Transferring the Blues
Can depression be transferred via microbes?
Posted July 15, 2019
The gut-brain axis–the fascinating connection between gut microbes and the brain–sounds like science fiction. How can such tiny creatures affect our mood and behavior? How much of this story is hype and how much is real, useful science?
In 2003, Nobuyuki Sudo and colleagues noticed that germ-free mice behaved differently than normal mice. They had a heightened reaction to stress and preferred to play alone. Since mice are generally sociable, this was a notable difference, and it all came down to their lack of microbes: when Sudo gave them a blend of non-pathogenic microbes, their behavior recovered. A healthy microbiota seemed to confer resilience to stress and made the mice more gregarious. The results raised eyebrows in all the fields affected: gastroenterology, neurology, psychiatry, immunology, endocrinology and microbiology. How could brainless microbes possibly affect the sophisticated mind of an animal?
Given that humans aren't in any way germ-free, the relevance of this study was lost on many researchers. Psychiatrists, in particular, were occupied with research into psychoactive drugs designed to address chemical imbalances in the brain. Although the early drugs weren't perfect, once the kinks were worked out, there were some big wins–dramatically helping many people with depression and anxiety. How in the world did microbes fit into this picture? One clue: the first antidepressant, iproniazid, was an antibiotic intended to treat tuberculosis. Remarkably, microbes have been a part of this story from the beginning.
The gut-brain axis has a long history
Scientists have known since the time of Hippocrates that gut issues could cause medical troubles. His uplifting motto was that "death sits in the bowels". Soon after bacteria were discovered, researchers realized that bacterial pathogens were behind many diseases, including some kinds of mental illness. The notion of beneficial bacteria seemed absurd. It would take many decades for Élie Metchnikoff to see the good side of microbes in the early 1900s when he noted the health and longevity of yogurt-consuming Bulgarians.
Sudo's work showing behavioral changes inspired many others who went on to push the frontier, among them professor of neuroscience John Cryan and psychiatrist Ted Dinan of University College Cork in Ireland. In 2013, they proposed that certain bacteria could help resolve psychiatric illness. They dubbed them psychobiotics. Their conviction sprang from the stunning observation that microbes could produce human neurotransmitters, including GABA, acetylcholine, serotonin and dopamine.
They also found a connection between microbes and the hypothalamic-pituitary-adrenal (HPA) axis, the body's hormonal stress system. An interesting story was developing around stress. Stress in children is a well-known precursor to psychiatric ailments later in life. Studies showed that stress was affecting the gut microbes of these kids as well. Could early gut problems be a factor in adult depression and anxiety?
Reasons to be skeptical
Since this formative work, hundreds of mouse and rat studies have explored the gut-brain axis and its contribution to depression and anxiety. Nevertheless, there are many critics, and they have some good points. These studies have mostly been done on mice, not humans. Still, researchers often use mice for pre-clinical antidepressant studies, so they can't be totally discounted.
Perhaps the most damning criticism is that most of these studies are correlational, not causal. They show an association between microbes and mood, but that doesn't prove that microbes can cause mood changes. It might be that depression causes changes in the microbes, not the other way around.
Another problem is the purported mechanism. Research has pinned down some relevant pathways, including stress hormones of the HPA axis, inflammatory cytokines of the immune system, and the wiring between the brain and the gut, especially the vagus nerve. These connections are tantalizing, but still somewhat vague. Just how, exactly, do microbes manipulate the brain?
Fecal transplants are revealing
Another study by the prolific partners Cryan and Dinan helped to address these issues. They called it "Transferring the Blues". Yes, I stole that wonderful title. In 2016, along with collaborators including John Kelly, Catherine Stanton, and Gerard Clarke, they performed a fecal transplant. The twist? They transplanted feces from depressed people into rats. When they did, the rats became anhedonic and anxious, the rat version of depression. The study showed that microbes could cause a change in behavior and induce depression – and it works across species.
They also provided some possible mechanisms.
- In both the depressed humans and rats the ratio of kynurenine to tryptophan was high. An elevation of this ratio indicates a breakdown in the processing of tryptophan to serotonin, limiting this important neurotransmitter in the gut.
- They found that a depressed microbiota was a less diverse microbiota. The bacteria that were diminished in the depressed microbiota might then be psychobiotic candidates, including Prevotella and Dialister genera.
- They showed that nerve cells have receptors to directly detect bacteria, making them act like immune cells, closely involved with the initiation of central nervous system inflammation.
Scientists have since found that the nerve mesh that surrounds the gut, the enteric nervous system, makes contact with bacteria in the gut through enterochromaffin cells. That allows messages from the gut to reach the brain through spinal nerves and the vagus nerve. Underscoring that connection, if you cut the vagus, several psychobiotic actions are extinguished.
This study showed fecal microbial transplants can alter mood in a rat, but the case for humans is still contentious. Fecal transplants are typically only done for people with severe C. diff infections. All samples are routinely screened for pathogens, but Cryan suggests that donors should be screened for depression as well, just in case. Clinical trials using FMT capsules (popularly known as crapsules) to treat depression are underway.
For such an unusual hypothesis, skepticism is warranted. There are still many questions unanswered. But it's hard to believe that microbes can reliably affect behavior in a rat or a mouse but not a human. Fortunately, new human studies are buttressing the psychobiotic theory. Trials with healthy women show an increase in stress resilience in those consuming probiotic yogurt. And a large-scale Flemish study this year indicated that specific microbes are associated with less depression and a significantly improved quality of life. It's probably time to bring the microbiota into the psychiatrist's purview.
What to do?
Of course, there are many reasons people get depressed. Poor health, death of a loved one, and financial problems are just a sampling. It's not all up to microbes! Genes are involved as well. But even here, most of the relevant genes are related to components of the immune system, reinforcing the role of microbes. Your gut may determine how well you can tolerate stress, and a balanced microbiota seems to moderate anxiety.
If you are a psychiatrist, you can take advantage of this research. Dr. Dinan has added these simple protocols to his psychiatric armamentarium:
- Ask your patients about gut problems. Depression is strongly comorbid with IBS and IBD.
- You might want to look at blood levels of inflammation.
- Recommend better diets (see below).
- Trial probiotics or prebiotics with patients who are averse or refractory to psychoactive drugs.
Psychobiotics are unlikely to replace antidepressants, but they can be excellent adjuvant therapies, helping to lower the dosage or the number of drugs used in treatment.
If you are a psychiatric patient, look to your gut:
- Fiber and polyphenols are preferred foods of your beneficial bacteria, so eat foods like artichokes, asparagus, broccoli, leeks, and dark-colored leafy greens.
- Exercise to improve the diversity of your gut microbiota.
- Avoid unnecessary antibiotics. They can be lifesavers, but they are useless against viruses and not without the side effect of damaging your gut microbiota.
- Get plenty of sleep and try to synchronize with normal day-night cycles. Your bacteria have circadian cycles too and it helps if you can coordinate with them.
For a lot of depression, microbes may be the main actors. Dealing with them may banish the blues, often without psychoactive drugs and their attendant side effects. What are you waiting for?
 Sudo, Nobuyuki, Yoichi Chida, Yuji Aiba, Junko Sonoda, Naomi Oyama, Xiao-Nian Yu, Chiharu Kubo, and Yasuhiro Koga. “Postnatal Microbial Colonization Programs the Hypothalamic-Pituitary-Adrenal System for Stress Response in Mice.” The Journal of Physiology 558, no. Pt 1 (July 1, 2004): 263–75.
 Dinan, Timothy G., Catherine Stanton, and John F. Cryan. “Psychobiotics: A Novel Class of Psychotropic.” Biological Psychiatry 74, no. 10 (November 15, 2013): 720–26.
 Karl, J. Philip, Lee M. Margolis, Elisabeth H. Madslien, Nancy E. Murphy, John W. Castellani, Yngvar Gundersen, Allison V. Hoke, et al. “Changes in Intestinal Microbiota Composition and Metabolism Coincide with Increased Intestinal Permeability in Young Adults under Prolonged Physiological Stress.” American Journal of Physiology-Gastrointestinal and Liver Physiology 312, no. 6 (March 23, 2017): G559–71.
 Kelly, John R., Yuliya Borre, Ciaran O’ Brien, Elaine Patterson, Sahar El Aidy, Jennifer Deane, Paul J. Kennedy, et al. “Transferring the Blues: Depression-Associated Gut Microbiota Induces Neurobehavioural Changes in the Rat.” Journal of Psychiatric Research 82 (2016): 109–18.
 “Fecal Microbiota Transplantation in Depression - Full Text View - ClinicalTrials.Gov.” Accessed July 12, 2019. https://clinicaltrials.gov/ct2/show/NCT03281044.
 Tillisch, Kirsten, Jennifer Labus, Lisa Kilpatrick, Zhiguo Jiang, Jean Stains, Bahar Ebrat, Denis Guyonnet, et al. “Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity.” Gastroenterology 144, no. 7 (June 1, 2013): 1394-1401.e4.
 Valles-Colomer, Mireia, Gwen Falony, Youssef Darzi, Ettje F. Tigchelaar, Jun Wang, Raul Y. Tito, Carmen Schiweck, et al. “The Neuroactive Potential of the Human Gut Microbiota in Quality of Life and Depression.” Nature Microbiology 4, no. 4 (April 2019): 623–32.