So in this series of 3 podcasts with Vet Record, we will be discussing the complex world of the microbiome, the diseases and disorders that can occur when it is disrupted, what the emerging research is saying, and what practitioners can do to re-establish a healthy bacterial balance in their patients. The series is sponsored by Protecting Veterinary in partnership with the British Veterinary Association. In this episode, we will be looking at the microbiome and how it works with the guts and behaviour.
We'll discuss how the microbiome can affect cognition and memory and how that declines in ageing animals, particularly in dogs. We'll also look at where neurological conditions come into the picture and whether there are interventions that can help the practitioner tackle this in their patients. So today we're joined by Holga Volk from the University of Veterinary Medicine at Hanover.
Holga also was for many years at the RVC. And Sara Sandor from from Utur Law and University in Budapest. Holga's clinical interests and research focuses on neurology, particularly epilepsy, and relation to this podcast, the gut brain barrier where whereas Sara investigates the genetics of cognition and the microbiome in ageing dogs.
So welcome to Holro and Sara. Thank you very much for joining us. So first, if I could perhaps ask both of you, perhaps Sarah first, perhaps if you just give us an overview of what we're talking about here as far as memory, cognition, and neurology, and, what population are we considering?
I mean, is this just dogs? Is there other things going on in other companion animals? Well, actually, I'm involved in the field.
As a co-author of a research paper where we investigated dogs, but more generally speaking, the link between cognition and the gut bichromyome, has been investigated in other species as well, including modern animals like the laboratory rodents, but, in our research team, our main focus were on dogs. Great, thank you. And Holga from your point of view, .
From the neurology point of view, where, where, what are we looking at here and, you know, what's a good, good overview of of the topic. Yeah, I mean, the, in general, I was quite flabbergasted to see, you know, the interaction between the, the gut and the brain. Obviously they're still, the brain is still winning and has a lot of more neurons, than the gut.
But we definitely have seen changes and done some research where we Looked at epilepsy, especially, but also in, in cognition, but there's less, less known at the moment and behaviour changes we have seen as well. For cats, there is unfortunately not so much data. I think there's, it's an unexplored field.
I think we always start in dogs and then. And then we go, to cats. Perhaps we should do it the opposite way, but at the moment, that's how it is.
And I mean, Sarah, particularly looking at your research, I mean, how does the microbiome make a difference? What kind of things are being affected by it, particularly when it's disrupted. Actually, if we look out.
Side of the research which I participated in with my research team, there are many, many papers which investigated its effects on behaviour and on different behaviour variables, mostly in dogs, usually as Holger mentioned, usually dogs are in the focus among the. Animals living with us. In our research, we, we were specifically focusing on ageing in dogs and the changes in, cognitive capacities in the aged dogs.
And what sort of thing were you seeing? What, what type of results were coming through? So first, one of the interesting parts of our research that we could involve family dogs because very often research is done, especially it was done in the beginning of dog microbiome investigations with laboratory dogs.
But we included family dogs and two main types of data were collected. One is the behaviour data, together with the other data about animals like age and the breed. And we also collected the poop samples from the dogs.
It was linked with the behavioural data collection. So after the behaviour tests, the dogs were taken for a walk. The researchers were going with the owners and the dogs and quickly tried to collect the poop and froze it in the water roof temperature freezer as as fast as possible because time counts.
So that, that was the methodology in short. And this allowed the research team to look for a. Correlations between the behavioural variables collected through the behavioural tests and between the microbial profiles which were analysed from the poop samples of the dogs.
And the two main findings, at least in this population, which unfortunately did not include as many dogs as would be optimal for a large scale study, but it's not, not so easy to, to to invite so many family dogs for a research projects because the owners need the time, etc. But we, we could still analyse around 30 dogs. So we found a connection between the age of the animals and the abundance of certain bacterial phyla, especially between the abundance of the age, between the age and the abundance of the fusobacterium la yum.
And actually, it could give us a hint on some interesting thoughts about the dog microbiome. But I think we can get back, to this a little bit later. And the other main finding was a correlation between the memory performance in the aged logs, so how well they could perform in a memory test and between the abundance of the actinobacteria type bacteria.
And this could also have some implications in the general notion that dogs can be used as model organisms for human. Neurological, disease and neurological, neuro neurobiology because some studies found similar connections between actinobacteria abundance and Alzheimer's disease. But so far, at least in our hands in our research team, we, we could only report these types of correlations and no other correlations with other bacteria even if several types of bacteria could be detected in these dogs.
Right, that's really interesting. So obviously some point is there between, yeah, cognition and memory and the microbiome. Hol girl, I mean, I know that your research team have been looking at, sort of diet and the effect on epilepsy.
How is the microbiome also come into to that research there? Yeah, so, so when we, so we, I, I guess we, we have 33 main areas. We also looked a little bit at cognition, we looked at, behaviour changes which were mainly associated with epilepsy and the, the seizure control itself.
And, one of the things I think in general, one always has to be a little bit careful. Because what I feel like we are very similar at the moment, like we used to be with gene research. At the beginning, we found a lot of mutations.
But, then we looked in the literature and then thought, oh, there might be some associations. And then, we never looked at the functional, changes, as well. And I think that's, that's one of the things, you know, you might, might see a difference in the If you think about a forest, and you might see that there are some, a couple of different trees, and then you find, you know, that, does it actually explain that the forest might do something different than the other forests.
I mean, so one has to be a little bit cautious. I think we are in the moment in a very explorative phase. We find a lot of changes between spec, between, certain conditions, between certain species and so on.
But, the effects, I think one has to be a little bit. Care careful about. So what we did is, what we did some medium chain eride diet trials, and we found that dogs, receiving those MCTs and have now done 3 studies.
There are responders to the medium chain gazerides. And there are some dogs which are not responding. And obviously, there was quite not, not rocket science that we said, OK, let's see, is there any changes in the microbiome.
So do we actually By doing this, instead of just the effect of increasing ketone bodies by giving those medium chain viscerides, do we actually also change the microbiome and, and guess what, we, we did, we did find, . Some changes. And we, if you look at our paper, you will see, you know, that we, make some suggestion how this could interlink.
Yeah. So we found some b to read to see. I can't say it in English anymore.
But we, we, we found something which was very close to some changes. Which has been seen in rodents, which, so that there's a really great study which was once published in Cell, where they transplanted drug response from rodents to each other. And what they found there was that, I mean, that's at least one of the hypotheses that Achamanzia was involved in that.
So they could have a, a, a drug resistant mouse, yeah, with, with a seizure. disorder. And then they could transplant, the faeces from the ones which were responsive, and to the MCT diet, or, oh, sorry, the ketogenic diet.
It was not an MCT diet, it was a ketogenic diet. And then they could transplant the success. So suddenly, the mouse, which we didn't respond, suddenly responded to it.
And they thought it was due to achamansia, and they also found changes in neurotransmitters like GAA. We, we kind of hypothesised that this is the same, we had. We have done on multiple other studies, but we also found differences, I think, where it becomes more interesting than what you asked Sarah a bit more, is we did a couple of follow-up studies where we, looked at short chain fatty acids concentration, and, and there we can see actually differences and changes in behaviours and potentially also in epilepsy control.
And, and we transplanted, FM I made did the FMT transplant, that's quite interesting as well. But then, let me, because otherwise, I speak for half an hour and then I'm sure Sarah wants to share some more and then I can, can give you something about these two tasters later. Great.
Thank you. Yeah, but I can tell you, Susan, my, my, my, my work is, my research is definitely quite shit at the moment. So we do a lot of work with faeces, so.
So so perhaps we could just pick up on that lipid diet and then I understand there's some some work that's been done that looked at how that has affected also mimicked sort of ageing and cognitive decline. I don't know if you could perhaps just chat about that for a little while. Yes, actually, to be honest, I'm not an actual expert on the effect of diet and microbiome because I'm originally a geneticist, but generally, what I read in the literature sometimes I also participate in education.
I see that several research teams investigate, try to investigate the link between the diet and especially the inclusion of different fatty acids and lipids and the effect. However, in our current research in which we participate, we did not have the opportunity to investigate that. When we analysed the data, we also checked the diet of the dogs because it was part of the data collection.
But at least in our population, we did not find any connection, any correlation between the diet and between the cognitive capacities, so between the cognitive measures of the animals. Yeah. I mean, it sounds from what both of you are saying, there's a lot to still find out.
So obviously an emerging area for the research, here. I mean, where do you think's promising as far as sort of next steps for research and, you know, things that might have, you know, good practical application. I go to you first and then hold.
Yes, actually, for the practical application, the research team I, I am part of, is basically originally a behaviour focusing research team. So one of the practical applications, which is not directly. To the microbiome is the development of these cognitive tests by which the different cognitive capacities of the old dogs can be reliably measured even if no complicated test laboratories are available.
But although this is practical, this is not directly linked to the microbiome, but probably it could be of interest to some who are looking to cognitive tests, for example, the memory test I mentioned was also validated as a test which can be used to compare the memory capacity of dogs under different circumstances. Regarding the microbio profiles, it is. Just a hypothesis of ours, but because of the finding of the high abundance of uzob bacteria generally in dogs and are especially relevant finding that in the aged dogs, so in the dogs, who, who were older.
The abundance of the bacteria was lower. And actually this finding was in contrast with the human findings because generally in humans, the opposite is seen in elderly people. So they have morphosa bacteria and also this type of bacteria is generally linked with this this biosis in humans.
And in other animals where the bacteria profiles are known, it was indicated by the literature that the fuza bacteria are mostly prevalent in carnivores. So our hypothesis actually based on our finding because this was a highly significant correlation is that the fu bacteria level, so this, this was on phil level. So these bacteria are probably having a different effect in the dogs than in humans.
And this could be an important implication because it is generally noted that dogs can be highly valuable models to investigate the microbiome and its effects on the neural health because the dog microbiome is very similar to the human. But some bacteria, because the dogs are originally carnivores, biologically, must be behaving differently at least, at least based on these findings. And this can have implications for probiotic design for dogs and also for research investigating the effect of this bacteria.
Yeah, that's interesting. Thank you. Yes, because I think there is perhaps an assumption that it's going to be fairly similar, isn't it, across the species, so it's really interesting to hear that.
Holga, where do you think is going to be, you know, a fertile area for research it coming up in your particular area? Yeah, let me, let me say a couple of things. So, so one study we did is where we gave dogs to drug naive patients with epilepsy, we gave them, phenobarbital.
And, which is a standard, standard drug. And what we found was that the dogs responding to phenobarbital had higher butyrate levels than the dogs without, you know. So, suddenly we found a change in short chain fatty acids, which I think is, you know, I, I would have never dreamed actually that.
They they do anything. So the idea was we started with a study where we wanted to see, first of all, how the behaviour really gets affected because we have reported multiple times that behaviour is altered in dogs with epilepsy and it was never clear, is it actually a drug or is it the disease itself. they get a bit more fear and anxiety type of behaviours.
And interestingly, when you get phenobarb, actually, that, that domain gets better. So it's probably the disease which is, which is doing, you know, pushing along the, behavioural aspect of, of, of the disease itself. And but the interesting thing was that we then found, you know, some minor changes in some bacteria, whatever, whatever it's for.
But, but we found interesting changes in the short chain fatty acid concentrations. And . The other interesting thing, I mean, we, we didn't find any changes in dysbiosis.
So we worked very closely with Jan Sokodowsky from Texas A&M, right? He does, he's kind of our microbiome guru. And, and the other interesting thing is we, we did another study, and you have to hang in there now, where we said, OK, let's go the next step.
You know, we, I think faecal transplants becomes. In a couple of years, probably, it already is, but for some, standard of care, for certain, you know, if they're not responsive to diets and so on. And so we thought, OK, let's look at, the behaviour of dogs with epilepsy, because we know that dogs with epilepsy not only get fear and anxiety, they also get ADHD like, clinical signs as well.
They have a problem with impulsivity control, with concentration, with the trainability, and so on. So what we did is we were looking for a donor dog, which had a very low score on the ADHD like behaviours. And then the dogs obviously which came for the trial.
It was just a pilot trial, but we had like, you know, 10 dogs, which were difficult to control. They were at really high scores. And then the cool thing was that, you know, if, if, if those dogs in the trial were here and the donor dog was here.
Then we did the FMT, so we did it, recly. So nowadays we would do it by poop pills, but at that time we did it recally and actually the behaviour of these dogs went down to the donor dog. So we definitely changed the behaviour of these dogs.
Epilepsy control is then your next question. Yeah, you know, when you do these trials, you always find 23 dogs, which might respond also from the seizure control, but the owners were, in general, very happy, for the behaviour, which was our primary outcome measure. And now the interesting thing is, we found again, changes in butter rate.
And then when you look at butyrate as a, as a molecule, and you, you, you might, you know, might know this, you know, they, they are very, have been studied, all these short chain fatty acids for gastrointestinal health, especially, you know, resistant starch is one of those classic things in, in, in human diet. So if you cook your potato, leave it overnight and eat it cold in the next day, you would have created a lot of resistant star that would boost your your large intestines to create those short chain fatty acids. And, they have shown that they not only locally might improve, intestinal inflammation and so on, but also in general, improve, inflammatory status in the patient.
And the interesting thing from our study was that the, they, they could, I mean, one of the theories was that they might also be. Another alternative full source. But we also found that dogs increased their GABA.
So in, we looked at, at, at GAA metabolism, neurotransmitter, and it was increased. So, so how this works, I have no idea. But somehow, you know, by giving them Poop, we changed it.
I would have never thought. So first, I never thought that you would change your guts in that way, that you suddenly, why would that suddenly shift it and then you have butterrate, right? And then the other thing is, I would have never thought with FMT you could have such an effect.
So we're now doing another studies to, you know, which are We were not initially we were not allowed to use, we had to get some pilot data because of animal rights, you know, to get to power analysis and so on. So now we are in the next stage. But, but still, it, you know, you couldn't.
You couldn't doubt it that the behaviour changed so much, massively. So isn't that amazing? So, and we know this from humans.
So this is not, you know, it's something, it's enough there. You know, we know that people with certain anxieties and depression, you give it to rodents and they show the same behaviour. And we, we know all that stuff, right?
But it's still, I think, absolutely fascinating. And then lastly, and then I, I shut up again, sorry, if I get excited, but we, did another study where we, where we, we put, poop from, so we didn't use the, the, the, the solid pumps, just as the faecal supernatant. And, and that's published now as well, where we use dogs which were, controlled drug, naive dogs, dogs which responded to phenobarb and dogs which did not respond to phenobarb.
And we looked at the firing rates of myoteric neurons. And the interesting thing is that they changed. So you kind of look at a couple of, of matrixes.
And I'm, I'm not, I'm not a, you know, a minderic neuron specialist or whatever, but we work with a very good group here in Hanover, which do normally gastrointestinal disease. But it, it look at the percentages of neurons firing and at the burst frequency. And it, it it looked like that you could replicate that the poop was changing the firing rate.
And it actually, one of the ideas afterwards was like, so if the drug resistance fired differently than the drug, responders, so could it be that even already in the, in the intestines, via the vagal nerve or via cascades like butterrate or whatever. Could modulate what happens in your brain, and we know that vagal nerve stimulation is a treatment for epilepsy and it is just. You know, I'm thinking out of the box.
I have no proof for that, but that I, I, I was, you know. Really, I mean, impressed by this data because I I never thought it would actually change anything. You know, why, why would Supern and whatever it is, who knows?
We, we did find potentially some changes again in short chain for the assets. That's why we went down this, this track a little bit. But it could also be just a, a wrong association.
But, you know, it is, it is interesting. So something is happening. So, you know, it changes behaviour, probably sy already on the firing level there.
And, and, you know, and there's now a lot of research going on in, in actually stimulating. not only the vagal nerve, but also other. Parasympathetic nerves and, and seeing if they can change inflammation pattern and so on, you know, big business going on at the moment.
So, but, but some, I mean, yeah, we are very much, I think at the beginning of, of, of, of the science there. Yeah, sounds exciting. I mean, I think the, the behavioural aspect of that's an element that a lot of practitioners are having to deal with at the moment.
Yeah, it'd be interesting to see. I mean, from the practitioner point of view, you're saying it's all very early days. Do you think there's anything that practitioners can do at this point to, to maybe help their their patients and.
What was it too early, you know, I, I, I think it's, I think it's probably too early to say. I think where we do have some more evidence is for, you know, if they have inflammatory bowel disease, IBD, and they do FMTs, which, which is also depending where you are, and you get this, you will also sometimes see a change in the behaviour of the animals. But that, if that is just because we know that if you have, I mean, if you know, humans will have IBD or some leaky gut syndrome, they can be quite disturbed by that, and that they can definitely have an effect on your mood as well.
If there's a secondary or not, I, I don't know. I think for our part, with Sarah and I do, I think we need probably more, more data. To see if there's been an effect.
And then the question would be, you know, can you replicate it? You know, I think they have some good data for the gastrointestinal, disease that they can replicate the results. But, but I, I still wonder how do we normalise and how we, how do we know which donor dog is the right one.
And, and obviously, in the first study, what we did is we had an epileptic dog which responded very well to, to phenobarb. How would it be if you actually take a, a dog without epilepsy, which doesn't have any behaviour issues, and then you would, would give it as a donor. To get a donor dog, and I mean, there's a lot of specialists in the UK one can ask, but in, in general, it's not as simple as it might sound.
You have to do, you know, check that they don't have any, This biosis, obviously, they don't have any parasites and so on. And, and, and make sure, and, I mean, Jan did check everything for us to make sure we're OK. Saying this, the other thing is what you have to consider as well, and that what's happened to ours.
We, we had The donor dog. And then at one stage, the lady got a baby, and so she was not as, was a bit reluctant to continue getting pooped for us, right? So, we also need to think about, you know, the donor's life as well.
So, yeah, treat them very specially. And somehow, the other question we don't know is, you know, some dogs, I, Augusta and Des, they have to go there every month. We found in our dogs, interestingly, That, that actually the, the main effect was even seen after 6 months and longer.
So we didn't have to be replicate it. So again, look, as always, when you find something, there's more questions than answers. Yeah, great.
Well, I think that's, like the, the, we always have to think of the client, don't we because so you brought that in there as well. So was there anything you would recommend to practitioners at this point? I mean, I know you talked about, you know, maybe looking at the dogs microbiome and, you know, people are developing products and things like that, that they're going to be different for people, anything that that you'd like to expand on.
But actually, regarding the possible recommendations, I think the main message from our study is the indication for the necessity about for the further research on the fusobacteria in dogs because as Holger mentioned, we always get more questions than answers. And this is especially true for, for the link between those billions of bacteria and, and health and behaviour. Just an interesting thing, however, it was not published, in the final study because this was just one case among the dogs we investigated, but, it, it could be, it was an interesting case because one of the dogs.
Was injured before the 2nd sample collection because we compared the bacterial composition of the dogs at two time points. There was only 3 months difference, so we collected poop samples at 1. Time point and 3 months later because we also wanted to get a glimpse into the normal changes in in this population of dogs.
One of the dogs accidentally had an accident before the second collection and received antibiotics. And it was actually very eye opening to see that the sample which was taken soon after the weeks when the dog received antibiotics contained much less bacteria. So the abundance of some type of bacteria was much higher while some others practically disappeared from the sample.
At least they were not detectable by the method used. This was 16 SRNA sequencing. So it was really remind eye-opening to see that this actually happens when the animals receive some kind of micro antimicrobial drugs, so antibiotics that it changes the microbiome fundamentally.
Yeah, yeah, that's . A good, another good reason to be cautious with those antibiotic prescriptions, isn't it? No, and it goes on for ages, you know, I mean, we all learn to give metronidazole, you know, for certain cases with .
Gastrointestinal disease, you know, we were giving it, I think, like, I mean, it sounds like a bit too much, but like sugar pills, right? It was, we didn't think so much about it. But now, suddenly we think like completely different because it ruins your microbiome for a long, long time.
You know, if you look at data, it can 777 to 12 months of, of not getting back to normal. Gosh, really, yeah, so pretty much a year. Wow, that's interesting in that, yeah.
Great. Well, thank you guys. We're sort of coming up to the end of our time, but it's been really interesting and I think what what what I would sort of sum up from this is it's a great area of interest to to keep looking at and sounds like it's got huge potential.
We just need to know a bit more. I mean, the behaviour element, you know, ageing and cognition is obviously always going to be an area that people will want to sort of improve for people and I mean the the things that you're putting out there whole or about the The, the, the, the change in behaviour being so significant, I think is probably going to be a really exciting area, and obviously Sarah, your Fusobacteria looks like let's watch this space, see, see what we get. And I suppose for the practitioners it sounds also like just as we're pulling out at the end to think perhaps before using those antibiotics because of the, the difference it can make and.
Anything they can do to help, you know, re-establish an animal's microbiome, sounds like it's only gonna be for the, for the better. So that leaves me just to thank Holga and Sarah for the discussion and, I for one will certainly be thinking differently about the gut cognition and behaviour and how that microbiome can make the difference. Thank you.
You are what you eat, right? Yes.
