Sixteen years ago, when Calliope Holingue was in high school, she had a problem. Two, actually. She developed gastrointestinal symptoms severe enough to force her to give up running, plus she had a long history of anxiety and obsessive-compulsive disorder.

"And I wondered if maybe there was a link between my mental health and the GI symptoms I was experiencing," she recalls now.

Her doctors shrugged off her questions. "That led me to start reading a lot about the gut microbiome, the autonomic nervous system, and their connection with the brain and mental health," she says.

Today, Holingue has joined the ranks of scientists seeking to understand the interplay between the brain (and the rest of the nervous system) and the gut microbiome – that is the vast array of organisms, including bacteria, fungi and viruses, that thrive in the human gut.

She's now an assistant professor of mental health at the Johns Hopkins School of Public Health and part of the faculty at the Center for Autism and Related Disorders at Kennedy Krieger Institute. She's currently leading research on gut microbes and symptoms that cooccur with autism, including GI and behavioral symptoms.

It's clear there's a physiological connection between brain and gut, says Dr. Glenn Treisman, a professor of medicine and psychiatry at Johns Hopkins. "Gut microbes make chemicals that affect your brain," he says. "They can be carried by blood directly to your brain, or they can be carried through nerves that connect to your brain. And your brain can speed up your gut and change what your microbes are."

"The arrows go both ways," he says.

There's also been some compelling – if preliminary – research showing the link between specific gut bacteria and serious mental illness. Several studies have shown that fecal transplants rich with bacteria from depressed rats, as well as from depressed humans, can induce depression in recipient rats. In December 2021, a review of 34 human studies showed a similar pattern of bacterial species in the guts of people diagnosed with depression, bipolar disorder and schizophrenia.

What's next is to find ways to potentially treat psychiatric conditions through interventions in the gut. Last February, what might be the first case report of fecal transplants in major depression in humans showed that fecal transplants successfully alleviated symptoms in two people. More research is underway.

For Holingue, the connection between the gut and mental health is both scientific and personal. Here's her perspective on where the field is headed.

This interview has been edited for length and clarity.

Tell me a little about how you got interested in this field.

Back in middle and high school I started noticing some really disabling gastrointestinal symptoms — severe abdominal pain and strong reactions to food. I had been on both the cross-country and track teams but had to give up running; it was something that I just couldn't feasibly do anymore because of the pain and feeling sick all the time. My life was getting narrower, I felt like I was turning down a lot of social activities out of fear that I would have a bad G.I. reaction when I was out and about with friends

It seemed like my doctors assumed my mental health conditions were causing all my GI issues. And that didn't make sense, since the onset of GI symptoms was relatively new and I had been dealing with mental health struggles my whole life. Missing from those clinical interactions was the acknowledgment that maybe these GI issues were contributing to my mental health issues, or even making them worse.

The gut and its microbiome has a very different function from the brain and nervous system. How are scientists investigating a connection?

We know that gastrointestinal symptoms like abdominal pain, diarrhea, constipation and conditions like irritable bowel syndrome are a lot more common in individuals who have neuropsychiatric and neurodevelopmental disorders like autism, ADHD, major depressive disorder, obsessive compulsive disorder, and bipolar disorder. The next piece of evidence is a large and growing body of animal experiments that demonstrate really robustly that there's a link between the gut and the brain.

And we know that in animal studies, the types of microbes that these animals have can influence the blood-brain barrier and thus how much stuff can go from the circulating blood into the central nervous system. And I think something most people can probably connect to is that if they feel nervous, they might have butterflies in their stomach — they may even have an upset stomach before giving a big presentation.

How could gut microbes influence the brain?

Microbes in the gut have a host of different functions. They produce vitamins and nutrients, and 90% of the body's serotonin (which transmits messages from nerve cell to nerve cell) is produced in the gut. Microbes in the gut play roles in metabolism and in our immune system. They even influence the expression of our own human genetics. And of course, they have a number of functions in the gut, like regulating gut motility and the permeability of the intestinal barrier. Whatever is happening in the gut seems to have these really strong downstream effects on really critical processes that happen in the brain.

How might understanding this connection help people with mental illness?

Ultimately we may be able to understand how the composition of the gut microbiome or metabolites that are produced by the gut microbiome helps cause mental illness or neurodevelopmental conditions, or the ways those conditions manifest in different people.

For example, one person with a diagnosis of major depressive disorder might be able to go to work every day and function at a pretty high level, despite feeling absolutely horrible emotionally, and dealing with lots of symptoms like headaches and abdominal pain. Another person might not experience those symptoms but may be bedbound on many days because they simply don't have the energy to function.

If we're able to understand what metabolites or neurotransmitters these microbes are producing or are involved in regulating, then perhaps we can get a better understanding of how to develop drugs that target those pathways. And maybe the composition and diversity of someone's gut microbiome is playing a role in determining whether that person is going to respond well to a particular psychiatric medication, and we can use that to recommend effective care.

There are reports of some people using fecal transplants for mental health issues already, yet some experts in the field are concerned about the safety and potential for transplanting microbes that could cause problems in recipients.

I think fecal microbiota transplants have a lot of promise. There has been a study of fecal microbiota transplants in autistic children, where investigators report seeing improvements in GI symptoms and also behavioral symptoms as well as changes in the microbiome. That is potentially exciting. But it was in a small group of children, and there was no control group.... So it's difficult to know how much of the change was truly due to the fecal transplant. I do think those types of research studies should be going on, with ongoing input from the communities that they're intended to serve. But I don't think they're ready for use outside of research studies.

We also need really rigorous longitudinal studies where we study and follow people over time, not providing any treatment or intervention, but to collect data on their diet, any medications they're taking, and what their microbiome looks like at various different points. This will contribute to an understanding of whether a disease is leading to a different microbiome, or if the microbiome is causing the disease, or whether it's something else entirely that's confounding that association.

You're doing research now looking at the interaction between the gut and behavior among autistic children. What are you trying to find out?

We're wrapping up a study at Kennedy Krieger Institute and Johns Hopkins where we're collecting physical health data, behavioral health data and gut microbiome data from a relatively small sample of autistic boys and girls, and trying to see if we find patterns between the types of microbes in their stool and what kind of co-occurring symptoms they have, like GI symptoms, sensory sensitivities, anxiety, and so on.

We know that the presentation of autism is very heterogeneous, and one idea could be perhaps the gut and the microbiome are playing a role in influencing that heterogeneity. If we start to see signals between specific gut bacteria and specific behaviors or symptoms, then that can provide evidence for a microbial pathway that influences autism presentation. And ultimately it could help us come up with targeted treatments for the behaviors or symptoms that autistic individuals want to change, like anxiety, sound sensitivity, and constipation.

Have you used your understanding of the gut microbiome and mental health connection to help with your own mental and digestive health?

Managing my diet has been big. I'm very mindful of the foods that are more likely to cause a reaction. I've found that probiotics are helpful to me and I take them daily. And I have found it helpful to also work on my mental health. When I'm feeling better mentally and emotionally, my [digestive] health is better. In college I started seeing a psychologist to manage and treat my OCD, and that's something I've maintained. I also take medication for it.

And then I do things like taking long walks, listening to music, writing music, spending time with my husband, my family, friends, my cats, you know, the things that bring me joy. But I also have times where my GI symptoms flare up even when I'm feeling emotionally well, and that can be very frustrating. I'm still learning all the time and hoping I can get more clarity on the root of these GI symptoms.