Polycystic Ovary Syndrome (PCOS) and the Microbiome

Hi everyone, this is Lindsey Parsons, your host of The Perfect Stool: Understanding and Healing the Gut Microbiome. In this week's show, I interview Dr. Varika Nathakuri, Associate Professor of Obstetrics, Gynecology, and Reproductive Sciences and a member of the Center for Reproductive Sciences and Medicine and the Center for Microbiome Innovation at the University of California San Diego School of Medicine. We discussed Dr. Thackery's recent article, Improved PCOS Symptoms Correlate with Gut Bacterial Composition, and the mouse study that served as the basis for her article. We discuss polycystic ovary syndrome, or PCOS, its causes and its treatments, and how her research study points to new potential avenues for treatment with novel probiotics. So on to the show, and don't forget to press subscribe.

Hi, Kina, and welcome to the show.

Thank you very much.

Thanks so much for being with us and for talking about your article and your research.

Great. I, it was a pleasure to speak with you.

Yeah, we're excited to have you. So tell me first, what is PCOS?

So PCOS is a disorder that about 1 in 10 women have in the US and around the world. And it was described in 1935, but it's one of these disorders that we really don't understand why women develop it. And we don't have that many treatments for it as well. So polycystic ovary syndrome, or PCOS, is currently diagnosed if you have 2 out of 3 criteria. So if you have elevated testosterone or signs of hirsutism, that's one of the criteria. If you have—

And let me stop you for a sec. Can you just tell for our audience what hirsutism is?

Yeah, so it's basically male pattern pattern hair growth. So for example, on your cheeks or chest, and, um, you will have more hair than typical. So that's something you might notice. You could have more acne, and you can have male pattern baldness as well. So that's characteristics, and it's usually scored on a particular scale that a doctor will go over with the patient. So you can look at that, or you can look at biochemically by taking a blood looking at in the blood actually about how much your testosterone levels are. And typically women are considered to have elevated testosterone levels if it's 2 times the normal or average level for women.

Okay. And when are women typically diagnosed with this? Like, what are the, what are the warning signs that they typically notice?

Um, yes, that's a really good question. So we're actually noticing women being diagnosed earlier because of some side effects that are things that happen with obesity and weight gain. But a lot of women actually are diagnosed with this disorder when they have irregular menstrual cycles and they, you know, they've kind of gone through adolescence and they're still having irregular menstrual cycles and they're not really sure why. So that's one thing. So that's one of the other diagnostic criteria, like I was saying. So there's the elevated testosterone levels, you can have irregular or no menstrual cycles, Or you have these polycystic or these kind of cyst-like follicles in your ovary that it's observed by ultrasound. So you have to have 2 out of those 3. And then women often notice, like I was saying, she— they have irregular cycles, or they're trying to get pregnant and they're having difficulty getting pregnant. So it's the number 1 cause of like anovulatory infertility. So they're not ovulating properly. Or women come in having a lot of weight gain or difficulty losing weight. That's the one of the other reasons that they might present.

Okay.

Yeah.

So with these 3 criteria, like I was saying, women would come in typically, I think the 2 most common complaints are issues with fertility or issues with weight gain.

Okay.

Yeah.

So you did mention that obesity might go hand in hand with this. Is there, what's the relationship? Yeah.

So what's interesting is that studies have shown that Women that have the elevation in testosterone levels and one of the other criteria, so they either having irregular menstrual cycles or, and/or they have the polycystic ovaries, they have a correlation with a metabolic phenotype. And this phenotype includes weight gain, abdominal adiposity, so that means that you're putting weight on in your tummy area, and elevation or increased fasting blood glucose levels and insulin resistance. Yeah, all of this together increases your risk for developing type 2 diabetes and some other disorders. So for example, you have an increased risk of developing hypertension and also non-alcoholic fatty liver disease.

Mm-hmm.

Yeah.

Okay. So beyond the reproductive effects of PCOS, what are the potential negative health effects that are specifically to PCOS, not sort of coexisting with?

Well, so what I wanted to make clear is, is that the effects that you're seeing in terms of metabolism and metabolic disease are arising from unique features of PCOS. So the way to think about this is, is just because you're overweight does not mean you're going to develop PCOS. So there's plenty of women that have weight gain that will not develop PCOS and do not have genetic susceptibility factors that could lead them to just develop this disorder. So the metabolic issues that women with PCOS deal with are unique to their disorder and probably arise from different mechanisms in the body that are dysregulated. And then they, they too develop, for example, type 2 diabetes, but the reasons why are probably different than the rest of the population. They also have issues with depression and anxiety that I think people used to think that this was tied to body image. If they have weight gain, you have some increased, um, hair, for example, or acne. But studies are now showing that there are things going on with the brain that are in addition to body image concerns. So legitimately, women have— with PCOS have increased risk of anxiety or depression, and this is something that should be discussed with the doctor as well. So That's kind of a concern as well.

So you mentioned genetic susceptibility. What is the— what does the medical community believe is the cause of the disease at the moment?

Really good question. So the studies that we have suggest that there— it does run in families and there's a high heritability component. So for example, the classic study to do is a twin study where you compare identical twins to monozygotic twins, as they're called, and dizygotic twins or fraternal twins, and you ask, what's the, what's the risk of them developing a disorder? And so what that shows you is how much is to do with the environment that you were raised in versus your genetics. And PCOS is highly heritable. So it's about 0.7 up to a scale of 1. And, you know, height, for example, which is highly heritable, is about 0.8. So what that suggests to us is that there are multiple genetic changes that can have occurred that predispose you to developing PCOS.

So you said 0.7 to 1 for PCOS?

No, it's 0.7 out of a scale of 0 to 1.

Oh, okay.

Yeah, so it's quite heritable, as opposed to like if it was half, you know, your environment affects about half of it, it would and genes explain half of it, it would be 0.5, right? So it's more heritable than environmental influences— influenced, but it's, it's 0.7, so it suggests that 0.3 of this has to do with what you're exposed to in your environment as well. So at this point in time, they don't really understand what are the risk factors in terms of the different genes They've done studies to map, you know, on a very genome-wide basis what could be linked to these, your risk factors, and they're trying to study that more, you know, on a population level. So then I think the studies moving forward are going to be trying to understand how these small changes are like single nucleotide polymorphisms.

Um, can you dumb that down a shade?

Sure. Yeah. So, Basically, you know, there's just normal genetic variation in, in our population, and it's, it's not— it's something that normally doesn't have that much of an effect, but potentially a change in one gene combined with an environmental influence would then result in you being predisposed to develop PCOS.

So that's what a single nucleotide polymorphism is.

It's basically there, you know, in a population, like for example, in one gene, like say the follicle stimulating hormone gene, which is important for maturing eggs, right, in the ovary. If you had a small change in that gene, you know, 80% of the population has one nucleotide, 20% of the population may have another nucleotide. So that could be a risk factor because it changes the way the gene works. And somehow that then leads to higher levels of testosterone, leads to potentially insulin resistance that results in vicious cycle where you then have changes in metabolism, changes in the reproductive axis that then result in PCOS.

Okay, so tell me what kind of treatments are currently available for women with PCOS.

Yeah, so for PCOS, uh, you know, as probably evident from our discussion, there's no cure because we don't really understand really how, why, how or why women are developing this disorder other than that there's a genetic component and an environmental component. So each of the treatments is kind of piecemeal. It's dealing with the specific symptoms. And having said that, because this is a women's health disorder, it's, it's been ignored. So even though 10% worldwide of women have this disorder—

10%? Wow.

10%. Yeah, there's no treatment that has been approved, for example, in the U.S. by the FDA just for PCOS. It has been approved for other conditions and then is used off-label for PCOS. So for example, for the treatment for hirsutism or the higher androgen levels, you could give a person oral contraceptives to, to lower their androgen levels. You can give them specific anti-androgens to combat that higher level of androgens, but those were not originally developed for PCOS. You, for example, dealing with the metabolic phenotype, the common— the, the first line treatment that is recommended is diet and exercise. Very generically, there's no studies really supporting one type of diet over the others. But people often are prescribed metformin, which is an insulin sensitizer. It has a whole host of different effects on the body, and that has really been developed for, you know, pre-diabetes and diabetes people, people with that, that disorder, and has now been applied to women with PCOS.

Now, 10%, this is a shockingly huge number to me. So I'm wondering, historically, has the rate been rising? Do you know?

I think it's not clear, but the suggestion is, is that it's worldwide. So it occurs in countries that hypothetically are not eating our Western-style diet. So it's, it's probably been around for a while, but it may actually— the, the presentation of the symptoms may be being worsened by our Western-style diet, which is, you know, increasing obesity. So you may present with this disorder more strongly than if you had a better diet. Or so it's really not quite clear, but the fact that it's worldwide and it really doesn't— I don't think the incidence rates vary that much from country to country suggests that it's, it's a pretty— it's not a disease that has just arisen from our modern lifestyle.

Hmm. I would not have expected that. Okay. So what made you start to think about the microbiome as a potential factor in PCOS?

Yeah, really good question. So there's been quite a few studies that have been looking at the role of the gut microbiome in terms of metabolism and metabolic disorders in general. And so for, for me, what kind of piqued my interest was this really strong metabolic phenotype that women with PCOS have and that it's correlated with the increased testosterone levels. So if you have higher— these higher testosterone levels, you have, you know, 80% of those women have metabolic dysregulation. So it made me wonder, does the gut microbiome play a role in the metabolic phenotype of PCOS, and is it potentially involved in the pathology?

Now, when you say the metabolic phenotype, does that— what I'm understanding is that a phenotype would be like, there are some people that present with metabolic syndrome and PCOS and some people that do not?

Yes, what's interesting is that women with PCOS are unusual in that they get a metabolic phenotype if they, especially if they have higher testosterone levels, whether they're overweight or not. So even normal weight women with PCOS have, often have insulin resistance. So they can more easily develop type 2 diabetes than another person that is normal weight, for example. So they have about four, fourfold or four times higher risk of developing type 2 diabetes than somebody in the normal population.

And is there a metabolic and a non-metabolic phenotype, or is there some other phenotype?

There's, I think it's more that the women that, for example, out of the three criteria that you can be diagnosed with, If you have, if you don't have hyperandrogenism, but you, for example, have irregular menstrual cycles and polycystic ovaries, this is so-called type D PCOS, and it's debated whether this actually is PCOS, but the criteria now says it's, includes it in the syndrome. Those women have a very small chance of having a metabolic phenotype. So they usually have reproductive issues, but not metabolic issues. Whereas the women that have the hyperandrogenism, 80% of them also have metabolic issues as well as having issues with their reproductive hormones.

Got it. So tell me about the experiment that you did.

Sure. So what we had initially done was a couple of years ago is we were, you know, the first question was basically to ask both in women and in rodent models, is there— if you have a PCOS-like disorder in that's being modeled in a, in a mouse, do you see changes in the gut microbiome? And so we had shown that we do see changes, and this has also been shown in women with PCOS as well. Okay, so that's kind of the first question is, do you see changes? And the second question that we were interested, interested in asking then is, okay, if there are changes are these changes occurring because of all the changes in metabolism, or is it possible that some of these changes actually are causal, or they lead to some of the metabolic dysregulation or the, the changes in the reproductive hormones? So does it play a role in the disease as opposed to just being a symptom? So the way we chose to do this was a really relatively non-invasive experiment. So what we set up was we have a mouse model of PCOS, and we normally house them 2 mice per cage. So we had our healthy placebo mice that basically were housed 2 per cage. We had 2 letrozole-treated mice, which are the PCOS model, and then we put the PCOS model with 1 healthy placebo mouse. We basically looked at whether they if they were cohoused together, did the PCOS mouse develop the type of dysregulation that we saw in metabolism and in reproduction? And the, the short answer is no, it didn't. So it had a profound— by basically having the mouse with PCOS-like symptoms cohoused with a healthy mouse where you're getting exchange of the gut microbiome Because they eat each other's poop, right? Because they're coprophagic, like a lot of rodents and rabbits. So you're getting this low-dose exposure to the gut microbiome, daily exposure. They basically were protected from developing the metabolic and reproductive phenotypes.

So tell me a little bit more about how you induced PCOS in the mice.

Sure. So what we model is like it, because we were just basically discussing before was we don't really understand the genetic causes of PCOS specifically, so we don't have a— we don't have genetic models yet of PCOS. What we do have is models where we basically induce elevated testosterone levels. So one of the ways to do that is through this non-steroidal aromatase inhibitor called letrozole. And so what letrozole does is we basically give it to the mouse and and this results in the blocking of an enzyme called aromatase. And so aromatase then, if it's not working, results in a buildup of testosterone and a reduction in estrogen because the job of aromatase is to convert testosterone to estrogen in the ovary. Yeah, go ahead.

And what is letrozole normally used for?

So letrozole is actually used for two reasons, actually. For one reason, it's used as a treatment for breast cancer. So with, for example, postmenopausal women that don't have very high levels of steroid hormones anymore because they've gone through menopause, if they basically, if they have a, they had breast cancer and they no longer want them to expose them to estrogen at all so that they don't redevelop their breast cancer, they'll put them on letrozole and minimize basically, or even lower even further how much estrogen they're being exposed to. That's like a long-term treatment. So it basically results in very, very low levels of estrogen. That's the main use of letrozole, kind of in pharmaceutically. And then the second thing that people use actually interestingly is for, uh, to induce ovulation. So for women that are having difficulty getting pregnant They've shown that if you do a short dose of letrozole, so for 3, 5, up to 7 days, it results in a boost to the reproductive axis that results in an ovulation. This is not done long-term in premenopausal women that are trying to get pregnant, but just short-term. So it, it does end up raising testosterone levels a little bit and lowering estrogen, but somehow that results in a boost to the brain and the pituitary and increases your chances of ovulating.

Okay, so let me just make sure I fully understand the experiment. So you basically have the mice— 3 cages, right?

Right, 3 different types.

Yeah. So did you— was it just 6 mice total in the experiment, or was it more?

No, we have usually 8 to 10 cages. So we have multiple cages representing that particular type. So for example, 4 cages of 2 healthy mice housed together, 4 cages of 2 of the PCOS model housed together, and then 8 of the cohoused situation. We want— we want to do that so we can kind of see the normal variation that you would see, for example, in some of these parameters that we're looking at.

Okay. And so in one cage you have a mouse that's on letrozole and one that is not.

Exactly. So that's—

And how long did it take for them to— so, so presumably they went in having increased testosterone or, or were they put together and then the letrozole was added? They were—

we did it at the beginning. So from the beginning they were cohoused together. And that's actually a really good question. We've measured most of our parameters at the at the end of the experiment. We didn't actually measure, for example, testosterone levels throughout the experiment, and would be very interesting to know as a future study when— was testosterone always low? So if you're getting this exposure to the microbiome, was it protective from the very beginning, or did it take a couple weeks to have a protective effect and then the testosterone levels went down? We don't know that yet.

And you presumably ended the experiment with the two living together. You didn't—

yes, yeah, yeah.

So it seems like an interesting experiment then would be to take away the healthy mouse and keep giving the letrozole and see what happens without that constant exposure.

Yeah, that, that would actually be really interesting to see as well. What we would postulate is that if you take the healthy mouse away, because you haven't fixed the PCOS phenotype, now your, your testosterone levels will go back up again, and we would suggest that you would then develop a PCOS-like phenotype. So we don't know that for sure, but the suggestion is, is that if you are not somehow removing or dealing with the elevation in testosterone, you're somehow get— if you're developing insulin resistance, you're going to start developing those PCOS-like Peanut Tag.

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So what do you think is the reason that the cohoused mice, mice with PCOS, were protected from the letrozole?

Good question.

Yeah.

So preliminarily what we know, like when, what we published in the paper is we went and looked, so you can look at the gut microbiome itself and ask, did it change? So because they were cohoused together, did the microbiome in the PCOS model change? And the answer is yes, there were definitely changes in the gut microbiome. And then what we also asked was, did we see changes in specific bacteria that could give us some hints as to whether there was a protective effect? And we did see some changes in bacteria that have been proposed as novel probiotics. So they're not used as probiotics right now. They haven't gone through the approval process or been used routinely, but they're known to be bacteria that are important for gut health and are associated with individuals that are not overweight versus being obese. So there's, there's some hints there that the co-housing resulted in some changes in the microbiome of the PCOS-like mouse, and that maybe we could use some of those hints to then figure out some potential strategies to intervene to help with this PCOS phenotype.

And what were those strains?

So one of them was Coprobacillus. So there's, there's like been several studies that have looked at bacteria that, that you could potentially reconstitute a functional microbiome. So for example, could you give, you know, 20 bacteria or 12 bacteria to an individual and have a similar phenotype as the whole microbiome. So, Caprobacillus is suggested that would, you know, in some of these companies that they're looking at as one of the components of a healthy microbiome. So, we'd like, one of the studies we'd like to do in the future would be, could you basically give the PCOS-like mouse Caprobacillus instead of doing a cohousing experiment? Could you just give them Caprobacillus or copper bacillus plus some of these other microbes and see improvement in the PCOS phenotype.

And you said there were some overall microbiome differences. What— how would you describe those?

So yeah, actually, it's a really interesting question. So one of the things that people have looked at in, in, in terms of the microbiome is they've talked about the overall biodiversity or the complexity of the microbiome, which is called alpha diversity. In ecology. And what's interesting is a lot of these disorders—so obesity, type 2 diabetes, and PCOS—you see a decrease in the biodiversity of the system compared to the healthy control. So what we did when we did the cohousing study, one of the first things we were curious about is when we cohoused the mouse together, did we see a restoration of the biodiversity? What was intriguing is that we didn't. So, what this suggested to us was that whatever was working or being protective in the cohousing model was not necessarily affecting the whole ecosystem itself, but potentially making specific changes in specific bacteria or in specific metabolites that the bacteria make.

And what metabolites were you looking at? So we haven't published that data.

We have some preliminary— it's called metabolomics data. One of the interesting things is we see differences in bile acids that are produced in the liver and then conjugated in the liver and modified by the gut microbiome. So we're starting to investigate that more closely because there's now quite a lot of literature suggesting that the ratio of different primary versus secondary bile acids actually has a huge influence on metabolism.

What is that? What's a primary versus a secondary bile acid?

In humans, it's a little different than in mice. So humans and rodents have slightly different primary bile acids. So for example, primary bile acids is, for example, things like cholic acid, and they're then modified in the liver to, for example, you add a glycine group, or a— so you get glycocholic acid or taurocholic acid, for example. And then what's interesting is that, you know, they're produced as bile acids and they go into, into the GI tract, and bacteria in the gut then change them even further. So they change them into these second— they take off those, that glycine or taurine group, and they then modify them so that they become secondary bile acids. So for example, you know, there's like these ursodeoxycholic acid— there's a whole bunch of different secondary bile acids. The intriguing thing is, is that there are many more forms of these than has— was appreciated in the past, and they may act as activators or repressors of certain nuclear receptors that are really important for metabolism. And, for example, insulin production or a function of fat cells and things like this. So the implication, you know, what people are getting very interested in is, are you seeing a change? If this— if you have this change in primary versus secondary bile acids, is this somehow then being influenced by the gut microbiome in your disease of interest? And if so, could you manipulate or change this, how this conversion of primary to secondary bile acids is working to benefit patients with, for example, PCOS? I think the most intriguing thing— there was a paper published this year that showed that metformin, for example, actually results in the production of a secondary bile acid that is quite rare in humans. So it's producing something novel or new, and that bile— a secondary bile acid may be having an effect on metabolism. So it could actually explain why metformin— one of the mechanisms of action of metformin, and that it may be connected to activity of the gut microbes themselves.

Interesting. So can I— this is a bit of a backup, but can you define what a metabolite is in case our listeners don't know what that is?

Sure. So a metabolite is something that is produced by the bacteria. So for example, the bacteria, they're doing their thing in within the environment of the intestine, for example. And so they make metabolites Those are useful for them in terms of communicating to other bacteria in the gut or having effects on the host. So in this example, on our physiology. So, and that can be beneficial to them in various ways. So they make a whole, you know, slew of these small compounds or molecules that can have effects on the host that are quite profound. So What people are starting to realize that it's not just enough to kind of get an idea of who the microbes are that are changing in the gut, but also their functional change. So are you producing more or less of certain types of metabolites that could have an effect on physiology or pathophysiology?

So let me back up to, you mentioned Caprobacillus. I'm not familiar. How do you spell that?

It's called Copro. Coprobacillus. Yeah. And how's that spelled? Copro? C-O-P-R-O bacillus.

And is that—

that's all one word? Yeah. Yeah.

Okay. And is there— is that the genus or is the species or—

That's the genus.

Okay. What species?

So we don't know yet. Yeah. So that's a really good question. I would say we're at the level of we're sort of describing— it's descriptive changes, but we're— we would need to do different types of studies to understand at the level of the species what is really changing. So that's kind of what we're also interested in looking at with these models is alluding to the metabolites, but also the species differences. You can use high-throughput sequencing where you're basically sequencing all of the genomes of, for example, the bacteria, so you can get strain or species-level information about what is changing. And then you can use metabolomics through instruments called mass spec or spectrometry instruments that can tell you whether the metabolites that these bacteria are producing, whether they are changing. And so that's kind of what we're doing right now.

So, but originally what you did was tested the microbiome of the mouse before and then after, and you saw that there was an increase in the genus Caprobacillus. Yes. Of the, of the letrozole mice. Right, exactly. Okay, and that was the only genus you noticed that was, that was increased? Because you said there was an increase in diversity, but that one stuck out as something that had increased.

It was the one that basically was— so it's high, it was high in the healthy mice, it became low when with the letrozole treatment. So in the PCOS model,. But then when we cohoused the PCOS model with the healthy mouse, it recovered. It was, it was back up again. So it was the main signature that we saw that suggested that the cohousing potentially maybe having more of this bacteria was protective.

And you noticed other genuses that decreased?

We had some that also decreased, but none of them in our statistical analysis then really changed with the cohousing treatment. So something to keep in mind is that the— what's going wrong with the PCOS-like model, there could be multiple things that are going awry, and the cohousing could have provided protection by just affecting certain— some things, but not everything. So it's possible that there is multiple ways to try and change or manipulate the gut microbiome that would potentially have a protective effect. There's not just one thing. You could potentially target more than one thing.

So now I'm going out here, but is it within the realm of possibility that the bacteria in some way know what's going wrong and self-select which ones need to, need to make it to help correct what's going wrong?

Yeah, well, so that's a really interesting question. So what you have to think about is the bacteria They're living— most of these are called commensals, so they live in a mutualistic relationship with us. They're not pathogenic bacteria, you know, as we classically consider them that. So we're living in balance with these bacteria. And the studies are suggesting that there are sex differences in the gut microbiome and that sex steroids may mediate some of these differences. So it's not— in my mind, you know, women and men have probably different microbiomes and different functions with their microbiomes, and that may have some bearing, for example, on diseases that have sex differences. So the thing that comes to mind is autoimmune diseases. So women are more susceptible to certain types of autoimmune diseases. And their gut microbiome may play a role in that susceptibility. Men may be protected from some of these diseases because of how the composition or the function of their gut microbiome.

Is it because the hormones influence which bacteria do best in the, in each gender? Potentially, yes.

So what we know, we don't know that much about this topic, but what we do know is, is that the gut microbiome is similar before puberty. Both in humans and in rodent models. And then after puberty, it diverges, it becomes different. So the suggestion is, is that the sex steroids are shaping the microbiome in slightly different ways in males versus female.

So I actually had— that's the first I've heard of this because I see, you know, you get your, your microbiome tested and you get your, you know, here's your layout versus the rest of the world, but they never mentioned, wait, here's your layout versus other women or other men. And so I'm interested, what are the differences that you know about between—

do you? So it's a really good point is that I would say it's a factor. It's not— when they did these initial microbiome, like with the Human Microbiome Project at the NIH, they were not able to see sex differences. So they basically said, we don't think there are sex differences. There's now been really large cohorts, such as the American Gut Project and some of these other cohorts, and they can see some differences between men and women. However, keeping in mind, there's also huge differences within men, for example, um, their microbiome. So it's a factor that can explain some of the variation, but it's, it's certainly not the factor. There's a lot of other things that are explaining that huge variation that you see in the microbiome. So I think right now we're at the level where we don't really understand what is— what the sex steroids specifically are contributing to this variation. And that would actually be really interesting future studies to understand that. We actually recently have a paper or a study out where they— we did look at differences between in the AGP Lindsey Parsons dataset, for example, and women actually have higher biodiversity than men as young adults. And then this seems to— the men seem to finally catch up in terms of their overall biodiversity of their gut microbiome by middle age. So what we suggested, and we don't know for sure yet, is women are going through puberty earlier than men. So it's possible that their gut microbiome starts changing a couple years earlier, and it takes a while for the male microbiome to catch up just in terms of that particular feature of the gut microbiome.

And here I would have thought that little boys tend to be more rough and tumble out in the dirt and they'd have a more diverse microbiome.

Right, right, right. So they may have some more diversity based on what they're being exposed to environmentally, but in terms of sex steroids coming on board and having an effect on the microbiome, that's going to happen earlier in girls than it is in boys. Boys, because boys go through puberty typically later than girls, right? So it's, it's just interesting in terms of, you know, what does that mean in terms of physiology and the influences that we are— how we're influenced by our gut microbes and they're influenced by us. I mean, it's really definitely an ongoing question.

Interesting. So what are you thinking about in terms of follow-up studies?

So we have quite a few follow-up studies. We, we've gotten funded by the NIH to do a study where, using this mouse model, where we're trying to start to ask mechanistic questions about how this potentially could occur. So one of the questions we have is, which is a pretty basic one, is are the gut microbes basically sufficient to cause a metabolic phenotype if they come from a PCOS-like model. So studies like this have been done with humans or high-fat diet-induced obesity models. So for example, if you take stool from, uh, someone that is obese versus someone who is normal weight and you do a fecal microbiome transplant into a germ-free mouse, so a mouse that doesn't have any microbes, the mouse that was given that had the donor from the— that was obese will gain more weight and had a metabolic phenotype compared to the donor that was normal weight. So the question for PCOS is, is it also sufficient? Is the gut microbiome actually playing a role? Could you take feces, for example, from the PCOS-like model? Could you transplant it into germ-free mice and do they develop a metabolic phenotype? So that's kind of like— because that would— if that is the case, that would imply that some of the metabolic pathology that we see with women with PCOS may be directly a result of their changes in their gut microbiome, right?

And of course, if you change your diet, you change your gut microbiome, which— right, exactly.

Which is what I always find really intriguing with PCOS is that First-line treatment is diet and exercise, and we don't really know what works, but we do know if women with PCOS can lose, say, 5 to 10% of their, of weight, they can have profound effects on their reproductive axis. So there's some, maybe we could suggest that some of this is microbiome related, maybe some of it is independent, but that provides us with a potential window of being able to— even though you're born with, you know, your genes aren't going to change, but you certainly could potentially change your diet, right?

And if it's 0.7, there's still that 0.3 left, right, in the genetic potential. Exactly.

So the suggestion is, is what, you know, what could we figure out in terms of potentially supporting, or can we support the microbiome with a specific prebiotics Can we supplement the microbiome with specific probiotics that would be good for women with PCOS? That, that's kind of what we would really like to figure out.

And are you looking at that Coprobacillus as a potentially a strain that you could potentially develop commercially?

Yeah, that's what we would like. First, I think we would go and ask, like you were saying earlier, look at the different strains because what's really interesting is a lot of this is strain specific. So for example, Lactobacillus. Is a very common probiotic, but there's actually data out there suggesting that certain strains of Lactobacillus are pro-obesity or obesogenic, whereas other strains are anti-obesity or protective. So I think with the, the coprobacillus, we would want to look at the array of coprobacillus out there and get an idea if there are specific strains that would be useful versus ones that are not.

And is that a strain that humans typically have in their guts, or is that a mouse strain? Yeah.

Um, so yes, that's a really good question, is that Copperbacillus is in human gut, not necessarily in the same proportion. So again, we would want to go back into a cohort of women and take a look at specific changes in the strains or species of Copperbacillus with them as well, with, and with that are either have or do not have PCOS.

Right. And so are you contemplating human studies at all related to this, or is that too far off at this point?

Actually, we are. What we would really like— we're thinking of— we're currently writing a grant to see if that can get funded. Um, we would really like to go back to women with PCOS and basically ask, you know, in a larger cohort of women that do or do not have obesity, and have the hyperandrogenism as the, the one of their cardinal features for PCOS, ask some questions about whether the hyperandrogenism or, and, or the obesity has an influence on the changes that we see in the gut microbiome and really get more into function. So are we seeing changes in specific gene functions or in metabolites as opposed to just doing this overview of who's— who is changing in terms of the bacteria. So we'd like to do that, and then we'd also like to propose to do a pilot study with an intervention of some kind. Such as? I actually think what the thing that would make the most sense would be to do dietary fiber. Oh, yeah. So there is a lot of studies suggest supporting now the effect of dietary fiber on the microbiome and correlating increased dietary fiber consumption with improved, very dramatic improvements in metabolic disorders. So for example, prediabetes and type 2 diabetes. So I think it would be really interesting to investigate if you supplement or, you know, increase fiber with, in women with PCOS, can you ameliorate some of their symptoms.

Are you familiar with the study that came out and it was pointing towards liver cancer as a result of the supplementary fiber, like the inulin, I think, from chicory root that is going into a lot of these protein bars and— Right.

I think what we would go for is a dietary— just changing your diet. So what's ironic about that is that's kind of the diet that you recommend for women with PCOS. But whether they comply with this, you know, it's, it's difficult for us in our Western society. But increasing fruits and vegetables, replacing refined grains with whole grains, adding some nuts, getting up to that 25 grams that is recommended of dietary fiber every day— that's, I think, what we would consider suggesting to the patients and seeing it. So not a specific type of— not if it's a fiber supplement. Yeah. Fiber supplement. Yeah. Although there may be a role for that in certain, you know, I'm not saying that couldn't be efficacious, but I think for us, I think it would make sense for us to really try and see, can we see an effect if we really just change the amount of dietary fiber these women are getting?

And you didn't mention beans.

That's like the powerhouse of fiber. Lentil, you know, lentils, like, yeah. Yeah, that would be great too. So I think that would, that would be really interesting to see. Could we see an effect on their microbiome? Could we see a correlation between responders that would, you know, if you see this change in the microbiome, are you more likely to have a change, for example, in your degree of insulin resistance or metabolic syndrome? And that would be very interesting to look at too. But this is all something we should proposed to the NIH that we're talking about.

Yeah. So one last question. Well, maybe second to last question. Sure. The first to last question is, because we have a lot of listeners and these are, these are, um, my listeners are typically just people. They're not necessarily medical professionals or researchers, but they're people who are interested in sort of hacking their own health. So given what you've learned from your research, if you had PCOS, What would you do for your health given the state of the research? Ah, okay.

I think that's a really good question. I think I would first find out what type of PCOS I had. So what I, when I've spoken to women that are diagnosed with PCOS, they often are given very little information. And so I would empower myself to talk to my doctor about what was, why, how was I diagnosed with PCOS? So for example, do I have the type A, B, and/or C type of PCOS that has elevated androgen levels, or do I have type D? Because the reason why I would say that is because if you have type A, B, or C, you have the elevated androgens, you have a very high risk of having metabolic syndrome and the diseases that are associated with that. So having a conversation with your doctor then about how should you be monitored in terms of your cardio metabolic health and then thinking about what I could do as an individual living in our Western culture. So you are supposed— if you have any signs of weight gain or insulin resistance, you are supposed to be monitored at least once a year. For prediabetes-like symptoms. But even before that, like we were kind of talking about in terms of diet, I mean, again, I think I would— lifestyle, you know, in one way it's encouraging. Lifestyle intervention can have a profound effect on women with PCOS. So it's hard. It's not an easy path. But getting regular exercise, eating healthy foods, eating fiber, eating vegetables, like we were talking about, I think you could— ideally, the, you know, the goal is to, at least if you have weight gain, is to lose about 5 to 10% of your weight. And that could have profound effects on your metabolic pathways and your reproductive axis.

And if you're a type D?

In a type D, you have less to worry about, I think, in that you are unlikely to have a strong metabolic phenotype. So you should be wary. It's not as if, you know, it's, it's possible you could develop hyperandrogenism later on. And so you should kind of be aware of what the signs are of hyperandrogenism or elevated testosterone levels that we talked about, like some acne or some hair growth. But if that's the case, then again, I think interestingly, even with those women, the, the best thing is lifestyle intervention. So you know, getting lots of sleep as well, you know, eating well, getting regular exercise can help you a lot.

And is there any relationship between stress or cortisol and, and any of these PCOS symptoms?

Or actually, yes. So I mean, I'm not an expert in, in stress. I have a colleague that is very interested in the impacts of stress on the reproductive axis, and there is quite a bit of literature suggesting that women with PCOS do not have a typical stress response. So they may be more hypersensitive to certain stressors and more resistant to others, but this is not well understood, and that's actually something we would like to look at with our PCOS-like model, is to ask how these, um, mice are different in terms of their response to different types of stressors. So for example, like psychosocial stress versus metabolic stress and things like that. But that's a really good question. You know, there's still not that much understood about that, but it's likely that women with PCOS have different responses to stress.

So stress management may be another potential tool. Yes. In the toolbox.

Right. Exactly. And it's like, I think all of these management things would apply to almost everyone. It's not as if right now we don't have things specific for women with PCOS. And so that's what got me excited about this work with the gut microbiome is trying to think, could we down the road develop interventions or therapies or, you know, some thought processes that are specifically tailored for women with PCOS and what's going awry with their physiology, as opposed to just kind of this generic, although helpful, but these generic recommendations that are basically for everyone in our society that's dealing with our Western lifestyle.

Mm-hmm. Okay. Now my truly real last question. Sure. Do you have any colleagues or other researchers who work on the microbiome that you would recommend for the podcast that you could connect me to?

Uh, yeah, I guess it depends on what you're, what you're interested in. So we have quite a few folks that are, they're more bioinformaticians, so they work with the data a lot. So these are some of my collaborators. I also have some colleagues that work with the microbiome in terms of the, what's called the built environment, so kind of the environment we live in, the, you know, our buildings and things like this, and they're looking at kind of the impacts of the built environment with relation to us living in that environment and different changes and understanding that?

Well, my focus is the gut microbiome. So that's—

Yeah, I'll have to think about it. Yeah, there definitely are. Yeah, there are more. There's definitely— there's a couple. There's one guy. I don't know if he's ready to publish yet, though. That's the thing. There's one guy who's looking at the gut microbiome in terms of obesity and circadian rhythms, which is kind of interesting.

Yeah. Definitely would be interested in that.

Yeah, yeah, let me— I can think about that and see if that makes sense in terms of gut microbiome. Yeah.

Okay, great. Well, thank you so much for coming on the show and talking about your research. Sure, no problem. It was my pleasure. Thanks for listening.

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