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Engineered Lactate Catabolizing Probiotics Reveal Timescale Dependent Microbiome-Host Metabolic Coupling
Noah T Hutchinson1, Ningyuan Ye1, Maria Jennings1
1Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, United States.
Biorxiv : the Preprint Server for Biology
|April 17, 2026
Summary
Engineered probiotics converting gut lactate to pyruvate acutely boost host energy expenditure and immunity. However, chronic treatment failed to prevent obesity, showing limits of gut-centric therapies against long-term homeostatic forces.
Area of Science:
- Microbiome-host metabolic interactions
- Gut microbial metabolism
- Probiotic engineering
Background:
- Lactate is a key metabolite exchanged between the gut and host circulation.
- Understanding lactate's role in host metabolism requires specific tools.
- Engineered probiotics offer a platform to investigate gut lactate's impact.
Purpose of the Study:
- To investigate the influence of gut lactate conversion on host metabolic status.
- To assess the acute and chronic effects of engineered probiotics on host metabolism and microbiota.
- To evaluate the therapeutic potential of engineered probiotics in metabolic and inflammatory conditions.
Main Methods:
- Engineered probiotic Bacillus subtilis PY79 to produce intracellular lactate oxidase (LOX).
- Oral administration of LOX probiotics in acute and chronic diet-induced obesity models.
- 16S rRNA sequencing, indirect calorimetry, in silico microbial modeling (MICOM), and metagenomic inference (PICRUSt2).
Main Results:
- Acute LOX administration remodeled the microbiota towards anabolic processes and increased host energy expenditure.
- LOX treatment improved thermoregulation and survival during LPS-induced sepsis.
- Chronic LOX administration reduced blood lactate but did not prevent diet-induced obesity or alter long-term energy expenditure.
Conclusions:
- Engineered probiotics (LOX) are effective tools for acute metabolic augmentation via gut lactate conversion.
- Gut-centric lactate conversion has limited long-term impact on chronic diseases due to homeostatic compensation.
- Findings inform the design of probiotic interventions tailored to therapeutic timescales and chronic conditions.
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