Figure 4: Serum lactate crosses the epithelial barrier into the gut lumen and colorectal propionate instillation is sufficient to enhance treadmill runtime.

A: SCFAs detected in spent media after 48 hours of growth with the indicated strain. LM = semi-synthetic lactate media; BHIL = brain-heart infusion media supplemented with sodium lactate; n/a = not quantified. Each table entry shows the mean ± s.e.m. (BHIL, n = 2; LM, n = 3). (p values from left to right, top to bottom: .0008, .003, 4.4E-7, 1.4E-6, .001, .023, .006, .03, .02, .015; compared with media control using two-sided Welch’s t-test). B: Schematic of the 13C3 flux tracing experimental design. Mice were injected with 13C3 sodium lactate, then sacrificed after 12 minutes. Serum and plasma were collected via cardiac puncture. Cecum and colon contents were collected by dissection. C: Abundance of 13C3 lactate quantified relative to abundance of unlabeled lactate. Each mouse sample is represented as an individual point, with the central bar representing the mean and error bars representing s.e.m. (n = 7). D: 13C3 lactate abundance normalized to the expected natural abundance of 13C3 lactate. Ratio of labeled/unlabeled lactate was quantified for experimental samples as well as for unlabeled lactate standard. Experimental samples are represented as fold-change relative to unlabeled standard. Each mouse sample is represented as an individual point, with the central bar representing the mean and error bars representing s.e.m. (n = 7). (p values are from two-sided one sample t-test vs natural abundance). E: Intracolonic infusion of propionate improves maximum run time in mice. Data shown are the maximum run time out of 3 days of consecutive treadmill running. The jitter plot shows each mouse as an individual point, with the central bar representing the mean and error bars representing s.e.m. (n = 8). (p value from two-sided unpaired t-test). F: Proposed model of the microbiome-exercise interaction. Black arrows represent the well-known steps of the Cori cycle, where glucose is converted to lactate in the muscle, enters the liver via blood circulation, then is converted back to glucose in the liver via gluconeogenesis. Red arrows represent the steps proposed in this work. First, lactate produced in the muscle enters the intestinal lumen via blood circulation. In the intestine it acts as a carbon source for specific microbes, including Veillonella species. This causes the observed bloom in intestinal Veillonella, as well as production of SCFA byproducts (predominantly propionate), which are taken up by the host via the intestinal epithelium. Presence of microbiome-sourced SCFAs in the blood improves athletic performance via an unknown mechanism. Together, this creates an addendum to the Cori cycle by converting an exercise byproduct into a performance-enhancing molecule, mediated by naturally occurring members of the athlete gut microbiome.