an illustration of a brain and intestines as plants growing above ground with roots connecting underground

The Gut Microbiome and the Brain

Emerging science is uncovering connections between the microbiome and mental health.

By Jackie Powder • Illustrations by Davide Bonazzi

On Calliope Holingue’s Twitter profile, one of her descriptors is “obsessed with the gut-brain connection.”

It’s a statement that she can back up: Her research centers on the gut-brain link in autism. She teaches the Summer Institute course Mental Health and the Gut. And as a teen, she began to explore the gut-brain connection on her own, years before “microbiome” became a household word.

Holingue, PhD ’19, MPH, has lived with obsessive compulsive disorder since early childhood, and started developing increasingly disabling gastrointestinal problems in high school.

Her medical doctors weren’t much help, so she sought solutions on her own.

“They viewed my GI issues as purely a psychiatric issue, so they would say, ‘This is anxiety, this is stress. You just need to relax and you’ll feel better,’” she recalls. “But I didn’t think that the stress and anxiety explained everything. I’d have crippling pain or severe reactions to food even when I was not stressed at all.”

Eventually diagnosed with irritable bowel syndrome, she embarked on a years-long process to improve her health. After lots of trial and error with probiotics, different diets, and mindfulness, she’s now in a much better place emotionally and physically, though the journey is an ongoing one.

Along the way, she channeled her knowledge of the field into graduate study and research, and joined the faculty at the Kennedy Krieger Institute, where she’s exploring the gut-brain connection.

A Two-Way Street

Trillions of bacteria, viruses, yeasts, protozoa, and fungi—at least as many as the number of human cells in our bodies and weighing approximately four pounds—inhabit the intestinal tract.

Collectively known as the gut microbiome, these microbes help us metabolize nutrients and protect us from harmful bacteria and toxins. They have also drawn intense study by scientists like Holingue eager to understand the microbiome’s connection to mental health. In addition to microbes, the gut-brain axis involves the vagus nerve, hormones, immune cells, neurotransmitters, and metabolites, all of which work together to allow the bidirectional communication between the gut and brain.

“The take-home message in everything we study is the arrow goes both ways,” says Glenn J. Treisman, MD, PhD, the Eugene Meyer III Professor of Psychiatry and Medicine at the Johns Hopkins School of Medicine. “The brain affects your gut. The gut affects your brain. The microbiome affects your gut, which affects your brain. The brain affects your gut, which affects your microbiome.”

Disruptions to the gut microbiome, say by infection or a change in diet, can trigger reactions in the body that may affect psychological, behavioral, and neurological health. For example, reactions such as the overproduction of inflammatory cytokines or slowed production of neuroactive metabolites have been implicated in depression.

Disruptions to the gut microbiome, say by infection or a change in diet, can trigger reactions in the body that may affect psychological, behavioral, and neurological health.

A 2020 review of research on depression and the gut microbiome noted that generally, people with depression have a less diverse gut microbiome, with higher levels of bacteria associated with inflammation, like Bacteroidetes, and decreased levels of bacteria associated with anti-inflammation, like Firmicutes.

“There’s been hundreds of studies at this point looking at various psychiatric and brain disorders and linking them with the gut microbiome,” says Holingue. “I feel like we’re in the place where the human genetics field was maybe 10 years ago. We’re drowning in associations and trying to figure out what does this mean, what is causing what, and what do we do with this information?”

Untangling the complex associations offers the tantalizing prospect of novel therapies for conditions from depression and anxiety to autism spectrum disorder.

A Happy Microbiome Is a Diverse Microbiome

The growing interest in the gut-brain axis emerged partly out of the recognition that people with psychiatric and neurodevelopmental conditions tend to have more GI problems, such as diarrhea, constipation, and abdominal pain, than the general population. It’s estimated that 50%–90% of patients with irritable bowel syndrome have a psychiatric comorbidity.

Key questions followed: Are the gut issues caused by brain disorders or is it the other way around?

A 2011 influential study led by Pankaj Jay Pasricha, MD, MBBS, then at Stanford and now director of the Johns Hopkins Center for Neurogastroenterology, demonstrated for the first time that irritation of the gut can cause long-lasting depression- and anxiety-like behaviors in rats.

The findings challenged the prevailing “it’s all in their mind” paradigm for patients with unexplained GI symptoms and depression or anxiety, says Pasricha. “What we have shown is that it actually works the other way around as well,” he says, “that you can have a gut problem that can lead to depression and anxiety.”

Pasricha and Treisman, who co-direct the Amos Food, Body and Mind Center, are now applying their combined knowledge of mood disorders, pharmacology, neurology, and gastroenterology to help patients whose gut-brain communication has essentially gone haywire. They are struggling with a constellation of gastrointestinal-, mood-, and pain-related disorders.

The patients receive a hyper-personalized standard of care that can range from customized probiotic drinks to diet modifications to electroconvulsive therapy (ECT), a treatment most commonly used for severe depression, that passes small electric currents through the brain. In most cases, Treisman says, a healthier diet to promote diversity in the gut microbiome is an important component of the treatment plan. “A happy microbiome is a diverse microbiome.”

On recent inpatient rounds, Treisman checked in on a young woman scheduled for discharge. When she arrived on the ward, he says, she was sleeping three days at a time, had chronic constipation, suicidal thoughts, and wasn’t eating.

“I’m pooping regularly, which is amazing!” she exclaims. “I’m so excited to go home.”

“By getting the pooping under control, your depression responded better to the ECT,” Treisman explains. ECT, he says, acts as a “control-alt-delete” for the autonomic nervous system, and in some cases helps to increase gut microbe diversity and ease GI problems.

“Their mood won’t get better until you give them something to make their gut work better,” he says. “We don’t know how that happens or why,” he says of the ECT strategy, “but it works.”

The Autism Question

Holingue’s gut-brain research centers on ASD, an area that is gaining traction within the field. The research builds on her doctoral dissertation, published in 2020 in Autism Research, which found that women who had the flu during their second trimester had increased odds of having a child with ASD—unless they took antibiotics at some point during their pregnancy. She’s planning to dig deeper into whether antibiotics in the maternal gut block the inflammatory response to infection, thereby reducing the likelihood of neurodevelopmental abnormalities in their babies.

In other ASD research, she’s conducting a small pilot study, funded by the Wendy Klag Center for Autism and Developmental Disabilities, to collect stool samples from 25 young boys with autism to see whether links exist between stool microbes and the boys’ behaviors, mood, sensory experiences, and overall health.

“My hope is to use the findings to do a much larger study in which we’re better able to understand how the gut microbiome is linked to physical and mental health in the autistic population,” Holingue says.

Ultimately, she’d like to pursue experimental research to study whether dietary and other microbial interventions can be used to improve gastrointestinal health, noting that children with ASD sometimes eat a very limited number of foods.

“I think that by improving GI health we can not only improve physical health but also emotional and behavioral well-being,” she says.

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