A Gut Signature for Major Depressive Disorder

“That’s the thing about depression: A human being can survive almost anything, as long as she sees the end in sight. But depression is so insidious—and it compounds daily—making it impossible to ever see the end. That fog is like a cage without a key.” –Elizabeth Wurtzel

Depression is the number one cause of disability in the world, according to the World Health Organization. There are many reasons people get depressed, from bereavement and stress to genetics. But if the depression lingers and is accompanied by other markers like insomnia, fatigue, brain fog, or weight change, it can be classified as major depressive disorder (MDD).

But there is another contributing factor: gut microbes.

Gut-brain axis

The gut-brain axis has been boggling minds for more than a decade now, and gut microbes that can improve mood are called psychobiotics. So where are the treatments for depression? Why don’t we have a pill yet?

Source: AI-generated with Midjourney

The research is clear: As microbes ferment in our gut, they produce thousands of substances called metabolites. Among them are neurotransmitters like dopamine, serotonin, and GABA, which are favorite targets for antidepressants.

We know that short-chain fatty acids, particularly butyrate, are nourishing to the gut lining but also important to brain function.

We know a lot about specific bacteria, and we know how to fix depression—if you’re a mouse. That’s because we can create germ-free mice in the lab, and then we can manipulate their microbiome to see what happens. We know a lot about mice and their microbes.

What about people?

Some of that is relevant to humans. In fact, we can transfer gut microbes from depressed people into mice and make the mice depressed, too. This astonishing result not only shows causality, but it also shows cross-species causality. That’s an important observation that we’ll come back to.

So, what’s happening with human clinical studies? The short answer is that we can’t experiment on germ-free people because there are no germ-free people. Without our own microbiome to protect us from the nasty pathogens of the world, we would die, quickly and horribly. We can’t just eradicate bacteria from people and then add them back in, one at a time, to see which ones make us happier.

Further muddying the waters are all the genetic variations of humankind. Germ-free mice are often chosen to be genetically identical to eliminate confounding variables. The closest we can get with humans are identical twins, and, yes, they are experimental gold.

Along with different genes, there are different climates, cultures, stress levels, and histories. Simple things, like childhood antibiotics, can change your gut for years. It’s not surprising that human studies are plagued by noise.

Looking past microbes

But what if we’re looking at the wrong thing? What if it’s not bacteria but the substances they produce that matter?

That’s exactly what a new review of the data in the journal Epidemiologia shows. The authors found a few microbes that were depleted in people with MDD, particularly Faecalibacterium and Roseburia. But they found much better correlations with the production of butyrate. The more butyrate, the less associated depression. They found that when microbes properly converted tryptophan into serotonin, there was also less associated depression.

They found that levels of something called lipopolysaccharide (LPS), a byproduct of certain pathogenic microbes, were associated with MDD. That isn’t new. We have known since the early 1800s that injecting LPS reliably induces instant depression and anxiety.

A leaky gut can let LPS enter the bloodstream, and from there it gets pumped to every organ in the body, including the brain. Over time, this causes chronic systemic inflammation, which wears down the blood-brain barrier that normally keeps the brain pristine. Once LPS gets into the brain, a whole new world of inflammation is initiated, tightly linked to MDD.

Microbes are less important than the metabolites they produce.

This explains how human microbes can cause mice to get depressed: They aren’t normal mouse microbes, and they would never be able to colonize the mouse gut, but they produce metabolites that do the job in transit. Metabolites are the real drivers of mood.

That makes it difficult to prescribe a specific probiotic based on mouse studies, but don’t despair. It may actually be easier to support your own set of microbes than to supplement.

How to fix a broken gut

Our microbiome tends to be well entrenched. Its primary job is to protect us from all other microbes. That means most probiotics can’t colonize our gut; our home-grown microbes just beat them up and flush them out.

Microbiome Essential Reads

Diabetes and the Gut-Brain Axis

Culturing Happiness With Psychobiotics

A better strategy is to feed our homies. To produce butyrate, microbes need fiber, which is composed of long chains of sugars (oligosaccharides) that escape digestion and make it to the microbial promised land: the colon. Fiber includes oligosaccharides like fructo-oligosaccharide (FOS) and galacto-oligosaccharide (GOS). These are well-studied prebiotics that can be bought as supplements.

Better yet, we can get fiber in a good Mediterranean-style diet that includes plenty of greens, nuts, beans, lentils, onions, and berries. As medicines go, that’s a sweet deal.

If you’re taking meds for depression or anxiety, don’t stop. But you don’t need a doctor’s permission to go Mediterranean. There are many working parts to depression, but diet is one of the few that is under your control. If you have MDD as well as gut issues, this is your lever to pull.