A Muribaculaceae-enriched microbiota exacerbates TLR4-dependent Acinetobacter baumannii-induced hyperinflammatory...

Area of Science:

• Microbiology
• Immunology
• Host-Microbe Interactions

Background:

• Host survival in sepsis is influenced by pathogen burden and inflammatory responses.
• The gut microbiota plays a critical role in modulating host immunity and inflammation.

Purpose of the Study:

• To investigate how specific gut microbiota configurations impact host survival during sepsis.
• To elucidate the mechanisms by which gut microbes modulate inflammatory thresholds and sepsis outcomes.

Main Methods:

• Utilized genetically equivalent female C57BL/6 mice with distinct gut microbiota.
• Employed fecal microbiota transplantation and co-housing to transfer microbial phenotypes.
• Performed lipopolysaccharide (LPS) challenge, ex vivo stimulation assays, and single-cell transcriptomics.
• Investigated the role of Toll-like receptor 4 (TLR4) and microbial metabolites.

Main Results:

• A gut microbiota enriched with Muribaculaceae, specifically Sangeribacter muris KT1-3, predisposed mice to fatal Acinetobacter baumannii sepsis.
• This microbiota configuration induced heightened TLR4-dependent inflammation, independent of bacterial replication.
• Microbiota-derived metabolites (<3 kDa) potentiated cytokine surges and lowered the TLR4 activation threshold.
• TLR4-deficient mice with the susceptible microbiota survived sepsis, indicating the microbiota-TLR4 axis dictates outcome.

Conclusions:

• Specific gut microbiota compositions, like S. muris enrichment, can drive lethal hyperinflammation in sepsis.
• The gut microbiota-TLR4 axis is a key determinant of sepsis severity by modulating inflammatory magnitude.
• Findings provide a framework for understanding how gut microbiota influences host susceptibility and infection resilience.