# Gut microbial fermentation products of muscle-derived lactate as mediators of exercise and metabolism

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2024 · $54,762

## Abstract

PROJECT SUMMARY/ABSTRACT
The gut microbiome makes significant contributions to whole-body glucose metabolism and insulin sensitivity, in
part, through production of short chain fatty acids (SCFA)1–3. Recent evidence suggests that microbial SCFA
production may be increased by exercise training, and that SCFA may be important positive regulators of
exercise performance and skeletal muscle metabolism and function4. However, it is not known how gut microbes
could regulate SCFA production in response to exercise. Our work identifies lactate utilizing bacteria (LU-Bac),
which can convert lactate to SCFA, as potential sources of SCFA during exercise5. As circulating lactate levels
increase during moderate to high intensity exercise, combining LU-Bac supplementation with exercise may result
in higher levels of circulating SCFA, thus enhancing the metabolic benefits of exercise. Individuals with impaired
glucose tolerance have lower gut LU-Bac content, and blunted metabolic and aerobic improvements in response
to exercise training4. Thus, in addition to improving metabolic health, LU-Bac supplementation may enhance the
health benefits of exercise by ameliorating the metabolic defects that lead to impaired training response. We
hypothesize that lactate produced by muscle with regular exercise is used by LU-Bac to generate SCFA, which
then act on skeletal muscle to improve metabolism and function. We propose this novel gut-muscle axis leads
to improved metabolic health and exercise response. One aim of this proposal is to test LU-Bac supplementation
as a treatment for impaired glucose tolerance and low response to exercise in mouse models of metabolic
disease that partially reflect the pathologies of type 1 and type 2 diabetes. A second aim is to determine the
specific contribution of lactate fermentation by LU-Bac to circulating and tissue SCFA levels with exercise, and
whether LU-Bac-derived SCFA contribute to the health benefits of exercise training. Our third aim is to define
the mechanisms in skeletal muscle by which SCFA lead to enhanced exercise performance and metabolic
health. Specifically, we will determine whether SCFA receptors and transporters in muscle are necessary for
the positive effects of SCFA on muscle metabolism and function. This work will have a broad impact on the
fields of exercise, metabolism, and microbiology by determining the mechanisms by which the microbiome can
enhance muscle metabolism and adaptation to exercise. We anticipate our results will lead to development of a
live biotherapeutic to improve exercise response and metabolic health.

## Key facts

- **NIH application ID:** 11003454
- **Project number:** 3R01DK129850-03S1
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** Aleksandar David Kostic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $54,762
- **Award type:** 3
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11003454

## Citation

> US National Institutes of Health, RePORTER application 11003454, Gut microbial fermentation products of muscle-derived lactate as mediators of exercise and metabolism (3R01DK129850-03S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11003454. Licensed CC0.

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