“I’ve been taking Ozempic to lose weight but now I want to go hiking and play badminton with my friends.” —Bob Janke

Researchers rejoiced when Ozempic and other GLP-1 drugs worked to shed weight in their patients. But there was an unexpected bonus: Some depressed patients started to feel better. Researchers from Southeast University in China, led by Honghong Yao, think they know why. They pieced together several related observations to solve the mystery.

(I apologize in advance for a few gnarly bacterial names up ahead in this article. But the story is compelling, and you really don’t need to remember the names of the characters to appreciate the plot, so hang in there.)

GLP-1s and Your Gut: What's the Connection?

When GLP-1 drugs like Ozempic, Wegovy, and Trulicity are injected, they find their way to the gut. That’s not unexpected; GLP-1 drugs act on your gut to make you feel satiated. That’s where your body makes its own GLP-1, after all.

Yet one of the researchers’ most interesting findings is that people with major depressive disorder or anxiety tend to have significantly lower natural levels of GLP-1. That’s the first piece of the puzzle.

When tested on mice, GLP-1 drugs not only make them lose weight; they also reverse depression-like behavior. So, higher GLP-1 appears to act as an antidepressant, which fits well with the first puzzle piece. (Mice are not perfect proxies for people, but they are surprisingly useful when it comes to studies of depression and anxiety. Scientists are not supposed to anthropomorphize, but if you saw a mouse with “depression-like behavior,” you'd probably recognize it immediately. Still, mice are not humans, so keep that in mind.)

Every hormone the body releases has a receptor. That goes for GLP-1 as well. Its receptor is parsimoniously named GLP-1R. Interestingly, the researchers found that if they block GLP-1R, the mice don’t lose weight anymore—but they still reverse their depression. That means that whatever is causing the weight loss seems to be unrelated to the psychiatric change. That is a major plot twist, and a big puzzle piece.

Intriguingly, depression is not reversed in germ-free mice. Whatever GLP-1 is doing, it apparently has something to do with microbes. Without microbes, there is no antidepressant effect. The researchers then used genomic sequencing to see what impact the GLP-1 was having on the gut microbiome, and they discovered a significant enrichment of Lactobacillus delbrueckii. The final piece of the puzzle came in the shape of a microbe.

The researchers say, “We demonstrated that liraglutide [a related GLP-1 drug] directly promotes the growth of Lactobacillus delbrueckii.” They showed that liraglutide helped the bacterium to produce endocannabinoids, which act a little like cannabis to reduce the effects of stress on the amygdala and hypothalamus. In other words, GLP-1 helps gut microbes make home-grown mood-boosters.

Most of these amazing results are correlational. To seal the deal and show causality, the researchers transferred poop from the GLP-1 mice to other depressed mice. You and I might not rejoice at an offering of mouse poop, but mice are into it. Like a shocking number of other animals, mice are coprophagic, or poop-eaters. The depressed mice that received poop from the GLP-1 mice were significantly cheered up.

The same antidepressant effect was seen when they gave depressed mice a straight shot of L. delbrueckii. That makes L. delbrueckii a psychobiotic: a microbe that can improve mood. The most common subspecies of L. delbrueckii is L. bulgaricus. And now we can reveal how to get some of this good stuff yourself. Your best bet is with live ferments, like yogurt, kefir, and cheese. These may even help you lower your cholesterol and fight off cancer.

(It is, however, a pathogen in your urinary tract. Hey, it’s a microbe, not a superhero.)

Putting It All Together: GLP-1s and the Microbiome

This is not the first study to find that GLP-1 drugs affect the microbiome. A recent Polish study led by Sylwia Małgorzewicz found an increase in Akkermansia and Ruminococcus species in humans and mice. These microbes are associated with improvements in metabolism.

Interestingly, while all GLP-1 drugs had effects on the gut microbiome, each individual drug had a slightly different impact. Dulaglutide, for instance, seemed to have a better impact on the microbiome than semaglutide. Doctors might want to give patients a short psych eval before choosing the appropriate GLP-1 drug.

It may be hard to remember, but GLP-1 drugs were originally meant for people with type 2 diabetes. And here, too, there is a microbial angle. People with type 2 diabetes have altered gut microbes, with a reduction in Bifidobacterium, an important denizen of our gut when we were babies. This genus slowly dies off as we age (and stop drinking milk), but it fades faster in people with diabetes. Interestingly, people who incorporate more fiber in their diet not only increase beneficial microbes, they also increase their own production of GLP-1 and lower their obesity-induced insulin resistance.

That means that at least some of the effects of Ozempic can be found in a few scoops of yogurt. It’s tasty and a lot cheaper.

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