My research on HIV infection has been fascinating to me because it's really, it, it helped us to understand potentially the role that microbes play in diseases that people with HIV have a increase incident. But also, HIV has een interesting because they virus attacks Primarily kind of the quarterback of the the adaptive immune system, the, the CD4 positive T-cells. And you think of HIV as a state of immune suppression. But in fact, people with HIV actually can have more Chronic Inflammation or an activated state in the gut. So it's not that, their whole immune system is impressed, it's, it's suppressed. It's one specific important arm of the immune system that's mostly affected. And so by looking at HIV I feel like we've also been able to get a better understanding at the role of adaptive immunity in shaping the gut micro-biome in health. And and we and other research groups have found a real several papers over the past year, actually. And independently reported that people with HIV do have dramatic changes in the composition of their microbes and of their gut microbes. Whether you look all the way up from the small intestine down through the colon to the feces. Very dramatic and characteristic differences. And what's interesting too is, you know, these days in this country, most people with HIV, their virus is suppressed on anti, by using Antiretroviral Therapy. And But their microbes don't return, for some reason. And so people with HIV are living a long time, with, with HIV and, and also a long time with this very altered micro, microbiome. And we, and at the same time, they suffer from many diseases and increased incidence that have been linked with the microbiome. They have more metabolic disease, more Cardiovascular disease. And so that's actually a research direction my lab is pursuing at the moment to try to understand. And individuals living a long time with HIV and Art, is there a link between this altered microbe composition in their gut and, and metabolic disease. Some of the microbes that we are seeing disappearing with HIV are, are ones that are known to induce these T regulatory cells. And so, these are the anti-inflammatory types of T cells. And there's the CD4 positive cells, the same one that HIV targets are ones that can be these T regulatory cells. And so, it seems that some microbes seem to seem that induce these cells to be anti-inflammatory, seem to disappear. And what I kind of think is that, what's going on is that those microbes, those beneficial microbes have come to rely on the arm of the immune system just to persist. And so when that immune, that arm of the immune system is compromised, they, they can't live anymore in the gut. They, they are co-evolved, you know, [LAUGH] to depend on our adaptive immune system and when it's compromised, they, they, they can't survive anymore. So that's kind of one of our core hypotheses that we're trying to, to look at. We're trying to really understand who are the t, t regulatory cell inducing bacteria in the gut. And are those, when we look more broadly across this class. Is it, is it just sort of these certain microbe that we've already seen that, that are dramatically being reduced or is this just some more general phenomenon. Our strongest phenotype are people with HIV look like. People who lived in other agrarian cultures who ate different types of diets. And it was totally something I didn't expect, but it made me start to think about the role that the adaptive immune system plays in, in shaping our gut microbes to our environment. And that and that's not a passive relationship, in that when the adaptive immune system is compromised. Then you, you sort of lose that ability to have microbes that are dynamic and respond to your diet. And, and so those correlations seem to go away and that was something that was very interesting that I didn't expect it at first to see it all. My lab has also been doing work looking at the Microbiome Autism Spectrum Disorder, and, you know, this is actually a much tougher nut to crack in some ways than HIV. HIV is more one disease, whereas you can tell just from the name, Autism Spectrum Disorder, is, is a spectrum. Where you know, there is an association between Autism and Gastrointestinal problems, but not all kids with, on the spectrum have them. And there's just a very wide range of, of symptoms. And so, there's been a few papers linking microbes or, or their products, their metabolates, and showing altered composition. With autism and some, one paper that said, well we looked and there was no difference in the microbes with Autism. And so, they so, right now the literatures a little divided and conflicting and one of the reasons I think this is the case is that, it, it's a more complicated disease and so I think right now. What the field really needs is, kind of better subtyping of, of the people evaluated on the spectrum. And also just looking with the same techniques at larger cohorts, and so really there's two different efforts that I've been involved in when it involved in the night labs effort through the American Gut to recruit a very large cohort of individuals. So that we just have a lot of people from all over the country and can relate to all the other people in the American Gut, as controls. And then I've also been collaborating with a group at Arizona State University headed by Rosie Krajmalnik-Brown. Where, we're recruiting, kind of a little more carefully controlled cohort where, you know, I'm working with a doctorate CU at Denver who, who we're only recruiting from her practice, so we have all their medical records. And we're getting, fecal samples, urine sample, blood samples. And we're going to try to match up the microbes that are there, the metabolites that are there, all the rich data on their, on their symptoms. And and another part of that project that that Rosie's group at ASU has, has gotten going is to actually they've got an FDA approval to use fecal transplant therapy. As an investigational new drug for kids who have autism spectrum disorders. And so they've been starting a first pilot study there to to do fecal transplants on kids who have autism who also have concurrent gastrointestinal problems. And our plan and is to actually. Take all these, rich data as well, the the blood, the urine, the metabolites, and and, the microbes, and see how all that changes before and after a transplant along with whether there's a behavioral improvement. Cause I think for some people it's hard to grasp, that a gut bacteria could effect behavior in any way. And there's just been not only with regard to Autism Spectrum Disorder, but all sorts of behaviors and very interesting research showing. That there is this link between your gut and your brain, that could effect things ranging from depression to stress to, to autism spectrum disorders that we believe. That's another, thing that I think years ago no one would have imagined. Let's look at microbes to understand this. And now it's becoming more and more accepted, in the scientific community that this isn't some. Crazy, whimsical idea this is, you know, something that really has merit. So I think that microbio research is, is, just, is a new frontier for biomedicine and we're just finding. So many unexpected diseases that the microbiome might, might be involved in. So I think right now it's it's the exploratory days where just figuring out all the roles of the microbes play, what what even these different microbes are, what are their properties and, and I think, that over time. That's going to play a, a larger role in, in an understanding of and, treating a variety of different diseases and, and we're already seeing it in some-, something like Clostridium difficile infection, I think more and more medical centers are starting to treat fecal transplants as, as one of their tools in their kit. You know, not some crazy, out-there idea for how to treat it, you know, they're. Shelving the antibiotics a little sooner and, and doing a, a transplant instead and that, and that, so, but I, I'd hope that oh, over time more and more in, therapy involving my groups become commonplace and I, and I think that their research is really building the foundation to support that. One thing I used to think is that, in terms of the gut microbiome, there's. There's one picture of health, you know, this is what a healthy gut micro-biome looks like. I don't believe that anymore the more, you know, that I, that I do research. I think a healthy gut micro-biome depends on context, it depends on your age, for one. You know, a healthy infant is not going to look the same as a healthy adult. It depends on diet, you won't look if you are. Gorging on steaks every night or you, you're eating you know, mostly maize cassava if you live you, the, you, the same microbes aren't going to optimally digest those different diets. And, and even just within this country the wide spectrum of diets that people eat. They're not all going to be. Best digested virus seen. Bits of microbiomes. And so you know when I I’m looking at something like the American gut then someone’s asking is my gut microbiome healthy. You know I can’t just I can say it generally looks healthy. It’s not crawling with a pathogen. It’s not you know uber loadaversity you know but at the same time. When I look at these HIV patients who clearly aren't don't have healthy gut microbiome, they, they're not crawling with a path-, pathogen, they're not super low diversity. And yet, they do have a state of dysbiosis, and you know that same, something similar to that state is healthy for someone who lives someplace diff-, eating something different.
