Gut Bacteria, Anxiety and Depression

Elisabeth Svoboda in Discover magazine, explores mounting evidence which shows bugs in your digestive system influence the brain. Experts are now testing psychobiotics as mental health remedies. October 2020.

Every muscle fiber in Tom Peters’ body seemed to be conspiring to keep him in bed. His depression — an occasional visitor for more than a decade — had reemerged in the summer of 2019, and his legs and arms felt like concrete. The thought of spending another 12-hour day at his computer filled him with dread. As a technical day trader for stocks, he responded to demanding clients constantly. That felt impossible when his brain kept blaring his past failures at top volume.

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Fielding the volley of work messages became a Sisyphean task. “There’s always the overriding fear that I’m not going to come out of it, that I’m always going to feel this way,” Peters says. “That probably is the scariest thing.”

Peters, 50, had read about mood probiotics, gut bacterial strains marketed to help with depression and anxiety, but never felt like they were for him. “I was very skeptical,” he says. When his wife, who was battling panic attacks, tried mood probiotics and saw her episodes diminish, he began to reconsider. After his depression symptoms returned last summer, and the Prozac he’d tried in the past had lost its potency, his wife went online and ordered him a bottle of the same oatmeal-colored capsules she was taking.

For decades, experts scoffed at the idea that gut bacteria affect our mental health. Many called it a fringe theory. Yet mounting evidence suggests that intestinal microbes profoundly shape our thinking and behavior. Human trials are now underway to investigate how these microbes boost our overall well-being. If the results hold up, new bacteria-based therapies could expand a mental health treatment landscape that has been mostly stagnant for decades.

“Current treatments [for mental health] are not great,” says University of Calgary psychiatrist and microbe researcher Valerie Taylor. “When they do work, many of them are intolerable. People are desperate.”

More Than a Feeling

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Anyone who’s sprinted to the bathroom moments before a speech or felt a wave of nausea after public humiliation knows the gut and the brain are connected. Doctors have speculated about this linkage since ancient times. Hippocrates, who is credited with saying “all disease begins in the gut,” speculated that black bile spilled from the spleen into the intestines and brought on dark moods.

Theories like these grew more sophisticated over the centuries as scientists learned more about the microorganisms in the human gut. (We now know there are literally trillions of them.) By the late 19th century, doctors argued that “melancholia,” a then-common term for depression, arose from overgrowth of intestinal microbes. But physicians at the time understood little about what these microbes did in the body. So, early gut-based treatments — including major abdominal surgery for schizophrenia — were doomed to fail.

Fast-forward a century, and data from speedy genome sequencing of gut bacteria in the 2000s revealed that microbes perform an array of bodily tasks. Further studies showed how some might affect mental health. Each of us, it turns out, is more microbe than human: Bacterial cells outnumber human cells in the body by a factor of at least 1.3 to 1. The human gut plays host to more than 100 trillion of these bacteria — a complex, interdependent microbial universe wedged between your ribcage and spine.

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While the human genome consists of roughly 25,000 genes, the swarm of microbes in your gut expresses about 3 million distinct genes. Many of these bacterial genes help build molecules that let you digest food, keep harmful microbes at bay, and even feel emotions. For starters, the bacteria in your gut produce about 90 percent of the serotonin in your body — yep, the same happy hormone that regulates your moods and promotes well-being.

For Peters, the prospect of a new path looked tantalizing after enduring the marathon of traditional options. He had gone through multiple stints on Prozac — a selective serotonin reuptake inhibitor (SSRI) — and wondered if he’d maxed out the drug’s potential. “I went off them for a while, then I went back on them, and I felt like I developed a resistance of sorts,” he says. It’s a familiar tale for almost anyone who takes SSRIs for long-term depression.

Years earlier, when Peters’ old dose of Prozac wasn’t working as well, his psychiatrist had prescribed him a new, higher dose, one that brought on annoying side effects. “On the higher dose, I felt like I was more sluggish,” Peters says. “It drove me crazy.” The memory of that unrelenting brain fog helped persuade him to give probiotics a try.

What Happens in the Vagus

In the mid- to late 2000s, John Cryan of Ireland’s University College Cork was among the first to explore gut microbes’ effects on the brain. A neurobiologist by training, Cryan had shown that rats stressed from birth later showed signs of both irritable bowel syndrome (IBS) and mood disturbance. “When they grew up,” Cryan says, “they had a whole-body syndrome.” This finding echoed doctors’ observations that many patients with digestive symptoms also had mental health issues, and vice versa.

When researchers at Cryan’s lab sampled gut bacteria from stressed-out rats in 2009 and sequenced them, they hit on something surprising: Stressed-out animals — those more prone to mental health issues — had a less diverse assortment of gut microbes, or microbiome, than their more relaxed counterparts. “It got us thinking — if you stress an animal, [maybe] there’s a signature in the microbiome that’s persisting,” Cryan says.

In the past decade or so, more labs have started reporting that gut bacteria produce a smorgasbord of compounds that affect the mind in surprising ways, both good and bad for your emotional health. Some bacteria in the Clostridium genus generate propionic acid, which can reduce your body’s production of mood-boosting dopamine and serotonin. Microbes like bifidobacteria enhance production of butyrate, an anti-inflammatory substance that keeps gut toxins out of the brain. Other species produce the amino acid tryptophan, a precursor to mood-balancing serotonin.

Rather than passing from the gut to the brain via bloodstream, some of these chemicals affect the brain through intermediate channels, says University of Pittsburgh clinical research psychologist Lauren Bylsma. A major one, the vagus nerve, functions like a communication superhighway between the brain, gut and other organ systems in the human body. Recently discovered neuropod cells can activate or deactivate the vagus nerve, which interfaces with neurons in the brain. Research shows that certain gut bacteria help activate those neuropod cells.

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While researchers continue to map the workings of what they’ve dubbed the “gut-brain axis” — the two-way communication link between the GI tract and the central nervous system — many already think it creates a major potential avenue for mental health treatment. Talk to psychiatrists about what causes mental illnesses like depression and “you get a list of 10 mechanisms,” says Philip Strandwitz, co-founder and CEO of biotech company Holobiome. “When you talk to microbiome folks and ask them if you can affect those mechanisms, the answer is largely yes.”

Since the concept of the gut-brain axis went mainstream, labs have accumulated even more evidence to support the notion. Earlier this year, Cryan and a team of international colleagues gave a group of stressed mice regular doses of a Bifidobacterium gut microbe for five weeks. By the end, the mice were more mobile and active than before. They were also more willing to interact and explore new areas.

The whole time, Cryan tracked changes in the mice’s gut bacteria. During a treatment with Bifidobacterium breve, their gut bacteria started making more tryptophan. Treated mice also produced more of a protein called brain-derived neurotrophic factor (BDNF), which helps new neurons grow.

Even as scientists highlight these kinds of connections between gut microbe treatments and symptom improvement, the question of causality has lingered: Do gut bacterial changes actually drive mood and behavioral changes? A growing body of research suggests they do.

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Several innovative studies since 2016 show that fecal transplants can shape behavior profoundly, according to Bylsma and Taylor. When mice in one Chinese study got transplants of feces from other healthy mice, their behavior remained unchanged. But when mice received fecal transplants from donors with signs of anxiety and depression, the mice started to show signs of mood disturbance. A separate study published in Molecular Psychiatry showed mice that received fecal transplants from depressed humans also developed depressive symptoms. On the other hand, stressed-out mice in a 2019 study received transplants from unstressed animals and began acting less depressed. By changing the intestinal microbiome, researchers “can actually change the rodents’ behavior,” says Bylsma, who was not involved with the studies. “That implies there is a causal effect.”

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