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December 4, 2015
IS THE MICROBIOME OUR PUPPETEER?
Cryan Explains Gut Feelings, Thoughts and Behaviors

“What he did took guts.” “I had butterflies in my stomach the whole time.” Language is full of expressions suggesting a connection between our gastrointestinal system, emotions, thoughts and behavior. It’s a concept that may actually make neurobiological sense, according to Dr. John Cryan.

Cryan is a neuropharmacologist and internationally recognized scientist in the area of interactions between the brain and enteric microbes. He is professor and chair in the department of anatomy and neuroscience and principal investigator in the APC Microbiome Institute at University College Cork, in Ireland. His recent talk in Masur Auditorium was part of NCCIH’s Integrative Research Lecture Series.

Dr. John Cryan (l) is greeted by NCCIH deputy director Dr. David Shurtleff.
Dr. John Cryan (l) is greeted by NCCIH deputy director Dr. David Shurtleff.

PHOTOS: BRYAN EWSICHEK

The topic of the human microbiome,or the community of microbes that live in and on our bodies, has expanded in interest beyond scientific circles to the public in the past few years. While the microbial cells in our bodies outnumber our human cells by about 10 to 1, they have been largely unstudied until recently. One major effort close to home has been the NIH Common Fund Human Microbiome Project to characterize human “microbiota” (i.e., the microorganisms in a specific region) and their role in human health and disease. Today, work is going on around the globe to explore the microbiome, its interactions and effects and potential approaches to manipulate it for health benefits, as with probiotics.

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The idea that probiotics could improve health is not a new one, Cryan noted. “Most of the things we call ‘probiotics’ today are not really probiotics, because they have not been proven to have a known health benefit.” He summarized work by his team and others on some specific strains of “friendly” bacteria, as might be found in fermented foods.

Gut bacteria, said Cryan, are “little factories” that not only digest food and vitamins, but also “pump out all sorts of substances depending on the substrates [base materials] they have,” from short-chain fatty acids, to neurotransmitters, to novel “neuroactives” not yet described or discovered. These metabolites produce chemicals that can influence the brain, the body (e.g., the immune and hormonal systems) and behavior, though many specifics as to how are not yet known. Among Cryan’s accomplishments has been identifying that microbiota-brain communication is a two-way street in which the vagus nerve is central: “As we like to say, ‘what happens in vagus’ affects your emotions.”

Stress and how it affects the brain and body—as well as related problems such as anxiety, depression, irritable bowel syndrome and drug dependence—are his lab’s major focus, because “stress has wide-scale effects in the body, including on the gut,” Cryan said. “In our pro-stress Western world, the incidence of stress-related disorders is increasing. Looking for novel ways to intervene to manage and treat those symptoms is very important.”

Cryan described some of his better-known studies in animals. For example, in a controlled study in healthy mice published in 2011, his team fed one group plain broth and the other group the same broth infused with Lactobacillus rhamnosus bacteria. He found that the infused broth modulated the gut microbiota; produced an array of neurochemical changes, including to neurotransmitter receptors in the brain (e.g., receptors for GABA, which are targeted by anti-anxiety drugs); and reduced anxious and depressed behavior.

A specialized, 100 percent sterile facility in Cork has made it possible for the team to study specific questions about disorders in germ-free animals (who lack normal gut microbiota) over time. Autism, for example, interests them, as it has a strong incidence of gastrointestinal symptoms. It is a genetic disorder, Cryan said, but it might be possible to affect some of autism’s symptoms by targeting the microbiome.

In one study, his team took mice raised germ-free and studied their social patterns. Normal, healthy mice are social animals, but the germ-free mice preferred to isolate rather than socialize with other mice and to not socialize with new mice, versus the ones they knew. The germ-free mice also showed more repetitive behaviors. “It tells us,” Cryan said, “that for normal social responding, we need the appropriate repertoire of bacteria in our gut. This is also in line with the growing body of literature and other emerging autism models that the microbiome is at play.”

Gut check time: Cryan discusses the microbiome.
Gut check time: Cryan discusses the microbiome.

Cryan has identified several “critical windows” for gut microbiota development and in which it might be most possible to transform them: early life, adolescence and old age. But, “on the whole, it’s the early-life period that’s instrumental for informing the microbiome composition, which informs our immune system and may shape aspects of brain development as well,” he said.

People receive their gut microbiome at birth, in a kind of “priming”—from their mother if a vaginal birth, or from skin and the birthing environment (like a hospital) if by Caesarean section. The latter mode of delivery creates “quite a different microbiome,” Cryan said, that makes people respond to stress differently throughout life, e.g., with higher levels of anxiety or depression. However, he added, many other early-life factors also affect the gut microbiome and rewire gut-brain signaling, including diet; exposure to antibiotics; hospitalization; stress, disease and/or infections in the mother; gestational age; and even where one lives (e.g., a “green environment” or an inner city).

Elderly people’s microbiomes are being studied, too. Changes in the microbiome in this age group have been correlated with negative changes in functional outcomes such as frailty, cognitive function and inflammation, Cryan said. This was seen in a study by his colleague Paul O’Toole at Cork, when participants moved from life in their regular community to a nursing home or “rehab.” Why did their health worsen? The answer was diet: the participants had eaten a more diverse, less-processed diet before they entered the care facility; this gave them a more diverse microbiome. Cryan’s team has found that another factor, chronic stress, “adds fuel to the fire” of the normal aging process and may give rise to some conditions commonly seen in this population such as cognitive impairment, anxiety, depression and social isolation. Currently, he is looking at behavioral changes at older ages in animals and whether there is a relation to microbiome changes.

Cryan and his colleagues Ted Dinan and Catherine Stanton in Cork have coined a term, “psychobiotics,” to describe probiotics in which the intended benefits are to mental health. “Small studies [in this area] have been emerging and more are coming,” he said. His team is studying it in the context of stress-related and neurodevelopmental disorders. In a controlled study in healthy mice, for example, one group of mice received a Lactobacillus rhamnosus probiotic for several weeks. Compared to non-probiotic controls, the stressed mice “were more chilled out,” said Cryan. “They behaved as if they were on Valium or Prozac,” showing reduced anxiety and behavioral despair. Changes were seen in their physiology and neurochemistry that were not seen in controls. Another study found lower anxiety and improved working memory in mice who had received a bifidobacteria supplement.

But Cryan cautioned against jumping to conclusions about benefits to humans from any of these approaches using lactic acid bacteria. The vast majority of studies so far have been in animals. Human studies are in early stages and “black boxes” exist—for example, how bacteria in the gut potentially signal the brain.

Cryan closed with another strategy to manipulate the microbiome: fecal transplantation. Yes, it is what it sounds like: transplanting the intestinal bacteria in fecal matter from one individual to another. “It might not sound that great,” Cryan said. “But if you had Clostridium difficile, a hospital-borne infection, you would [take it], because [it has shown] a 90-percent success rate. People are looking at newer, more aesthetically pleasing ways to deliver this ‘new old’ medicine. Does it have any effect on brain health? I’m not aware of any human data and I’m scared to see what I might find on YouTube.”

In an animal study, Cryan said, Dr. Stephen Collins at McMaster University took two strains of mice with different microbiomes and different behaviors and performed fecal transplants between groups. Post-transplant, each group switched behaviors to those of the opposite group on specific tasks related to anxiety or cognition. So, Cryan suggested, “If you have to get a fecal transplant, in addition to having the donor worked up for infectious disease, you might want to get a good psychological profile of him or her, just in case.”

He concluded, “My message today is that your state of gut will affect your state of mind. To have a healthy brain, we may need a healthy gut. We’re beginning to see, as in Pinocchio, a kind of puppet and puppeteer relationship, especially early in life, between the brain and microbiome...In the 20th century, all the focus in microbial medicine was on killing [microbes] with antibiotics and saving lives at the same time, which was great. But now we can really appreciate the importance of the microbiome in having a beneficial effect on health, including brain health.”

Cryan’s lecture can be viewed at http://videocast.nih.gov/Summary.asp?File=19216&bhcp=1. NCCIH’s portal of science-based information on probiotics is at https://nccih.nih.gov/health/probiotics.

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