December 12, 2022

Pain in the body and the brain

By Conor McKechnie and Dodi Axelson

Pain in the body and the brain

In this episode, we are focusing intently on the microbiome and how it is increasingly being linked to disease and illness. It seems that this is true for understanding illness of the body and the brain. Dr Amir Minerbi, the Deputy Director of the Institute for Pain Medicine at Rambam Medical Center in Haifa, Israel talks to us about how the microbiome may hold the secrets of fibromyalgia. This chronic disorder causes widespread pain, fatigue, cognitive dysfunction, and potentially dozens of other symptoms.

We are also joined by Prof Illana Gozes, Director of Elton Laboratory for Molecular Neuroendocrinology in the Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine in Tel Aviv University. She elaborates on her research surrounding the role of specific microbiota signatures as a biomarker for PTSD.

The link between physical and mental health and the microbiome is a fascinating connection, and one we intend to explore to the fullest.

Show notes

  • Minerbi, Amir, Gonzalez, Emmanuel, Brereton, Nicholas, Fitzcharles, Mary-Anna, Chevalier, Stéphanieh, Shir, Yorama. (2022) ‘Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity’, PAIN Vol.10 (1097). doi:10.1097/j.pain.0000000000002694.
  • Levert-Levitt E, Shapira G, Sragovich S, Shomron N, Lam JCK, Li VOK, Heimesaat MM, Bereswill S, Yehuda AB, Sagi-Schwartz A, Solomon Z, Gozes I. (2022) ‘Oral microbiota signatures in post-traumatic stress disorder (PTSD) veterans,’ Mol Psychiatry. doi:10.1038/s41380-022-01704-6.

CONOR: Dodi, today I want to talk about both mental pain and physical pain. Pain of human existence is what makes us human right?

DODI: Maybe so. I guess not the pain that you cause or the pain you suffer, but basically, the experience of pain, which is something that we have in common with animals and plants. I mean, everybody feels pain.

CONOR: Do plants feel pain?

DODI: Yes, they do.

CONOR: Oh, I feel bad eating my salad now. But for this episode, never mind the existential pain, I spoke with two researchers whose respective research has found that understanding the microbiome could really actually help us understand pain.

DODI: So, this touches on one of your favorite topics, the microbiome, and the various different areas of research that apply from an epidemiology and from a treatment point of view.

CONOR: Exactly. It's just incredibly fascinating that we're living in a time where our understanding of human health and what it means to be a human being. It's putting the human in the center of a much more complex combined set of organisms and animals in our microbiome, and then the link to the work that we do, which is really very interesting at the moment. Of course, the idea that dysbiosis or upsets in our microbiota are responsible or even signals for ill health is very, very interesting at the moment.

DODI: Oh, what a tangled web. I guess we better get started on this episode of Discovery Matters.

CONOR: Let's begin with the body, shall we?

AMIR: My name is Amir Minerbi. I'm the Deputy Director of the Institute for Pain Medicine at Rambam Medical Center in Haifa, Israel. I'm also a researcher at the Faculty of Medicine at the Technion Israel Institute of Technology.

CONOR: And this work is about the link between a condition called fibromyalgia and the microbiome. Fibromyalgia is a long-term condition that causes pain all over the body and it predominantly affects women.

DODI: My mother included.

AMIR: The main symptoms are pain, muscle soreness, sometimes skin tingling, profound fatigue, sleep disturbances, what they call fibro fog which is difficulty to concentrate and some cognitive problems, and many other symptoms. The bottom line of all of that is that the quality of life of the affected people is affected badly. I always imagine it's like having a bad flu with all my muscles sore, and I am tired, and I don't have the energy to do anything, only that it's going on for years, and years, and not just for a few days.

CONOR: It's been recently sort of brought to the fore actually. And for many years, people didn't know what it was.

AMIR: This goes back to 2014, when I just began my residency in pain medicine, and all these studies came out about the different fields of medicine affected by the gut microbiome. Initially, it was just with gastrointestinal diseases, but then also cardiovascular, endocrine, and rheumatic etc. I thought to myself, wouldn't it be cool if chronic pain were somehow associated with the microbiome, and it just marinated there. When I finished my residency, I wanted to do a research fellowship, and I contacted Dr. Yoram Shir, who at the time was the head of the Alan Edwards Pain Management Unit at McGill University. I told him, ‘I have a very stupid idea. I'm even embarrassed to tell it to you.’ But I did tell him, and he said that this was exactly what we should do. The rest is history. We never anticipated how far this would go, really just a hunch, I don't know. A gut feeling maybe.

DODI: A gut feeling? Well, there we are with one of our favorite tricks to use a pun for the gut microbiome. These bacteria are actually causing the symptoms, and maybe they have a role in the development of the syndrome. Is that what I'm understanding?

CONOR: Yes, exactly. It's the interplay between the microbiome and the immune system on how it supports and potentially works with the immune system, or how disorders of the microbiome can upset the immune system. This is what sparked his interest. Amir has been looking at the clinical implications of this and the study involved 77 women with fibromyalgia and 79 without.

AMIR: We sampled the composition of the gut microbiome; we use DNA sequencing to identify the bacterial species that live in the gut. Initially, we were very disappointed, because the overall composition of the gut microbiome was no different. We just found very similar microbiomes, in fibromyalgia and in healthy controls. But then when we looked at higher resolutions, we found that despite the fact that most of these bacterial species are really more or less the same, there is a small group of something like 20 bacteria, that are different in fibromyalgia. So, some of them were increased in abundance, some of them were decreased in abundance. But this was the first hint that we might be headingin the right direction.

DODI: But when Amir saw this association between the condition and the microbiome, how did he disentangle whether that was a cause or correlation?

CONOR: You're absolutely right to ask the question. It is not easy to disentangle correlation and causation. Indeed, we know that correlation doesn't mean causation. There are two steps really. First is to look at how you plan the experiment in a way that there will be as little or as few confounders as possible. In this case, they're focused on women of a certain age with no other conditions. And then secondly, he evaluated their dietary intake, physical activity, and sleep. He thought, by accounting for all these factors, he could have a view of what the influence of the gut microbiome could be on fibromyalgia.

DODI: So, how did he go about figuring out whether it was one particular bacterium that was responsible for the condition?

CONOR: Yeah. That's the big question. Is a mixture of things going on in our bodies, with viruses and bacteria and fungi all playing a role, or is it one bacterium? Well, this is where his research moved into establishing causality.

AMIR: What we're doing is very preliminary and hasn't been published yet. We are transplanting gut bacteria from women with fibromyalgia to germ-free mice. What we see is that these mice develop pain in as little as two weeks. So, the pain thresholds are decreased.

DODI: Fascinating, so the microbiome could have a role in the development of pain.

CONOR: Yes. And now what he's trying to figure out is, which mechanisms may allow or cause bacteria to do that.

AMIR: We took it one step further and looked at the type of bacteria that are altered in fibromyalgia. We are trying to see if we can guess or know what kind of metabolic activities these bacteria are responsible for. What we found is that out of these 20 bacteria, we have five that are responsible or that are involved in the metabolism of bile acids. This was unexpected, because we know that bile acids are secreted by the liver to help in digestion. But these are also metabolized by the gut bacteria and reabsorbed into the bloodstream. What was new to me is that in our body, we have lots of receptors for these secondary bile acids. So, for these bile acids that have been metabolized by bacteria, and are found in the liver, in white blood cells, and even in the spinal cord, where apparently, they could somehow modulate the way that we feel pain.

CONOR: Interestingly, one of these bacteria was almost completely absent in patients with fibromyalgia. Amir and his colleagues found that there was a striking correlation between the levels of bile acid in the blood and the level of pain that was reported by patients. The more bile acid you have which is called alpha-muricholic acid, the less pain a patient will have.

DODI: Oh, that's so fascinating. So, it's the presence or the absence. So that hint that it not only has a different composition of gut microbiome, but also a different function of it in those who suffer from fibromyalgia.

CONOR: Exactly. And almost every time we've dug into the microbiome, you start to peel an onion. With every layer you cry more because it just gets increasingly complicated, right? More to dig out, and we are just beginning to scratch the surface.

AMIR: It takes over four years for a patient to have a diagnosis. I'm hoping that using machine learning, using the composition of the gut microbiome, and the composition of gut microbiome derived metabolites such as bile acids, we will be able to classify and make a diagnosis. So, this is where we are headed. This is one thing. The second thing is obviously to try and manipulate the gut microbiome in a way that will make it more – and I quote – ‘healthy.’ And if the microbiome has a role in chronic pain, as we suspect, then by manipulating it we can maybe push it to be in a healthier composition to improve symptoms, and this could be an important development.

DODI: For years, you can imagine how this also impacts the mental health of those with fibromyalgia.

CONOR: Yeah, absolutely. I can't imagine what it's like for your mother right now, suffering from a disease that, until recently wasn't really recognized. This really sort of leads us to pain in the brain. Let's talk to Professor Illana Gozes.

ILLANA: I am the Director of Elton Laboratory for Molecular Neuroendocrinology in the Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine in Tel Aviv University. I'm also affiliated with the single school of neuroscience at Tel Aviv University. And I'm also affiliated with Adam Sokol Centre for rent studies in Tel Aviv University, and I used to help the other super Centre for many years. I'm also the Chief Scientific Officer of a TED therapeutics, which is enabled we call it active , which means good future, which is developing the volatile fragment of IBMP, originally, initially for the treatment of ADNP syndrome children, and then the sky's the limit.

CONOR: Illana has been looking at the link between specific microbiota signatures as biomarkers for Post-Traumatic Stress Disorder (PTSD). Originally, she was looking at activity-dependent neuroprotective protein (ADNP), and whether there could be a telltale sign for ADNP in blood, which might help work with PTSD sufferers. So originally, she wasn't looking at the microbiome at all.

ILLANA: We actually looked at soldiers and we saw that there is a change in the blood if they are exposed to stress. So, that's what kind of made us embark on a large study on PTSD.

CONOR: But the link between the microbiome and PTSD was a completely unexpected discovery.

DODI: Oh, we do like serendipity on this podcast.

NEWS ANCHOR: The Lebanon invasion was the first time the Israelis went to war without their very existence being threatened.

ILLANA: Zahava Solomon, a professor at Tel Aviv University, who works on PTSD collected a cohort of soldiers from the first Lebanon War. She was following the soldiers in my whole region, and I thought that she might have blood samples we could use. And then thought we will see what the difference is in these soldiers genetically and why some of them are suffering from PTSD compared to others?

CONOR: But the team could not get blood samples as many of the veterans were at a very advanced age by that stage. So, a PhD student, and one of the first named authors on the paper which is in the show notes, Ella Leverett Levitt collected saliva samples from the veterans. She hoped to see the RNA from the veterans in the saliva and use those samples to see what genes were being expressed and whether that could be linked to stress and PTSD.

ILLANA: But we didn't really have human RNA we had mostly bacterial RNA. We wanted to have human genes but what we were getting were these bacterial genes, so I made lemonade out of lemons. It took some convincing. Everybody got convinced eventually. So, then we thought, ‘Why look at RNA, let's look at DNA.’ And we had lots and lots of DNA, which was intact and nice. So, we did the complete sequencing, and we looked at the bacteria. And it took a while to do this analysis because it's human material.

DODI: So, the point of the study was to find biomarkers, which Illana and her team did find, but it was in microbiota rather than RNA.

CONOR: That's exactly right. So, Illana was pointing out that biomarkers for sufferers and potential sufferers of PTSD could be very, very important. They go through psychological testing, as potential patients, but many remain undiagnosed. And if we could understand why some people might be particularly prone to developing PTSD, you could make different choices about who you deployed in particularly stressful situations. She was working in collaboration with the Israeli Defense Force. You could think about where and how and when you might deploy uniformed personnel.

DODI: That's always a tough choice, and why not have better information when making those decisions? So, what does that mean she's going to do next?

ILLANA: I mean, one of my major aspirations is actually to bring the treatment to the clinic. In terms of PTSD, I'm in a planning mode and I am in touch with the authors of the paper, and we are still thinking about it.

CONOR: On a sidenote, the team also combined these findings with air pollution data and the zip codes or postcodes that the veterans lived in.

ILLANA: We know that air pollution is not good for you. And those that live in polluted regions are more likely to struggle with PTSD. The other thing that we've asked them is, in terms of education we saw that the more educated a veteran the lower the PTSD signature. So, using what we learned, which is very simple and effective is education. Education is not medicine, but it is.

DODI: So, if I'm to summarize that, to diagnose PTSD we can look at biomarkers in the microbiome. Then to minimize the impact of post-traumatic stress disorder, we need better air and more education.

CONOR: That's exactly right. Cleaner living, more education. Everyday should be a school day. And then we have a definitive way of diagnosing PTSD through microbiota signatures through an accident of Illana's research, rather than relying purely on a battery of psychological tests.

ILLANA: The psychological criteria are sometimes very subjective. So, you can feel excellent in the morning, and then not so much when the test is carried out, and then terrible in the evening. So, that's where maybe something that is totally objective could help.

CONOR: So, isn't it just cool? You know, the more we learn about the microbiome, the more it tells us about who we are, what we are, and the complex interaction between all the organisms that live on us and in us and around us.

DODI: And now you have justification for another one of your obsessions.

CONOR: I know exactly. And it started a long time ago with almost the first episode.

DODI: When we talked about how you were stopping using soap in the shower.

CONOR: And fortunately, I continued using soap after a short experiment.

DODI: Right, right. Let's just sum up then the episode about pain. Understanding the microbiome allows us to better understand what's causing pain, whether that is mental or physical.

CONOR: Exactly, whether it's pain in the mind, or pain in the body it all needs treatment, it all needs assessment, and it all needs to be taken seriously.

DODI: We all need education and cleaner air. We hope this episode was pain-free to listen to. So, this podcast but not the puns are produced with the help of Bethany Armitt-Brewster, editing, mixing and music is by Tom Henley and Banda productions. My name, as always, is Dodi Axelson.

CONOR: I'm still Conor McKechnie, make sure you rate us on Spotify or whichever platform you use to listen into your podcasts. You'll hear more from us when we come back with another episode of Discovery Matters.

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