Exploring Microbiome-Based Therapy

Paul Sax: [00:00:12] Hello, this is Paul Sax. I'm editor-in-chief of Clinical Infectious Diseases. And welcome to the Let's Talk ID podcast. Joining me today is Doctor Elizabeth Hohmann, who's an ID specialist at Massachusetts General Hospital, where she's the director of the Fecal Microbiota Transplant Lab and runs the C-diff treatment program there. She's also an associate professor of medicine at Harvard Medical School. And trivia for you, was a co-fellow with me a million years ago. Libby, welcome.

Libby Hohmann: [00:00:42] Great to be here.

Paul Sax: [00:00:43] Tell us a little bit about you. Tell us about how you got into medicine in general and to ID in particular.

Libby Hohmann: [00:00:50] Well, I always liked science and I liked practical science, so I decided to go to medical school. And my favorite class in my entire medical school career was microbiology. I really thought it was fascinating. I loved the classic plagues of mankind, all the old diseases, and the fact that we continue to have new diseases. So that's how I ended up in ID.

Paul Sax: [00:01:15] And did you have any role models, physicians or other people who might stand out for you that that made you go into medicine or go into ID?

Libby Hohmann: [00:01:24] Well, actually, that professor in medical school, he wrote his own textbook for the medical students.

Paul Sax: [00:01:30] Wow.

Paul Sax: [00:01:30] Which was a little kind of home published thing. And he was a role model and really interesting guy.

Paul Sax: [00:01:37] Great, great. Well, you know, I invited you on because you are a specialist in an area of ID that I think many of us really struggle with, and that is something I'm going to call microbiome-related therapy. It's not antibacterials, it's not antivirals, it's not antifungals, but it's this whole new way of treating some infectious diseases. And before we get into it, I want you to help me out with the terminology. How would you explain the difference between things called prebiotics, probiotics, and synbiotics? Our patients are using these terms now, and frankly, I have no idea what they're talking about.

Libby Hohmann: [00:02:18] Yeah, I find most doctors don't really understand this and it's pretty complicated. So I think we all know what probiotics are. There are live bacteria that are intended to, you know, benefit our health or well-being in some way. So that's a probiotic. A probiotic is actually typically a carbohydrate source or other food source for those probiotics that enhances their ability to act or survive, or makes the particularly intestinal milieu something more friendly towards the good bacteria that we want to keep. Synbiotics are a combination of a prebiotic and a probiotic, so sort of feeding the probiotic, giving it the right stuff to survive. There's also something called postbiotics, which are compounds that are beneficial or make a good environment that are produced by these, either probiotics or by natural organisms. So those are sort of chemicals. And those in fact can be given on their own. To try to maintain a better environment for bacteria.

Paul Sax: [00:03:43] Really it's fascinating. I have to say, when you walk into a health food store, I mean, or a grocery store, you can buy these, how do you choose? I mean, we'll get into that momentarily, but I want to also just say that you've joked to me that the GI docs think of you as an honorary gastroenterologist. And why is that?

Libby Hohmann: [00:04:02] Just because I'm one of the few ID specialists that actually has a big fecal transplant program and has been involved in the development of these live bacterial products, as the FDA sometimes calls these sorts of therapeutics. Just by whatever misfortune I ended up studying GI infections. I mean, as you know, some of my other expertise is in salmonella and listeria, which has an intestinal phase. And so I do kind of have an affinity for the gastroenterologist. I meet them a lot at meetings. I've gone to some of their meetings and I think they're a fun group.

Paul Sax: [00:04:43] How do they compare to ID doctors?

Libby Hohmann: [00:04:45] They're kind of very practical people. They get to the point they like to do procedures. They don't like to fuss around with things. They just like to cut to the chase. And it's fun to go out to dinner with a group of gastroenterologists.

Paul Sax: [00:04:59] So they're not ones to spend 15 minutes going through the differential diagnosis that names every microorganism in Mandel?

Libby Hohmann: [00:05:06] Not even close.

Paul Sax: [00:05:08] Okay, so I have to say a lot of us are skeptical about probiotics and related therapies because they are completely unregulated. Your thoughts about the limitations of studies so far? Most of them at least, that have come out?

Libby Hohmann: [00:05:23] This is one of the problems with the studies. Most people don't know, there's actually now by this time last I looked it was 90, but it was probably 100 different probiotics that you can purchase in the United States. They're not sold as drugs. They're sold under wellness claims. They're very variable. It's like going to the store and buying a cup of yogurt. That's sort of the level of oversight of them. It's basically the food side of the FDA, not the drug side. And the standards are completely different.

Paul Sax: [00:06:02] So you mean that a person can't just take one off the shelf and assume it's going to work for them?

Libby Hohmann: [00:06:08] No, you can't assume anything about taking it off the shelf. You can't really understand how many live bacteria are in there. You can't assume that what they tell you is in there probably is in there. It's like buying a stock of asparagus, or it's probably less accurate than buying a stock of asparagus, because you can at least look at the asparagus and know I think that looks like an asparagus.

Paul Sax: [00:06:38] That's right, that's right. You know, you could actually do when you're when you're checking out at the grocery store now, they can do an image search for you on some of these scanners and that, you know, it's an asparagus. You can't do that with bacteria. So I'm going to ask you if you're a company and you're in the probiotic business, which would be a faster route going the supplement route or going the FDA approved therapy route. I know the answer, but you tell me.

Libby Hohmann: [00:07:07] It's like the difference between a sprint and an ultramarathon. You can market a probiotic with some very basic oversight of production, and you make a wellness claim, you know, this is going to help your GI health, something as nebulous as that. And you're off to the races and you're selling it. And as you know, to get a claim for, you know, microbial restoration after recurrent C diff, it's taken Seres Therapeutics, which is across the river here in the Boston area, a decade to get their live microbiome therapeutic through the FDA process as a drug.

Paul Sax: [00:07:55] Well, you know, that brings us to my next question, which is related to C diff. This is one area where ID doctors might know a little bit about it, although not nearly as much as you. Catch us up with what we can do sort of microbiome wise for treatment and prevention of C diff. I know there are a bunch of things. Give me give me a short list.

Libby Hohmann: [00:08:18] Well, in 2023 we have two new approved microbiome therapeutics. The first approved is called Rebyota. And that's basically an enema preparation for prevention of C difficile colitis. It's frozen. It can be administered by a nurse or a doctor. And it's been approved for almost a year now for recurrent C diff. Clearly for us infectious disease doctors, enemas in clinic are not a happy thing. I've never done it. I never will do it. Some gastroenterologists are able to do it either by enema and some are also using it as a colonoscopic administration, although that is not on the label. That's the first of the recently approved drugs. The second one is called VOWST and I kind of have to use the trade name because there really is no generic name. It's got some letters and then says microbial spores and that is a microbiome therapeutic. It's 12 capsules over four days and two is derived from human stool specimens. And it's given to prevent recurrence of C difficile colitis.

Paul Sax: [00:09:38] And how do these play into a program where you might have FMT to prevent recurrence C diff or you might have Bezlotoxumab to prevent recurrent C diff. So how do we strategize?

Libby Hohmann: [00:09:52] Well, you know, this varies by doctor preference and patient preference and what you have available to you and what the patient has available to them. These newer approved live bacterial products are quite expensive, as I've already alluded to. There's different kinds of administration, different patients may have it preference for one or other of them. I personally like microbial restoration to treat recurrent C diff, because I think it for a couple of reasons. It fixes one of the primary underlying problems, which is a disturbed microbiome. And because patients feel better after getting these therapies, which in my experience is not really true of Bezlotoxumab.

Paul Sax: [00:10:40] Well, that's very interesting. And what about, you know, sort of the home grown FMT programs since you were a pioneer in developing one?

Libby Hohmann: [00:10:50] Well, home grown, you mean hospital grown or you know, there is patient home grown as well, which of course, we speak highly against because of the lack of any screening for infectious agents. And I do have a New England Journal CPC, where I discuss a case of a patient who may have given themself CMV colitis from their child who was in daycare's stool. Real home grown is kind of off the table and somewhat dangerous.

Paul Sax: [00:11:26] Yeah, good. Good reminder. It's all over YouTube, isn't it?

Libby Hohmann: [00:11:30] Yeah it is.

Paul Sax: [00:11:31] So my mistake saying home grown. I'm talking about hospital grown or you know, ID clinic grown.

Libby Hohmann: [00:11:37] Yeah. I mean I've been doing this for over a decade now. And if you're going to do this and provide fecally derived materials to particularly outside clinicians outside of your immediate group, you do need to have an IND. You need to submit it to the FDA. You need to get their approval for all of the screening of the donor, the stool samples and whatnot. So it's quite an arduous task, not something that that most people are willing to undertake, especially now that we do have these approved products which are coming into clinical use.

Paul Sax: [00:12:18] Yeah. No. Exactly. I mean, we having recently seen a person with recurrent C diff, I was faced with a whole new array of options actually. And when discussing it with her, interestingly, the one, the one that she favored the most was bezlotoxumab. But, you know, perhaps this issue of feeling better quickly and restoration of the, of the microbiome, uh, is not one that she or I understood as clearly.

Libby Hohmann: [00:12:46] I never use that one first. That's a fallback for me. With the exception of people who are really freaked out by fecal transplant.

Paul Sax: [00:12:56] That's it. Exactly.

Libby Hohmann: [00:12:58] Or the other instance in which that's a better choice. I think cancer patients who are immunosuppressed, where you might want to avoid any of the infectious risks of fecal transplant, or people who have B cell depleting therapies like rituximab, where you might be repleting, you know, the antibody response that they're missing.

Paul Sax: [00:13:23] Yeah, very helpful perspective. So shifting now to a different area entirely, I couldn't help but notice a randomized clinical trial in everyone's, uh, least favorite disease, which is Covid 19. And in particular, one of the hardest things about Covid 19, which is long Covid. And Lancet ID recently published a paper called Synbiotic preparation SIM zero one for Post-Acute Covid 19 Syndrome in Hong Kong. The recovery trial and IT demonstrated a significant improvement in long Covid symptoms with the use of this microbiome-related therapy. I just ask you, Libby, do you believe it?

Libby Hohmann: [00:14:09] I do believe it.

Paul Sax: [00:14:11] Wow.

Libby Hohmann: [00:14:11] You know, I have a lot of skepticism for probiotic studies, but things that are double blind, placebo controlled are important and worth doing. And there is a biological reason why it's possible.

Paul Sax: [00:14:26] You know, obviously, this is a fascinating topic because these post-infectious fatigue syndromes have been so intractable to for treatments. Why might a microbiome related treatment work in this condition?

Libby Hohmann: [00:14:40] I'm not an immunologist, but so much of the immune system resides in the gut and the tissues around the gut, the lymphatic system, the intraepithelial cells. It's a huge part of the immune system, and we evolved with the microbes that are in the gut. I think this is one of the most exciting areas of medicine, showing how the microbiome, and what you put in your gut can make a difference in your immune response, how you feel, how your brain works, the whole gut, brain access. It's just a fascinating area of medicine, and it affects how it affects the regulatory status of your immune system. I recently, just yesterday, somebody sent me a paper that showed differing immune signatures, again in a reputable a very good journal between a vegan diet and a keto diet, which are kind of on the extremes of the dietary spectrum that we have. But, you know, I think I believe these things. I have very high standards for belief. But I do believe them.

Paul Sax: [00:15:56] Yeah, yeah. And, you know, you're long-standing head of the Mass General Brigham IRB, so you've certainly have seen your share of clinical trials. This leads me to another question I have, which is that there have been other Covid 19 studies that that I know have caught your eye.

Libby Hohmann: [00:16:14] You mean with respect to the microbiome?

Paul Sax: [00:16:17] Yes. Microbiome-related treatments.

Libby Hohmann: [00:16:19] Well, there was one out of a company in the Boston area called Kaleida, which actually went under recently. But they too had an intestinal therapy that was designed to modulate the immune system pre-COVID and post-Covid. Their intervention was a prebiotic, a specific set of um oligosaccharides, again directed at influencing the gut microbes and the responding cells. There's also a study that, a long ago study, that showed you could affect the quality and quantity of the immune response of older people receiving flu vaccine, injectable flu vaccine, by giving them a probiotic. There's lots of really good data. They're not huge effects, but these are simple interventions that are, for the most part, safe.

Paul Sax: [00:17:26] Great, great. Well, you know, with the caveat that, of course, I'm biased by mentioning this. We did recently publish in CID, a study that looked at prophylactic oral and or vaginal probiotic supplementation to prevent recurrent urinary tract infections. And it brings up a whole other area of potential use of this treatment. Any thoughts about this particular strategy?

Libby Hohmann: [00:17:53] Yes. Again, I think these are viable strategies. When you can demonstrate, as that study did, that there was an incremental improvement in patients who got vaginal probiotics plus oral probiotics. I think these are valuable studies. They're not as effective as, say, FMT in somebody with a completely bombed out microbiome. But they can make a difference. And I think patients are really interested in them.

Paul Sax: [00:18:26] Great. Well it's incredibly frustrating problem in outpatient ID in particular. This particular study was in younger women. But it's a problem for older women and men, recurrent UTIs, and often with highly drug resistant organisms. So anything that can prevent recurrence is really to be welcomed.

Libby Hohmann: [00:18:48] One of the problems is that we don't have enough of these studies, and we don't have them done with studies that are easily available in North America. And the probiotic that you can, you know, most easily get at CVS or Rite Aid or your local store. So we need more of that.

Paul Sax: [00:19:07] So why aren't more studies like this funded?

Libby Hohmann: [00:19:10] Because nobody wants to fund them. Because the companies making the probiotic can make just as much money by having a nebulous health claim and selling it without investing all of the money in doing the rigorous studies.

Paul Sax: [00:19:28] What about our famous NIH?

Libby Hohmann: [00:19:30] Well, you know, I've tried to submit a few projects to NIH, and it's quite difficult to get such things funded.

Paul Sax: [00:19:40] Is it because this falls in between areas of expertise, maybe, or is there some other reason or?

Libby Hohmann: [00:19:47] I think it's just it's not viewed as rigorous science. I hope the publications like the one you're describing, might inspire NIH to look in more detail at these things. There is a whole complementary and alternative medicine arm of NIH, and unfortunately, they don't tend to be focused on this sort of live bacterial product kind of study. You know, it's been my hope that they might move towards this and help doctors and patients make these kind of decisions by focusing on specific probiotics that are available in the US.

Paul Sax: [00:20:34] Okay. Well help us look into the future. Now, we've got, uh, 5 to 10 years from now, what is your expectation and or hope for where this field is going? You can talk about specific areas like C-diff or just anything you like.

Libby Hohmann: [00:20:54] Well, one of the things that I would really love to have, and I'm sure there's some smart people out there working on it, is a microbiome test for a bad microbiome. Um, a simple stool test that might show confirm for us that, oh, this patient with cancer has been excessively treated with antibiotics, and they might benefit from something like vows before they go into their bone marrow transplant, for example, greater screening for overgrowth of resistant organisms against. We might have a better target for use of therapies like this. Who after their first episode of C diff do we know is likely to recur. So maybe again, we could target that population. So I think there's a lot to be done on the diagnostic and phenotyping of patients that could be of value. And then, you know, more new products. And there are some companies working on this. Um, I'm hoping to participate in Vedanta, another company in this area, in their phase three study for C diff of a defined consortium. So not derived from stool, no stool involved, all synthetic super probiotics. There's a number of companies internationally that are pursuing that that sort of work.  And then you can combine it with the prebiotics and, you know, super combinations, fibers or oligosaccharides with microbes, that I think all of these things are going to be happening. Another area where there already is some good work, some of it coming out of Israel, is in metabolic manipulation, you know, with this kind of a microbiome and this sort of a glucose phenotype advising people regarding diet, microbes, lifestyle changes. And there are already things that you can purchase that allow you to do that again in the pay by patient space, not approved by regulators. So I think there's so much potential for these things. And as you know, I'm a cynical negative person. So the fact that I'm enthused about these things does mean that there I think there's a lot of potential here.

Paul Sax: [00:23:37] Well, I would redefine that, Libby, as a person with high standards.

Libby Hohmann: [00:23:42] [laughs] Well that does sound better. I'll go with that.

Paul Sax: [00:23:45] So speaking of high standards, I can't resist getting a consult right now. I've got a patient here, uh, with, uh, first episode of C diff. Your therapeutic recommendation, independent of price?

Libby Hohmann: [00:24:02] Oh, absolutely. I would go with fidaxomicin. Narrower spectrum, less likelihood of relapse, same likelihood of cure of the episode. I would give it in the extended dosing paradigm. Five days bid dosing. If they're improved significantly, go to every other day. I would advise them to go to their local store and buy some kefir. Get two varieties. Figure out which flavor you like that. That would be my advice for my own parent if they had a first episode of C diff.

Paul Sax: [00:24:40] So that brings us to a pharmacoeconomic issue, which is what on earth happened with the pricing of that drug?

Libby Hohmann: [00:24:48] Fidaxomicin?

Paul Sax: [00:24:49] Yeah, it's crazy.

Libby Hohmann: [00:24:51] I know. And you know, it's not even available. I just saw a patient in clinic this week who couldn't get it on the South Shore of Boston. It varies a lot by site. It varies by plans. You can get it. Almost all New York plans pay for it first right off the bat here it's a hassle. So there's lots of variability. It's just crazy. And it's so challenging that the society recommendations are for that is first line. You know, part of the reason they made that was to try to make it more available. And it's not.

Paul Sax: [00:25:30] Hmm. Interesting. Okay. And one last consult question. Your dietary spiel that you give to every c-diff patient?

Libby Hohmann: [00:25:39] Absolutely. The K foods - kefir. It's a fermented milk drink with multiple different probiotics. Unlike yogurts, which typically only have 1 or 2 kinds of organisms, comes in many flavors. There's a study out of the University of Minnesota which shows you can cure people who couldn't afford or didn't want fecal transplant by using pulsed vancomycin and kefir. I have colleagues, some of them, you know, at Mass General who used to send me a lot of patients for fecal transplant. They started giving kefir to all their patients. And I don't get those referrals anymore. So it can work. Other fermented foods are kimchi, crowds, live pickles, fermented things. These are all great for the microbiome and you should eat them.

Paul Sax: [00:26:35] Okay, well, Libby, it's been a real pleasure talking with you about this fascinating subject. I want to thank you for joining us. And once again, I've been talking with Dr Elizabeth Hohmann. She is a ID specialist at MGH and on the faculty at Harvard Medical School, where and she is a specialist in something I'm calling microbiome-related therapies. Thanks, Libby.

Libby Hohmann: [00:26:58] Thank you.