82. Microbiome 2: Microbiotoxicity

In this episode, the ID:IOTS Podcast Microbiome Correspondent Dr Anastasia "Tash" Theodosiou, finishes educating Callum and Jame (mostly Callum) on the concept of Microbiotoxicity!

This episode is part 2 of 2. Here we discuss: 

- What is microbiotoxicity?
- Risk factors for microbiotoxicity
- Which antibiotics are associated with microbiotoxicity?
- Mitigating microbiotoxicity

https://www.researchgate.net/profile/Anastasia-Theodosiou

https://x.com/doctoranastasia

Transcript

Jame: 0:00

Hi everyone. Welcome to the Idiots Podcast. That's infectious disease insight of three specialists. I'm Jane. That's Callum. This is Tash and we're going to tell you everything you need to know about infectious disease. Callum, how you doing?

Callum: 0:21

I am great. I we've got our first, first time guest. Does that count now?'cause it's been three episodes.

Tash: 0:30

I think so I'll take it.

Jame: 0:31

well Did you give her official title as our official Idiots podcast? Microbiome correspondent, or are you waiting for me to bestow that upon her?

Callum: 0:39

I did mention it last time, but I think you've done it in a much more formal way.

Jame: 0:44

Tash, how you doing?

Tash: 0:45

Yeah. No, very good. Thank you for the opportunity to come back. That's supposed to be a poo joke. I.

Jame: 0:51

Well, I'll be honest, Tash, it's not the worst. We've had

Callum: 0:55

What?

Jame: 0:57

Tash.

Callum: 0:57

It was good. Probably the best.

Jame: 0:58

What is microbio toxicity?

Tash: 1:01

I am so glad you asked Jane. So I was feeling profoundly frustrated that we have all this chat about the multiple side effects of antibiotics on our kidneys, on our livers, but we don't. Tend to talk about the most obvious side effects that they have on one of our most neglected organs being the microbiome itself. And it sounds a little bit, tort logical to say, antibiotics kill bacteria. Well, of course they do. That's why you're giving them. But we're not so much concerned with, we're not looking at the intended killing effect of bacteria, but rather the unintended bystander effect on your community of microbes. And we talked lots in the last episode about the sort of functional importance of the microbiome. So today we're gonna completely geek out about how the antibiotics that we give can damage the microbiome and what the sort of downstream consequences are. And taking it a step further by giving you some really practical tips about how you can think about this in prescribing and actually some little changes that you could make to your prescribing right away.

Jame: 2:03

So I suppose the problem that you're having with unrecognized Della tedious effects on the host microbiome is the, it's the same issue with resistance, which is the other big consequence of unrestricted antimicrobial use, which is that the bugs are always paying attention. And so if you expose them to something which kills them, that makes them much more likely to develop some kind of resistance or amplify some preexisting resistance that they've got. So I suppose microbio toxicity the the opposite problem of resistance. The the problem there is that the

Callum: 2:36

They're sensitive.

Jame: 2:38

colonies are being decimated. So they're dying.

Tash: 2:41

I would actually even argue that microbio toxicity is the umbrella term and that antimicrobial resistance sits within that.

Jame: 2:48

Quite a big land grab for microbio toxicity, isn't it?

Tash: 2:51

I think so. Well, we know we have to be ambitious with these things if you're trying to get it to take off. But yes, I think antibiotic resistance isn't about individual genes in isolation. It's about how these genes move through a population, especially when you're looking at mobile genetic elements, how they move through individuals and how, using some bacteria but not other bacteria expressing antibiotic resistance changes the community profile. So I think it's one subset of microbio toxicity, but it's not the whole story. And I think something that I really wanna tease out here is that often the two go hand in hand. So, the antibiotic spectrum or duration that is most strongly linked with resistance is often the most microbio toxic, but not necessarily always. So I wanna really highlight some of the times that resistance and microbio toxicity don't completely overlap, because I think that's important when we wanna think about how we can change practice.

Callum: 3:47

So you mentioned there before that there was the effects of antibiotics. So I guess if we start to delve into some of more of the detail, what are the effects of antibiotics on the microbiome?

Tash: 3:59

Okay, so let's look at sort of short term. So as soon as you take the antibiotic and. gets absorbed, goes through your bloodstream. What it's gonna start doing is immediately reducing the overall biomass. So that is the number of living bacteria that make up your microbiome. So that happens really quickly, and it's not just the total number, but it's also the diversity. So specifically the alpha diversity, by which we mean the number of species and the evenness of those species in that niche. And we talked last last time about all those sort of bioactive molecules. So because you're killing the organisms that orchestrate those bioactive molecules, you get a reduction in those molecules. So things like the short chain fatty acids, the neurotransmitters, the hormones, and the vitamins. And then you also get a drop in those sort of, anti-inflammatory health associated commensal organisms that we like. So those are typically, especially in the gut, those would be your sort of large communities of anaerobes. And then the flip side to that is you then create space for other what are supposed to be minority organisms that then start to outcompete. And not only are those organisms potentially pathogenic, so it tends to be the, the patho that your microbiome usually keeps in check. It's also that they, so it's not only that they can cause disease in their own right, those patho, but also that they are pro-inflammatory. So then you end up in a vicious cycle because then you start encouraging inflammation in the mucosa. You start leaking some of those pro-inflammatory media, aiders, systemically. So that's like the short term effect. And it's not only. The bugs themselves, but we talked about antimicrobial resistance because the antibiotics are selecting out these genes. You get an a, an increase in what's called the ome. So the ome is the sort of sequencable entire resistance profile of your microbiome niche. So you could get the REO of the gut say that would be all the antibiotic resistance genes in that niche. Usually done by metagenomics, but it's not just antibiotic resistance. So this is why I think microbio toxicity is the umbrella term, because it's also other bacterial gene sequences that we should be worrying about because it's virulence factors as well, more generally, or being upregulated when you give antibiotics. And I think if we take a little bit of a step back, I think as microbiologists, what I feel incredibly passionately about is that we are aware of some of the difficulties when we try to extrapolate from what we know in vitro to what we know in vivo. So if we think about spectrum of activity, it's based on what we do to bacteria in a Petri dish. But we've spent the whole of the last episode saying that these bacteria exist in networks. So if you have an antibiotic that knocks out a key player and that key player feeds other bacteria, or it detoxifies the metabolites of other bacteria, then your antibiotic could indirectly kill far more bacteria. Then your spectrum would necessarily suggest because your spectrum is based on in vitro evidence, not in vivo evidence of what's happening across the microbiome. So I think that for me, that's really important and that's part of the reason why I think it's not enough to think about antibiotic resistance. It's not enough to just think about what's happening in vivo. You need to think community wide.

Jame: 7:05

Yeah, so it's like taking a predator out of a food web. The downstream effects will be much greater than the apparent removal of one member would initially seem to be.

Tash: 7:15

Exactly. So you, we talk a lot about this concept of resilience when we think about the microbiome. So resilience is how much it can resist change. And one of the kind of cardinal things that antibiotics do is that it drops the resilience of the community. And that's really important because it means that when you have another insult, another antibiotic or another intercurrent illness, potentially another inflammatory insult, you're less, you're again, even less able to cope with that insult. So you get this kind of vicious cycle of, inflammation disease state. Susceptibility to infection, more antibiotics, more microbiomes regulation. And again, I don't wanna keep laboring the point, but you know, we talk about antimicrobial resistance as if it's this sort of, binary thing. It's either there or it isn't. But actually the way that the resistant behaves within the microbiome can be quite nuanced. So if you have, so for example, mobile a MR genes, then when you give antibiotics, those can spread through the community. Whereas if you have something that's static, like a chromosomal gene, then actually you might change the balance in the community far more profoundly. So I think, you can't think about it just in these black and white terms. It's really happening in a kind of a community effect. So those were all the kind of really short term changes that you get and. They might not last all that long. So, in, in a healthy young person who's got a, nice, healthy gut that's very resilient. It might bounce back within days to weeks. Usually a month or two is quoted as being expected to bounce back to normal, but. Depending on your host and the kind of baseline microbiome that could take a lot longer. And there's definitely cases where it's been documented to be different for as long as a year later. And a thing, I wanna take that a step further, is just because the microbiome profile goes back to what it was before the antibiotics, it doesn't mean that all the harm is undone, because depending on when you're giving the antibiotics, so just say you're giving it to a baby. And we saw last time that the microbiome in babies is instrumental to programming the immune system and the kind of set points for how the immune system's gonna respond to later insults. Even if the microbiome signal goes back to looking exactly as you'd expect it to, that doesn't mean that all those downstream inflammatory set points have gone back to normal. They're just a bit harder to test.

Callum: 9:32

that you mentioned there, Tash, that most people recover by eight weeks, but it can last up to a year and that there's different factors that would influence how quickly someone recovers. So I was thinking there, what the host factors,'cause I guess you, as you described that sort of story you gave of people where they've had antibiotics. So they get a, abnormal gut microbiome and then they get inflammation and they get more infection and, I can almost picture that patient that's coming in with current infections and they, they come to the general practitioner and they say, I've just keep getting infections. Why do I keep getting infections? So who are these people that are more likely to have a worse impact on their microbiome from antibiotics?

Tash: 10:14

So there's no real big surprises here'cause it's the same people who tend to do worse across the board. So it's your very youngest, your very oldest. And then people like immunosuppressed or those with inflammatory intercurrent illness. So the kind of likely candidates, but in terms of what's going on with the microbiome, it's either because there's active inflammation already. There's something that's already nudged the microbiome towards a less resilient state. So that would be things like your, your people with incurrent inflammatory illnesses. Or those where the microbiome is still in that kind of critical developmental period. So that would be early life. And importantly, it's not just the newborn itself, but also antibiotics given to the pregnant woman or even the mother after she delivers because of the fact that her microbiome is actively seeding the newborns microbiome. So those would be the way I think about it. So early life very elderly immunosuppressed and intercurrent inflammatory illnesses. And the one that's getting a lot of attention at the moment is malignancies. So there does appear to be an independent association between antibiotic use and mortality. And that's being actively investigated in the context of things like immunotherapy. And it, it seems to be that it's the efficacy of oncological treatments is being reduced in people who've had antibiotics and they're looking into whether that's being causally mediated by the microbiome, but it's still in progress.

Jame: 11:36

I take it you're not talking about the toxic old stuff. You're talking about the biological stuffs, your MIBs and your nabs,

Tash: 11:41

Especially things like checkpoint inhibitors are where I think the signal has been particularly interesting.

Callum: 11:46

And it's really fascinating because, we know that patients that have cancer get infections and they come in and they're immune compromised. And so people weigh their risks differently. And so I think, almost every health board essentially will be like, well, their immune compromised, therefore we'll give them more antibiotics. And we give them broader spectrum and we'll give a lower threshold for giving antibiotics, which then ties into the.

Jame: 12:08

get drowned in antibiotics.

Callum: 12:10

Yeah. And then it comes into this thing where we're saying, actually, like estimate this year there was a talk on oncology practices and trying to establish, deescalation and saying, actually we don't need to give long course antibiotics for neutropenic sepsis when there's no pathogen. Actually we can give shorter course antibiotics to these people. And this microbio toxicity angle potentially is helpful here because it's another tool in our repertoire of things to say, actually we need to give people less antibiotics, not more even when they're immune compromised. That's really interesting.

Tash: 12:42

Absolutely, because I think the traditional conflict when you're faced with a quite vulnerable oncology patient, is that your sort of stewardship motivations are somehow in conflict with that patient's own needs. And it's almost positioned as, they're a really vulnerable oncology patient, so therefore stewardship's allowed to go out the window. Whereas actually we should be reframing that as saying, well, this patient could be potentially most susceptible to harm caused by those antibiotics.

Callum: 13:10

Yeah. That's so true so Yout, you've taken us through there, the different host factors that impact on how much microbio toxicity there is. What about the different regimens of antibiotics that we might be choosing to use? So on this podcast and elsewhere, infection medicine, we're often talking about, broad versus narrow. We're talking about shorter versus longer. So how do these things affect the microbiome?

Tash: 13:37

So again, much like with the host factors, some of these things are really intuitive and not particularly surprising. So, broad spectrum antibiotics appear to be more disruptive to the microbiome than narrow spectrum. Antibiotic regimens with multiple agents appear more disruptive than single agents. And having multiple courses is also more disruptive than a single course of antibiotics. And longer courses more disruptive than shorter courses. So again, no surprises there. I think there are a couple where it is worth highlighting. So traditionally how we think about antibiotics would be in terms of the risk of antibiotic resistance and where they sit in availability and things like the WHO Aware classification. But I think there are a couple of surprises here. So ones that we maybe don't feel particularly concerned about would be things like, metronidazole, macrolides, but actually those rack up quite a lot of microbiome microbio toxicity. And again, when you think about it in terms of everything we've said about the function of the microbiome and the importance of these kind of anti-inflammatory, commensal anaerobes, then that makes a lot of sense. Especially since so Metro is obviously because it's has a lot of anaerobic anti anaerobic activity, but macrolides because they have. Several mechanisms of action that aren't directly to do with their bacterial killing, but rather their sort of metabolic effect that they interface with the host. So both of those I think would be ones where I would urge us to think of them as being slightly more high risk antibiotics than maybe we would traditionally think of.

Jame: 15:11

So the, for the macrolides are you talking about the anti-inflammatory effect that they have or some other effect?

Tash: 15:17

So it appears to be a sort of effect directly on, on the microbiome. So when they look at deviation from the baseline, you get larger deviations in people who've had macrolides as opposed to say, doxycycline or Trimethoprim. Coach ole. So they've had some studies have looked at head to head. Some studies are more based on meta-analysis of ones where they didn't look head to head.

Callum: 15:40

Have a couple of questions. I think I've got loads of questions, but I'll try to limit myself because time, so. I'm really interested in the metin niaz angle because I think often that gets thrown in. So one thing that we've been doing locally is trying to move away from aspiration pneumonia automatically triggering prescription for metconazole along with amoxicillin usually is what we were using. We've changed our guidelines and to be more in line with the IDSA guidelines, we suggest on using MET IOL for a certain late aspiration or certain other criteria. And, I think this is a another tool to say, actually we shouldn't do that. But I guess my question is, so sometimes in regimens we metro eye results added in, and if a person is viewed as high risk for c diff, right? Then there's this kind of thought or discussion point that sometimes comes up where people say, well, if you keep going, if the metronidazole. Lower the risk of the c diff, which never really made sense to me

Jame: 16:41

you still getting that now that it's been removed all but removed from the c

Callum: 16:45

because we know there's such a high resistance rate in C Diff to Metronidazole. And I think people are maybe confusing that with, there's some trials where you're suggesting that if you give Vancomycin prophylaxis orally to patients that are high risk of c diff, there seems to be some data that suggests that lowers the risk of c diff infection, whether that's outweighing the harms that I'll probably have in the microbiome. But I guess, I guess people can view Metronidazole as, oh, it's good to give metronidazole because we might stop harm, but it's having a huge impact on the microbiome, which then means that much more likely to get c diff from my reading.

Tash: 17:23

I mean, all of us walking around without symptomatic c diff infection, the barrier to symptomatic c diff infection is our normally functioning microbiome. It's not because we're taking prophylactic antibiotics. And I think the idea that you would give an antibiotic, which, disrupts the resilience and stability of the microbiome in order to prophylax, I would need to see some very compelling evidence to convince me of that. I think by and large reduction and I. Careful use of antibiotic prescribing would always be preferable to chasing a microbiome signal with more antibiotics. And actually, I mean, that gets to the root of treating c diff in general. I mean, part of the reason why it's expected that things like forget metronidazole which hopefully is no one's first line anymore, but even vancomycin fed dexamycin still have high recurrence rates. And part of the reason is because although they are, narrower in spectrum than broad spectrum antibiotics that got them into the mess in the first place, they are still antibiotics. And so you are still driving further microbiome disruption. And although, I don't wanna pretend like FMT is the panacea. I mean, certainly the way that it's regulated means that it isn't applicable for everyone and has some of its own risks and issues. But equally it would be disingenuous to pretend like it is not. Significantly more effective than any antibiotic treatment we have ever had for c diff. And it's because it's restoring the underlying driver rather than just chasing it further away.

Jame: 18:57

If it was a drug vancomycin and phy, dexamycin would not be used.

Tash: 19:01

But actually now there are licensed live Biotherapeutic products. It remains to be seen what their clinical utility will be because at the moment we're working on the basis of the phase three data, which is promising. I think about, about 70% efficacy for Rebi ota, but again, not been used in widespread clinical practice yet. But it's exciting

Jame: 19:21

Reta. That's a brilliant trade name though, isn't it? Isn't it just,

Callum: 19:25

Re biota. Yeah. Yeah.

Jame: 19:28

Hats off to the

Callum: 19:29

came up with that.

Jame: 19:30

There for that. Yeah.

Callum: 19:32

Yeah. So maybe in the future, if you're listening to this podcast, then there'll be easy access to these LBPs,

Tash: 19:38

live biotherapeutic products.

Jame: 19:40

Okay. Oh, maybe we're taking them for everything.

Callum: 19:43

but yeah, but just after your course of antibiotics, we'll just give you some of that and then we won't have to worry about the microbiome. We can give everyone meropenum.

Tash: 19:51

Yeah, I mean, I think it's important. I'm never one to say, oh, this is gonna be the thing that fixes everything because we'd be proven wrong for far more often than proven. Right. But I think it's important to be aware that live Biotherapeutic products are coming, that they are regulated as drugs rather than FMT, which, varies so much country to country in terms of how it's regulated and is often only used in the context of research indications. In some countries it's still regulated as a human tissue, so that amount of interation variability, the amount of interdose variability means that it's never gonna be the widespread intervention that maybe there was hope that it could be. But I guess we have to watch the space.

Callum: 20:32

And I, just to clarify, I was being quite face facetious there. I don't think we should give Meropenem to everybody. Even if we can fix the microbio toxicity, there's gonna be obviously big implications for resistance and we will still have stewardship.

Jame: 20:46

you ever actually do that, I will come to your house and burn it down.

Callum: 20:49

This reminds me of that Dr. Comb video where someone's trying to order meropenem from the pharmacist and they give'em a really hard time and an infectious disease turns up in sunglasses, and that's for all Meropenem. They have, and they give them it spoilers for that video, but you should check it out.

Jame: 21:02

a good video.

Callum: 21:03

So s you've talked about the different antibiotic choices and I guess is there sort of data for causality between which antibiotics are like, where's this data coming from? How do we know?

Tash: 21:14

So some of it is from, so observational studies of people who have had a clinical indication for certain antibiotic regimens. Some of them are people with an indication, but they've been randomized to a regimen expressly to study the effect of the microbiome. I think what's really exciting albeit quite a small number of studies is patients where there was no clinical indication for antibiotics. It was healthy volunteers who were given antibiotics purely to study the effect on the microbiome. You can discuss the ethics of that at will, but I guess what was really interesting about that is that it conclusively showed that it's the antibiotics themselves that are causing changes in human microbiome signatures rather than the intercurrent illness itself. Now obviously the goal there was not to induce, a phenotypic disease state or harm. It was just to measure what the impact on the microbiome was. But it is interesting that helped us unpick the relationship between. Current illness and the microbiome and the antibiotics. I think as we talked about in the previous episode, there's a lot of the data that you would use to support a causal role comes from animal models. And then the human interventional stuff would be the things that we've already covered in terms of mainly c diff so FMT and LBPs in the context of c diff to a lesser extent. The restorative properties of FMT in conditions like ulcerative colitis or inflammatory bowel of irritable bowel syndrome. And then an interesting one is probiotics.

Callum: 22:45

Yeah, I've been wondering about probiotics and when that would come up, because that's something that sometimes I'm asked by patients about, or I've heard about, and I've been listening to the Microbiome Medics podcast and they talk a lot about probiotics, fermented foods, et cetera. And so I just wondered what, where we're at with that how do we mitigate this microbio toxicity? Are probiotics potentially an answer?

Tash: 23:09

So probiotics is a very interesting term because we've talked already about LBPs, which are drugs and therefore have to be demonstrated in a clinical trial to be efficacious or you're not allowed to use them just like any drug. Whereas probiotics aren't regulated by and large as drugs. So they usually are regulated as food supplements, which means they can be available over the counter with no obligation on the manufacturer's part to show efficacy. So what this means is that there is some excellent probiotic research, but there is also some very shoddy probiotic research, and I hope it's okay to say that there are post-marketing studies done on proprietary products, often with heavy industry involvement, where you take something off the shelf and you look at what it does to the microbiome and you look at what it does to a few clinical parameters. And that, for me is incredibly different to probiotic research that is rooted in hypothesis driven science. And so I can give you a couple of examples. So you might have something that's, a literal Holland and Barrett product where you just get some microbiome readouts on the one hand, and on the other hand, you have a. A strain that is selected based on observational data for say, an important bifidobacterium strain that comes up time and time again in healthy infants and doesn't come up in, in premature or unwell infants. You then take that, you supplement it into breast milk. You not only measure the microbiome, you look at the, downstream t-cell assays and cytokine profiles and host transcriptome. You look at the metabolites in the stool to show that it's actually influencing host metabolism. That's a very different kettle of fish. So when you show efficacy in the latter study, I'm inclined to pay a lot more attention than when you show efficacy In the former study. Now the trouble is at the moment, there seems to be a very frustrating trend where people will take both of those studies and lump them into one systematic review regardless of whether the study design is completely different, regardless of whether the strains of probiotics are completely different. Now, to me, that feels like someone doing a meta-analysis on whether antibiotics in general are effective, or whether chemotherapy in general is effective. It's not a useful research question. So I think we need to get better at differentiating between hypothesis driven probiotics research where you are engaging your brain when you choose a strain and you're engaging your brain when you design the study from purely post-marketing, proprietary product research. So, having said all those caveats before I get a accused of being too credulous, I would say that. In certain situations, certain strains and certain indications, there is hope for certain probiotics. So the ones that I think for me with microbio toxicity come up would be antibiotic associated diarrhea. Not necessarily c diff, but antibiotic associated diarrhea. Certainly there's a Cochran I think two iterations of the Cochrane Review supporting their use, especially in young children, although that hasn't made it into practice and guidelines. But again, it's important to highlight that this is strain specific. So certainly the strains with the highest evidence base would be Croce Boi. And then second to that lactobacillus s gg. So again, I think there is a role for these as a prescriber. None of these are advocated for in the guidelines. So when asked by a patient, I don't feel like I can really recommend anything. What I would, my pragmatic view would be these are probably low risk in an otherwise healthy patient and they may help. So if you feel that, that would be helpful, go nuts. In the same way that I would say a, a varied plant-based diet, including some fermented foods, is probably quite a low risk thing to do and it may help you. And we are very unlikely to have ever the level of evidence required to conclusively show a clinical benefit in the way that you would with the drug. And there's a very pragmatic reason for that. When you do a drug trial, you spend millions of pounds and recruit thousands of people and you do it because at the end of it you have a marketable product that recoup that cost. You cannot do that with kafi and kombucha because there is no product that is gonna make a drug company that money. And that's not me being cynical. That's just a very pragmatic view of how clinical research works.

Jame: 27:40

But also Tash, the probiotics market is comparable to the current drug market in terms of size. And so, drug companies will invest in stuff to make a profit. They're already making that profit with fairly nebulous claims about, this probiotic will help you poop more. And that's probably good enough for them, so that there, there's absolutely no incentive to do complex dedicated randomized control trial research to result in the evidence base for an outcome, for a, for it being used as a drug or an intervention or a product that they don't need in order to make a profit.

Tash: 28:21

Exactly, because it's not a barrier to entering the market because they don't have a legal obligation to demonstrate efficacy. So my point is that provided it's a relatively low risk intervention, I think the pragmatic thing to do is go, you could consider this as part of a holistic approach. However, I do not think it is the only thing, and I would much rather our listeners be thinking about how they could modify their prescribing practice in the first place, rather than getting bogged down with which probiotic, if any, to recommend.

Callum: 28:51

It makes me think of the recycling terms. Reduce, reuse, recycle. So it's reduced antibiotic use. I dunno what reuse is. Maybe I should cut this out

Jame: 29:00

No don't you

Callum: 29:00

microbiome trans.

Jame: 29:02

You've just struck on gold there because reuse might be something like, repurpose your antibiotics. So, use your doxycycline for your, UTI use your cotrimoxazole for your, streptococcal infection. So as time goes on, our knowledge of, what covers what, Using that to try and tailor your therapy a bit more, a bit away from the broad spectrum and more towards the narrow spectrum that repurposing. So that reusing. That's perfect. Callum, that's a perfect analogy. Now you have to think about recycle. So over to you, Callum

Callum: 29:36

yeah, just come back

Jame: 29:37

antibiotic again, but maybe a bit less for a

Callum: 29:40

Yeah. Dunno. Yeah, I don't know. I didn't think it viewed properly,

Tash: 29:44

surely fecal microbiome transplant is the ultimate recycling. Your one man's waist is another man's gold and whatnot.

Callum: 29:52

Oh yeah, that's it. Yeah. Yeah, that's it.

Jame: 29:55

I I guess so. I'm not sure that's how the re bioTE is going to be advertised. One, one man's waste is another man's treasure is that would be a bold step from the advertising boys.

Tash: 30:05

The optics aren't great.

Callum: 30:08

So, so two more questions. So, first question is, so we've talked about this and there's obviously studies looking at this, but it's quite complicated science from what you explained, like, to get the details. So if I have an individual. Patient. Is there anything on the horizon or anything that's existing at the moment? We say we're comparing this to an organ system or we're saying it is an organ system, so we can check your rean electrolytes for kidney dysfunction. We can check our liver function tests to see if we've got a ox disease. Is there any way that we could say, okay, let's measure microbiome toxicity.

Tash: 30:43

Yeah. And that is an incredibly fair and appropriate criticism because at the moment there isn't a widely available biomarker for microbiome toxicity that exists outside a research lab. So it is impractical to sequence everyone's microbiome every time they have antibiotics, what you would be looking for. And I think what has had some interest is, so we talked about gut inflammation and gut permeability. Again, this is one where the moment you start saying words like leaky gut, people jump on you because it's again, one where the research is unfortunately peppered with both good and bad science. However, I think because I am relatively convinced by the sort of inflammation as being a plausible, mechanism by which this is all happening. Then looking for molecules associated with with that gut permeability seems a sensible place to start. And the things that people have been looking at are things like those short chain fatty acids, things like lipopolysaccharide, which shouldn't really be in the bloodstream and could be markers of low grade bacterial associated inflammation in the gut. But you're absolutely right, those biomarkers are not validated and not currently used in clinical practice. I don't think that's a reason why we should be afraid of using the data we have so far. If anything, it should be a motivation for us to do more of this kind of research and find those biomarkers and quickly because we're, we've quantified what the problem is so we don't stop when we realize we don't have all the answers.

Callum: 32:17

It is, it's interesting to me sometimes when we think about, like, I think about battery mail locks, that's a lot of what I do, but we quite often get. Bacteremia with low virulence organisms, which are part of the gut microbiome and the trigger, the automatic like reflexes, bacteria and blood culture bad. But sometimes I, and I'm not sure I'm advocating not to treat bacteremia, but like, when you say get like lactobacillus or a bifidobacterium in a blood culture, sometimes I just end up thinking, well, like, sure, this is a sign they've got a leaky gut, or, this bacteria shouldn't have gotten into these come in from the gut. Is giving antibiotics here actually the right thing to do? Or is this actually is this causing harm?

Jame: 33:01

But then I guess the account, you have to have the, courage to let the immune system do its thing. You get bacterial translocation. To a certain extent from brushing your teeth every day from your gut to a lesser extent. But you will still be getting some bacterial translocation. The whole reason that your entire blood flow from your gut goes into the portal vein, and then that portal vein feeds to the liver. And so the liver, which is packed full of coup for cells, which are just tissue macrophages hanging about with the hepatocytes, can filter out all of those bugs from the from the bloodstream before it hits the systemic circulation. So like the, the influence of your gut microbiome or the. The risk, I suppose, of your gut bugs invading your systemic circulation has been, is, is so great that you've evolved to have a whole filter there that takes up 1.4 kilograms of the 70 kilogram mail. Uh, some things in medical school you never forget. Specifically, it's not, its only function, but one of its functions is that it's the great filter for gut translocation.

Tash: 34:14

I think it really depends on the host as well. Like I, I had a really interesting four month SHO job involving mainly the gut failure unit at a tertiary hospital. And that was fascinating. And the bugs we got from the bloodstream. So I don't wanna give the impression that, ignore them. It's fine. It's just translocation.'cause those were sick people with some real moldy specials that none of us had ever heard of, and they looked sick, so I don't wanna I'm not an expert on, when you should and when you shouldn't treat these strange bugs that are almost certainly translocating across the gut. But I've certainly seen sickies with these translocating gut bugs.

Jame: 34:52

I think it's more a sort of a spectrum. So like in a healthy individual, say it turns up in Callum's bloodstream, I don't really care. And not just'cause, I don't care about Callum in general but specifically because he's an immunocompetent,

Callum: 35:05

up?

Jame: 35:06

because he's an immunocompetent individual. And as you get more and more immunocompromised I start to think my threshold for treating a bifido bacterium or a lactobacillus or a mouthy strep, it kind goes, it gets lower and lower. Do you know what I mean? And Over time.

Callum: 35:22

that's true. So we've covered a lot and I guess I might summarize a little bit what we've spoken about and then ask the final question if that's so, in this part, second part of the two-parter, if you've got this far through and you didn't listen to the first part of the two-parter. You'd probably be quite confused, so I should have gone and done that. We talked about what, or task told us, I guess what the microbio toxicity. Idea is, and it's essentially this idea of the unintended bystander effect of antibiotics in the microbiome. We were told about the short terms effect of antibiotics. So on the amount of the microbiome, the diversity and the reduction in the function. So the production of these bioactive molecules we talked about in the first part of this. And the effect that this has including the omes or resistance mechanisms and ence factors we heard about how long that recovers, so mostly about eight weeks, but it could be up to a year. But we don't know if there is immunological sequelae that go on for longer. Different host are at higher risks. So elderly newborn immunosuppressed, intercurrent illness, cancer association, potentially there and in different antibiotics, no surprise that multiple worse than single, broader is worse than narrow. Longer, worse and shorter, And then we talked about causality. So the studies are done in a variety of populations, in ill health, but also in healthy individuals showing that the antibiotics had the effect. Talked a little bit about how to mitigate this and some of the newer things that are coming alongside fecal microbiome transplants, but also LBP, which I've forgotten what stands

Tash: 37:03

Live by a therapeutic product.

Callum: 37:05

There you go. I'm sure some listeners have forgotten as well, so I'm glad I could provide that service there. And briefly touched about biomarkers summary. Done come to the final question. So the question is, how do we take this concept and put it into clinical practice? How would you suggest our listeners that we use this? What, where are we gonna, where are we gonna be talking about microbio toxicity?

Tash: 37:28

So I think it's mainly something that we're gonna be chatting about with our colleagues because as you've said, we don't have the biomarkers yet. It's got the word toxic in it, so it might be slightly alarming to all our patients, although I think the bones of the conversation would be entirely appropriate to help with patients too. I think in the first instance, I think this is something we need to start talking about with each other. And I think what's really useful about that is it provides a whole narrative. It reframes how we think about people and how we think about antibiotics. And up until now our stewardship narrative has had to rely quite a lot on antibiotic resistance, which is a problem in the individual.

Jame: 38:05

But, But, Tash, I understand that EMR is simply a subset of microbio toxicity. Isn't that so?

Tash: 38:11

Did you read that somewhere? But although obviously a MR is relevant to the individual patient, let's not kid ourselves when we talk about it, we're really talking about the global massive, potentially catastrophic problem more than we are about that one person in front of us. And although we as antibiotic stewards have to think about the big picture, it's really difficult when you're talking to a clinician who has one patient in front of them or to a mother who's got their child in front of them, or just to a patient who's got their own health to be having to think about a global health problem when they make individual decisions, which is why I'm hopeful that thinking about the microbiome and microbio toxicity is a useful way to reframe that narrative. Because essentially what you're doing is you're weighing up every time you prescribe an antibiotic, what is the potential for benefit? With that antibiotic versus what is the potential for harm. And so obviously if you have a very high probability of infection or or a possibility of very serious infection, then it sucks. But you're just gonna have to deal with the fact that you have microbio toxicity. It's an entirely justified, unfortunate bystander consequence of a very necessary therapy.

Jame: 39:26

Same as if you've, you've got nephrotoxicity with Gentamicin, but if it's the best drug, then you just have to suck it up and give it and deal with the consequences down the line. Yeah.

Tash: 39:36

Absolutely. Or chemotherapy. I mean, look at what chemotherapy does to our patients. It's harrowing, but you've gotta do it. So what I'm hoping is that we're really gonna focus on when people go, oh, well, just to be on the safe side. Because just to be on the safe side assumes that it's a risk neutral decision. Whereas actually I have hope we've convinced you that there's all these other things that we have to think about. So that's the kind of big place where I see this. The other place is as a bit of a call to arms, because with all this beautiful evidence, and totally take the point that it's not necessarily translatable right away into, not all of it is translatable into clinical practice. That's. Completely take that on board. However, I would argue that there are messages in here that are far more rigorously demonstrated than some of the science that we based our guidelines on to date. And I practice evidence-based medicine. I will of co I'm not coming onto a podcast to say we should ignore the guidelines. What I would say is that some of our guidelines almost certainly need revisiting because none of our guidelines, barring the c diff guideline, take into account the microbiome in any way, shape or form. Callum mentioned a great one. So, should we use metronidazole for for aspiration pneumonia? Up until now, that would be a tossup between, is it helping aspiration pneumonia? And that's the end of the conversation, rather than is it helping aspiration pneumonia and is it harming the microbiome? Same with things like, asymptomatic bacteria, uia in pregnancy. The guideline, I'm not saying that these guidelines are wrong, I'm saying they're based on what is the risk of infection with antibiotic versus what is the risk of infection without, they're not based on what is the risk to the patient holistically with antibiotics versus what is the risk without. So what I'm saying is that we revisit what we have and we factor in some of this. And we also be honest with ourselves. Some of our guidelines are based on a lot less. So yes, it's an imperfect science. Yes, we don't have all the biomarkers. Yes, we need more large scale clinical trials, but in the meantime, we are sitting on a lot of evidence that is warning us that we are harming our patients. And that feels uncomfortable to me.

Callum: 41:44

That is, I think, I'm not sure we could end that on any more of a succinct message or a clear call to thinking

Jame: 41:51

that's perfect and quietly rinsing the guidelines that aren't based on evidence as well. I could that's classic idiots right there, Tash. So you can come back anytime. You take that back.

Callum: 42:05

just just touching on this example of me for aspiration pneumonia. So basically all the national guidance and the big bodies have changed this a long time ago. And the initial data for including me on aspiration pneumonia was based on papers in 1970s where people were much more severely unwell with complicated aspiration. Ammonia presented late of puration. And it's interesting that like obviously the, there was this high quality evidence now saying it's not needed and there's national guidance that say we don't do it, but yet it's still in that sort of culture of practice. And what you would come up against is sometimes I've had discussions with people where I've said, well actually, the evidence says that we do not need to do this because it doesn't benefit people. People have no better and sometimes potentially even worse outcomes when we look at the data and the guidelines say don't do it. And the response I've had is, well I think, there could be anaerobe so we should cover it just in case.

Tash: 43:02

in case.

Callum: 43:03

And as you said earlier on, Tash, you, this just in case is a complete mis weighing of the harms. And because microbio toxicity, we can't measure it and invisible harm, I feel like that's just medicine in so many places is that we place higher weight on risks and harms that we can measure, that we can see, and we ignore things that are longer term or harder to measure or not attributable. And so we end up accidentally doing harm. And I guess this is a really nice way to, to frame that in a way that people can understand and then make it hopefully more visible. It's not gonna be an easy thing to, to change practice on as is all stewardship interventions, but I really like it as a way to, to explain that.

Tash: 43:54

Thank you.

Callum: 43:55

Great. Well, I think you had the really punchy outro and then Jae and I have just started talking at the end. So, sorry. Hopefully everybody's taken stuff from that and some of the references that Tash has shared with us kindly will be in the show notes lovingly produced by Jane. And given that you are now our official microbiome correspondence we look forward to the next time that you're with us.

Tash: 44:19

That is a thoroughly unearned title, but very kind

Jame: 44:22

And just to be clear, it's an unpaid position.

Tash: 44:29

isn't all of medical education.

Jame: 44:31

Well, that's what we are rapidly finding out

Tash: 44:33

Yeah,

Jame: 44:34

questions, comments, suggestions, and send them into Idiots podcasting@gmail.com. Have a five star review in your pocket, Callum, and I would love to have it. Please drop it in your podcast player of choice. We tweet at idiots OnCore pod and if you want to donate to support the show, there's a link to do so in the description. But until next time, I'm Jane

Tash: 44:50

I'm Tash.

Callum: 44:52

I am Callum.

Jame: 44:53

See you then.