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Our (my wife and co-coach, Megan and I) baby Leo is a normal 10-week-old infant in most respects. He mostly poops and sits there, like a houseplant that is gradually gaining sentience. But there is one place where he is exceptional: rolling over.
Starting at 2 weeks, Leo would roll over from his stomach to his back. He might have a lower IQ than a dog for the next two-ish years, but when it came to rolling over, he was LeBron James mixed with Albert Einstein. By two months, he would roll over 10 times consecutively, like he was really nailing 1/3 of the directions for extinguishing a fire on his pants. We always hear about prodigies in chess or calculus, which implies that there are also prodigies in less useful things like Yahtzee or listening to podcasts on 3x speed. Leo fell into that second group.
Last week, though, his powers vanished. After his shots, he lost the ability to even try to roll over. We expected 24-48 hours of fatigue, but this was worse than fatigue: we couldn’t post any Instagram stories of his exploits for almost a week. The horror! He’s back to rolling over now, not quite where he was, but getting there. Even LeBron sprains his ankle. And I think there’s a fascinating lesson there about physiology research.
For human participants in research studies, the brain plays a massive role in influencing results. The placebo effect is often around 2% across study interventions. Mental strategies can change performance up to five to 10% depending on the protocol. Whenever behavior and/or performance are measured, we’re panning for gold in a flowing stream of psychology.
That’s why I love studies on mice as a first step for establishing some mechanistic explanation for novel physiological variables before following up on human subjects. Mice are not changing their performance based on some bad dreams they had the night before. It’s similar to what happened with Leo. An adult who got a few shots would probably say they feel normal a few days later, while Leo was dragging ass in the only performance metric we have–his world-class rolling-over ability. Basically, a baby is a lot like a mouse, except at the end of the experiment, it is recommended that you don’t cut the baby open for more answers.
All of that brings us to an incredibly exciting mouse study that could have implications for how we think about performance and motivation for humans too. The big finding: the gut microbiome could influence motivation and performance via dopamine in the brain, which might change how we think about what drives physiological/training variation across the life cycle.
The Microbiome and Running
Published in December 2022 in Nature, it asked a thrilling question: how are motivation and performance affected by the microbiome? Because mice have fewer confounding variables to worry about, whether related to psychology or life history, doing biology research on them allows the isolation of dependent variables–in this case, microbiome status. The findings were absolutely bonkers, possibly making it my new favorite study of all time.
First, a step back. There is an extensive body of research on the microbiome and athletic performance, which we reviewed last year. The microbiome consists of thousands of bacterial groups, millions of genes, and non-bacterial cells and viruses. It’s extremely hard to determine what different gut biota actually do because there are so many interrelated functions.
The big conclusion is that we are in the early stages of this field, and more is unknown than is known, but the microbiome seems to do… well, just about everything. As outlined by a 2020 review article in the Journal of the International Society of Sports Nutrition, the microbiome is essential for “nutrient uptake, vitamin synthesis, energy harvest, inflammatory modulation, and host immune response.” Those mechanisms touch everything for healthy life function, from metabolic processes to disease processes to even things like VO2 max. Certain biota have even been identified as especially important for athletic performance!
A 2019 study in Nature found a post-marathon spike in Veillonella, which is known to metabolize lactate. After isolating Veillonella in a runner, the researchers inoculated mice with it, and those mice were able to run 13% farther on their adorable mice treadmills. A human-to-mouse poop transplant! Science is wonderful.
Mice studies are important at every stage of the research. Some of the initial findings in the field were first made with mice, whose microbiomes were selectively knocked out to track downstream impacts, which gave hints into just how important gut biota was, both in a general way and related to specific patterns. Later, as demonstrated by the 2019 study, mice can show efficacy prior to human trials via cross-species tests. Prognosticators say that microbiome interventions could present a massive opportunity to reshape how we think about human health and performance. And we’ll owe a substantial portion of those breakthroughs to mice.
So far, the research has demonstrated that the microbiome is instrumental in health and performance. But how does the microbiome impact the brain and motivation for athletics? That is the question asked by the 2022 study, following up on some research that found a gut-brain connection in other areas.
Studying the Microbiome
The researchers started with 199 untrained mice with complete microbiome modeling consisting of 10,500 data points per mouse. “Subsequently,” the authors said, “the mice underwent exercise profiling by either voluntary running in wheels or endurance running on treadmills.” My life will not be complete until I become a certified mouse coach. You’d think the mice would be similar in their volitional exercise habits given their similar genetic profiles, right? In fact, the mice had wildly different exercise capacities!
But how can they isolate the cause of that variability? Here’s where the study goes from fun, to extremely important. They profiled genetic signatures, blood metrics, metabolic parameters, and microbiomes, then trained a machine learning model to identify correlations with performance. “Notably,” the authors said, “a prediction based solely on [microbiome] sequencing results achieved accuracies that were almost as high as those achieved with the serum metabolome or all measured parameters combined, despite encompassing a much smaller number of variables.” That finding seemed to indicate that the microbiome was driving a substantial portion of performance variance.
The researchers next completed loss-of-function (microbiome depletion) and gain-of-function (microbiome transplant) studies. You can see why it’s important that these interventions are conducted on mice–it would be very unethical to knock out microbiome in humans who rely on it for healthy functioning. Depleting the microbiome reduced athletic performance by about 50%. When they transplanted the gut biota from high-achieving mice into mice that were raised without a microbiome, the poop-powered mice excelled to the level of the donor (through further antibiotic-specific tests, they narrowed down potential culprits in the Erysipelotrichaceae and Lachnospiraceae families). WOW! Microbiome variance seemed to be overpowering every other variable in predicting performance.
Now is when we return to the concept of the intro. I am sure mice all have rich internal worlds, but for the sake of science, we can assume that individual variance can be explained by physiological parameters. The researchers hypothesized that the performance changes were due to the microbiome’s role in muscle function. “However,” the authors said, “ex vivo tests of muscle function, oxygen consumption or transcriptomics did not reveal major effects of antibiotic treatment, suggesting that the pronounced effect of the gut microbiome on voluntary and endurance exercise may not be mediated by changes in muscle physiology.” I regret to inform you that ex vivo tests should not be something you type into Google, another reason these tests are not conducted on humans.
Microbiome and the Brain
The authors completed RNA sequencing of neuronal regions in the treated mice following exercise, finding variation in neuronal regions associated with dopamine. Measuring dopamine levels, they found much higher responses in mice with healthy microbiomes. “Strikingly, the authors said, “this dopamine response was nearly eliminated in antibiotic-treated animals… An impaired striatal dopamine response was only observed in the exercised state, whereas basal levels of dopamine were unaffected by the microbiome.” And other neurotransmitters were not affected by exercise or the microbiome at all! So microbiome status seems to be directly impacting exercise-related dopamine response in mice, which alters reward pathways and motivation.
But the researchers didn’t stop there! “Dopamine degradation is regulated by the enzyme monoamine oxidase (MAO),” and when MAO was inhibited with medication (a task completed by a healthy microbiome in the high-performing mice), the performance levels of the mice rebounded. They also isolated the types of neurons that mediated this pathway, along with signaling pathways that were important, which will be key for future research. To summarize the entire finding for fellow freaky science friends, the authors put it all on the table: “Our results show that the gut microbiome contributes to the generation of intestinal [fatty acid] metabolites that trigger CB1-expressing TRPV1+ sensory neurons, which in turn send an exercise-induced afferent signal to the brain and promote the downregulation of MAO expression in the striatum. This downregulation of MAO contributes to higher levels of dopamine and enhanced exercise capability.”
Study Implications: Runners and the Microbiome
Oh my god, how cool is that study? In addition to being an incredible piece of science with dozens of experimental steps I counted, it was beautifully written, destined to be an iconic piece of literature in the field. The authors theorize that the research may explain a gut origin for variable endocannabinoid releases that result in different levels of “runner’s high” among different people. They also found a relation to pain-relieving effects of exercise, “indicating that the pathway discovered in this study may regulate additional aspects of exercise physiology.” They even come in hot with an evolutionary explanation, saying that the coupling of microbiome and motivation could be because nutrient availability correlates with “the readiness and capacity to engage in prolonged physical activity.” Eat enough always, evolution edition.
What are the implications for humans, including dumb babies? The final sentence of the article lays it all out there: “If applicable to humans, our findings imply that interoceptomimetics that stimulate the motivation for exercise might present a powerful opportunity to counteract the detrimental health impact of a sedentary lifestyle.” I’ll add that the exercise physiology implications could be pointing toward explanations for differential responses to training interventions, somewhere at the murky and very-human valley between mind and body. And it may have implications for how we think about training while taking antibiotics.
The trillion-dollar question is whether this finding will be applicable to humans. We aren’t really close to that answer. As a commentary in Nature said: “Although tempting to consider the human implications of this research, gauging the practical relevance of these findings will require extensive further assessment.” That further assessment will need to be multifaceted and it will likely take many years, because “a variety of other factors influence motivational states in people, requiring a range of strategies to strengthen motivational and reward circuits in unfavourable environments.” Like baby Leo trying to roll over, it’s much harder to discern what makes a human tick, even when that human is a dumb baby.
Comedian Sheng Weng has some commentary that is important to consider too: “How many more times are we going to have to read an article about how they found a new cure for cancer that only works on rats? Can we stop printing this article? Can we agree that it does not belong in the human newspaper? No, man. That’s rat news.”
The next steps in the field are definitely uncertain, but a range of mice and human studies are unveiling a complex interlinking between the gut and almost every variable that goes into health and performance, including in the brain. In the future, we are probably talking about microbiome transplants and individual-specific supplements that have stunning benefits for health (and possibly mental health). For now, focus on your gut health via a range of foods including those with probiotics and prebiotics, eating enough, and considering supplementation if it’s at the recommendation of a doctor or nutrition professional.
There isn’t yet a pill that will give you motivational superpowers. But stay tuned. The Earth-shaking field of microbiome research is just getting started.
David Roche partners with runners of all abilities through his coaching service, Some Work, All Play. With Megan Roche, M.D., he hosts the Some Work, All Play podcast on running (and other things), and they answer training questions in a bonus podcast and newsletter on their Patreon page starting at $5 a month.