We've become quite interested in, in the connections between the [INAUDIBLE] and neurological states in most, most specifically in animal models of autism, or autism spectrum disorder. And the way we got into this, this area was really, it was really almost, you know, sort of a hunch more than anything else. Based on the fact that there were many similar or there are many similarities between the immune system and the nervous system. So if you think about all the different organ systems of the body these are the two that learn from their environment. They have memory. Okay, and on an molecular serial level there's, there's a lot of overlap between how the two systems work. And so, as you may know, cytokines are, are, are widely studied as immune molecules. But they are both sensed and produced by neurons and conversely neurotransmitters are you know, exclusively studied by neuroscientists in the context of neurobiology, but almost all cells have receptors for neurotransmitters and main cells produce neurotransmitters. And if fact, if you go back, about 30 or 40 years, there's literature showing that immune cells actually synapse with neurons. So in other words immune cells and cellular nerves actually touch each other and presumably communicate. So very understood And so I think those were sort of the, the initial pieces of evidence that made us think that if microbes were impacting the immune system so, so profoundly, that perhaps it's not such a huge leap of faith to believe that similar associations were occurring with the nervous system. And over the past several years, over the past like I said five years, we've been able to show that indeed in mouse models back up bacteria do affect conditions related to Autism Spectrum Disorder as well as anxiety which is related to autism but also separate from autism. And it's really, in many ways to caffeinate our imagination for how cup microbes can be used to really understand behavior, psychiatric disorders, and even neurodegenerative disorders we work on Parkinson's disease and Alzheimer's disease as well. 70% of your peripheral neurons, the, let's say the neurons that leave your central nervous system and go into your periphery are in your gut. Right, so 30% of the rest of your body, so think about all your touch and taste receptors and pain receptors and all the neurons that are making your heart beat and your and you breathe, that's only 30%, right, of your neurons, 70% are in, you know, go to your gut. And so of course many of these are involved in gut motility. By, but bugs have access to our brains. And, and, and through the enteric nervous system, via the vagus nerve, they have direct access to the central nervous system, the brain and spinal chord. So microbes are involved in the development of the immune system, which, once again, ten years ago it was heresy to even suggest. Because you know, we all grew up thinking and believing, because it is true that the immune system evolved to repel microbes, to fight off infectious agents, right? [CROSSTALK] So it's just sort of this perspective that there is this one-way communication that any microbe that it stinks that the means to recognize that the immune system would immediately be attacked. Right? But the work that, that we did, which I think really opened this, this field is show that, that the dialogue is, go, goes both ways. Like how microbes impact the development and the function of the immune system. Whether it's on a cellular level, what, these are different cell types that develop under the instruction or education of microbes. Function in those cell types that develop under the instruction of microbes, as well as entire tissues and organs. So if you look in a, in a, in a sterile germ free mouse its tissues, its tissue architecture is underdeveloped even in an adult animal. Right, and so if you look at the spleen or different, different immune structures in the gut. Very immature even in adult animals. As we understand them we can think about ways for augmenting immune function, fighting off infections. Therapies for autoimmune or inflammatory allergic disorders. And so I think that this, the role of gut bacteria in, in improving the development and function of the immune system is something that we can harness for new therapies. So our laboratory's been studying a particular molecule called polysaccharide A which is produced by bacteris flagellus which is a common human gut bacteria. And this has worked, one thing is that it goes back about twelve years or so now. Where we discovered that a particular molecule from this organism bacteria fragilis as both required and sufficient for the development of the immune system. And when we started this work it was initially, you know, very much at sort of a coarse level because we were just trying to understand various different effect on how PSA polysaccharide A [INAUDIBLE] affected the development of the tissues or a specific, and tissues in specific anatomical locations. But, more recently what we've discovered is that PSA is very specific in the cell types that it interacts with. And what PSA does, is it augments the function of a particular immune cell called a regulatory T-cell. And so to take maybe one step back is, our immune system can be broadly characterized as having an innate immune system as well as the adaptive immune system. I won't go into the finer details of that, and within the adapted immune system there are both E cells and T cells. And these are the cells that are, that learn from interactions from microbes and have memory. And so in trying to understand the role of PSA in augmenting immune function, we ask initially is it working through their immune system. It's by and large working through the There's an innate component. But that's secondary. And in particular what we started asking is, are there different subsets of adaptive immune cells that PSA was directly interacting with? And, in fact, there's, there's a lot of specificity to PSA's activity. PSA improves the function of a specific category of immune cells called regulatory T cells. Right? So within even the T cell population there are very specific sub-sets, and each of those sub-sets have different functions. And so by and large, most of our T cells are pro inflammatory in nature. And so these are sort of the weapons of our immune system. And the reason that they are pro inflammatory is that they now have been inflammatory response is when there is an infection. The immune system is a very, very powerful, it's very powerful function because, you know. If you get a cut on your hand let's say, you see there is a tremendous amount of tissue damage during both to control the infection as well as the wound healing process you can visibly see host damage, and so as the adaptive immune system is trying to fight off microbes, it's also causing damage to our own cell, right? Because many of the, that say the weapons of the immune system can't fully distinguish between a microbial and our own cell. Right? And so in fact what we now know is that if the immune system becomes activated. In the absence of infection this is the cause of allergic and auto immune disease. Right? So the cause of, let's say, asthma or food allergies on the allergic side or of multiple sclerosis and lupus and type 1 diabetes is an adaptive immune system, primarily the T cells that have become activated. And cause cause a cascade that leads to tissue damage that results in, in the symptoms associated with these diseases. And so where PSA comes in is that PSA activates the other arm of the T-cell response, the other arm of the admser which is the anti-inflammatory arm. And so the reason why I don't have multiple sclerosis, or the main hypothesis for the reason why how, how people don't have multiple sclerosis, is that we have a good balance between the pro-inflammatory cells that cause tissue damage. And then the anti-inflammatory cells which are the brake on the immune system, which, which prevent uncontrolled inflammation. And unfortunately, one can, this is still a hypothesis, but there's a lot of evidence for this. Unfortunately what goes wrong in autoimmunity is that there are defects in the regulatory cells, the brakes. So, so the check, the check, so the in check. And what PSA is evolved to do is to augment that, that particular cell type, which produces an anti-inflammatory response. And so the two aspects of this that are really exciting in both, both in terms of, of knowledge as well as and therapies, is that, you know, what PSA represents is a novel paradigm in biology, is that there are microbial molecules which activate beneficial arms of the immune system. Unlike you know, what's been studied more prominently are microbial molecules which incite inflammation. These are virulence factors. Right? So here's my certain molecule which actually induces an anti-inflammatory response, as opposed to a pro-inflammatory response. And another aspect, as you might imagine, based on the description of why this is exciting is that if we can now harness this activity, we can boost the regulatory T-cell response, we can boost the anti-inflammatory response, which is missing in patients with allergies and autoimmunity [INAUDIBLE]. And we are hopeful that in the next two or three years we can start clinical trials using PSA as a therapy for for human diseases. Because we've already shown in animals that PSA both pre, prevent and treats inflammatory bowel disease and multiple sclerosis.
