Remission Biome could represent a new paradigm in patient-led research

I have a new story out in National Geographic this week about a growing area of research connecting the gut microbiome—the diverse community of microorganisms that live in our digestive systems—with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the chronic disease that often occurs after viral infection and has many commonalities with Long COVID. (Here’s a non-paywalled link to the story.)

Two recent papers, both funded by the National Institutes of Health, point to specific differences between the gut ecosystems of ME/CFS patients and those of healthy controls. The new studies built on previous research in this area, but utilized larger patient cohorts than typical ME/CFS studies. Their findings provide avenues for better diagnosing and treating ME/CFS patients, as well as people with Long COVID who meet the criteria for ME/CFS. (Some studies suggest about half of Long COVID patients fall into this category.)

Continued gut microbiome research could identify specific bacterial supplements that help alleviate ME/CFS symptoms, along with new drugs that target specific changes in these patients’ metabolisms and immune systems. But many people with ME/CFS and Long COVID aren’t waiting for the clinical trials; they’re experimenting with the supplement and diet changes that are already available.

One big project in this realm is Remission Biome, a study by two ME/CFS patients who were working scientists before their symptoms became disabling. Patient-researchers Tamara Romanuk and Tess Falor both have experienced “remission events,” in which their ME/CFS symptoms faded after taking bacterial supplements. When they met on Twitter, they started a project attempting to recreate those events—but it quickly grew into a much larger effort to understand how the microbiome interests with post-viral illness symptoms.

I talked to Romanuk and Falor for my National Geographic story. We discussed how to design a study in which the scientists are also the patients, how their project builds on big data in microbiome research, communicating with the patient community, future plans for Remission Biome, and more. Since most of the conversation didn’t make it into my story, I wanted to share it here.

This interview has been lightly edited and condensed for clarity.

Betsy Ladyzhets: I wanted to start by asking how you all came to do this project, specifically replicating remission events that you’d experienced in the past, and how that intersects with other research that’s been done in this area of ME/CFS and the microbiome.

Tamara Romanuk: I had always been planning on trying to replicate the event… It had been in my mind constantly to try to recreate the experience. I actually did, at one point, take another course of amoxicillin [an antibiotic] but I didn’t do anything else. I didn’t do the probiotics. I didn’t do the sort of the full suite that I was that we’re proposing here [in the Remission Biome protocol].

So, it’s something I would have come to on my own regardless. But when I met Tess and she told me that she had had a similar event, it seemed like, okay, this was something we were probably going to do in the future together. It was just a matter of when. I think we must have talked about it even within the first weeks of meeting each other.

Tess Falor: It was, 10 days [after we met]… I had an interesting experience, in that that I didn’t realize that it was the antibiotics that might have done this [alleviated symptoms]. So back when I had my event in 2009, I went gluten-free and started the antibiotics at the same time. And two days later, after I had my major remission, I accidentally ate gluten. And then I felt worse the next day. So for 13 years, I’ve been assuming that it was going gluten-free that made the difference. And I never consider that I could recreate it because I’ve been gluten for that whole time.

It wasn’t until I met Tamara last fall that I realized that, wow, this [remission event] actually could have been the antibiotics. So when that came up, then, Tamara had this idea to try to recreate it. If it was actually the antibiotics that did it, could we create this really extreme remission event?

BL: I see. In terms of identifying the antibiotics, the probiotics, and the other treatments that you’re using in this study, how did you arrive at this protocol that y’all are following?

TR: Yeah, great question. When we decided to recreate it, the plan started as, “let’s take the antibiotics, and let’s throw in some probiotics, and let’s see what happens.” But we’re scientists, so it morphed very, very quickly into something much, much bigger.

Where Tess and I went in our minds was directly to the theory and the models that would have given rise to a phenomenon like this. Instead of starting at a protocol, we went, “this is our pet theory [about why remission occurred], and if our pet theory is right, how do we work backwards and recreate the protocol?” One of the really interesting things about doing it from that angle was that most of the stuff that I had initially thought I would include I actually threw out very, very quickly. The probiotic that I thought we were almost for sure going to use has ended up being, “oh, that actually might have stopped my event from continuing rather than promoting it.”

And we’re working in an age where there’s some really new cutting-edge databases and information sources out there. I wouldn’t have actually been able to do this type of protocol development a few years ago, even. [For example], we knew that we wanted to manipulate tryptophan metabolites in the gut. And so we needed to find strains of bacteria that were involved in tryptophan metabolism. And then we also knew that we wanted really specific metabolites to be produced in the gut and get to the brain. We were able to go into a database and actually follow that chain, identify specific strains of bacteria that would do exactly what we wanted in terms of gut and brain metabolites, and then trace it back to probiotic manufacturers. That’s pretty phenomenal. And that wouldn’t have been possible two years ago.

BL: Yeah, that’s incredible that you could just follow it all the way through like that.

TF: Absolutely. I’ll also mention that we’ve gotten advice from experts, too. Three people who study the microbiome gave us specific advice, and it all kind of converged in the same ideas, the same strains. So that was cool, too.

BL: Actually, it’s interesting that you mentioned tryptophan, because that was one of the processes identified in the recent papers [the two studies that were the focus of my National Geographic story] as well. I think the main one they looked at was butyrate.

TF: Yeah, those are both things that we are thinking about as part of our hypotheses. When those papers came out, we were like, “wow, this is really cool timing.” We read the papers, and found [their findings] line up with what we’re thinking. And we’ve already been thinking about this for months.

TR: There’s a really neat tie-in here in terms of the tryptophan metabolism. Because initially, my theory had been surrounding Robert Phair’s idea of the “Metabolic Trap,” which is, of course dependent on tryptophan. But the [remission] event itself was also incredibly unique because it was a bit psychedelic. Colors were brighter, smells were smellier, the world was amazing, we felt overwhelming gratitude. I tell people that it was a little bit like a mix between doing MDMA and psilocybin mushrooms. But without the hallucination. It was just this overwhelming change in my mood.

So I was thinking about tryptophan, serotonin, the same receptors that might actually get activated during a psychedelic trip. It really seemed that this entire pathway—from tryptophan to serotonin, to some good and some bad molecules like kynurenine, which can be both pro- and anti-inflammatory, and then quinolinic acid, which is absolutely pro-inflammatory in the brain. When you start at tryptophan, you keep going along this pathway, and whatever path it ends up following, you get different neurotransmitter activity going on. [The remission] was a microbiome event, but it’s really a microbiome-mediated event that’s occurring in the brain.

BL: That makes sense, yeah. Because it’s the microbiome that impacts these metabolic processes that then impact what’s happening in the brain, right?

TR: Absolutely.

BL: In terms of tracking what happens when you do this protocol, what are you using to study the changes in your gut and the further progression that you were talking about?

TF: Tamara knows more details than I do, but I’ll just say we are measuring a ton of biomarkers.  Everything from specific composition of the gut, to measures of the immune system, like cytokines, and measures of what’s going on in the brain.

TR: We probably have about a thousand metabolites that we’re gonna track. When you consider that we’re doing a lot of these pre[-trial], hopefully during as well as post, it really adds up. It’s actually one of the most exciting parts about the project, for Tess and I. We both have an explicitly systems thinking approach to science, and we love big data. This is something that actually really excites us, we’re going to be able to really dig in.

All of these tests really work in concert as well. The immunogenetics angles are really key for us. And Tess and I have some unique, similar genetic backgrounds, so that’s going to tie in. Then tracking neurotransmitters: actually tracking tryptophan, tracking serotonin, tracking kynurenic acid and quinolinic acid, as well as their ratios. And all of these metabolites.

BL: I see. Yeah, I feel like that will be really interesting to look at all the interactions between these different things. I know you mentioned that you’ve consulted with folks on the protocols, are there other things that you’re doing to maintain the safety of the experiment?

TR: Absolutely. So we’re working with one of my personal GPs [general practitioners], and she’s kind of acting as our GP safety liaison. She will be on hand if anything strange happens. But really what we’re doing in terms of safety is we’re testing ahead of time. We’re making sure we don’t have leaky gut, we’re making sure we don’t have a compromised blood-brain barrier, or making sure that we don’t have certain pathogenic bacteria in our system that could explode if they weren’t affected by the amoxicillin—and lead to a massive, very adverse reaction.

The main tests we’re doing there is from a company called Cyrex, they do these amazing immune tests… And then we’re doing tests like the GI effects from Genova, which will actually tell us if we have high levels of any pathogenic or potentially-pathogenic bacteria in our guts, before we actually start. If any of [certain concerning biomarkers] turn up as being really high for one of us, then we will take some time out, try to correct that specific defect and then proceed again.

BL: That makes sense.

TF: We do have a clinician who has a lot of experience with these specific tests, and specifically with the gut, who’s helping us. In addition to Tamara realizing it was a good idea to do all this pre-testing, she recommended it, too. So she can take a look at our results, and give us her perspective.

TR: One of the things we want to do there is, we want to actually figure out a very simplified testing protocol, which we can suggest to people to do for themselves before they do this [experimenting with supplements]. Because we want to actually bring this work to people who really need it, but we also want to make sure they’re safe. Hopefully, all of the testing that we do will help us arrive at a couple of biomarkers, which we can then tell people, “Look, if you test these one or two or three things, then you can do this without worrying so much about having side effects or adverse consequences.”

Right now, it would cost the regular person probably about $2,000 to test everything that we’re testing, in terms of making sure all these levels are safe. We want to figure out a way to decrease that cost, break that down into specific biomarkers. And then, hopefully, when we move into our Phase Two of Remission Biome—which is actually bringing this work to the patient population—we might even be able to give people these tests, or at least provide them with very significant discounts for these tests.

BL: Yeah, that’s something I wanted to ask you more about, too, is how you have been communicating with other people who want to try this sort of thing. I know from following y’all on Twitter and seeing some of the discussion around this project that folks are so interested. And generally, of course, there’s a big interest among people with Long COVID, ME, other similar conditions just trying to see what would work while there are no official FDA-approved treatments.

How have you found that experience? And, as you look towards Phase Two, what are some of the things you’re going to be thinking about, in bringing these results to other people?

TF: I’ve been talking to people on Twitter. And I would say, we’ve mostly been recommending, “wait until we do this first experiment, so that we can learn from it.” But for people who happen to be getting prescribed antibiotics [for an infection or something similar], then they have their doctor watching them. In that case, we can say, “you want to protect your gut, here are the probiotics that we’re doing, and you might possibly want to do a biome site test while working with your doctor.”

TR: We have had such an overwhelming response. I think hundreds of people must have contacted you [Tess] personally now with a story that they thought might be a revision event, like the one that we’re describing. And hundreds more have said that they’ve had some sort of a positive or negative reaction to antibiotics. And they’ve had ME/CFS, or Long COVID. Those stories are really the jumping-off point for us. We want to put together a very formal survey to actually figure out how people are responding to antibiotics in post-viral illness, in general. There are a lot of clues in people’s stories.

And the response of our community has been almost overwhelmingly positive, but there have been a few people who’ve had pretty severe baseline decreases after taking antibiotics. It’s always hard to know if the antibiotic itself was responsible for that decline or something else. But we really want to delve into that and figure out whether there’s a subset of people that seem to be having negative reactions.

BL: I also wanted to ask about communicating the results from this work. What are you thinking about in terms of both sharing with other people in the community, and also, are you looking towards like a preprint, or scientific publication?

TF: Yeah, we’ll be communicating in real-time with the community on Twitter, and getting input from all the scientists that we’ve talked to. That’s also something that we didn’t really mention yet is, we’ve talked to over 20 different researchers and gotten input from them. We have some that are interested in analyzing our results afterward. So, there’s community communication, but we are also planning to publish it, at least as a preprint.

TR: We’re going to be a great case study. And it’s going to be a great paper. It’s not going to end up in a formal journal, but we’ll definitely pop it into one of the preprint servers.

In addition to the case study, though, we really want to do a meta-analysis. A formal meta-analysis of all the studies that have ever looked at antibiotic use and post-viral illness. We think there are a lot of clues there. One of the things that’s really fascinating to us about this is that there are a number of similar situations that have happened in other conditions. One of the really key ones is PANS, or PANDAS, which often occurs in children when they get a staph infection—and then they get this crazy neurological event where their behavior changes and they develop OCD. Well, turns out, in an enormous number of those cases, if you give them antibiotics of the right type quickly enough—and a lot of the time, it’s amoxicillin plus minocycline, or doxycycline—you can actually completely put that child into remission.

And there’s other disease groupings that seem to have these remission events, in very similar ways. Even Alzheimer’s, many people who have a grandparent with Alzheimer’s will tell stories of moments of complete lucidity. This indicates that maybe brain damage isn’t the ultimate issue, maybe there’s something going on with the communication networks. And that’s really what we’re targeting here [in our research].

BL: That’s really interesting. I was actually just talking to another researcher for this story [Sonia Villapol at Houston Methodist Hospital], who mentioned that her lab, where she is studying Long COVID and the microbiome, has also done work on Alzheimer’s, and even traumatic brain injuries, where there’s some kind of microbiome interaction. I thought that was really interesting. It definitely seems like there’s so much more to be explored here.

TF: Yeah, one of the researchers that we talked to is also doing ME/CFS and Long COVID research, and then Parkinson’s—using probiotics for Parkinson’s. I think a lot of what we’re doing can apply to other conditions, too.

BL: Right. I also wanted to ask if y’all had any other comments about the two recent studies?

TR: Well, I was pretty excited to see butyrate as sort of the highlight molecule. Very early on, we decided that we were going to try to increase our butyrate levels… So we were really excited to see that both of those papers linked to butyrate-producing bacteria, which was really key for us. It’s not just that we want to increase butyrate during the experiment itself, but it’s also a great way to actually help heal leaky gut issues. So it’s a really great intervention.

BL: Yeah, that’s something that has come up a lot in the research I’ve done for this piece—the value of intervening early and trying to help people out before they’re going to have long-term symptoms, or at least in the earlier stages of illness. Which I know is one of the reasons why there’s so much interest in Long COVID, because you’re ideally diagnosing people earlier than what’s historically been the case for ME and some of these other related conditions.

TR: To me, the really exciting application of this is that antibiotics are a very safe intervention that have been used for dozens of years. If it turns out that there’s a chance that taking a quick course of amoxicillin and a tetracycline like minocycline or doxycycline, can take someone who might have developed much more severe Long COVID and then MECFS out of that track, well, that’s phenomenal. If there was actually something that you could go to your doctor and say, “hey, I’m having these Long COVID symptoms, what can we do right now?” And the answer is, “well, it’s pretty safe, why not just give you a week’s worth of antibiotics?” It’s a pretty exciting possibility that we could stop some of these more severe cases.

BL: Yeah, absolutely. I also wanted to ask, in terms of the institutional side of this, what do you think the NIH and other government agencies could be doing to better support this kind of work, and integrating ME/CFS and Long COVID research, as we try to understand the common mechanisms here?

TR: Well, they could actually be treating us. This is really the biggest roadblock: there are hundreds of thousands of people out there who are undiagnosed and untreated, and are trying to biohack their way out of serious post-viral illness. None of these people are seeing clinicians that know what they’re talking about. So, we need treatment centers—but not just the Long COVID treatment centers, where they just tell people to rest, but centers that actually do biochemical testing, figure out what’s actually going on in their bodies, and then doing targeted treatment.

Even if you can’t cure ME/CFS right now, it doesn’t mean that you can’t help people feel phenomenally better, and make sure that they don’t slide from moderate into severe. What you said before is so key, because most of us slide from moderate to severe when we get comorbidities. When we get MCAS on top of the Long COVID, for example. All of these comorbidities compound, and then they get people to a state where almost any intervention is aggravating to their systems, and they literally can’t tolerate light or sound or food. Treating someone at that stage is almost impossible, unfortunately, at this point. So early intervention is really key—but to get early intervention, you need clinicians that know what they’re doing interacting with patients.

BL: Which we don’t have nearly enough of.

TF: Yeah, that’s a major problem. Another angle that I’ll mention is more funding for research, specifically for ME/CFS. There are a lot of really great ME/CFS scientists who haven’t been able to get funding, but they’ve been trying to study this for decades. I keep hearing people saying that there’s these new researchers coming into Long COVID, who don’t really understand a lot about the history and what’s already been done. I think we need more funding for ME/CFS research, plus particularly funding for people who have been doing this for a long time.

TR: Absolutely. One of the things that Tess and I are really excited about is—I guess what we’re going to be calling Phase Three, but it’s starting now—is we’re putting together a hybrid DAO, plus a nonprofit, to actually provide funding for researchers in this area. It’s not just for researchers, it’s specifically for PhD patients.

We really want to tap into this community of sick scientists who’ve been sidelined by ME/CFS, by COVID, by other disabilities, and offer them the chance to actually get back into research in a way that they could do and would be supported. We’re really seeing a new model, a new way of being able to conduct research that is outside of academia, yet has checks and balances and support. Remission Biome has been, hands down, the best thing for my mental health that has happened in 10 years. If I could bring little bit of that to other people in my position—that’s what I would like.

TF: We’ve actually had a lot of people volunteer to help. And I’ve gotten the comment many times, people saying, “this feels so good to use my expertise again.” These are people that have been on disability for 10 years and haven’t been able to do any work or any research. And now they’re able to give their expertise towards our project, and help us gain momentum and move forward, and they’re just really happy about it. I think there’s so much untapped expertise out there.

BL: Yeah, that makes so much sense. And I hope I can keep following this project as y’all expand it.

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