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

Summary

A Muribaculaceae-dominant microbiota, driven by Sangeribacter muris KT1-3, primes macrophages and lowers the TLR4 activation threshold, producing lethal hyperinflammation in A. baumannii sepsis. The phenotype is transferable by FMT/co-housing and mediated by heat-stable <3 kDa metabolites; Tlr4−/− mice survive despite bacterial dissemination.

Key Findings

• A Muribaculaceae-enriched microbiota dominated by Sangeribacter muris KT1-3 predisposes mice to fatal A. baumannii sepsis.
• The lethal hyperinflammatory phenotype transfers via fecal microbiota transplantation and co-housing.
• Fixed-dose LPS challenge elicits exaggerated TLR4-dependent cytokine responses independent of bacterial replication.
• Single-cell transcriptomics reveals a transcriptionally pre-activated macrophage state.
• KT1-3 releases heat-stable, <3 kDa metabolites that potentiate systemic cytokine surges.
• Tlr4-deficient mice with the susceptible microbiota survive despite persistent bacterial dissemination.

Clinical Implications

Microbiome profiling could identify patients at risk of hyperinflammatory sepsis and inform TLR4-modulating or microbiota-targeted interventions; translation requires human validation and metabolite identification.

Limitations

• Findings are limited to murine models; human validation and generalizability remain to be established.
• Specific metabolites were not chemically identified; mechanism of TLR4 threshold modulation requires elucidation.

Future Directions

Isolate and characterize KT1-3 metabolites; validate microbiota signatures and TLR4 priming in human cohorts; test microbiome or TLR4-targeted modulators in translational models.