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Jane Foster, PhD: The Science of Gut–Brain Communication

Interview by Craig Gustafson


Jane Foster, PhD, joined the McMaster University faculty in 2003. She holds a research appointment with the University Health Network in Toronto, Ontario, Canada, as well as a scientific position with St. Michael’s Hospital. Dr Foster is an active researcher with two translational networks, The Province of Ontario Neurodevelopment Disorders Network (POND) and the Canadian Biomarker Integration Network in Depression (CAN-BIND). Her research focuses on the role of immune-brain and gut-brain interactions on neurodevelopment, behavior, and brain function.


InnoVision Professional Media (IVPM):  You've spoken quite a bit on the science explaining the connection of the gut and the brain and the different networks the body uses to accomplish that bidirectional conversation. Could you start by outlining what those are and how that gut-brain axis communication works?


Dr Foster:  When we talk about the gut-brain axis, what we mostly are talking about is everything from the microbes, to the gastrointestinal tract, to the systems that surround that such as the mucosa, the immune system, and the enteric nervous system that then extend out and influence other parts of host physiology, including the immune system, hormones, and metabolites. All of those things that happen at the interface between the microbe and the host can then effectively influence brain function in the long run.


There are several pathways that connect the microbes [to the host]. In the gut-brain axis the attention is really on the microbes, so when I talk about that I'm usually talking about the microbes influencing other things.


First of all, locally, microbes themselves are little machines. One of the functions of our microbes is that they help us digest plant products that we wouldn't normally be able to digest. They do that by fermenting fiber that comes into our diet. By doing so, they actually produce a whole host of molecules, including things called short-chain fatty acids. Short-chain fatty acids—[compounds] like acetate, butyrate, or propionate, are the primary ones—can act locally to affect mucus production, affect barrier integrity, and affect general gut health, but [they] can also act remotely. For example, acetate [affects] systems as far away as the brain. So, these bacterially derived molecules are one way that communication occurs along the gut-brain axis. That is a very exciting area because it's linked to metabolism. The idea that diet might influence the way microbes influence the brain [works] in part through the mechanism of how microbes are important for metabolism.


Another pathway used is the immune system. The adaptive immune system develops mostly after birth and happens to overlap exactly with the way maturation and colonization of the gastrointestinal tract by microbes occur. The two systems interact continuously throughout that early part of life, and those microbes are necessary for the immune system to develop. The feedback microbes get from the immune system is also very important to the way the microbes develop. That is why early exposure to antibiotics and other stressors can influence some of the systems that are influenced by your gut-brain axis.


Another [link] between your gut and your brain is neural pathways. The gut is wrapped by the enteric nervous system, which has as many neurons in it as the entire spinal cord. Those neurons actually have projections that go right next to the microvilli that surround the gastrointestinal tract, and can respond to changes in the milieu of the lumen of your gut and can also respond to other signals. For example, one of the things that happens in response to changes in gut microbes and metabolism is a change in serotonin production in your gut and tryptophan metabolism across your [entire] system.


When we think about mood we often think about serotonin. Most of the time we're thinking about serotonin in the brain and how selective serotonin reuptake inhibitors, or SSRIs, might impact neurotransmitters, like serotonin, in the brain. There is actually more serotonin produced in the gut, and some of the ways that the gut influences peripheral influence [of the] brain is through modifications in tryptophan metabolism. [That mechanism] can go towards the path of serotonin, or it can go towards the path of kynurenine, which can be more inflammatory.


The vagus nerve is also a big player in how the gut influences the brain. The vagus nerve is the longest cranial nerve and connects all sorts of peripheral organs, including the gastrointestinal tract through the spinal cord up to the brain. It is very important in stress response and inflammatory responses, and seems to be one of the key mediators of gut-brain signaling.


IVPM:  You mentioned the level of serotonin production in the gut and how it pervades the enteric nervous system. Does gut-produced serotonin affect the brain by crossing the blood-brain barrier?


Dr Foster:  Theoretically no, but it doesn't need to. Serotonin is the product of tryptophan metabolism. [Dietary] tryptophan is metabolized by the enzyme tryptophan hydroxylase to produce serotonin. Cells take up the tryptophan and then they make the serotonin, which can then be released. That is where, perhaps, it could cross the blood-brain barrier if the proteases or the other things that are out there where it is released didn't chew it up. All the serotonin in the brain is made by the dorsal raphe neurons, housed in the brain stem. Tryptophan has to get to them from the diet, so [the amino acid] comes across the blood-brain barrier. Those neurons, then, produce the serotonin, and they release the serotonin at synapses through projections to every place in the brain. There are [several] different serotonergic receptors, [and they] can change the nature of the effect of that serotonin. But the production of the serotonin is just in those dorsal raphe nuclei in that middle part of the brain.


Within the lining of the gut enteroendocrine cells, a type of specialized epithelial cell, produce a lot of serotonin. So, 95 percent of the serotonin in the body comes from these cells in your gut lining. That serotonin bathes the bacteria in the gut, [signals] the enteric neurons, and even talks to the immune cells—some immune cells have serotonergic receptors. So the concept of a neurotransmitter existing just for a neuron is a little bit mythical, and in fact, those serotonin molecules have a whole host of effects on motility and physiology of the gut.


Taking an SSRI anti-depressant is thought to modify the availability of serotoninergic [activity] at those key synapses in the brain, but there is no reason to think that it is not also having key effects at the level of gut physiology that might improve gut physiology. That would, in turn, improve some of these bottom-up signaling events that could influence brain function.


IVPM:  You talked about one of the main jobs of the microbes being to educate the immune system and help the brain develop. Can you elaborate?


Dr Foster:Microbes are essential for the development of the adaptive immune system, the T-lymphocytes and B-lymphocytes. They develop postnatally, so in the absence of microbes, for example in a germ-free mouse, the adaptive immune system [remains] underdeveloped, particularly in the mucosal system. It seems like a lot of the systemic immune system might still survive, but the nature of that window where in early life—in humans it might be the late third trimester into early postnatal life—there is a point where T-cell and B-cell expansion takes off. That's the point where all of those T-cells go circulating around and the immune system develops a tolerance. It figures out what is self so later in life it knows how to recognize foreign [bodies].


All of those steps seem to be reliant on the presence of bacteria in the gut. Some of that signaling is through those short chain fatty acids I mentioned earlier. Some of that signaling, I'm not sure that we know the details of, but in our work in my lab and some work that has yet to be published, taking away the T-cell in mice completely redirects the trajectory of microbiome development to something that looks very different. I'm not sure that there is evidence in the human literature of that yet, but the concept certainly [has traction]. The reason immunologists were interested in microbes in the first place was because they could manipulate them and manipulate the development of the immune system in order to study different [aspects] of the immune system. That is where the germ-free mouse came from in the first place, to help the immunologist figure it out. Because at any point, when you [reintroduce] the microbe, you can reconstitute the entire immune system.


The innate immune system, that response to quick infection, doesn't seem to be affected [in that way]. It might be affected by the microbes, but it is not critical that they are there for its development. The other thing that is important, in the early window between birth and the first three years of life as the microbiome matures, exposure to antibiotics, or C-section, or some of these other early postnatal events can influence the trajectory of the microbiome. That is one of the mechanisms that reserchers think might drive allergy and asthma. [In those cases,] the microbiome is altered in a way [that does] not educate the immune system, the immune system fails to figure out self and foreign, and then some allergy and asthma [emerge]. One of the biggest consequences of antibiotic [exposure] around the birth time is risk of allergy and asthma, certainly [after] C-section. Part of that is thought to [stem from] this lack of the normal trajectory for microbe-host interaction.


There is a lot of interest at the moment in the microbiome sector of nonantibiotic drugs and their impact on the microbes themselves, because if we start to understand how the microbes sort people into their individual differences—which is one of the things I think is most interesting as mine is completely different than yours—and if that is somehow a fingerprint of gene-environment interaction and risk factors for illness, then understanding which of those microbes are responsive in different individuals to antibiotics or nonantibiotic drugs is going to revolutionize the precision-medicine approach and help physicians give people the right drug—or not give them [a particular] drug—right from the get go. That's the bang for your buck [that will come from] the microbiome world.


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