurred without overt enteropathy, indicating luminal ecological shifts rather than mucosal injury.
• Mechanism: TLR4-dependent rise in gut-luminal reactive oxygen species transiently halted microbiota fermentation.
• Facultative anaerobes expanded via oxidative respiration fueled by increased oxygen species.
• Findings suggest systemic immune activation transiently disrupts microbiota homeostasis, increasing infection risk.

Clinical Implications

Although preclinical, findings imply that mitigating luminal oxidative stress or modulating TLR4 signaling could reduce gut pathogen blooms and secondary infections in critically ill patients. It also supports cautious use of interventions that alter redox balance or fermentation.

Limitations

• Mouse model limits direct clinical generalizability to human sepsis.
• Short-term observations without interventional reversal studies in patients.

Future Directions

Test antioxidant, TLR4-modulating, or fermentation-supporting interventions in translational models and early-phase trials to prevent pathogen blooms and secondary infections in critical illness.