A Gut Feeling

Could bacteria be the answer to treating autism, depression and anxiety?

Does a healthy gut lead to a sound mind?

It is a question that intrigues professor of biochemistry Rob Knight, who has a family history of schizophrenia and bipolar disorder. Knight is a trailblazer in the expanding field of microbiome research, studying the trillions of microscopic organisms that live inside the human body, especially the intestinal tract.

A better understanding of these organisms — how many species exist and how they interact in our bodies to cause or prevent disease — could revolutionize how doctors diagnose and treat such gut-related illnesses as colon cancer, obesity and diabetes.

What’s more, researchers like Knight believe it could lead to better treatment for depression, anxiety, schizophrenia and autism, diseases that at first glance seem more neurological than gastrointestinal.

Knight believes the people who suffer from these conditions may have different gut bacteria than that found in healthy individuals. As a result, he and others are busy gathering fecal matter samples from individuals so they can identify and categorize the hundreds of different species of bacteria, fungi, viruses and other microscopic organisms that live in the human gut.

In the case of autism, researchers have already published several studies showing that autistic individuals have a different gut microbial makeup than those without it. Most recently, a study published in Cell in December, for which Knight co-authored an accompanying commentary, has revealed that this different microbial makeup contributes to a mouse-based model of the disease.

If successful, these studies would support clinical trials in both depression and post-traumatic stress disorder.

In the study, lead researcher Elaine Hsiao of California Institute of Technology injected pregnant mice with a mock virus that triggered an infection-like immune response in the mothers-to-be. She did so because research has shown that women who contract particular kinds of viruses while pregnant have a higher risk — about double — of giving birth to a child with autism. The virus doesn’t necessarily have a severe effect on the mother; the trigger is immunological. The mock virus did its job, and the mice gave birth to offspring that displayed such autistic-like behaviors as obsessively licking themselves and refusing to socialize with other mice. They also had leaky gut syndrome, a condition where the intestinal lining becomes permeable, allowing bacteria to slip out into the bloodstream, perhaps adversely affecting other bodily functions.

But after Hsiao fed the offspring food laced with a well-known friendly gut bacteria called Bacteroides fragilis, most of their autistic symptoms disappeared. Gut bacteria are often categorized as either friendly, a mutualistic or symbiotic bacteria or unfriendly, a pathogen, or commensal, which is neutral.

“What’s so exciting about this study,” Knight says, “is it provides the first mechanistic example of how the immune system and the gut bacteria work together to cause a complex behavioral phenotype”— in this case, the autistic-like behaviors.

“The other thing that’s really groundbreaking about it,” he says, “is the use of a beneficial strain of bacteria to reverse the symptoms. It raises the prospect of being able to develop either probiotics or other therapies that target the microbiome.”

The study echoes, in part, a neurological-microbial study conducted by Christopher Lowry, a CU-Boulder associate professor of integrative physiology. In 2007 Lowry found that when mice were given the friendly bacteria M. vaccae a group of neurons that produce the brain chemical serotonin became activated. Researchers believe serotonin imbalances contribute to depression.

Last year Lowry co-authored a review paper that examined evidence from a plethora of studies showing that rising rates of depression in industrialized countries are linked to a loss of human contact with friendly bacteria, including strains of mycobacteria once ubiquitous in soil, food and the gut. These strains have disappeared because of hygienic practices but played a critical role in helping the human immune system to tolerate inflammation. Without them, our immune system can go into overdrive when presented with a pathogen.

Lowry and others believe this hyper-inflammation has led to a sharp rise in inflammation-related diseases in industrialized countries, including depression, which has been linked to increased production of inflammatory cytokines.

His lab is conducting preclinical studies in rodents to determine if “vaccination” with a heat-killed preparation of M. vaccae can prevent stress-induced inflammatory responses in their immune systems and associated anxiety responses. In addition Lowry has teamed up with Knight to investigate the effects of the vaccination on the rodents’ gut microbiota to see if it indirectly brings beneficial changes by altering which microorganisms are present.

“If successful, these studies would support clinical trials in both depression and post-traumatic stress disorder (PTSD),” says Lowry who views depression as “one of the great mysteries related to the human response to stress.”

Although Knight and Lowry are excited about the potential benefits of their research, they are quick to point out that it is still in the early stages and individuals should not try to self-treat.

“It’s important to remember with any animal study, and especially studies with mice, it can be difficult to translate into humans,” Knight says. “Parents of autistic children should not run out and give the same kinds of bacteria that were used in the studies to their kids because very frequently the same bacteria have totally different effects in different species.”

He says Hsiao is hoping to start clinical trials soon on autistic humans. In the meantime, Knight is working to sequence human gut microbes to better understand what a healthy human gut microbiome looks like. Last spring he co-launched The American Gut project with Jeff Leach, an anthropologist, and Jack Gilbert, an environmental microbiologist at Argonne National Laboratory, a nonprofit research lab operated by the University of Chicago for the U.S. Department of Energy.

Their crowd-funded initiative is designed to gather 100,000 oral and fecal samples of human microbiota from people around the world. The researchers want to have a huge dataset of the modern microbiome to compare with the more ancestral gut microbiome of hunter-gatherers and subsistence farmers in the undeveloped world.

They also hope to gather gut microbiomes from people with autism, Crohn’s Disease or inflammatory bowel disease, as well as from vegans, omnivores and athletes. They even have some celebrity participants — Michael Pollan, author of the The Omnivore’s Dilemma, and Dean Karnazes, the ultramarathon runner known for running 50 marathons in 50 days.

Interestingly all three researchers have children who have influenced the project in one way or another. Leach’s daughter has Type 1 diabetes and Gilbert’s son has autism. Knight’s daughter, born in 2012, has had samples removed from her diaper daily to help her dad understand how humans go from a microbial blank slate before birth to a gut microbiome mirroring that of an adult by age 3.

She’s not the only family member to submit to a sampling routine. Knight has taken his own specimens daily for 15 months to understand how an adult gut microbiome changes day to day. He also convinced his wife to submit samples several years ago.

She was not, however, as gung-ho as he was.

“She let me do it for about six months,” he says. “Then she got fed up with it.”

Luckily, Knight has plenty of fecal samples to decode — about 8,000 and counting through The American Gut project. He received $1.9 million in April 2013 from the National Institutes of Health for a supercomputer to help with the analysis. With a goal of 100,000 participants, he’ll need it.

Contribute Professor Knight welcomes donations to support costs associated with The American Gut project. Go online to make a donation at www.cufund.org or contact Jessica Wright at 303-735-0973 or jessica.wright@colorado.edu.

Illustration by Anna and Elena Balbusso; Photography by Peter Hibl, Philip Siebler and Zach Werner