Low-Dose Antibiotic Reprograms Gut Bacteria to Extend Lifespan in Worms and Mice
A sub-antibiotic dose of cephaloridine triggers colanic acid production in gut E. coli, extending C. elegans lifespan and reversing age-related changes in mice.
Summary
Researchers discovered that exposing commensal Escherichia coli to a low dose of the antibiotic cephaloridine triggers overproduction of colanic acid (CA), a bacterial polysaccharide previously shown to promote longevity. In C. elegans, this chemical treatment significantly extended lifespan. In mice, oral cephaloridine activated the CA biosynthesis gene operon in gut E. coli at body temperature and attenuated age-related metabolic changes. The mechanism bypasses temperature-dependent suppression of CA synthesis via the membrane histidine kinase ZraS, independent of the drug's antibiotic activity. This work establishes a proof-of-concept for using small molecules to chemically reprogram gut microbiota metabolism for host longevity benefits.
Detailed Summary
The gut microbiome is increasingly recognized as a key modulator of aging, yet deliberate chemical strategies to reprogram bacterial metabolism for longevity remain largely unexplored. This study addresses that gap by identifying a novel pro-longevity mechanism triggered by sub-antibiotic concentrations of cephaloridine, a first-generation cephalosporin antibiotic.
The researchers first demonstrated that wild-type E. coli strains exposed to low-dose cephaloridine dramatically overproduce colanic acid (CA), a capsular exopolysaccharide previously shown to extend C. elegans lifespan when bacteria are fed to worms. Using genetic knockouts of the cps operon — the gene cluster responsible for CA biosynthesis — the team confirmed that CA production is required for the lifespan extension observed. Worms fed cephaloridine-treated E. coli lived significantly longer than controls, with effects dependent on intact CA biosynthetic machinery in the bacteria.
A critical challenge was that CA biosynthesis is normally temperature-suppressed at 37°C (mammalian body temperature), making in vivo translation seem implausible. Remarkably, low-dose cephaloridine overcomes this thermosuppression. The mechanism was traced to ZraS, a membrane-bound histidine kinase that senses cell envelope stress. Cephaloridine activates ZraS signaling, which in turn induces cps operon transcription even at 37°C. Importantly, this effect is independent of cephaloridine's classical antibiotic (beta-lactam) activity, as shown by experiments using cephaloridine analogs and bacterial mutants.
In a mouse model, oral administration of low-dose cephaloridine successfully induced cps operon transcription in gut-resident commensal E. coli, confirmed by metagenomic and transcriptomic analyses of fecal samples. Aged mice treated with cephaloridine showed attenuation of age-related metabolic changes, including improvements in markers associated with metabolic dysfunction. Gut microbiome composition analyses suggested the low dose did not drastically alter microbial community diversity, supporting the specificity of the metabolic intervention.
This study establishes a compelling framework for 'microbiota pharmacology' — using targeted chemical agents to redirect bacterial metabolic output toward host-beneficial molecules. The findings raise the prospect that existing drugs, used at sub-therapeutic doses, could be repurposed to modulate gut microbial metabolism for longevity and metabolic health. However, questions remain about long-term safety, effects on antibiotic resistance, and translation to human microbiome complexity.
Key Findings
- Low-dose cephaloridine induces colanic acid overproduction in commensal E. coli, extending C. elegans lifespan.
- The membrane histidine kinase ZraS mediates cephaloridine-induced CA biosynthesis independently of antibiotic activity.
- Cephaloridine overcomes temperature-dependent suppression of CA synthesis, enabling induction at mammalian body temperature (37°C).
- Oral low-dose cephaloridine activates the cps biosynthesis operon in mouse gut E. coli and attenuates age-related metabolic changes.
- The pro-longevity effect requires intact bacterial CA biosynthetic genes, confirming CA as the active microbial mediator.
Methodology
C. elegans lifespan assays were conducted feeding worms cephaloridine-treated wild-type and cps-mutant E. coli. Mouse experiments involved oral administration of low-dose cephaloridine to aged mice, with gut microbiome and transcriptome profiling via metagenomics and RNA-seq (SRA: PRJNA1111054, PRJNA1265280). Genetic and pharmacological dissection identified ZraS as the mechanistic sensor.
Study Limitations
The study used laboratory E. coli strains and inbred mouse models, which may not reflect the complexity of the human gut microbiome. Long-term safety of repeated low-dose antibiotic administration — including antibiotic resistance development and off-target microbiome disruption — was not fully characterized. Mechanistic translation from C. elegans and mice to humans requires further validation.
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