Gut-microbiota has been found in recent years to have a significant impact on both physical and mental health. Ted Dinan, the Medical Director at Atlantia Clinical Trials, was interviewed about his work at Atlantia in investigating the impact of gut-microbiota composition and how it might be targeted to improve mental health in human beings.
Drawing on the analysis of rodents and other mammals, Dinan details the routes by which gut-microbiota can influence brain function, exploring how impactful gut-microbiota can be when it comes to illnesses like anxiety, depression, and irritable bowel syndrome, as well as detailing potential treatment avenues deploying these newfound links. 
Please could you introduce yourself and outline your role at Atlantia Clinical Trials?
My name is Ted Dinan, and I am the Medical Director at Atlantia Clinical Trials.
What research has Atlantia undertaken in the field of microbiota as linked to mental health?
Over the past few years, Atlantia has undertaken a significant amount of research into how the gut-microbiota influences brain function and how we might target the gut-microbiota to improve mental health. The average adult gut contains over a kilo of bacteria. The main phyla are bacteroidetes and firmicutes. There are over 400 species of bacteria within the intestine. The actual mass of bacteria within the large intestine weighs approximately the same as the human brain.

What are the factors that determine the composition of the gut microbiota?
It is important to look at what determines the composition of gut microbiota in humans, as this composition varies from one person to another. Gut composition is arguably as unique as our DNA profile or our fingerprint.
There are many different factors that determine our gut-microbiota. Our genetics play a significant role because genetics will determine what bacteria can actually colonize the colon, but in terms of the initial microbiota, the main determinant is how we were born. If a baby is born per vaginum, then the initial bacteria are acquired from the vagina of the birthing parent, which are called lactobacilli.
A baby born per vaginum – what is sometimes referred to as a ‘natural’ birth -  the baby will have a microbiome largely consisting of lactobacilli. On the other hand, if a baby is born by cesarean section, the initial bacteria that are acquired will be from the skin of the doctor, the nurse, or the birthing parent. It will therefore be a far more diverse microbiota than that of a baby born by cesarean section.
Now, at what we might think of as ‘the other end’ of life, the microbiota also alters as we age. It is now clear that, as we age, the loss of diversity in the microbiota precedes the onset of frailty. It is important to maintain a diverse microbiota as we age. The factors that can impact that microbiota as we get older would be things like stress, which can have quite a dramatic impact on the gut-microbiota; antibiotics – and medications in general - which can dramatically alter the gut-microbiota; and, of course, as regards a positive impact, diet and exercise. It is true that certain diets are associated with good microbiota, and there are certain diets associated with poor microbiota. Likewise, in terms of exercise, there is an abundance of evidence to indicate that people who engage in regular aerobic exercise tend to have a much healthier microbiota than subjects who do not.
How do gut microbes influence the brain?
Gut microbes influence the brain in a number of different ways. The vagus nerve is the long, meandering nerve that connects the brain and the gut, through which signals travel from the gut to the brain and from the brain to the gut. Certain microbes require an intact vagus nerve for brain-gut communication to take place.
A number of years ago, it was proven that certain lactobacilli could not transmit signals to the brain if the vagus nerve was severed. The vagus nerve is important, but there are other important roots of communication. Another of these is the production of 5-HT and the 5-HT metabolite, tryptophan. Tryptophan is the precursor of 5-HT.
We know that the human brain requires a constant supply of tryptophan. Tryptophan needs to cross the blood-brain barrier on a regular basis in order to maintain normal human mood, normal sleep patterns, and normal appetite. It is clear that certain bacteria, particularly bifidobacteria, which has been focused on previously in Atlantia’s studies, can increase the levels of tryptophan and the plasma. There is more tryptophan available to cross the blood-brain barrier.
Another important route of communication is the production of short-chain fatty acids. There are various short-chain fatty acids. The most extensively studied are butyrate, propionate, and acetate. They are produced by the metabolism of fiber in the intestine and can have a profound impact on brain function. Butyrate is an epigenetic modulator and, very specifically, an HDAC inhibitor. It can impact how genes in the brain function and also act on classic G-protein-coupled receptors. There are two receptors, FFAR2 and FFAR3, and butyrate connects through those receptors.
What are some of the other ways in which gut microbes can influence brain function?
There are other routes that seem to work in parallel. For normal brain function, we require the production of a variety of molecules by the gut-microbiota. Gut microbes produce molecules that we ourselves cannot otherwise produce and our brains require some of these molecules. It really is a synergistic interaction. We feed our gut microbes, and, in turn, they produce molecules that our brains require.
An essential point to note is that if we were to take all the genes from the gut-microbiota, whose products we require, and we were to put all those genes into ourselves, we would not be big enough to contain all that DNA. There is, therefore, an important synergistic interaction between humans and gut microbes.

What do studies into animals reveal about gut microbiota?
It is interesting to look at animals who have no gut-microbiota. It is possible to breed germ-free animals which have no microbes in their gut. These animals tend to be fairly abnormal in terms of their behavior. A number of papers have been published on the topic, which refers to a diagnosis of - an admittedly oft-used term these days - autistic patterns of behavior in these animals. 
For instance, if you allow the animal to socialize with another animal e.g., if you allow a mouse to socialize with another mouse and to spend time with an object (e.g., a pen), the animal with no gut microbiota is as likely to spend time with the object as it is with the other animal. Like ourselves, mice are sociable creatures, but there are many additional different anatomic abnormalities in animals that have no microbiota. Their myelination patterns and myelin is obviously a very important sheath in many neurons in the brain. Their myelination patterns are abnormal. Their neurotransmitter production, particularly serotonin production, is abnormal. Their synapse formation is also altered.
It has become clear in recent years that the mammalian brain, even in adulthood, is capable in some regions of producing new neurons. We know that these animals have abnormal neurogenesis. Their capacity to produce new neurons is actually altered. There are major changes, not just in behavior, but at a structural level in animals that are devoid of a gut-microbiota. Therefore, intriguingly, microbes are capable of producing most of the classic neurotransmitters.
These neurotransmitters are confined to the gut or the enteric nervous system surrounding the gut, but it is still remarkable that they produce most of the neurotransmitters like GABA, serotonin, dopamine, and noradrenaline that we have in our brain as active neurotransmitters.
Can human beings change genes in ourselves or our microbiota?
At present, human beings cannot change the genes within themselves, but there are a  variety of ways in which we can change the genes in our microbiota. Diet is a key component, as is the use of drugs like antibiotics as well.
Some of the common ways in which the gut microbiota can be altered include probiotics, which are now referred to as Live Biotherapeutics by US regulatory authorities, and prebiotics, which are fibers that promote the growth of good bacteria.
In addition to the more generative dietary approach, there is a more radical way of altering the gut microbiota through fecal microbiota transplantation. This approach is used for treating conditions like C. difficile infection in the elderly, but it must be noted that over 75% of the commonly prescribed drugs in clinical practice, and all commonly prescribed drugs, impact the gut-microbiota - some in very dramatic ways.
Proton pump inhibitors are used very widely for the treatment of hyperacidity or peptic ulceration, and while they do have a dramatic impact on the gut microbiota, so do many different drugs that are routinely prescribed in clinical practice.
Stress is another important driving factor for many psychiatric disorders like anxiety disorders and depression, along with physical ailments such as irritable bowel syndrome. This is why it has been described as “the disease of the 21st Century”. Although perhaps that is slight hyperbole, stress certainly is an important driving force to be analyzed.
Can stress responses be altered by altering the gut microbiota?
The short answer is yes. Data from a study published several ago in biological psychiatry was the first study to show that when animals were stressed - whether by specific stress or early life stress – has less diverse gut microbiota than animals who had not been subjected to this particular stress. The study revealed that they had an overactive hypothalamic pituitary adrenal axis by comparison; they released more corticosterone and had a less diverse microbiota.
In terms of translating this to human understanding: I was interested in exploring the situation in relation to patients who were attending my clinic at Cork University Hospital, where I primarily tended to see patients with depressive illnesses. We took a group of patients who were attending with a clinical diagnosis of depression. We compared their gut microbiotas with that of healthy subjects.
What we found as a result was that the gut-microbiota of the depressed subjects lacked the diversity and richness that is seen in healthy subjects. We then went on to do a transplant from the gut microbiotas of depressed patients. We transplanted them into animals - rats in this case – and these animals received a transplant from a healthy object of a depressed patient.
To our surprise, we found that when animals had a transplant from a depressed patient - in marked contrast to what happens when they had a transplant from a healthy subject - their behavior changed: the rats seemed to develop a depressive behavior pattern. The rats additionally had more inflammatory markers post-transplant, and their metabolism of tryptophan, which is the key building block for serotonin, was altered. This was certainly unexpected and potentially very significant.
The gut microbiota is altered in stress-related conditions, but there are a number of other scenarios in which the gut microbiota has been implicated: within disorders like schizophrenia and autism. It has also been implicated in a variety of degenerative conditions. The most widely-studied degenerative condition in relation to the microbiota is Parkinson’s disease, but there have recently been suggestions that the gut microbiota may also be involved in addiction, particularly in relation to alcoholism.