Role of Gut Microbiota in Hypertensive Women

Welcome to the AJP Heart & Cirque Podcast. I'm Kara Hansel-Keyhann. Today we'll discuss a new study by Shah at all, titled "Altered Triptophan Metabolism and Gut in Yun Cross Talk in Hypertensive Middle-aged Women." This research article was published November 11, 2025, as part of our call for papers on Women's Health Research and Cardiovascular Disease. Joining me today are Associate Editor Dr. Keith Brunt, author Dr. Shrushdi Shah, and expert Dr. Yisanka Subchivich. Let's get started, Keith. Great, thank you for being here with us. Dr. Shah, Dr. Zubchivich. I'm pretty excited to get the scoop on the poop that we will certainly keep our listeners' attention here today. The research article we will discuss is, of course, as mentioned, part of the AJP Special Issue on Women's Health Research and Cardiovascular Disease that explored the relationship between the cardiovascular system and the gut microbiome. AJP Heart & Cirque continues to be the best place to send integrative physiology data such as this, which helps create awareness and set the foundations for particular changes, but in this case, appear to affect middle-aged women and the risk for hypertension greatly. The gut microbiome is a complex and diverse part of our natural physiology, making up about 1% of our total body mass and containing nearly 40 trillion with a T microbial cells. So major alterations in this part of our bodies for various reasons can be critical determinants to health or to disease. And here, Shah and colleagues found something quite compelling from the Alberta's Tomorrow Project, and included a hundred and seventy-five women between thirty-six and sixty-five years of age. This study provided the opportunity for a matched, unbiased proteomics and omic study of serum biomarkers with concurrent fecal microbiota analysis to compare fifty-four hypertensive and fifty-four normal tens of participants. This reveals shifting populations of microbiota that are associated with pro-inflammatory states, like increased anaeroticis, bluachia, colonicella bacteria, and I probably didn't pronounce those properly. And a marked change in biomarker changes associated with circulating triptophane, and it's metabolite, chinerony, and I hope I get to get that one right. These changes also coincided with less anti-inflammatory endowals and the bacteria in the gut that make them. These shifts were more remarkable in women of middle age, and those women were more likely to have hypertension. Let's talk some turkey, or rather, and trip to them, with Dr. Shah and Zubchovich. Welcome. Thank you so much. I'm happy to be here. Great. Dr. Shah, I wanted to open up. You're the lead author on this work. I hope I summarized it correctly, and maybe even pronounce some of those bacteria close to the phonetic approximation. It's always a little bit challenging with Latin. I was kind of curious if you could tell me a little bit first about the Alberta's tomorrow project, what it is, and how you were able to access these clinical specimens. Firstly, thank you so much, Hazeepic team, and also Dr. Brent, for having me. It's a great pleasure to be here and talk about our research. So to begin with, with the Alberta's tomorrow project, more commonly known as ATP, is one of Western Canada's largest and long-running health population studies. It was launched in 2000 and has since followed about 55,000 Albertans between the age of 35 and 69 participants from across the province have provided detailed health information over many years, making ATP and incredible resource for studies like ours, which aim to understand how lifestyle factors such as diet, physical activity, and aging can interact with our biology over long periods of time. Particularly for this study, ATP's wonderful research team, re-contacted the participants on art, based on our inclusion and exclusion criteria. And then later on participants were interested and also eligible for this study. They provided blood and fecal samples and the required physical measurements, such as blood pressure, height, weight, heart rate, etc, which were also undertaken during the same appointment. And why was it that women were of particular interest for you in this study? Well, I love that question and we particularly decided to focus on women because for a very long time, this population has been understudied, underfunded, and often misdiagnosed. In fact, middle age women are at a greater risk of developing hypertension due to hormonal changes occurring during and after menopause. Given that hypertension is one of the most prevalent modifiable risk factor for cardiovascular disease progression, I was particularly interested in knowing whether the gut microbiome and its metabolites might help explain why some women develop hypertension whereas others do not, even when they have similar age and BMI. That's interesting. Now, I want to circle back to something here which is trip to fan. This is a common vernacular when it comes to amino acids. Trip to fan is typically associated with that happy sleepy post-tricky kind of dinner feeling. It's an amino acid that is known to be essential for making serotonin and melatonin. So I think this is why people associate it with it. But your paper found some distinct metabolite changes, more in line with canaryne and less indol. So we have more of this canaryne metabolite and less of these indol. But for those of us that are not ex-propiocevists, what are these exactly? Are they unique to middle age women or something that everyone has? That was definitely an interesting part because even for me when it came to Turkey, I would relate it to melatonin and then of course the serotonin because of the gratinine axis which has been widely researched topic. Trip to fan is an essential amino acid as you say it which means that our body doesn't produce on its own. We have to rely on the diet that we take. This once ingested tipto fan is metabolized into three major pathways, chyronein, indol and serotonin. Now the overwhelming majority which is about 95% of the tipto fan gets metabolized into chyronein pathway and only 2 to 5% gets metabolized into the indol pathway or the serotonin. Now chyronein is produced by our own cells and is host regulated immune pathway. However its levels have been shown to increase when the body is under chronic low grade inflammation or stress which could be obesity, hypertension, etc. Indols on the other hand are produced by the gut microbiome with like the microbes that reside in the gut when they break down the tipto fan. This inol can have protective effects or can also have harmful effects depending on its derivatives. They have been known to help with the gut barrier function and also help regulate inflammation as well as blood pressure. To answer your second question this metabolites are not unique to women, everyone makes them but the balance between them depends on the age, hormones, immune activity, gut microbiome composition and also the overall metabolic health of an individual. In our dataset we did not see changes in the less abandoned tipto fan metabolites like serotonin, melatonin, chyroneic acid, indol propionic acid which is also recently coming up, widely in the literature or even the tipto mind. Even the chyronein to tipto fan ratio which is often used as an inflammation marker did not change. What stood out instead was this decrease in microbially derived indols and the few species that make them that have the enzyme to produce inol from tipto mind. I think the story that we get here is middle age women don't have special metabolites, it's just that this life stage may amplify certain metabolic shifts especially even combined with the microbiome changes. Interesting so it's a classic homeostatic maintenance phenomenon but one that's shifting here. Dr. Zubichov, you know what was your first impressions of this work? Why does this stand out to you when considering hypertension and women of this age group in particular? Yes, yes thank you so much. It was my pleasure to review this paper due to my long term interest in gut microbiome and trip to phantom metabolism as it pertains to cardiovascular health. My first impression of this work was that it, Trin and middle age women is a biologically distinct group for hypertension. Rod and Denik extrapolating from studies that are male dominant studies that we've seen in the past. What makes it stand out is that it links hypertension in these women to functional changes in the gut microbiomes. So pathways like trip to phantom metabolism that we're discussing now leading to immune signaling and these we know can regulate cardiovascular inflammation and the tilion function in many other conditions in the GI tract. Well women this is especially relevant because unlike men like Shurshadee just said who tends to develop hypertension earlier and more gradually women experience a sharp increase in blood pressure during midlife which coincides with hormonal transitions that we know or already increase vascular stiffness inflammation, autonomic imbalance right they're all contribute to hypertension. So what we're saying is that the gut despiosis may be a compounding factor the drives cardinal of Asclar outcomes in middle-aged women. And this is something that we are only beginning to recognize now, which makes this work particularly impactful. What's interesting to me, if you look at the methodology and the results, the hypertensive women in this study also had lower adherence to mediterranean style diet. They had significant lower fiber intake, which is interesting. We know that's mechanistically meaningful, because as we know dietary fiber is a driver of microbial metabolic output. In a population of middle-aged women, where reportedly we have hormonal protection, that is declining. The disdied driven disruption of microbiome can amplify vascular and immune dysregulation, maybe an autonomic dysregulation. And this mechanistically can help us explain why hypertension emerges and becomes more difficult to control in women of this age group. So, let's expand on that, Dr. Shaw, just to help ground this theory for any listeners. Were your findings in your opinion somewhat causative or associative, and should we be changing our diets to reset the microbiome or target ingestion of microbiotic species of a certain type, or maybe what substrates they prefer in order to make more endoles, for example, or are the circulating trip fan levels, something that we have control over in some way based on what we eat, or they just a general change in microbiotic climio stasis. Most people want to take action to improve their health, I would imagine. So, what were your thoughts on that? Pete, that's a great question. And I want to be very clear to the listeners are findings for this study are not evidence of causation. What we observed is an association from an observational study. Women with hypertension tend to have higher chyrinine, as you mentioned, an lower endol metabolites is the main key finding that we are finding, but we can't say that this metabolites cause high blood pressure. That said, there is a good growing evidence suggesting that microbiome can influence blood pressure as we have seen it in many animal studies. One striking example comes from the wins UK study, where researchers were able to transfer the fecal microbiome from the hypertensive donors into the jump free mice, and the mice did develop higher blood pressure. So that is, there is a causative pathway where microbial communities and its metabolites they produce can have the causative physiological fact effects, but based on our results, I would say it's not entirely causative, but if we do take key metabolites and then try to do fecal microbiota transfer, we might have some causative results as the next experiment. Now, in terms of whether we can reset this pathway to diet, we do have some influence, but not total control, because to find levels in the blood, don't fluctuate dramatically, just because we eat more triptophane-reached foods. However, this is mainly because body tightly regulates the circulating levels, but the pathway that triptophane gets routed into the another one, which is the endole. That shift can happen depending on two big factors. One is the state of the immune system, and the other is composition as well as the function of the gut microbiota. Microbial endole production, for example, depends on whether we have specific bacterial species that produces those, and whether they are getting the substrates that they prefer, just as you mentioned. So many of this bacteria thrive on the dietary fibers, the polyphenols, and plant-rich diets, so we can indirectly support them through what we eat, but I'm not entirely sure if there is any single food that can directly turn the endole levels up. I think the safest and most accurate takeaway in this would be diet matters, the microbiome matters, but they work within a broader ecosystem of immune health, hormones, aging, and genetics as well. We are really looking at a whole body homeostasis issues and not just a single nutrient that we can hack. I know this answer doesn't give one pill health solution as everybody wants, but we are getting towards more specific personalized supplementation and also dietary pattern route. That's great. I think the interesting elements of these papers were certainly the diverse results that you had. You were looking at the patient's fundamentals, vitals, but also their microbiome and their metabolites. What were your thoughts on those broad spectrum methods to make these associations and develop a better fundamental understanding of what the population looks like from a hypertensive or a normal, tense perspective and participants? How does this fit into the broader field generally of what we need to do? What struck me about the methods and just generally the study, which is where I think this line of research should be going to is really recognizing what is going on in women first before we can try to understand how to apply treatments. The paper addressed several gaps that unfortunately persist in hypertension trials still in women. Those clinical studies still classify participants based largely on blood pressure and medication responses. They fail in some ways to deep, bleak, clean, or type the biological pathways that are influenced by sex and age. In this paper, the author's integrated blood pressure status with the gut microbiome composition, the functional pathways immune signaling, and detailed dietary assessment. I feel that's critical because we know that hypertension in middle-of-women is not driven by single mechanism, just like Shushty said. There is a convergence of hormonal changes, immune activation of asuka, dysfunction, autonomic dysfunction, and metabolism. Like I said, current trials really capture this fully. The study helps us distinguish hypertensive from normal, intensive women in a way that reflects the real life and the biology and does not solely rely on the clinical labels, such as blood pressure. We can start to define mechanistic targets that are largely absent from conventional hypertension trials that we have going on right now. Without measuring these pathways, we risk creating hypertension in women as a uniform condition, which we know it's not. In reality, the drivers in middle-of-women may be fundamentally different from those in men or younger women. That's so interesting because it might also explain perhaps some of the controversial findings that have been come before this, which here I'm thinking of the La Tia species of microbiome where it's been associated or not associated with the condition. What is your take on how this work fits in the broader scope? How should we design those kind of future human physiology studies like this? Can we rely on just targeted single individual species monitoring or do we need to use unbiased analysis and de-biased ourselves and how we categorize our patients? I agree. I think this work really fits well into where the field is right now. We are moving away from labeling bacteria, either as universally good or universally bad. The example of Blautia is a great example of that complexity. Some studies, that bacterial species is associated with metabolic health and inflammatory effects. In others, including cardiovascular and hepatitis C cohorts, they correlate with adverse outcomes. What this tells us is that in microbial effects, there are highly-confects dependent. We are only just scratching the surface here. They vary by host physiology, sex, age, diet, hormonal state, and by the surrounding microbial ecosystem. The study emphasizes microbial function, which is important, so not just taxonomy. This is critical for interpreting these inconsistencies. It also highlights why future human physiology studies need to incorporate diet microbial pathways, host immune, autonomic, and vascular phenotypes. The push is towards precision probiotic, or microbiome based medicine, where interventions of tailored to individuals' biology and disease context, rather than assuming a single microbial will have the same effects across all conditions. That's great. It's so important for listeners to understand and help communicate. We won't just be able to solve this by eating one type of yogurt, for example. In fact, I was struck, and I'll put this to both of you to touch on. The majority of the participants, 76%, were being medically managed for hypertension. The cardiologists were on top of this. I'm curious to know, what are the implications here for pharmacology? Are the drugs, therefore, influencing these microbiome shifts? Or are they failing to work, at least in part, to resolve the underlying risk profiles? How do we deal with this complexity of active treatment and response when we're studying these populations? Because we're not going to leave somebody hypertense without treating them. But are the drugs acting in a positive or negative way, do you think, in some of these reactions? And how do we account for that? That's a really, really important point, and something very close to what I have my background in, which is pharmacy. So what we saw that even when women who were being treated for hypertension, the metabolic and the microbial differences didn't disappear. In fact, when we adjusted the blood pressure values according to account for the medication use, the differences between the groups actually became more pronounced. So that suggests two things. First, anti-hypertensive medications are clearly effective at lowering the blood pressure. That is their job. but they may not fully address the upstream biology contributing to the hypertension, such as low-grade inflammation or microbiome-related metabolic changes that happen. Second, the blood pressure itself, particularly uncharactered blood pressure, was the strongest contributor to the variability in the microbial composition. This was done using redundancy analysis where we had a bunch of factors that could influence. And blood pressure was actually the highest that was contributing to the changes in the microbial composition that was even more than BMI or the diet. That tells us that physiological state of hypertension does matter regardless of whether numbers are being controlled pharmacologically. At least this is what I understood. Some blood pressure medications are known to interact with gut microbiome, but our study wasn't designed to distinguish the drug-specific effects. It would overfit the model if we have each and every medications. So rather than saying medications are failing, I would prefer framing it as they may be treating the symptom effectively, but not necessarily resetting the broader cardiometabolic or the microbiome environment that contributes to the risk-cut force place. I agree with Shushty said to me, the medication statistic doesn't really weaken the message. It actually sharpens in my mind the translational question, which is that these women are treated, but when you correct for blood pressure medication, the hypertensive phenotype separates even more. So suggesting that there is a persistent upstream biology, something upstream of the blood pressure, and that the microbiome is really mapping onto an underlying risk rather than being fully explained by the medication. Shushty mentioned that microbiome and the drugs can have a bidirectional communication, and that's been shown in some papers. The hypertensive drugs can potentially reshape the microbiome, but the microbiome can also reshape the drug exposure and response. So the controlled blood pressure, what we call, may not mean the underlying dying microbiome risk profile has been resolved. This just means that we are somehow controlling it. So in many life women, we may be treating the blood pressure, but not the biology. And the gut microbiome explains why the risk doesn't really fully go away. That's so great. And it really helps galvanize the understanding here that we rely so heavily in our guidelines on how we separate patients out, and then how we follow them in categorizing, but we may have not be able to rely solely on that categorical distribution fully for how our populations are responding in the real world evidence. So cardiologists out there need to kind of be thinking about this a little bit more proactively and saying, look, you might be treating the downstream symptoms, but there might be a series of problems for their upstream that could be acted upon, and we could have curative potential and hypertension, and stop it letting it be a chronic disease that needs chronic medication if we could get at the root cause for their upstream. And I think that's really brilliant. But you touched on something else there. I just want to circle back to, which is the age of the women here seems to be also quite important. How do the hormones influence these results? And would measuring these directly have had an impact on the findings, do you think? Do you think the hormones either systemically, for example, oral contraceptions or approximately, like with a hormonal IUD being close to the GI, influence the microbiome at all directly? Because I know in this age range where we have hypertension sort of emerging is coinciding with perimenopausal states and the treatments that are associated with that. So we get this added layering in of complexity from a clinical perspective. I was just kind of curious what both of your thoughts were on that. Age is absolutely central to interpreting this results. Middle age is women. In women is marked by profound hormonal influences. As you mentioned, particularly fluctuations and even the decline in estrogen and progesterone. This hormones can influence the immune function, vascular tone, the gut permeability, which would change the microbial composition as well as the function. So it's very likely they are part of the story that we are seeing overall. One of the limitations of our study was we were not able to directly measure the hormone levels, but it's important to recognize that hormone levels fluctuate significantly day to day and also cycle to cycle. So single measurement might not fully capture something longitudinal might be a better way because also the microbiome is not constantly similar. The food that we eat it dramatically changes. So it's not easy to control for hormones as well as the microbiome. And that being said, there is a growing evidence that systemic hormones, just as you mentioned, like the oral contraceptives or the hormone therapy and localized hormone delivery as well with the IUDs can influence the gut microbiome. But potentially in different ways like systemic hormones appear more likely to affect the immune signaling and the microbial metabolism broadly, while localized hormones may have indirect effects and maybe more subtle. The idea that hormone signaling could alter the diffusion or the signaling gradients between the gut as well as the reproductive organs is still very much an emerging concept, very interesting, but as I said, it's also very difficult. And I think it's also interesting to learn that how interconnected all of the systems are. I know we are talking about the homeostasis. So the overall body homeostasis. So hormones, just because they don't act in isolation, they do shape the microbial ecology, the metabolism and the inflammation that we are seeing, the low grade chronic inflammation, all of which would have some contribution to the cardiovascular risk. Yes, I agree. I think it's very important to consider the hormones. And I agree that it's difficult. So in that context, we have to be careful how interpret age in this particular paper as, you know, in women as well. The age here is a big deal, but the age does not necessarily correspond with hormonal profiles, right? Which one of this is one of the strongest hidden variables shaping the gut biology in mid-life women, right? Estrogen and progesterone, we know influence GI function, immune system, vascular autonomic function. They interact with what is now been called an estriboleum, which are microbial enzymes that can modulate circulating estrogen and they can respond to estrogen, right? So if we do not incorporate hormonal status of women in our future trials, we risk mixing together women with very different endocrine profiles, which can blur or even flip the microbiome associations, measuring these, which sharpen the signal because it helps us develop what is truly a potential associated from what is menopause biology associated. And I appreciate that, you know, it is it is a hard thing to do. Certainly, but it is so relevant for clinical trial design inclusion and even, you know, some group analysis in future. So you might have primary outcomes designed around one profile or categorization, but you should certainly be thinking about these follow-up studies that need to be done after the fact, especially if a drug isn't performing as you thought it would or it hoped for. That might just mean that you haven't picked the right population to study it. And it kind of does back into this concept of met inflammation. Our metabolism is changing, our microbiome is changing and we're having these inflammatory pathways, both local and systemic influencing sort of the gut dysbiosis that we associate sometimes with the microbiome changes. I'm curious if if either of you have any thoughts beyond hypertension, thinking of things like cardiovascular disease risk in general, a-fid, MI stroke, how applicable do you think these dysbiosis could be to other cardiovascular or metabolic diseases? I think that's a reasonable concern and mostly because hypertension doesn't exist in isolation generally. The metabolic signature we observe, which was higher chyronyne, lower endoles and the evidence of systemic inflammation, has been linked to other studies with endothelial dysfunction, atherosclerosis and increased cardiovascular risk, altered tryptophan metabolism and gut microbiome composition have also been associated with actual fibrelation and vascular stiffness in other population. For this study, we particularly were able to have a set of population just with hypertension because it was preliminary data and we did not want to have other complexities to see what is the direct impact or the direct role between gut microbiome and hypertension. And while our study did not directly assist, this outcomes the pattern does suggest that hypertension may be a part of the broader cardiometabolic risk constellation. This reinforces the idea that controlling blood pressure numbers is necessary, but not always sufficient for the long term cardiovascular health. But yeah, prevention is definitely better than cure. I agree. The biology in the study suggest that cardiovascular risk that goes well beyond blood pressure alone. If you look at the combination of hypertension with microbiome linked inflammation, metabolism and the telulid dysfunction, that's a well-known substrate for atrial fibrillation, myocardial infarction, just and stroke, just like Schrochety said. So where we lose hormonal protection like we do in midlife women, this could amplify vascular inflammatory risks. So it could lead to other complications that are hypertension associated. you've opened up a lot of thought for a lot of different types of listeners. Clinically fundamental physiologists, microbiologists, biochemists, clinical chemists, I hope you realize that this will probably spiral out into various forms. And I'm so glad that I had the opportunity to speak with both of you today. Do you have any final thoughts that you wanted to share about where you think this might go next? What might the next five years look like for either one of you? I do realize our study doesn't suggest any quick fixes or single target solutions, but it does highlight opportunity by understanding this interconnected pathways earlier in life. We may eventually move toward more personalized strategies for prevention, once that complement the pharmacology rather than completely replace it. That would be my takeaway from this. I think in my mind, and it kind of aligns with what my research is going to go in the next five years, hopefully, is. And if the study really shows us anything, there's a couple of other studies. They were similar. They were really exciting. It's that the women's cardiovascular biology, especially during the menopausal transition has been vastly understudied and underfunded. And we've spent decades treating women models built in men. Yet menopausal represents one of the most profound biological transitions in cardiovascular risk. And until we invest seriously in women's specific research, that integrates hormones will keep managing numbers instead of just preventing the disease. And certainly a market upside potential here too, to develop precision therapies, as Dr. Shaw mentioned, to titrate our medications or identify female specific medications for hypertension or metan inflammation. So even industry needs to be thinking about this, not just as a liability, but an opportunity. So that's fascinating to be thinking about, because if we can get more at the root cause, we don't just have to manage the blood pressure. We might be able to prevent the need to manage the blood pressure. And that's fascinating to be thinking about. Thank you both so much. I hope everybody gets a chance to give this paper a read and and look at the field in general and see how it applies directly to their work. It was pleasure to be here. Thank you so much. And I congratulate Dr. Shaw on this wonderful work. Thank you all so much. This is our really special study close to art, literally and figuratively. And it was the last part of my PSP. So thank you so much for having me. Thanks for listening to this episode of the AJP Heart and Cirque podcast. Our scene music was written and performed by Ray Mitchell. Catch the latest episodes of our podcast at physiology.org/journal/jpheart.