Liggins Institute Public Lecture March 2026 - The Good Sh*t: turning microbiome science into therapy

[00:00:01]Kiora, everybody. No, my heart is my No, my heart is my kitty and I fall.

[00:00:05]Uh eat a root of [ __ ] maroona of the funny canoe Kiora, everybody. Welcome. Welcome to this evening's presentations as part of the 25th anniversary of Liggins. It's lovely to see everybody here. We've got another theater next door here. So, it's wonderful to see all everybody come here tonight to listen to our fantastic presentations.

[00:00:27]Before I hand it over to the to lovely Katie to discuss all of our all the housekeeping rules. I'll just say a cut of here for us to begin. All right, let's start to go to dinner quota. No, my heart is my If you know ready uh making Get book ready. I'm a [ __ ] with a [ __ ] mother and I don't want to take your monkey. It's a two two to [ __ ] mower katana. Tina home here Kiora, everybody. Enjoy the evening.

[00:01:12]Thank you.

[00:01:18]>> Na me he no we he no we I'm secure tattoo. My name is Katie Groom. Um I'm a professor here at the Liggins Institute and absolutely honored and delighted to be here to welcome you all this evening.

[00:01:29]And I think it's phenomenal to have two lecture theaters running because we had so many registrations for tonight. So, welcome to you all and you'll see our speakers doing a bit of running up and down the stairs, but we've got very well coordinated. So, it should run really very smoothly for you.

[00:01:45]Um So, as he know we said we are celebrating our 25th anniversary. Um and it's really is a big year for the Liggins Institute. We have got a lot to celebrate over the last 25 years, but also a real opportunity to look to the future for the next 25 years. So, again, really grateful that you're here to kick off our celebration with us for the year.

[00:02:07]So, I am going to introduce all three of our speakers um at the beginning now, just so that we can keep our uh momentum going.

[00:02:16]Um and I am really feeling very honored to introduce three great speakers who I have or heard all speak before, and they are absolutely fabulous.

[00:02:25]Um our first speaker is Professor Justin O'Sullivan, and Justin is the director of the institute. So, I guess normally it would be him up here, but he can't be introducing himself.

[00:02:36]Um and he is an amazing leader for us at the institute, and it is very exciting to see his vision that will take us into that next 25 years.

[00:02:45]Um but more than just being our director, he's a molecular microbiologist and computational biologist um with honorary appointments at the Garvan Institute of Medical Research and the University of Southampton.

[00:02:58]Um and Justin's research that he leads focus is on how the microbiome, environments, and genetics interact. Um and he also um runs an acute care genome sequencing program for critically ill children. So, though although he's a scientist, he really is impacting directly already on clinical health.

[00:03:20]Our second speaker is a research fellow, Dr. Theo Portlock. And he is a systems biologist with a specialization in AI and metagenomics. And his research focuses on understanding the fundamental molecular mechanisms that underpin human health and disease.

[00:03:38]And he specializes in understanding how relationships between the gut microbiome, blood metabolites, and brain function influence our everyday lives using interpreted machine learning methodologies. And he joined the Gut Bugs team in 2023.

[00:03:53]Um and then our third speaker who will come and join us is Professor Wayne Cutfield. Um he's Professor of Pediatric Endocrinology here at the Liggins Institute um and an honorary Professor um at the Children's Hospital in Jiang Yang University in China.

[00:04:09]Um and he and Justin lead the Gutbugs research program.

[00:04:13]Um and Wayne also leads research examining the role of the human milk oligosaccharides, so coming from breast milk, in preventing obesity, promoting healthy brain development, and predicting the gut microbiome in young children through studies, the NIPPA study and OAK study.

[00:04:29]Um he also leads the NIPPA New Zealand longitudinal study and undertakes clinical research that examines how environmental influences early in life can affect childhood growth and development in ways that could lead to those chronic conditions in adult life.

[00:04:44]So I had to read that out cuz they're pretty cool clever guys and I must say I find it a bit intimidating. But as I said, I've heard them speak before and I know they're going to deliver us with fabulous lectures that we will all be able to understand and see how that really translates into the real world.

[00:04:59]Um so I am going to pass over to Justin now and a very warm welcome to you, Justin, and we're looking forward to hearing from you.

[00:05:07]>> [clears throat] [applause] >> Thanks very much for coming. Um it's a real pleasure to see you all here and and be able to talk to you today about some of the work that we're doing here at the Liggins Institute.

[00:05:23]Actually, we we normally try um to have titles that that challenge people a little bit. So we only had a few complaints about this one. Um we normally get complaints about them. Um but today's talk is is really it is about the good [ __ ] um and it's turning the microbiome into something that's useful.

[00:05:40]And so we've been doing this now for for nearly about 10 years. Um and we've been working on the microbiome, uh, Wayne and myself, and and and a lot of other people. Um, you'll you'll see them at the end.

[00:05:52]But this talk tonight is basically going to cover the progress that the team has made towards the development of probiotics and the way that we're looking at certain conditions and and that people have, um, and how the microbiome interacts with those.

[00:06:08]And so we're going to run you through the process from from the idea, um, through the clinical design, through the delivery of the trials, um, all the way through to not quite the retail sale yet cuz we're not quite there, uh, but definitely through to to the animal testing.

[00:06:24]So science and medicine has treated us for a long time as individuals and also as cohorts.

[00:06:33]But we haven't really treated us in terms of our own cells and our own composition, perhaps the right way.

[00:06:40]And that's because you are all in a partnership.

[00:06:45]And you're in a partnership with the organisms that live on you and in you.

[00:06:49]And so the organisms that live on and in you, and about 2 kg by some estimates, there's actually more microbes that live on you than there are your own cells.

[00:06:59]And those microbes all have genomes.

[00:07:02]All of them. They all have the genes that are necessary for life or for their replication, at least.

[00:07:09]They all make different products and they all do different things and they work as a community.

[00:07:15]And tonight we're going to talk about your gut microbiome, which is the ones that live largely in your intestine, your large intestine.

[00:07:23]But there are other microbes that you have as well that are part of that flora, on your skin, and all of those microbes do different things.

[00:07:32]Now because there's so many of them and because they have all their own genes, there are way more microbial genes that are part of you than there are your own.

[00:07:40]And that means that the processes and things that microbes do are a part of you.

[00:07:45]And those things are really the critical thing for us to understand in many ways.

[00:07:51]And there's a hypothesis called the hygiene hypothesis, which effectively talks about the fact that over the course of of the last sort of 40 to 50 years as more and more detergents and things that kill bacteria and things have become a part of our lifestyles, as we've become more sedentary and we live in environments that have fewer surfaces of different types for things to inhabit, as we eat less dirt, as we interact less with pets, that as we've done that our microbes have become simpler. Our populations of microbes that we have in our guts have become simpler.

[00:08:27]And that that is associated with different conditions that many of us suffer from.

[00:08:34]And so that is where we start.

[00:08:38]And so as a group, we really have been trying to ask some fundamental questions about the microbiome and its partnership with us.

[00:08:50]So, we know that the microbiome has many negative effects or microbes have negative effects on us.

[00:08:57]We know that from Koch's postulates, which tell us that things are pathogens and that they can kill us.

[00:09:03]Well, that's true. There are organisms that can do that, for sure.

[00:09:07]But there are a lot of organisms that don't.

[00:09:10]And there are some organisms that do that under certain circumstances, like C. difficile, which can cause a very nasty recurrent form of diarrhea that rapidly becomes antibiotic resistant.

[00:09:24]But that organism also can live in you quite normally and not cause any problems.

[00:09:30]So, things can become pathogens opportunistically.

[00:09:35]So, we know that there are pathogens. We know that they affect inflammation, they signal to our immune system, they change the way it works.

[00:09:42]And chronic immune responses are not good for us.

[00:09:46]We know that they can interfere with our brain, that they can signal to our brain, and that that changes some microbes have been linked to Parkinson's, for example.

[00:09:55]But we also know that the microbes that you have have really positive effects.

[00:10:00]That the things that can be negative often are really positive.

[00:10:05]So, the microbes that you have digest foods.

[00:10:10]Things that we can't digest, things like some fibers, the microbes will ferment them, and will produce products from those that are actually beneficial to us, to our immune system, to our endocrine system, and to our brain and our brain development.

[00:10:26]We have things that will produce, effectively, they interact with nerves, they interact with our whole system, and in doing that, they modify you and your well-being, and the longevity of that well-being.

[00:10:40]So, this is really where we started as a group.

[00:10:44]And we focused, effectively, on three questions.

[00:10:50]And the first question is, can microbes make us slimmer?

[00:10:56]We've also focused on the idea that microbes can interact with your brain.

[00:11:02]We know from other studies, the ones that we do in Bendigo and other places, that the microbes can actually modify your brain development.

[00:11:09]So, one of the interesting things we thought about is, can the microbes actually make us less anxious?

[00:11:18]And finally, we're thinking about, can microbes be precisely manipulated?

[00:11:24]And these are the things that we're going to talk about tonight, and where we've got to a certain amount of these.

[00:11:30]So, I'm going to start with a trial where we were trying to treat recovering individuals who were recovering from anorexia nervosa.

[00:11:39]So, anorexia nervosa affects about 17 people in a in a in a thousand in New Zealand.

[00:11:45]It's the third most common chronic illness in adolescent women.

[00:11:51]It has extremely high mortality rate in people that have it.

[00:11:55]Uh 30% of people in in a 10-year period will die. Uh and 50% of those is is by suicide.

[00:12:05]But, anorexia is a complex condition.

[00:12:09]It's not just metabolic, although that is a significant part of it.

[00:12:15]It's also psychiatric, okay, or psychosocial, psychological.

[00:12:22]And so, anorexia is really interesting from the context of its chances of having what's called a general anxiety disorder.

[00:12:29]And so, anxiety, which many of us will know about and many of people know suffer from, can be quite a debilitating thing.

[00:12:38]And in fact, anorexics have about a sixfold increase in their chances of having a general anxiety disorder compared to normal population.

[00:12:50]And that's pretty pretty severe.

[00:12:54]Now, for the anorexia trial here, we ran a pilot trial because we didn't know whether or not the FMT treatment that we do, which is transferring the microbiome from a healthy person to somebody else, whether that was actually safe to do in a population who were as extremely impacted as recovering anorexics.

[00:13:17]So, what we did is we set up a trial on some pilots, so it's a very small trial, and it didn't have a controlled arm.

[00:13:24]So, it's an open trial.

[00:13:26]And what we did is we took young females who have anorexia, 20 of them, and we measured their microbiome when they were recruited and 3 weeks before they were treated.

[00:13:36]We subsequently measured their microbiome again 3 weeks later here, when they were actually being treated with FMT, and that's baseline.

[00:13:46]We had four healthy female donors, and we got the microbiomes from those donors, and we put those microbiomes into some tiny little capsules. I have them in my pocket.

[00:13:57]Not ones that are actually food, but but they're just that size there, right?

[00:14:03]So, they're they're little things here, right? We'll show you some small ones that we use in a bit.

[00:14:09]We put the microbiomes into that, and effectively we did this is the encapsulation, and then we did a treatment.

[00:14:15]And so, we treated these individuals here with this microbiome. And so, the might came in they came to the clinic, and they swallowed 20 capsules each.

[00:14:25]Most of them did it sort of at one sitting, uh which is good. Some people came one day and then came the next.

[00:14:31]But they took these capsules.

[00:14:33]They didn't They were just non-fed, so it was after a night's rest asleep.

[00:14:38]Um there was no bowel cleanse or anything.

[00:14:40]We took these individuals, and then what we did is we followed their clinical assessments here at 3 weeks, 6 weeks, and 12 weeks after the FMT.

[00:14:50]And so, what we looked is we looked at their bodies and the way their bodies responded on the DEXA.

[00:14:55]But this wasn't about weight recovery, this was about safety.

[00:15:00]We followed other things. We did surveys with them, one of which was a survey of general anxiety disorder.

[00:15:09]We looked at their microbiomes, and we looked at their bloods, so that we could tell whether or not the FMT and the microbes that we were putting in had any negative effects on them, but also if they had any positive effects.

[00:15:22]Now, doing this, what we found basically was that the conditions that these individuals had and the transfer of the FMT didn't negatively affect their biochemistry.

[00:15:35]There was no negative effect of anything in the liver.

[00:15:38]Their vital signs were all fine. Their bloods were all fine.

[00:15:43]They had some adverse events, but that's very common in things that have significant psychological conditions like this. Nothing that was adverse and was linked to the actual trial of the treatment itself.

[00:15:57]That was all really good. So, no no adverse events there. No adverse effects.

[00:16:02]We looked at the microbiome.

[00:16:04]And we looked at the complexity of the microbiome.

[00:16:07]See, because the complexity is what we think actually helps your microbiome work properly.

[00:16:13]If you have a very simple microbiome, the thought is that it's like a mono forest, like a pine tree forest.

[00:16:19]And effectively, not much grows there.

[00:16:21]Not much happens.

[00:16:23]But, if you have a really diverse forest, there's a lot of life.

[00:16:28]There's a lot of things happening.

[00:16:30]So, a diverse microbiome is there to help.

[00:16:34]So, here we see at 3 weeks before they were treated. And this is baseline, so that's just before they got their treatment.

[00:16:40]And you see that there's a little drift here.

[00:16:43]It goes down by about 10 species over that period of 3 weeks.

[00:16:46]And that's really normal for the microbiome. All of our microbiomes change day by day, week by week, depending on what you eat, what you do, what you drink.

[00:16:57]And here that was changing.

[00:16:59]But, of course, we gave them an FMT. And that FMT came from healthy individuals, did a lot of exercise, ate diverse diets.

[00:17:08]And what we saw there is that when we did this, their microbiomes jumped.

[00:17:12]So, the complexity of their microbiomes increased a lot. So, So, 40 species or more came into the microbiomes. And that diverse increase is what we were looking for.

[00:17:24]But, we didn't know whether or not that diverse increase actually had an effect.

[00:17:32]It's good to say you've changed the microbiome. Nice one.

[00:17:36]But, does it actually do anything?

[00:17:39]And so, in these individuals, and bearing in mind this was a trial, a pilot trial, so a very small trial, we didn't really expect to find anything that was statistically significant.

[00:17:50]But, so often we do that and we're wrong.

[00:17:54]And here again, we were.

[00:17:58]What we saw was that their eating behavior and body shape concern did not change.

[00:18:06]That's That's okay.

[00:18:11]But, when we looked at the GAD-7 survey, which is a survey for generalized anxiety disorder, what we saw was something different.

[00:18:21]And what we saw here was at a baseline, this is the population structure here.

[00:18:27]So, red means they have severe anxiety, yellow, moderate, this is mild, and minimal is green.

[00:18:35]So, a lot of people had anxiety, which is consistent with what we know about anorexia nervosa and the rates, a sixfold increase in the rate of having a generalized anxiety disorder.

[00:18:48]But, when you see here at week six and week 12, you see that the mild or the minimal here has increased a lot.

[00:18:56]This has dropped.

[00:18:57]This red disappears.

[00:19:01]And so, what we were seeing was a decrease in the amount of severe, moderate anxiety that these individuals were having over a very short period of time. That's 12 weeks from treatment.

[00:19:12]Now, it doesn't look like a lot, but this is a significant statistically significant result.

[00:19:18]And when we looked into it, and we looked at the microbiome, what we found was actually there were four bacteria that were linked to that pattern that we were seeing.

[00:19:27]Four different bacteria, and the levels of those bacteria corresponded to the change in the anxiety survey.

[00:19:35]And one of them, this one down here, Desulfovibrio piger, is an interesting organism, because it actually makes a molecule that signals to your neural system.

[00:19:47]And it does that at low levels. And at low levels, it's really good for you, and it's important. At really high levels, if you have too much Desulfovibrio piger, it's not good for you.

[00:19:56]But what we were seeing was an increase in the levels of that within the normal population, which was basically bringing it to a standard level within the microbiome, and that's how we think that that is acting.

[00:20:08]And this organism is one that we are trying to make a our probiotic out of.

[00:20:15]But we've also, running another trial, come across similar thing.

[00:20:21]And so, this is a trial that we're just finishing the analysis on at the moment, although our latest results indicate that's going to have to go on for a bit of time, which is basically we were looking at treatment for autism in autistic individuals. So, it's not a treatment for autism, sorry. It's It's a treatment for gut function in autistic individuals.

[00:20:40]So, these are autistic children that we were bringing in. It's a double-blind placebo-controlled trial, so it actually has a blind control, which is the sort of gold standard for these trials.

[00:20:50]And our goal here was to really see whether the FMT capsules could improve gut health and well-being.

[00:20:55]So, again, we looked at the gut health measures, and also at their anxiety levels.

[00:21:03]When we did the FMT in these individuals, what we actually saw was again consistent with what I've just shown you and consistent with everything else we've done.

[00:21:11]When we gave them an FMT here, basically, we gave them the microbiome from these other people, particular bacteria came out of those treatments. They became part of the individuals flora and they stayed there for a long time.

[00:21:27]They grew, just became part of the normal ecosystem.

[00:21:32]And so this is out to 26 weeks here and you see here in red, these are the kids that had the FMT and their microbiomes increased in complexity here compared to the placebo. Okay?

[00:21:44]And that is what we want to see. That's what we saw for anxiety, uh for anorexia, sorry. That's what we saw in the obesity trials that we've run previously.

[00:21:51]It's consistent with everything that we know.

[00:21:54]Here, these children had more microbes in their guts than the anorexics, but again, that's because the autistic children are eating in a different way, feeding their microbiomes differently.

[00:22:05]So, that's again consistent with what we know.

[00:22:09]Anxiety in in autism is also much higher than in the general population, about two to three-fold.

[00:22:18]And what we see here is again a result that's [clears throat] quite interesting.

[00:22:23]Initially, the placebo and the FMTs behaved the same way.

[00:22:26]But after 2 years, the placebos here have more severe anxiety than the people that were treated with FMT.

[00:22:35]It's not completely gone, but here, it is again at a point which is borderline significant.

[00:22:42]Won't get any more significant because of the size of the of the people that we had or the the number of people we had in this trial.

[00:22:47]But also with this, we see that there was a decrease in perceived stress and also an increase in the sleep patterns for those children who had FMT as opposed to the placebo.

[00:22:59]So, the FMT is doing this thing again and low and behold this vibrio parahaemolyticus is actually present in their guts following the FMT. And so we think that's really important.

[00:23:11]But the original Gut Bugs trial, which of course was what the documentary The Good [ __ ] was about, actually was set up to treat obesity.

[00:23:20]And when we ran this trial, what we found was that after 4-year period, 4 years after one single treatment, right?

[00:23:31]4 years after one treatment, what we found was that the people that were treated with FMT, their weights stayed very stable.

[00:23:38]The children who had the placebo, their weights increased on the same trajectory that you would expect them to follow.

[00:23:46]There's a big gap here, but you just have to excuse there's no sampling. The 4-year time point was because we actually went back to treat the placebos, and we tested everybody um because we'd seen a small effect at the end of 6 months, but COVID happened, and so we had to go back later.

[00:24:02]Uh and so we saw this, and and this was quite remarkable. When we looked at this, what we actually saw again was that this was due to a change in metabolic syndrome.

[00:24:09]It was a big change in metabolic syndrome in these individuals. It wasn't so much about their weights.

[00:24:16]Looking at that, we looked at the microbes again, and what we saw was that this particular organism, which we just call theta, okay, cuz for obvious reasons, but this organism here, if you look at the metabolic syndrome and the change in metabolic syndrome, what you see is that people that have more theta have better health, and people that have less theta have worse health.

[00:24:38]Now, theta is another one of these organisms that we're trying to now make into a probiotic.

[00:24:44]And that's where Theo comes in, and he's going to tell you about how we're doing that.

[00:24:51]>> Kiora katoa.

[00:24:53]It's great to see so many of you here tonight.

[00:24:56]I'm going to talk about designing the next generation of probiotics.

[00:25:00]Not something you might find in your local chemist, but something that may in the future be used to treat human disease.

[00:25:07]Before I do that, I want to introduce you to a concept of bacterial politics.

[00:25:12]So, bacteria are like you or us.

[00:25:15]They're a lot like people.

[00:25:17]You get some guys that just won't get on.

[00:25:20]They might be after the same resources or they have different objectives.

[00:25:24]There's not much you can do about that.

[00:25:26]Then you get these guys.

[00:25:28]They work together to form a shared objective. They help each other grow.

[00:25:32]Sometimes they need each other to grow.

[00:25:36]And sometimes you get these fellows at the back. Smaller number, but they control the ebb and flow of different bacterial populations that go into your gut.

[00:25:47]So, how do we understand these bacterial relationships?

[00:25:52]Well, we're in the age of AI.

[00:25:56]It's actually possible to simulate a lot of these bacteria on the computer. Their genomes are roughly a thousand times smaller than ours.

[00:26:04]And you can predict them pretty darn well using a technique called genome-scale metabolic modeling.

[00:26:12]What does that mean to predict? It means we know how they grow, we know what they eat, and we know what they make as byproducts.

[00:26:19]And this is a tool that allows us to very quickly screen different bacterial combinations to work out ones which might be favorable to be turned into a therapy.

[00:26:29]So, Justin finished his talk by saying about this bacteria theta.

[00:26:34]And um it wasn't the only guy that was associated with response to this original gut bugs obesity trial.

[00:26:42]There was also this other species we're calling bacteria X that was associated with response to the treatment. So, when In other words, when the recipients have these bacteria in their guts, they lost weight.

[00:26:55]Their metabolic syndrome improved.

[00:26:58]So, I got excited by all this and decided to have a look to see if there may be a positive beneficial relationship between these species. Just traditional modeling.

[00:27:10]And turns out that when both these are and bacteria X are present simultaneously, that increases the rate of treatment response more than the sum of their parts.

[00:27:22]So, that gets me excited.

[00:27:25]Um so, basically, I next decided to download uh a load of different kinds of theta and X from online databases and did a kind of bacterial speed dating.

[00:27:38]Some kind of bacterial Tinder.

[00:27:40]And some of them gave more than they received. So, an unequal relationship.

[00:27:45]Um and some of them were a lot more happier than others in their their relationship. But, these guys were married at first sight.

[00:27:53]Very happily together.

[00:27:56]And uh so, I decided to take them forward to see how they might uh cooperatively grow with one another.

[00:28:03]So, we created the models and we created the conditions in which they grew and we started them off and they started eating.

[00:28:12]And they ate until there was no more glucose left.

[00:28:15]Um but interestingly, they were starting to grow.

[00:28:21]And they grew quicker when they were together than when they were apart. So, there was some constructive interaction that they were that they were experiencing. So, I'm very excited about all this.

[00:28:33]Um they also produce uh metabolic byproducts as we all do.

[00:28:38]And uh some of those are more interesting than others. Acetate is something that has known uh positive association with human immunity. And there's also very small amounts of ethanol, but definitely not enough to get you drunk.

[00:28:52]And then, like all of us, they die.

[00:28:57]So, in a nutshell, what we found was we were able to screen these combinations of bacteria very quick quickly from online, find a couple of strains that seem to be highly cooperative, and showed that they were significantly associated with an improvement in response to treatment.

[00:29:15]And we showed in that we can simulate that they had a potential to help each other grow.

[00:29:21]So, the next step is to move from simulation to reality because all models are wrong, some models are useful, as they say.

[00:29:30]So, now I'm going to describe the results of another guy in our lab who's across the road, who you will speak to you after the presentation, called Amila, who is our lab guy.

[00:29:41]And he had the task of trying to find these bacteria.

[00:29:47]And how do we do that from the the bacteria from our study?

[00:29:52]It's from stool. So, yeah, once every couple of weeks at the Liggins, we get a mysterious polystyrene box that comes the hallway that contains Yeah, we're not having our dinner yet, we'll we'll wait for the for later.

[00:30:05]And yeah, he basically will take samples of that stool and try to grow it on petri dishes in all sorts of conditions, so to try and find the species that I I thought were, you know, pretty useful to be working together.

[00:30:18]So, it sounds easy, right?

[00:30:20]It's absolutely not easy.

[00:30:22]And fishing is a great analogy because, you know, you don't know what you're going to catch.

[00:30:27]You just chuck in, and you try to find the species that that you're interested in, but it could be a whole lot of others. You know, the average adult human has somewhere in the region of 200 to 300 species, and so you can imagine the odds of trying to get the one that you want.

[00:30:42]That's not the end of the difficulties.

[00:30:45]Also, you've got to keep them alive if you want to use them as as probiotics in the future. You know, it's no good taking out bacterial corpses.

[00:30:52]Um so, the conditions in which they live are very tightly controlled. You know, if they have to mimic the human gut to as large extent as possible.

[00:31:02]The gut has very little oxygen. Um those probiotic species generally are very oxygen sensitive. So, we have a fancy anaerobic chamber upstairs that sets up that he has his hand in the machine about 8 hours uh every day. He's very diligent.

[00:31:18]Um so, we also have to control their nutrients, so what they eat. So, the different kinds of metabolites that go into the plates.

[00:31:25]And finally, some of them, you know, will have to grow together. They need that sort of support. So, it's a very difficult job. The odds are against him, but luckily, Amila is an Olympic-level fisherman.

[00:31:36]He knows what he's doing.

[00:31:39]And he knows the golden rule, which is to catch the fish [clears throat] you want, you've got to use the right bait.

[00:31:45]And so, the bait in our case is a is a specifically tailored media.

[00:31:50]And he can tailor that media based on the bacteria looking for, because we know, as I said previously, what bacteria enjoy, what their favorite food is.

[00:32:01]Again, it sounds a lot easier than it actually is because we don't know the precise amounts of each of the ingredients that we need to put into the plates, but nonetheless, it it helps the odds.

[00:32:14]Uh there's also competition between slower and fast-growing species that make this process a whole lot difficult.

[00:32:20]Nonetheless, he went in with his rod.

[00:32:24]And first try, to the surprise of everybody, he got theta.

[00:32:31]So, he's he a lot of um I'm not joking when I say he knows what he's doing.

[00:32:36]Um took a few more goes for this bacteria X, but eventually we get there. Uh, the challenge doesn't end there. I mean, you you know, it's not like they're Pokémon. They don't scream their name at you. Uh, uh, they're just grayish, whitish blobs on a plate. So, how do we know which one's Peter and which one's bacteria X?

[00:32:55]You have to do the DNA sequencing on all of them. And eventually he worked out that hundreds of different versions of these Peter and X's, and we have this database now that we can use.

[00:33:09]But, the best thing of all is that he found the happy couple, the ones that were, you know, the most important interacting, uh, versions of bacteria X and Peter. So, what he was able to do then is this experiment. And now, it's called a cross-feeding experiment.

[00:33:27]It's complicated, but I'll I'll walk you through it.

[00:33:30]The long and short of it is that you take a one of the bacteria.

[00:33:36]You grow it up in a flask with the media under certain conditions alone.

[00:33:42]Then, you remove the bacteria from that flask, but you keep what it's made, so the byproducts.

[00:33:49]Then, you introduce the other bacteria into that flask.

[00:33:52]And you see if it encourages growth or if it suppresses growth.

[00:33:56]And what he found was when the bacteria were grown alone, they had this slow growth rate. They were slow growth, but when Peter was grown in the media of bacteria X, he saw an acceleration of growth. They were helping each other out. And vice versa, when X was growing in the media of Peter, there was an improvement in growth.

[00:34:17]So, what he proved was that the bacteria were cooperating to improve survivability.

[00:34:26]So, in a nutshell, what we've shown is that using modeling, uh, Uh the two bacteria together were in were increased the odds of response to the treatment by FMT.

[00:34:39]We showed that we simulated that the bacteria would help each other grow.

[00:34:44]And then Amelia went and proved it in the lab.

[00:34:47]Because I you know I make a lot of random guesses, but you need somebody there to actually prove you know do the work.

[00:34:54]So the next step now is I'm very excited to uh leave to Professor Wayne Cutfield, which is the introduction of these species now into rat models that we can prove to see if they have the same clinical efficacy in animal models.

[00:35:11]Thank you all.

[00:35:15]>> Kia ora everyone. It's um incredible to see such a turnout. I've now been in two lecture theaters, and I have to say across the two lecture theaters, I'm pretty confident there's about 100 trillion of you.

[00:35:27]>> 100 trillion? You're kidding me.

[00:35:29]>> Yeah, there's about 500 of you, and all the rest of you are gut bugs.

[00:35:33]So great crowd. You've heard about the the challenges of I I of modeling, isolating, and culturing up these bacteria.

[00:35:45]Now, what these didn't what Theta what Theo, who's closely related to Theta, didn't say is that effectively what he and then Amelia have done is they've picked out strains of Theta and strains of bacteria X. So what's a strain? Think of your extended family, that's a species. You are a strain, you.

[00:36:13]You are unique, that individual. So we're picking out unique individuals.

[00:36:18]So now I want to sort of finish up with what are we doing now, and I'll I'll about our rat studies and a really interesting clinical project that we're we've just started and another that we're leading into.

[00:36:33]Now, you would have seen the slide from Justin and it shows our research pipeline where we take an idea that relates to gut microbiome treatment and we look at the particular condition, design the trial, deliver the trial.

[00:36:47]That's when Theo steps up with a very complex data analysis and from that we try and model to identify as he showed you the key bacteria.

[00:36:55]We then, as he showed you also, we isolate, culture those bacteria up. Then we need to test that cocktail mix and we test it in rats because it's faster and more efficient. We can't just tweak we can't just tweak a probiotic mix and a probiotic mix is a cluster of of bacteria together um in a clinical trial because every time we tweak it, there's another 1 and 1/2 million dollars in 3 years every time we tweak it to do a clinical trial.

[00:37:23]We can take an a human disease model in a rat and test it and have an answer in 6 months at a sliver of price.

[00:37:32]Then, if indeed we find that that probiotic is effective, we can then produce it and manufacture it and we're actually looking into that and ultimately sell it. The significance of that is that in the not too distant future, if these studies continue demonstrating positive results, these bespoke probiotics will be available more widely to Now, so we're talking about rats now.

[00:37:59]And what we're going to do is we are going to do two large studies. So, we take an obesity model and we use Mark Baker's high-calorie, high-fat model which makes rats really fat, really fast.

[00:38:14]Then we give them uh we give them the gut microbiome treatment. Now, see these little guys here? This is a human capsule life that did Justin show you those?

[00:38:27]He did. Okay, he won't have shown you these, right? Cuz you can't see them.

[00:38:32]So, these are the capsules that we give to rats. So, one of the things about the rat studies is they're really complex, complicated studies to do and there are lots of challenges and our team have been utterly amazing at stepping up and working out how to problem-solve uh and stepping up to the challenge here with these ultra-tiny capsules. We tried to make them ourselves. Why did we do that? Because you know what one of these costs? It's about half the size of a match head. It contains a fifth of a drop of gut bacteria.

[00:39:02]Uh they are $400 each and we managed to get the price down to $160 per empty capsule. They are unbelievably expensive.

[00:39:14]Unfortunately, that's what we're having to use. So, in the first study, we're just going to use theta and treat the animals once and then follow them up and this time period is equivalent to about the four years that Justin talked about with our obesity trial. So, that's the other thing that can happen with rat studies. They have an effectively an accelerated lifestyle.

[00:39:37]So, you know, 20 or 30 days is suddenly four or five years later.

[00:39:41]And then we can look at their body compositions using a DEXA scanner. We can look at blood pressures and metabolic parameters and we can look at the gut microbiomes. And then we repeat that same large experiment using the combination that Theo talked about of theta and Bacteroides, which might turn out to be a super combo.

[00:40:01]And then, and you heard from Justin about our anorexia and autism studies and that he told you about Pija and how that was related to anxiety. So, we've developed an anxiety model in rats and to do that, we give them a chemical that induces anxiety and does it very effectively.

[00:40:23]And they continue on that throughout the trial.

[00:40:26]Um and we treat them again once, and then we do a whole bunch of different field and maze studies that are very good indices of anxiety depending upon how and where the amount the the rats move around and they're computer and camera watched and how long that takes. So, that those are measures of anxiety. And we'll look at how their gut microbiomes change and we'll look at what's happened to their EPS levels.

[00:40:56]So, that's the rat studies. And if those studies turn out to confirm in fact a reduction in anxiety or an improvement in metabolic syndrome or uh less obesity or reversal of obesity, then we're moving into production.

[00:41:11]Now, let me move to an another project.

[00:41:14]We've talked a lot a lot about probiotics, which are bacteria.

[00:41:18]But then there are prebiotics and prebiotics effectively uh chemicals that feed gut bacteria, prebiotics.

[00:41:27]And that introduces me to a trial that we have literally just launched launched called the oat study.

[00:41:35]And we're studying whether HMO supplements, and I can come back to that, can support gut health of children taking antibiotics, promote healthier weight gain, less eczema, less eczema.

[00:41:47]So, by way of background, one in three New Zealand children are overweight or obese the day they start school.

[00:41:55]And those are the second worst obesity statistics in the world. The Americans have got the United States and France still.

[00:42:03]We also know that obesity tracks. An obese young child becomes a very obese teenager who goes on to become a very very obese adult. Adults who are who have obesity don't just wake up one morning and go, "What happened?"

[00:42:16]overnight.

[00:42:17]It is a process and evolution.

[00:42:19]Now, another piece to the story is that antibiotic use in New Zealand infants is common. This is from a study that I did not too long ago of more than 150,000 children.

[00:42:30]And what we found is that 2/3 of children in the first 2 years of life had two or more courses of antibiotics and a third had more than five courses of antibiotics in the first 2 years of life. And of course each course of antibiotic nukes their microbiome. Your gut microbiome does not like antibiotics. It usually recovers, but it can get knocked around and I'll come back to what that means in a minute.

[00:42:53]In addition, we also showed that with every course of antibiotics, the risk of obesity increased. You're thinking, "Ooh, what's the link there?" And the link is the gut microbiome because it's the antibiotics that are knocking the microbiome around.

[00:43:09]We all started life when we were born effectively with no gut bacteria.

[00:43:14]And by about three, we had an adult-like microbiome. So, it's a period of rapid development of the gut microbiome and it's very vulnerable to getting knocked around like by things like courses of antibiotics.

[00:43:30]And breastfeeding which contains human milk oligosaccharides, I'll tell you what that is in a minute cuz it's like a big complicated word. You're thinking, "Where did that come from?" That can that can help protect against protect against use of antibiotics.

[00:43:45]So, what are human milk oligosaccharides?

[00:43:48]It's the third most common component of breast milk, believe it or not, but it doesn't feed the baby at all. There's no nutritional value in them. They're big complex sugars. The baby swallows them, then what? The infant swallows it swallows them and they go straight down.

[00:44:03]They're not broken down or absorbed and they hit the the gut large bowel where they feed the gut microbiome. So, they nurture the developing gut microbiome.

[00:44:15]Now, there's more than 100 of those and not only do they feed the gut bacteria, they also support immunity and they can actually block some of the harmful bacteria as well. So, they're quite important. Now, we all know that uh the recommendations are for women to breastfeed until at least 6 months of age, at which time weaning begins.

[00:44:36]So, these um helpful fertilizers, if you like, are there in the early part of the development of the microbiome, but then they disappear.

[00:44:48]So, our hypothesis our our hypothesis is that if you give a combination of the more common human milk oligosaccharides, call them oligos, every time a child has antibiotics, will that re- mitigate some of that nuking of the microbiome and will it aid in the recovery because we know from studies that is that when a child is given gut um given antibiotics, their microbiome gets knocked and it can take quite a long time to recover and it doesn't quite get back to where it was before.

[00:45:21]And then what happens?

[00:45:23]Bashed again by another course of antibiotics. Doesn't quite get back to where it um was before.

[00:45:30]And we hypothesize, in fact, that it will reduce obesity and excessive weight gain, reduce wheezing illnesses because of the help it has with the immune system, reduce eczema, reduce infections and also prevent the development of antibiotic resistance. So, it's got to have a multitude of potential benefits.

[00:45:51]Now, if our trial does indeed turn out to demonstrate those things, any toddler or infant who go is going to get a course of antibiotics will never get a course of antibiotics alone.

[00:46:01]They'll get antibiotics and HMOs to protect the microbiome. So, it could completely change the way in which antibiotics are used in very young children.

[00:46:11]So, who are we recruiting? Toddlers age 12 to 15 months who are starting all antibiotics. They need to mostly be off um breast milk and formula, and then we follow them up for 18 months. And every time they have a course of antibiotics, we give them a course of HMOs during that follow-up period.

[00:46:27]Now, so that's the exciting things that we're doing. What are we planning? And what we're planning is going to focus on a drug that you all have heard about, and I'm sure all of you know about.

[00:46:39]And that's called the GLP-1s. You've heard the term GLP-1s, the weight loss drug.

[00:46:44]Where did that story begin? Well, more than 30 years ago, believe it or not, it began with the Gila monster.

[00:46:51]This is a half-meter-long venomous lizard, one of the few venomous lizards in the world, but it produces this chemical called exenatide, which binds to GLP-1. And that chemical, exenatide, is associated with weight loss, and that was the forebearer of GLP-1 agonists, like Wegovy.

[00:47:10]You've heard about that, and Ozempic, and Zepbound.

[00:47:15]Um Now, how do they work?

[00:47:18]Their main mode of action is in reducing appetite and making you feel full.

[00:47:23]People who have the drug tell you that it really dramatically suppresses without a lot of effort their appetite.

[00:47:31]Tirzepatide, I'll come back to that in a bit more detail in a minute.

[00:47:34]Slows gastric emptying and makes you feel fuller. It also makes helps insulin to work much more effectively, and it also increases um burning up of fat cells, if you like, the breaking down of fat cells. So, multitude of different effects, but this is the big one.

[00:47:52]How big is the industry? Well, Novo Nordisk, who make Wegovy and Ozempic are now the largest company in and Denmark and they have made tens of billions of dollars selling this drug. How many New Zealanders are taking Wegovy right now?

[00:48:10]It's not funded, they have to buy it.

[00:48:12]Um within the first 6 months of it being launched, 65,000 New Zealanders were buying it.

[00:48:18]Now, this is the first back-to-back study of two of these drugs. This one is here and this one has just arrived in New Zealand and they have different names.

[00:48:30]Here's the chemical name, semaglutide and the other one is tirzepatide.

[00:48:35]Now, and this is the most studied one, semaglutide, and it's either known as Wegovy if it's being used for weight loss or Ozempic if it's used for diabetes. Why they did that? Called two different names, the same drug.

[00:48:49]Two different names. Anyway, that's what they did.

[00:48:52]Same with tirzepatide and if it's used for weight loss, it's called Zepbound and if it's used for diabetes management, it's called Mounjaro.

[00:49:03]Now there are lots of studies but you can see that tirzepatide is associated with more weight loss over about a year and a half than um semaglutide.

[00:49:15]And generally most studies show that tirzepatide is associated with about a 22% weight loss over just over a year and generally Wegovy about 15%. So, this is a bit more conservative than most studies.

[00:49:30]One of the reasons and you're thinking, why are they different? Why are they different?

[00:49:33]Tirzepatide works in two different ways.

[00:49:36]It's a slightly different chemical structure and it works at two different places, GLP-1 and GIP. So, it has two modes of action.

[00:49:44]Having said all of that, it's not without its problems.

[00:49:48]And the biggest one of those is that here's what happens when you take Wegovy.

[00:49:54]You lose weight. Good, good, good.

[00:49:56]Impressive. Look at that.

[00:49:58]16, 17% loss in body weight. The dashed lines are those who had pre-diabetes, in other words, early diabetes. These are just So, obesity and pre-diabetes, just obesity. But, look what happens the day they stop taking it. What happens to the weight? Back it comes. So, the weight regain is a huge problem with GLP-1 agonists like uh Wegovy or Zepbound. And you've probably heard the expression these are drugs for life.

[00:50:27]How do you get off them? How do you get off them? What do they cost?

[00:50:30]Um the price is coming down, but they're not free. So, uh Wegovy is about $5,500 a year, and tirzepatide is about $15,000 a year, on year, on year, on year.

[00:50:43]And they're not altogether free of side effects. So, the question is, can we stop this?

[00:50:49]Can we do something to stop this and just keep it here?

[00:50:53]Now, Justin showed you this slide way back when, remember, with our obesity 4 year follow-up study.

[00:51:00]And what we showed, just to remind you, is that the placebo group during our trial over 4 years, they just did what you would expect. They continued to just keep gaining weight.

[00:51:12]But, the FMT group, they stayed the same weight over 4 years after a single treatment.

[00:51:18]So, in conclusion, I hope we have collectively convinced you that we're not just engaging in science for the sake of novel discovery, that we're actually trying to make a difference with a pipeline that begins with a a good idea, a research trial delivering it, analyzing the data, and from that informing what the key bacteria are, growing them up, then been that that combination in a rat model of human disease and then potentially getting into um production and retail for you.

[00:51:54]Thank you.

[00:51:57]>> [applause] [applause]