Missing Microbes and Weight Gain

This Week’s Research Highlight

The Hidden Cost of a Sanitized World

In the 1990s, scientists noticed something curious.

Children raised on farms — especially those surrounded by cattle, hay, and soil — had remarkably lower rates of asthma and allergies than their city-dwelling peers. This “Farm Effect” defied expectations, and sent researchers on a search for answers.

The key factor? Microbes. The immune systems of farm-raised children were shaped by constant exposure to a diverse array of microorganisms, training their bodies to resist excessive inflammation.

This discovery hints at a much broader paradox of modern health. Despite profound advances in medicine, nutrition, and exercise science, rates of inflammatory diseases — autoimmune disorders, allergies, metabolic dysfunction, and obesity — continue to rise. While poor diet and sedentary lifestyles are obvious culprits, researchers began asking a deeper question: Could something essential be missing from our modern environment?

Think about the world you live in now. Today, our daily lives are quite sterile, compared to those of our ancestors. We spend most of our time indoors, scrub our food clean, filter our water, and rarely touch unprocessed soil. Of course, these changes have been life-saving, dramatically reducing infectious disease and extending life spans to an unprecedented degree. But in the process, we have severed a relationship that once helped regulate our immune and metabolic health — the relationship between humans and environmental microbes.

One of those missing microbes is Mycobacterium vaccae, a bacterium naturally found in soil. For most of human history, people would have regularly encountered M. vaccae through farming, breathing in dust, interacting with animals, or eating garden-grown foods. But as our world has become increasingly sanitized, exposure to M. vaccae and other microbes has faded.

A new study has uncovered a surprising link between M. vaccae and weight regulation — suggesting that the absence of key environmental microbes might be influencing metabolism in ways we never imagined before. Let’s take a look at what they found.

Inside the Experiments

To examine the effects of M. vaccae in the context of a fattening diet, researchers at the University of Colorado Boulder designed an elegant experiment.

They started with 48 male mice, dividing them into four groups to examine how two key variables — diet type and M. vaccae treatment — might interact.

The research team began their intervention a week before changing any diets. During this time, half the mice received their first injection of M. vaccae, while the other half received an injection of a control solution. These weekly treatments would continue throughout the entire study.

Then came the dietary intervention. Half of each treatment group (both M. vaccae-treated and control mice) were switched to a "Western-style" diet specifically formulated to mirror typical American eating patterns. In other words, loads of unhealthy fats and added sugars.

The other half remained on a standard laboratory diet that was much lower in fat and sugar.

So, this created four distinct groups of rodents:

• Mice eating a normal diet and receiving the control solution

• Mice eating a normal diet and receiving M. vaccae

• Mice eating the Western diet and receiving the control solution

• Mice eating the Western diet and receiving M. vaccae

Throughout the ten-week study, researchers tracked the mice's weight and food intake while collecting fecal samples at key time points to monitor changes in their gut bacteria. At the study's conclusion, they conducted analyses examining not just body weight, but also internal fat deposits, markers of inflammation, and detailed profiles of the gut microbiome.

This design allowed researchers to determine not only whether M. vaccae could prevent weight gain, but also to understand how it might be working.

An Unexpected Shield Against Weight Gain

Just as humans tend to gain weight on a diet high in fats and sugars, laboratory mice typically pack on extra pounds when fed a "Western-style" diet. The mice in this study proved no exception — those receiving the Western diet along with a control solution began gaining significant weight within just six weeks.

But something remarkable happened in the mice treated with M. vaccae. Despite eating the same unhealthy diet, these mice maintained weights similar to their peers eating the healthy control diet. It was as if they had been immunized against weight gain!

The differences became even more striking when researchers examined visceral fat — the type of fat that accumulates around internal organs and is most strongly associated with chronic disease. Mice on the Western diet without M. vaccae showed substantial increases in abdominal fat tissue, while those treated with M. vaccae largely avoided this unhealthy fat buildup.

You would probably assume, as I did, that M. vaccae must be suppressing their appetite, causing the mice to eat less. But the researchers ruled this out immediately — meticulous food tracking confirmed that all groups consumed similar amounts of food.

So if M. vaccae wasn’t reducing calorie intake, how was it working its magic? Was it somehow changing how the mice processed their food? That led to the next big question: Could M. vaccae be reshaping the gut microbiome?

The Microbiome Mystery

The research team's first stop in solving this mystery was to examine the gut microbiome — the vast community of bacteria residing in the digestive tract. They had good reason to look here: previous research has shown that Western diets typically disrupt this bacterial ecosystem in ways that promote weight gain.

Sure enough, the Western diet had profound effects on the gut microbiome. The most striking change was a significant decrease in microbial richness — the total number of different bacterial species present in the gut.

This wasn't just a technical footnote; reduced microbial richness is often one of the first dominos to fall in a chain reaction of problems. It can weaken the intestinal barrier, leading to increased intestinal permeability, or "leaky gut.”. This allows bacterial fragments to enter the bloodstream, triggering low-grade inflammation. Over time, this inflammation can impair metabolic regulation, contributing to excess weight gain and visceral fat accumulation.

Given that M. vaccae had prevented weight gain, you might expect that it had also protected against these unhealthy microbiome changes. But here’s where things took an unexpected turn: it hadn’t.

The gut microbiomes of M. vaccae-treated mice were just as disrupted as those of untreated mice on the Western diet. Their bacterial communities had shifted in the same way, yet somehow they weren’t gaining weight.

This finding sent the researchers looking in a different direction. If M. vaccae wasn't working by protecting the microbiome, how was it preventing weight gain?

The answer, it turned out, was in how the body responds to signals from the disrupted microbiome, rather than in the microbiome itself.

The Leptin Connection

The breakthrough in understanding how M. vaccae prevents weight gain came when researchers examined leptin, a hormone that plays a crucial role in regulating body weight. Often called the "satiety hormone," leptin is generated by fat tissue and tells the brain when we have enough energy stored. Generally, higher leptin levels mean dampened hunger, while falling leptin levels— such as during caloric restriction — trigger increased appetite.

In obesity, this system goes awry. When mice were fed the Western diet without M. vaccae, they exhibited a classic pattern: their fat tissue produced far more leptin, and levels of the hormone in their blood rose significantly.

At first glance, this might seem counterintuitive — shouldn’t more of a satiety hormone help prevent weight gain? The problem is that chronically high leptin leads to leptin resistance, much like how prolonged elevations in insulin contribute to insulin resistance in type 2 diabetes. Over time, the brain stops responding to leptin’s signal, driving further weight gain instead of preventing it.

But mice treated with M. vaccae followed a strikingly different pattern. Despite eating the same Western diet, their leptin levels stayed normal. Their fat tissue didn't overproduce the hormone, and their blood levels remained similar to mice on the healthy control diet.

This wasn't simply a case of suppressing leptin production. When the researchers examined the hypothalamus — the brain region that responds to leptin — they found that M. vaccae-treated mice maintained normal expression of leptin receptors and other appetite-related genes.  This suggested that rather than disrupting leptin signaling, M. vaccae was helping preserve its normal function.

Earlier, we touched on how inflammation plays a role in metabolic dysfunction —and here’s where it all comes together. In obesity, fat tissue becomes inflamed, triggering excess leptin production. At the same time, inflammation in the brain further disrupts leptin signaling, making the hypothalamus less responsive to leptin’s message about energy balance. The result? A vicious cycle where the body produces more leptin, but listens to it less.

This is where M. vaccae steps in. By reducing inflammation in both fat tissue and the brain, it helps keep leptin signaling intact, allowing normal leptin levels to do their job effectively.

The Bigger Picture: Inflammation & Metabolism

The leptin findings led researchers to a broader realization: M. vaccae doesn’t prevent microbiome disruptions — it helps the body stay metabolically resilient despite them. Instead of blocking diet-induced changes in gut bacteria, M. vaccae protects against the inflammatory chain reaction that typically follows, keeping metabolic regulation intact.

One way it does this is by reducing inflammation throughout the body. In the brain, M. vaccae lowered expression of key inflammatory genes, including Nfkbia and Nlrp3, which are known to disrupt metabolic control. This is critical because chronic brain inflammation impairs the hypothalamus’s ability to regulate appetite, energy balance, and leptin sensitivity — all of which drive further weight gain.

The effects weren’t limited to the brain. M. vaccae also reduced inflammation in visceral fat tissue, a major player in insulin resistance and metabolic dysfunction. Lower inflammation in fat cells helps maintain insulin sensitivity, allowing the body to process glucose efficiently rather than storing it as fat.

Crucially, this mechanism works downstream of the gut microbiome. Instead of preventing microbiome shifts caused by a poor diet, M. vaccae helps the body interpret microbial signals differently — dampening inflammation and preventing metabolic dysfunction. This insight is key because it suggests M. vaccae might be beneficial even for individuals with long-term microbiome disruptions from poor diet.

Rebuilding Our Connections with Lost Microbes

For most of human history, we lived in constant contact with nature, regularly encountering microbes like M. vaccae. This wasn’t incidental — our immune systems evolved alongside these microbes, learning to distinguish friend from foe. Unlike parasites, which suppress immunity to survive, M. vaccae took a different approach, helping fine-tune our immune system to prevent harmful inflammation while still defending against real threats.

This idea forms the basis of the "Old Friends" hypothesis: just as our bodies evolved expecting regular exercise, our immune systems evolved expecting regular microbial exposure.

While therapeutic applications of M. vaccae are still far out on the horizon, we don’t have to wait for medical interventions to reconnect with beneficial microbes. Simple lifestyle choices can help restore some of these lost exposures:

Gardening – Handling soil and consuming homegrown produce has been shown to enhance microbial diversity and immune regulation.

• Try gardening without gloves (in safe, chemical-free soil).
• Focus on organic growing practices to promote healthy soil microbes.
• Remember that benefits come from both touching the soil and eating the produce.

Spending time in green spaces – Studies show that regular exposure to forests, parks, and gardens can:

• Increase bacterial diversity
• Reduce inflammation
• Support robust immune system function

Mindful food handling – While food safety is essential, we can make choices that balance safety with microbial exposure:

• Grow your own vegetables or buy from local farmers' markets.
• Wash garden-grown produce gently—remove visible dirt but avoid harsh scrubbing or sanitizing.

For families with children, these habits may be especially valuable. We know that early-life exposure to diverse environmental microbes helps shape a resilient immune system. Activities like family gardening or unstructured nature play provide these benefits while encouraging lifelong health habits.

By thoughtfully increasing our interaction with the natural world, we can restore some of the beneficial microbial exposures our bodies evolved to expect — all while maintaining the public health practices that protect us from harmful pathogens.

Summary: Researchers discovered that a common soil bacterium, Mycobacterium vaccae, could prevent diet-induced weight gain in mice. When mice were fed a Western-style diet high in fats and sugar, those treated with M. vaccae maintained normal body weight and showed reduced visceral fat accumulation, despite eating the same amount of food as untreated mice. Surprisingly, while the Western diet disrupted the gut microbiome in all mice, M. vaccae didn't prevent these microbial changes. Instead, it appeared to work by reducing inflammation throughout the body and maintaining proper leptin signaling, effectively helping the body stay metabolically healthy even in the face of an unhealthy diet. The findings suggest that our modern, ultra-clean environment might be affecting our metabolism in unexpected ways, potentially by depriving us of beneficial environmental microbes that help regulate inflammation.

Random Trivia & Weird News

🪱  Back in the day, some people desperate for weight loss turned to an extreme (and highly questionable) method — swallowing tapeworms.

Dubious diet trends are nothing new. Perhaps nothing illustrates this better than the Victorian-era tapeworm diet.

The concept was deceptively simple: dieters would swallow a pill containing a tapeworm egg. Once hatched, the parasite would grow inside the host's digestive tract, consuming a portion of whatever the person ate. In theory, this would allow someone to eat freely while still losing weight.

Recognizing the obvious risks, FDA has long since banned the use of such interventions. Yet remarkably, this dangerous practice may not have been fully abolished.

In a recent case report from Beijing, a young woman intentionally consumed tapeworm eggs for weight loss, leading to a serious condition called disseminated cysticercosis, where parasitic cysts developed throughout her body — including her brain, muscles, and liver. Though she eventually recovered after extensive medical treatment, the case serves as a stark reminder that when it comes to weight loss, if something sounds too good to be true, it probably is.

Photo credit: US Food & Drug Administration

Podcasts We Loved This Week

• Steven Austad, Matt Kaeberlein, & Richard Miller: Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more. Via Peter Attia.

• Sarah Shomstein, Adam Zemen, Cornelia McCormick: What happens in a mind that can’t “see” mental images? Via Quanta Science.

Products We Like

Seed Sprouting Kit

This is one of my favorite tools for bringing some of that garden-to-table experience right into your kitchen. This simple sprouting kit transforms ordinary seeds into fresh, living sprouts in less than a week. I particularly love using it for broccoli sprouts, which contain an order of magnitude more of the health-promoting compound sulforaphane than mature plants.

Nowadays, you can find broccoli sprouts at grocery stores, but they’re pretty expensive on a per-serving basis. Growing your own is not only more economical but also ensures you're getting the freshest possible produce.

The process couldn't be easier: pour some seeds into the jar, rinse them twice a day, and within days you'll have sprouts ready to add to salads, sandwiches, or smoothies.

PS: If you’re looking for some good broccoli seeds, I’ve had great success with these, and am using them for this week’s batch of sprouts.

humanOS Catalog Feature of the Week

Stress & Weight Control — Link

This week, we’d like to highlight one of the courses from the Ideal Weight Program, designed by neurobiologist Stephan Guyenet.

In this course, Stephan covers:

• How stress affects physiology and consequently how much you eat
• Why some people overeat under stress, while others lose their appetite
• The science behind “comfort food” cravings and stress hormones
• The impact of controllable versus uncontrollable stress
• Practical techniques for stress management that support weight control
• Strategies for creating environments that make healthy choices easier during stressful times

Wishing you the best,