Il meraviglioso mondo del microbioma intestinale
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CORDIScovery podcast- Episode #29 - The wonderful world of the gut microbiome
This is an AI transcription.
00:00:00:00 - 00:00:10:03
Abigail Acton
CORDIScovery.
00:00:10:05 - 00:00:36:05
Abigail Acton
This is CORDIScovery. Hello and welcome to this episode of CORDIScovery. With me, Abigail Acton. Today's episode is exploring the wonderful world of the gut microbiome that diverse realm of microorganisms that plays a vital role in our digestion, interacts with our brain chemistry, and even influences are immune systems. The question is what else does it do and how?
00:00:36:07 - 00:01:00:12
Abigail Acton
The microorganisms that live within our gut are completely unique to each one of us. As humans, we have over 100 trillion of them, the gut microbiome as opposed to the microbiome as a whole, which includes all microbes living on us and in us is gaining more and more scientific attention. This essentially breaks down into two main areas taxonomic diversity to identify who is there and functional metagenomics to figure out what they're doing.
00:01:00:14 - 00:01:19:24
Abigail Acton
So how can you tell in real time what chemical signals are being sent to other organs by the microbiome? And do those signals change how our brains work? How does our immune system interact with the microbes we host? Can that have an impact on how someone, for example, responds to chemotherapy? And what about other animals? How does the microbiome of a fish differ from ours?
00:01:20:01 - 00:01:44:22
Abigail Acton
And what common ground is there? Research is rapidly evolving, and all three guests today are ideally placed to guide us through some of the most intriguing aspects of the work being done in this area. With support from the EU's horizon funding programs. Carmen Giordano is associate professor of Bioengineering at the Department of Chemistry, Materials and Chemical Engineering at the Polytechnic University of Milan in Italy.
00:01:44:24 - 00:01:54:18
Abigail Acton
She leads a team of researchers developing innovative technological tools to help scientists learn more about how central nervous systems function. Welcome, Carmen.
00:01:54:20 - 00:01:56:19
Carmen Giordano
Hi. Thank you very much for inviting me.
00:01:57:00 - 00:02:12:19
Abigail Acton
We're delighted to have you. Nicola Gagliani heads the laboratory of the same name, studying the mechanisms of T-cell biology at the University Hospital, Hamburg-Eppendorf in Germany. He is focused on the interface between environmental factors and immune responses. Welcome, Nicola.
00:02:12:21 - 00:02:15:08
Nicola Gagliani
Hello everyone, very happy to be here.
00:02:15:10 - 00:02:32:22
Abigail Acton
Molecular and evolutionary biologist Morten Limborg is associate professor at the Globe Institute in Copenhagen, Denmark. He is interested in making aquaculture more sustainable by using tools such as metagenomic sequencing to boost healthy microbes in fish and other farmed animals. Hello, Morten.
00:02:32:22 - 00:02:35:03
Morten Limborg
Hello Abigail. Thanks for the invitation. Excited to be here.
00:02:35:07 - 00:02:58:19
Abigail Acton
Yeah, we're happy to have you as well. Carmen, I'm going to turn to you first. A relation between our intestinal microflora and our brains referred to as the microbiota gut brain axis was hypothesized more than 100 years ago. Now, innovations in technology are helping researchers investigate more deeply. But obstacles do still remain, which is where the Minerva Project your project comes in.
00:02:58:24 - 00:03:05:02
Abigail Acton
So, Carmen, what is our current understanding of how our brains and our gut microbiota interact?
00:03:05:04 - 00:03:32:24
Carmen Giordano
Well, the relation between our intestinal microbiota and the brain, both in a healthy and the pathological scenarios, is firstly in what is more than a century ago what was neglected for many decades. Only recently it has been reevaluated, becoming a new, exciting hypothesis in the world of science. Today we have the proof that aging bad elementary habits for food quality and stress can affect our intestinal microbiota.
00:03:33:01 - 00:03:53:08
Carmen Giordano
Indeed, a huge amount of data indicates that microbiota might affect the brain functionality. True, the bidirectional communication would prefer to have the microbiome and our brain active. That involves complex multiorgan, crosstalk and many biochemical pathways that are still not completely elucidated.
00:03:53:10 - 00:04:03:05
Abigail Acton
Okay, so what's holding us back from a better understanding when you say it's still not completely elucidated? What are some of the barriers to research?
00:04:03:07 - 00:04:40:00
Carmen Giordano
Well, even if the current available data showed that the intestinal microbiota modification might impact functionality, the absence of suitable research tools keep the researchers far from moving from correlation to causation. So actually, if we investigate the microbiota brain communication, we can use the animal models that are more representative of the real situation in vivo. But it's very difficult to exactly investigate all the biochemical signal involved or the fate of the biological molecules that can move from one organ to the other.
00:04:40:02 - 00:05:00:08
Carmen Giordano
The in vitro tools are basically based on the cell cultures that are more useful to understand how the biochemistry works. But they are just the basis of the whole scenario. So they are not fully representative of the complex multiorgan crosstalk that happens.
00:05:00:10 - 00:05:20:08
Abigail Acton
Okay. So basically what we're saying is we either look in animals, in which case of course a lot is hidden and a lot remains not understood because we just can't see what's happening or we break it down into much smaller, as you say, cell cultures and we look. But it's an isolation. It doesn't take into account the complexity of the interactions, the sophistication.
00:05:20:10 - 00:05:22:14
Abigail Acton
It's a little too reduced. I think that's what you're saying.
00:05:22:18 - 00:05:40:18
Carmen Giordano
Exactly. So what we are trying to do is to create a bridge between these two models by using a biology based approach in order to represent some key features, like, for example, that peristalsis that are not easy to represent in the classical standard to be produced.
00:05:40:24 - 00:05:55:14
Abigail Acton
By peristalsis, we mean the process of digestion, how food passes through the alimentary canal. Yeah. And so how is the equipment that you're developing helping us to be able to see that and can we see it in real time? If I was to walk into your laboratory, for example, what would I actually see?
00:05:55:18 - 00:06:26:06
Carmen Giordano
And we decide to develop a new technological tool that jointly represents all the main biological players involved in the microbiota brain crosstalk what in physiological pathological condition. So the final goal was to provide the clinicians and biologists working this area with an innovative engineering platform to allow them investigating in vitro, cellular and molecular level the chemical mechanism in both the microbiota and brain and multiorgan crosstalk in a completely new way.
00:06:26:08 - 00:06:47:00
Carmen Giordano
Our platform represents the connection among all the main biological players of the Axis and relies on three compartments one for each component of the microbiota and that brain active and innovative. A technological device relying on state of the art technology known as organ on a chip.
00:06:47:02 - 00:06:55:17
Abigail Acton
So to break that down further, how does that physically represent itself? What do you actually have in front of you when you're using the new equipment that you've developed?
00:06:55:19 - 00:07:24:07
Carmen Giordano
Okay. So our platform is composed by a kind of holder inside of that to drive some fish culture wealth where we can capture different cells representing the different organs. All these devices are interconnected hydraulically in order not to allow the mix of molecules produced by one culture to move from one organ to the other and see what happens at each level.
00:07:24:09 - 00:07:33:21
Abigail Acton
So it's in fact, it's like a window into the actual process in real time, in much more complexity than we've ever been able to do before.
00:07:33:23 - 00:08:03:05
Carmen Giordano
Yes, because we have some key features of our profile. For example, is possible to like monitoring of each culture using a microscope, also a confocal microscope. So the holder can sits inside a holder in order to allow us to see what happens in each organ. And different experiments are change in tailor in the microbiota compartment. Human microbiota strains can be cultured and produce a mix of molecules named secreted.
00:08:03:07 - 00:08:46:06
Carmen Giordano
The secreted is transported to the gut compartment where a human gut depicted herself, and cells from the immune system modified it as of course in vivo even the so-called metabolize secrete on the metabolize secrete on which the brain compartments that have complete blood brain barrier model, followed by two new human brain cell models, where neuro astrocytes and microglia that are the main cellular population of the brain can be well cultured in order to explore the microbiota effects on brain cells interconnected SVR in the real tissue and cultured individually to investigate microbiota impact on each cell type.
00:08:46:07 - 00:09:03:19
Abigail Acton
Okay, that's wonderful. So Carmen are you seeing any difference with the way that healthy or unhealthy brain cells are responding to the chemicals that are reaching them through this imitation, if I can call it that way, or simulation of a natural digestive process?
00:09:03:21 - 00:09:21:22
Carmen Giordano
Yes, because we compared the healthy and pathological scenario and we observed the same breath in response to detrimental microbiota. Extremely. This is reported in literature. This confirms that our by engineer approach and tool can really help in abbreviating microbiota brain interpret triggers.
00:09:22:02 - 00:09:34:14
Abigail Acton
Okay, so basically what you're saying is that what you've developed is reinforcing in what has been put forward in the literature and that therefore shows that your new tool works basically.
00:09:34:18 - 00:09:35:08
Carmen Giordano
Exactly.
00:09:35:12 - 00:09:55:00
Abigail Acton
Because it's doing what it's meant to do. Yeah. Okay, Super. Thank you very much, Carmen. That sounds like a really revolutionary way of seeing in real time in much more complexity and detail what's going on. Can I ask our fellow guests? Nico, do you have a question or do you have a question Morten, Yes, Morten.
00:09:55:02 - 00:10:14:24
Morten Limborg
Thank you, Carmen. This is really cool. And I know from my own colleagues here in Copenhagen they're working with the gut and a chip model system. So I was just wondering exactly how advanced you are with your multi-organ chip model and actually which organs of the human body are in there and what it looks like.
00:10:15:01 - 00:10:15:11
Carmen Giordano
Okay.
00:10:15:12 - 00:10:46:02
Carmen Giordano
I'll try to answer one piece at a time. So my arm chips now can represent the gut capilium, the immune system, the blood brain barrier, the brain. But we have also developed a liver model because we have another project that is an early proof of concept that moved the my platform in an industrial environment. And we were aimed at investigating the impact of some drugs at brain level.
00:10:46:04 - 00:11:11:12
Carmen Giordano
And as you know, the drugs are metabolized by the liver. So it was necessary to also develop this organ inside the platform. The other question was, how advance this? Okay. So we have cultured human microbiota from healthy donors, but also Alzheimer disease patients. And we were able to use their secretum to see what happens at the cellular level.
00:11:11:14 - 00:11:41:22
Carmen Giordano
We have seen that the molecules in particular the detrimental molecules that we have investigated that are the lipopolysaccharide from this particular body, are able to move from the microbiota compartment to the brain compartment. And we see that mental defect there, at industrial level that's been tested. And they told us that the platform was very user friendly. They were not, you know, frightened and in using it or had some difficulties.
00:11:42:02 - 00:11:53:12
Carmen Giordano
They were biologists basically. So the idea was to allow all the clinician and biologist that are not expecting the engineer accusing. I don't know if I have an answer to your question, What if something is missing? Just tell me again.
00:11:53:14 - 00:11:58:20
Morten Limborg
No, it's great. I'm just trying to fathom a brain in this left.
00:11:59:01 - 00:12:06:24
Abigail Acton
Brain on a chip. I know. This is why I invited comment, because it's so intriguing. Is it such a wonderful thing? Yeah. Nico you had a question. You're raising your hand.
00:12:07:04 - 00:12:16:17
Nicola Gagliani
Thanks, Governor. That was very interesting. The question is very simple. Are you able are you planning to also culture the microbiota in your system?
00:12:16:19 - 00:12:46:12
Carmen Giordano
Yes. What we are trying to do is to culture the human, the complete human microbiota from also different patients with different pathologies. Because as I said, we started with the microbiota Alzheimer patients. But the idea is that our platform can be used to investigate potentially all the diseases where Multiorgan crosstalk is involved because we designed the platform in order to be very versatile.
00:12:46:14 - 00:13:21:08
Carmen Giordano
By changing cell type of cultured condition, you can represent other organs that you are interested in showing this way you can also think about some preventative autocratic strategies managing the microbiota composition and see what happens at the end. For example, all the research about probiotics possibly or probiotics, could be very interesting to understand how we can use this tools to help in these pathologies that are still very severe and very impairing of the patient life quality.
00:13:21:10 - 00:13:27:14
Abigail Acton
So it's very modular. Yeah, you can just add in a section or take out a section and change what you're looking at completely. Yes.
00:13:27:14 - 00:13:47:03
Carmen Giordano
The idea is that you have to imagine a tissue cultured system where you can change the cells so you can structure the cells in suspension in 2D, in 3D, interconnected by feeding them in the two side of a forest membrane as the biological barriers are. So you can imagine different applications.
00:13:47:05 - 00:13:51:01
Abigail Acton
Okay, that's wonderful. Thank you very much. Carmen. Yeah. One more question from Nicola.
00:13:51:03 - 00:14:05:24
Nicola Gagliani
Sorry. I mean, diffusion, diffusion of the molecules, how predictable is that? Is there a point where we would not need to do any more experiments? But based on the similarity of the structure of the different metabolites, can you predict the rate of diffusion?
00:14:06:01 - 00:14:52:17
Carmen Giordano
We have to consider this point and we never have developed the many computational models to understand how each molecule can diffuse. We we've seen a good correlation between our model and the real the real diffusion of the biomolecules we have followed. It depends basically on the molecule you want to see because you have to change. Also, for example, some characteristics of the platform, such as the ferocity of the membrane, because if you are using a molecule that is very let me say big or a particular kind of chemical structure, you have to consider also the porosity on the membrane and if and how the molecule can pass through one organ to the other.
00:14:52:22 - 00:15:12:19
Abigail Acton
Thank you very much. And that was an absolutely fascinating and very good questions. Thanks, guys. Okay, so now I'm turning to you Nico. Immune related diseases are on the rise and the typical Western diet might be to blame, but all theories need to be backed up. So the Diet-namic project wanted to know how short term dietary interventions can impact our health by modulating our immune systems.
00:15:12:21 - 00:15:19:03
Abigail Acton
Nicco How dynamic is the relationship between what we eat and the composition of our microbiome, and why does that matter?
00:15:19:05 - 00:15:48:01
Nicola Gagliani
So to show where is extremely dynamic, so the microbiome extremely rapidly responds to the diet. There are very clear studies in humans that just a couple of days of a very drastic change in your dietary habit dramatically impacts the composition of your intestinal microbiome. And then you ask me why this matters. And that was actually the question that we were trying to answer.
00:15:48:03 - 00:16:16:14
Nicola Gagliani
As Carmen alluded to, the microbiome can directly impact our health and different organs in our body, although we also found is that the microbiome is extremely connected with the immune system and being the microbiome. So dynamically change by the diet, you can infer that by changing our diet via the microbiome, you very rapidly also can change your immune system.
00:16:16:16 - 00:16:20:13
Nicola Gagliani
And that's what we have been studying in the last five and six years.
00:16:20:17 - 00:16:33:02
Abigail Acton
So can you tell me more about your findings regarding the impact of the microbiome that could be considered perhaps therapeutic? For example, I know that you're interested in studying its impact on chemotherapy and the efficacity of that process.
00:16:33:07 - 00:17:04:07
Nicola Gagliani
So what we found, I would say by serendipity in a way, is that patients affected by pancreatic cancer, they have different microbiome if they do or do not respond to chemotherapy. And that's where everything started. And we found that some bacteria that were highly abundant in those patients that responded to the chemotherapy were actually able to use an essential amino acid that as as it was ingested by a certain diet.
00:17:04:07 - 00:17:32:09
Nicola Gagliani
And we found indeed that these specific microbiome, specifically rich in responding patients was extremely efficient in producing a metabolites which is called 3-IAA, is a metabolite. The name is boring, but that's what it is. And these metabolites is very powerful in improving the efficacy of the standard care for these pancreatic patients.
00:17:32:11 - 00:17:43:05
Abigail Acton
That's absolutely fascinating. That's really, really fascinating. I mean, obviously you've published papers on this and you shared your findings. Are you getting any feedback from the medical community of interest on this or is it being picked up.
00:17:43:05 - 00:17:45:04
Nicola Gagliani
Too many!
00:17:45:06 - 00:17:49:21
Abigail Acton
Yes, I can imagine. But it's wonderful news. I mean, it's you know, such a natural way to.
00:17:49:23 - 00:18:16:11
Nicola Gagliani
This is obviously extremely in a way also risky. Right. So what we have provided to the scientific community is a proof of concept of the power of these metabolites. Now, to really move from the basic science to the clinic, much more needs to be done. This is obvious. We always say that, but especially in this case is extremely important because pancreatic cancer is extremely bad cancer.
00:18:16:11 - 00:18:26:22
Nicola Gagliani
A lot of people are suffering from this type of cancer, survival is not extremely high unfortunately, and that's why we need to not provide full hopes in the field.
00:18:26:22 - 00:18:45:09
Abigail Acton
Absolutely. No, no. It needs to be tested thoroughly to make sure it's completely robust. But it's an interesting concept that you found. Could you tell me a little bit more about the science? So you mentioned that you have studied the molecular mechanisms of T-cell adaptability. So in other words, your research has led to the discovery of a signaling pathway.
00:18:45:09 - 00:18:55:06
Abigail Acton
So you touched on that in your last answer. You were talking about the metabolites, but could you break that down a little bit more again, for a non-technical audience? But exactly what what is happening there, do you think?
00:18:55:08 - 00:19:18:24
Nicola Gagliani
So I need a little bit to step back. So there are those those were two a way independent findings. On one side, we found the impact of the diets on the efficacy of chemotherapy in pancreatic cancer patients. On the other side, we also found how T-cells dynamically respond to changes in the diet. And this is due to the fact that T-cells are perceived.
00:19:18:24 - 00:19:58:06
Nicola Gagliani
That's what we found even earlier are extremely plastic. So they can adapt to the changes in the environment. And within the environment there is also the diet and as I said before, the diet guide, the microbiota changes the immune system and among the cells of the immune system, T cells respond very rapidly to the changes in the diet because again, as the cancer cells alter T- cells respond to certain metabolites that are produced by the bacteria, their own cells of our body, and they all respond quickly and profoundly to these interaction between the diet and the microbiome.
00:19:58:11 - 00:20:17:16
Abigail Acton
Okay, that's fascinating. Thank you. Nico what attracted you to this area of research? There's for me, there's something very elegant about looking closely at a natural process and seeing the impact of of what we put enormous has further down the line in all sorts of ways. What attracted you specifically to this, though?
00:20:17:18 - 00:20:43:03
Nicola Gagliani
So I've always been interested in understanding how the immune system works. And so when we usually immunologists try to understand that by using classical immunological perturbations such as pathogens. But I thought that would have been also very interesting to understand how the immune system and the cells of the immune system respond to less classical immunological perturbations.
00:20:43:05 - 00:20:45:13
Abigail Acton
Something more natural, maybe just our environments.
00:20:45:15 - 00:20:54:13
Nicola Gagliani
Exactly. And I was always wondering, okay, now I go to eat something. Do I can I impact my mind system as rapidly as if I would take a pill?
00:20:54:15 - 00:20:59:20
Abigail Acton
Yeah. And in fact, you're finding that it's similar so far. What you're seeing so far is it's similar.
00:20:59:20 - 00:21:02:01
Nicola Gagliani
Yes. Yes. As very dynamic.
00:21:02:01 - 00:21:11:07
Abigail Acton
It's fantastic. That's good. That's good. Well, that's good to know. I've done that. Yeah, that's excellent. Okay, So do we have any questions for Nico please? Yes, Morten.
00:21:11:10 - 00:21:38:13
Morten Limborg
Thank you, Nick. That is quite fascinating. So I can see you have a strong focus on the food and the diet here. But I was just wondering, even though there's undoubtedly a huge effect of the diet, did you, by any chance observe any potential effect of their specific genes, a genotype of the different subjects? For instance, were there any variation of differences amongst subjects that got the same treatment in your experiment?
00:21:38:19 - 00:22:06:14
Nicola Gagliani
Really Morten, this is fantastic. So thanks for asking. Unfortunately, we cannot really answer those questions because as you know, to answer those questions, what you need is a huge amount of patients, in essence to really trace these genetic diversities and you know, in using mice, you are biased because mice are genetically identical. So you completely neglect that key aspect, but definitely will be fantastic to associate.
00:22:06:14 - 00:22:12:20
Nicola Gagliani
And I can tell you that definitely the genetics impacts the way you respond to the diet.
00:22:12:22 - 00:22:15:20
Abigail Acton
Excellent. Thank you. Carmen, you have a question.
00:22:15:24 - 00:22:31:03
Carmen Giordano
First of all, thank you very much. Very fascinating and very interesting. It might if a curiosity, what do you think could be the impact at long and short term of the diet of astronauts that are in a very particular situation?
00:22:31:05 - 00:22:34:01
Abigail Acton
Wonderful question, Carmen. It's such a lovely question.
00:22:34:06 - 00:22:57:18
Carmen Giordano
There is a reason Recently I read an article, very interesting article. They said that they are starting to understand if the life of these astronauts into space can impact their brain functionality, and they found something. So my question was, do you think that there is an impact also due to the diet they are forced to follow in space on their health in the long and short term?
00:22:57:23 - 00:22:59:11
Abigail Acton
Lovely question.
00:22:59:13 - 00:23:18:15
Nicola Gagliani
Of course. I mean, talk could be that that has it has an impact right. So I haven't tested but I think you're quite right if I can extend your question and I was thinking about that because a couple of weeks ago I was hiking, what about gravity as being, you know, gravity. Could that currently also, I think, impact the our immune system?
00:23:18:20 - 00:23:30:17
Nicola Gagliani
And I think we should find a way to dissect how gravity impacts directly our immune system and not via altering the way we eat because obviously that would be a very strong confounding factor.
00:23:30:19 - 00:23:39:05
Abigail Acton
Carmen I'm seeing your wonderful system, your wonderful tool being taken up into the space station to see what happens with the various organs you've got in the various worlds.
00:23:39:07 - 00:23:51:17
Carmen Giordano
Yeah, it's very interesting because I've read something about the impact of gravity also on brain functionality and the impact on gravity, on the interior of the brain and pathological.
00:23:51:17 - 00:24:11:21
Abigail Acton
It this sounds like this is a potentially another episode gravity. And then we could do all sorts of impacts here also underwater as well. Okay super. Thank you very much, guys. I'm going to turn to Morten. Mortne HoloFood consider the impact that feed has on the microbiomes of farmed animals. And also, I know that you're very interested in the genomic impact, too.
00:24:12:02 - 00:24:28:17
Abigail Acton
So excellent last question that you had. We've talked about humans, but the relationship between the health of any animal and its microbiome must be very close if we are what we eat as humans and presumably the same can be said for animals. How does that play out when it comes to feeding farmed animals? Morten?
00:24:28:19 - 00:24:53:15
Morten Limborg
Yeah, thanks for the question, Abigail. So and thanks for the excellent from Nico. So the main challenge when we when we look at production animals in order to to feed a growing population of humans there. The challenges if you look at the microbiome literature, it is extremely biased towards studies and human or lab mice with very little variation a snake alluded to.
00:24:53:15 - 00:25:15:10
Morten Limborg
Right, But if you look at the animal production today, there's a huge need for for replacing the current ingredients used in the feed. For instance, many animals are fed fish meals, but this come from wild populations where there are only so many fish in the sea. A lot of protein and fat comes from soy or other crops that necessitate deforestation in certain areas.
00:25:15:10 - 00:25:43:04
Morten Limborg
So we simply just need to replace this these ingredients in the animal seeds. And we don't really know what it does to the animal health. But here, obviously, we think the microbiome has that has has to play a role. And another example is that the biotech industry is already heavily marketing these so-called functional feeds where they add probiotics so basically a life culture of beneficial bacteria like we do in our own dairy products.
00:25:43:06 - 00:26:09:17
Morten Limborg
And often it's just like a one type fits all solution that you would feed the same probiotic strain to all chicken and the whole world for instance. Right. But I have in our team we have developed this new model that is more inspired by evolution in saying that even though the environment and the diet means a lot in shaping our microbiome, as Nico just told us the genotype 0f the host animal is
00:26:09:17 - 00:26:31:09
Morten Limborg
Important too. And so in our project and the HoloFood project, we set out to study some of the more pertinent challenges in either chicken production or salmon farming in aquaculture, because we believe in the future we can more intelligently tailor these feed solutions to the actual genotype of whatever food stock your farming in you are famining in your location.
00:26:31:11 - 00:26:43:09
Abigail Acton
So at this so much diversity across the same species, can you tell us something about species that are radically, radically different? So for example, your interest is fish. What's going on in a fish is microbiome.
00:26:43:11 - 00:27:05:06
Morten Limborg
Yeah, thanks for asking. So science, years ago when we started to study this topic on microbiomes and fish, I would say the same thing as in human in mice. And again, this goes back to the fact that the literature is so biased towards studies in humans or other warm blooded animals that has a constant body temperature and and which are nice, nicely warm.
00:27:05:08 - 00:27:31:24
Morten Limborg
So, so actually I can exemplify this through a series of students that I have had. So the first student Matisse was supposed to analyze the microbiome of hundreds of salmon, but he never, never ever managed to actually get microbial DNA out of the samples in the lab. That's what we thought. So actually, he ended up writing his whole thesis about comparing different methods to store the sample from the feed to the lab, because we thought we were doing something wrong.
00:27:32:01 - 00:27:51:12
Morten Limborg
And then another student, David, took over and and studied some microbes in some salmon we had where some were sick and some were healthy. And he was also getting deriving his expectations from the human literature. But when he, like, sorted out all the contaminants of the nonsense of the microbes, he only had two microbes left in the whole system.
00:27:51:12 - 00:28:16:05
Morten Limborg
And there were. But it was really interesting because there was one dominant microbe in the sick and one dominant in the healthy. So we can use it to to look at this. And then lastly, Jacopo did a whole phd, and he was supposed to sequence and study of the hundreds of microbes in salmon, and he ended up publishing five papers in just one specific bacteria that live and take the association with salmon.
00:28:16:05 - 00:28:22:21
Abigail Acton
So so that's really amazing. So we're talking about trillions and trillions in humans and you're talking but there's like a handful in the fish.
00:28:23:02 - 00:28:40:13
Morten Limborg
Exactly. I mean, and indeed, and the HoloFood project funded by the EU, we did what is called shotgun sequencing. So basically was sequenced all the DNA in more than 500 different salmon and after putting all of that data together we were able to assemble ten bacterial genomes.
00:28:40:15 - 00:28:41:13
Abigail Acton
Isn’t that fascinating?
00:28:41:19 - 00:29:01:02
Morten Limborg
There was all of the diversity. So coming from redoing our methods because we think we're doing something wrong, we have so now it took us five years to realize that this is just very, very different in salmon. Yeah, and remember, fish are exothermic, which means the body temperature inside the salmon actually ranges by 20 degrees over a season.
00:29:01:02 - 00:29:05:13
Morten Limborg
So that might be part of the explanation, but it's just very, very different.
00:29:05:15 - 00:29:12:08
Abigail Acton
It does beg the question why I mean, that seems to me to be the next question, the reason for these radical different numbers. No?
00:29:12:10 - 00:29:25:09
Morten Limborg
Yes. And I'm not saying that just because this is what it is in salmon, it might be different in other fish and salmon are carnivorous, so they may not eat meat as much microbial function compared to maybe so before.
00:29:25:11 - 00:29:29:10
Abigail Acton
Yeah, but I mean that would be the next place to look. Yeah.
00:29:29:12 - 00:29:30:12
Abigail Acton
Yeah, yeah, yeah, yeah.
00:29:30:12 - 00:29:36:11
Abigail Acton
Okay. Your background is in evolutionary biology, so how does that feature in your research? What insight does that bring to the table for you?
00:29:36:16 - 00:30:03:18
Morten Limborg
So yeah, just to elaborate a bit on the model I talked about in your first question. So our, our kind of different approach to this whole field is, is to look at the host organism and all of the microbes that live inside it as one single scaffold and part of the lectures referred to as a hollow by. So it means all of the life cells here and then and why we know the environment is really important in explaining to microbes.
00:30:03:18 - 00:30:24:06
Morten Limborg
It doesn't mean that these genes are not important. So if you think about us, we are all genetically different, right? When we look at each other and we also have a surface on the inside. So if you turned us inside out the epithelial surface in our stomach and intestines, also different environments, right? So you could actually think of the four of us
00:30:24:06 - 00:30:47:22
Morten Limborg
As four different types of brains of flypaper. And then imagine like a swarm of insects come flying through all of us, and then after the swarm is gone, it's a little bit different. What remains on our flypaper? So the same that happens even though we eat the same diet through intestinal tract, it's a little bit different. Which of those microbes actually are selected to stay in our environment and what not.
00:30:47:22 - 00:30:57:13
Morten Limborg
And that is where the host genotype comes into the equation of where this whole evolutionary angle actually can hopefully help do this in a slightly more precise way.
00:30:57:15 - 00:31:13:05
Abigail Acton
I think that's fascinating. I love it when you get kind of slightly impacts from cross-disciplinary backgrounds. You know, it's like a it shines a new light. It's a little bit like common as well, being a you know, with the engineering concept as well. That's excellent. Thank you so much. What do you hope the impact of your research will be?
00:31:14:02 - 00:31:48:07
Morten Limborg
What I hope is, first of all, that if we if we learn how the genotypes and the genes important, we would be able to actually in the future predict or even select four for healthy microbiomes in our production animals and eventually humans as well. But my main hope for the field in microbiome research is that we won't lose our humility when we get all these new data sets and have to interpret them in this complicated context, and then we don't get locked into our prior expectations about how it should be and how it should be.
00:31:48:07 - 00:32:16:06
Morten Limborg
Right? So so it's really, really key to maintain an open mind because the pace by which new huge datasets are generated is just so much faster than our theory and and bona fide models. Right. And I'm talking out of personal experience here. So I really think it's key to keep this open mind, even though we test hypothesis when we get these datasets and that we interpret them in a more holistic and evolutionary context.
00:32:16:06 - 00:32:27:08
Morten Limborg
But if we do that, I'm also super excited that this field, this microbiome research, will keep surprising us, but also enriching us and enable us to tackle our future societal challenges.
00:32:27:08 - 00:32:40:20
Abigail Acton
That's excellent. That's wonderful. Yeah, exactly. It's true. When you get a huge amount of information, you have an urge to just sort of classify it quick. No, not quickly, exactly. But you know, your preconceptions can step in coming. Any question? Yes. Carmen You have a question.
00:32:40:20 - 00:33:17:20
Carmen Giordano
I completely agree with your idea to lower down our expectation and see what the nature is telling us, because otherwise you can lose the pieces of the whole picture. So we have to see what is going on, what happens and what's the our experiments are giving back to us. So apart this my question is, do you think that your method can be applied to also other kind of animals in order to fine tune and help to fine tune the diets and the potential impact on our microbiota?
00:33:17:22 - 00:33:39:01
Morten Limborg
Yes, I think so. So I don't personally have a lot of experience from other animals, but within our our team, for instance, the whole evolutionary motivation comes from some previous studies on, for instance, the vampire bats. So they're like complicated mammals just like you and I, but they are adapted to live on a very specific and extreme diet.
00:33:39:01 - 00:34:00:24
Morten Limborg
They only get blood from other warm blooded animals. So there's a lot of essential vitamins, amino acids that are that they don't get through their diet. So it's only by actually looking beyond the pet's own genome, but also the microbes living inside it, how they see this. And then you might be able to relate studies like that to specific dietary diseases.
00:34:00:24 - 00:34:03:12
Morten Limborg
So metabolic diseases in humans.
00:34:03:14 - 00:34:13:10
Abigail Acton
Excellent. Thank you. Well, listen, I want to thank you all very, very much for your time today. And yeah, I think it's been a wonderful episode because it's all been so fascinating. Right?
00:34:13:12 - 00:34:14:21
Nicola Gagliani
I think it was very nice.
00:34:14:23 - 00:34:20:00
Carmen Giordano
Thank you very much.
00:34:20:02 - 00:34:44:12
Abigail Acton
If you've enjoyed this podcast and are interested in the latest scientific research coming out to the EU, have a listen to previous episodes. Follow us on Spotify and Apple Podcasts and check out the podcast homepage on the Cordis website. We've looked at apps designed to make finding missing children more effective. Trace the production of glass and related medieval trade routes and asked what it would take to make space exploration from the moon possible.
00:34:44:14 - 00:35:02:17
Abigail Acton
In our last 28 episodes, there will be something there to tweak your curiosity. So do have a listen. Perhaps you're curious about what other EU funded projects are doing in the area of microbiome research. The Cordis website will give you an insight into the results projects funded by Horizon 2020 and Horizon Europe that are working in this area.
00:35:02:19 - 00:35:22:18
Abigail Acton
The website has articles and interviews that explore the results of research being conducted in a very broad range of domains and subjects, from epigenetics to Epictetus. There is something there for you. Maybe you're involved in a project who would like to apply for funding? Take a look at what others are doing in your domain. So come and check out the research that's revealing what makes our world tick.
00:35:22:20 - 00:35:30:14
Abigail Acton
We're always happy to hear from you. Drop us a line. Editorial at CORDIS dot Europa Dot EU. Until next time.
This is an AI transcription.
00:00:00:00 - 00:00:10:03
Abigail Acton
CORDIScovery.
00:00:10:05 - 00:00:36:05
Abigail Acton
This is CORDIScovery. Hello and welcome to this episode of CORDIScovery. With me, Abigail Acton. Today's episode is exploring the wonderful world of the gut microbiome that diverse realm of microorganisms that plays a vital role in our digestion, interacts with our brain chemistry, and even influences are immune systems. The question is what else does it do and how?
00:00:36:07 - 00:01:00:12
Abigail Acton
The microorganisms that live within our gut are completely unique to each one of us. As humans, we have over 100 trillion of them, the gut microbiome as opposed to the microbiome as a whole, which includes all microbes living on us and in us is gaining more and more scientific attention. This essentially breaks down into two main areas taxonomic diversity to identify who is there and functional metagenomics to figure out what they're doing.
00:01:00:14 - 00:01:19:24
Abigail Acton
So how can you tell in real time what chemical signals are being sent to other organs by the microbiome? And do those signals change how our brains work? How does our immune system interact with the microbes we host? Can that have an impact on how someone, for example, responds to chemotherapy? And what about other animals? How does the microbiome of a fish differ from ours?
00:01:20:01 - 00:01:44:22
Abigail Acton
And what common ground is there? Research is rapidly evolving, and all three guests today are ideally placed to guide us through some of the most intriguing aspects of the work being done in this area. With support from the EU's horizon funding programs. Carmen Giordano is associate professor of Bioengineering at the Department of Chemistry, Materials and Chemical Engineering at the Polytechnic University of Milan in Italy.
00:01:44:24 - 00:01:54:18
Abigail Acton
She leads a team of researchers developing innovative technological tools to help scientists learn more about how central nervous systems function. Welcome, Carmen.
00:01:54:20 - 00:01:56:19
Carmen Giordano
Hi. Thank you very much for inviting me.
00:01:57:00 - 00:02:12:19
Abigail Acton
We're delighted to have you. Nicola Gagliani heads the laboratory of the same name, studying the mechanisms of T-cell biology at the University Hospital, Hamburg-Eppendorf in Germany. He is focused on the interface between environmental factors and immune responses. Welcome, Nicola.
00:02:12:21 - 00:02:15:08
Nicola Gagliani
Hello everyone, very happy to be here.
00:02:15:10 - 00:02:32:22
Abigail Acton
Molecular and evolutionary biologist Morten Limborg is associate professor at the Globe Institute in Copenhagen, Denmark. He is interested in making aquaculture more sustainable by using tools such as metagenomic sequencing to boost healthy microbes in fish and other farmed animals. Hello, Morten.
00:02:32:22 - 00:02:35:03
Morten Limborg
Hello Abigail. Thanks for the invitation. Excited to be here.
00:02:35:07 - 00:02:58:19
Abigail Acton
Yeah, we're happy to have you as well. Carmen, I'm going to turn to you first. A relation between our intestinal microflora and our brains referred to as the microbiota gut brain axis was hypothesized more than 100 years ago. Now, innovations in technology are helping researchers investigate more deeply. But obstacles do still remain, which is where the Minerva Project your project comes in.
00:02:58:24 - 00:03:05:02
Abigail Acton
So, Carmen, what is our current understanding of how our brains and our gut microbiota interact?
00:03:05:04 - 00:03:32:24
Carmen Giordano
Well, the relation between our intestinal microbiota and the brain, both in a healthy and the pathological scenarios, is firstly in what is more than a century ago what was neglected for many decades. Only recently it has been reevaluated, becoming a new, exciting hypothesis in the world of science. Today we have the proof that aging bad elementary habits for food quality and stress can affect our intestinal microbiota.
00:03:33:01 - 00:03:53:08
Carmen Giordano
Indeed, a huge amount of data indicates that microbiota might affect the brain functionality. True, the bidirectional communication would prefer to have the microbiome and our brain active. That involves complex multiorgan, crosstalk and many biochemical pathways that are still not completely elucidated.
00:03:53:10 - 00:04:03:05
Abigail Acton
Okay, so what's holding us back from a better understanding when you say it's still not completely elucidated? What are some of the barriers to research?
00:04:03:07 - 00:04:40:00
Carmen Giordano
Well, even if the current available data showed that the intestinal microbiota modification might impact functionality, the absence of suitable research tools keep the researchers far from moving from correlation to causation. So actually, if we investigate the microbiota brain communication, we can use the animal models that are more representative of the real situation in vivo. But it's very difficult to exactly investigate all the biochemical signal involved or the fate of the biological molecules that can move from one organ to the other.
00:04:40:02 - 00:05:00:08
Carmen Giordano
The in vitro tools are basically based on the cell cultures that are more useful to understand how the biochemistry works. But they are just the basis of the whole scenario. So they are not fully representative of the complex multiorgan crosstalk that happens.
00:05:00:10 - 00:05:20:08
Abigail Acton
Okay. So basically what we're saying is we either look in animals, in which case of course a lot is hidden and a lot remains not understood because we just can't see what's happening or we break it down into much smaller, as you say, cell cultures and we look. But it's an isolation. It doesn't take into account the complexity of the interactions, the sophistication.
00:05:20:10 - 00:05:22:14
Abigail Acton
It's a little too reduced. I think that's what you're saying.
00:05:22:18 - 00:05:40:18
Carmen Giordano
Exactly. So what we are trying to do is to create a bridge between these two models by using a biology based approach in order to represent some key features, like, for example, that peristalsis that are not easy to represent in the classical standard to be produced.
00:05:40:24 - 00:05:55:14
Abigail Acton
By peristalsis, we mean the process of digestion, how food passes through the alimentary canal. Yeah. And so how is the equipment that you're developing helping us to be able to see that and can we see it in real time? If I was to walk into your laboratory, for example, what would I actually see?
00:05:55:18 - 00:06:26:06
Carmen Giordano
And we decide to develop a new technological tool that jointly represents all the main biological players involved in the microbiota brain crosstalk what in physiological pathological condition. So the final goal was to provide the clinicians and biologists working this area with an innovative engineering platform to allow them investigating in vitro, cellular and molecular level the chemical mechanism in both the microbiota and brain and multiorgan crosstalk in a completely new way.
00:06:26:08 - 00:06:47:00
Carmen Giordano
Our platform represents the connection among all the main biological players of the Axis and relies on three compartments one for each component of the microbiota and that brain active and innovative. A technological device relying on state of the art technology known as organ on a chip.
00:06:47:02 - 00:06:55:17
Abigail Acton
So to break that down further, how does that physically represent itself? What do you actually have in front of you when you're using the new equipment that you've developed?
00:06:55:19 - 00:07:24:07
Carmen Giordano
Okay. So our platform is composed by a kind of holder inside of that to drive some fish culture wealth where we can capture different cells representing the different organs. All these devices are interconnected hydraulically in order not to allow the mix of molecules produced by one culture to move from one organ to the other and see what happens at each level.
00:07:24:09 - 00:07:33:21
Abigail Acton
So it's in fact, it's like a window into the actual process in real time, in much more complexity than we've ever been able to do before.
00:07:33:23 - 00:08:03:05
Carmen Giordano
Yes, because we have some key features of our profile. For example, is possible to like monitoring of each culture using a microscope, also a confocal microscope. So the holder can sits inside a holder in order to allow us to see what happens in each organ. And different experiments are change in tailor in the microbiota compartment. Human microbiota strains can be cultured and produce a mix of molecules named secreted.
00:08:03:07 - 00:08:46:06
Carmen Giordano
The secreted is transported to the gut compartment where a human gut depicted herself, and cells from the immune system modified it as of course in vivo even the so-called metabolize secrete on the metabolize secrete on which the brain compartments that have complete blood brain barrier model, followed by two new human brain cell models, where neuro astrocytes and microglia that are the main cellular population of the brain can be well cultured in order to explore the microbiota effects on brain cells interconnected SVR in the real tissue and cultured individually to investigate microbiota impact on each cell type.
00:08:46:07 - 00:09:03:19
Abigail Acton
Okay, that's wonderful. So Carmen are you seeing any difference with the way that healthy or unhealthy brain cells are responding to the chemicals that are reaching them through this imitation, if I can call it that way, or simulation of a natural digestive process?
00:09:03:21 - 00:09:21:22
Carmen Giordano
Yes, because we compared the healthy and pathological scenario and we observed the same breath in response to detrimental microbiota. Extremely. This is reported in literature. This confirms that our by engineer approach and tool can really help in abbreviating microbiota brain interpret triggers.
00:09:22:02 - 00:09:34:14
Abigail Acton
Okay, so basically what you're saying is that what you've developed is reinforcing in what has been put forward in the literature and that therefore shows that your new tool works basically.
00:09:34:18 - 00:09:35:08
Carmen Giordano
Exactly.
00:09:35:12 - 00:09:55:00
Abigail Acton
Because it's doing what it's meant to do. Yeah. Okay, Super. Thank you very much, Carmen. That sounds like a really revolutionary way of seeing in real time in much more complexity and detail what's going on. Can I ask our fellow guests? Nico, do you have a question or do you have a question Morten, Yes, Morten.
00:09:55:02 - 00:10:14:24
Morten Limborg
Thank you, Carmen. This is really cool. And I know from my own colleagues here in Copenhagen they're working with the gut and a chip model system. So I was just wondering exactly how advanced you are with your multi-organ chip model and actually which organs of the human body are in there and what it looks like.
00:10:15:01 - 00:10:15:11
Carmen Giordano
Okay.
00:10:15:12 - 00:10:46:02
Carmen Giordano
I'll try to answer one piece at a time. So my arm chips now can represent the gut capilium, the immune system, the blood brain barrier, the brain. But we have also developed a liver model because we have another project that is an early proof of concept that moved the my platform in an industrial environment. And we were aimed at investigating the impact of some drugs at brain level.
00:10:46:04 - 00:11:11:12
Carmen Giordano
And as you know, the drugs are metabolized by the liver. So it was necessary to also develop this organ inside the platform. The other question was, how advance this? Okay. So we have cultured human microbiota from healthy donors, but also Alzheimer disease patients. And we were able to use their secretum to see what happens at the cellular level.
00:11:11:14 - 00:11:41:22
Carmen Giordano
We have seen that the molecules in particular the detrimental molecules that we have investigated that are the lipopolysaccharide from this particular body, are able to move from the microbiota compartment to the brain compartment. And we see that mental defect there, at industrial level that's been tested. And they told us that the platform was very user friendly. They were not, you know, frightened and in using it or had some difficulties.
00:11:42:02 - 00:11:53:12
Carmen Giordano
They were biologists basically. So the idea was to allow all the clinician and biologist that are not expecting the engineer accusing. I don't know if I have an answer to your question, What if something is missing? Just tell me again.
00:11:53:14 - 00:11:58:20
Morten Limborg
No, it's great. I'm just trying to fathom a brain in this left.
00:11:59:01 - 00:12:06:24
Abigail Acton
Brain on a chip. I know. This is why I invited comment, because it's so intriguing. Is it such a wonderful thing? Yeah. Nico you had a question. You're raising your hand.
00:12:07:04 - 00:12:16:17
Nicola Gagliani
Thanks, Governor. That was very interesting. The question is very simple. Are you able are you planning to also culture the microbiota in your system?
00:12:16:19 - 00:12:46:12
Carmen Giordano
Yes. What we are trying to do is to culture the human, the complete human microbiota from also different patients with different pathologies. Because as I said, we started with the microbiota Alzheimer patients. But the idea is that our platform can be used to investigate potentially all the diseases where Multiorgan crosstalk is involved because we designed the platform in order to be very versatile.
00:12:46:14 - 00:13:21:08
Carmen Giordano
By changing cell type of cultured condition, you can represent other organs that you are interested in showing this way you can also think about some preventative autocratic strategies managing the microbiota composition and see what happens at the end. For example, all the research about probiotics possibly or probiotics, could be very interesting to understand how we can use this tools to help in these pathologies that are still very severe and very impairing of the patient life quality.
00:13:21:10 - 00:13:27:14
Abigail Acton
So it's very modular. Yeah, you can just add in a section or take out a section and change what you're looking at completely. Yes.
00:13:27:14 - 00:13:47:03
Carmen Giordano
The idea is that you have to imagine a tissue cultured system where you can change the cells so you can structure the cells in suspension in 2D, in 3D, interconnected by feeding them in the two side of a forest membrane as the biological barriers are. So you can imagine different applications.
00:13:47:05 - 00:13:51:01
Abigail Acton
Okay, that's wonderful. Thank you very much. Carmen. Yeah. One more question from Nicola.
00:13:51:03 - 00:14:05:24
Nicola Gagliani
Sorry. I mean, diffusion, diffusion of the molecules, how predictable is that? Is there a point where we would not need to do any more experiments? But based on the similarity of the structure of the different metabolites, can you predict the rate of diffusion?
00:14:06:01 - 00:14:52:17
Carmen Giordano
We have to consider this point and we never have developed the many computational models to understand how each molecule can diffuse. We we've seen a good correlation between our model and the real the real diffusion of the biomolecules we have followed. It depends basically on the molecule you want to see because you have to change. Also, for example, some characteristics of the platform, such as the ferocity of the membrane, because if you are using a molecule that is very let me say big or a particular kind of chemical structure, you have to consider also the porosity on the membrane and if and how the molecule can pass through one organ to the other.
00:14:52:22 - 00:15:12:19
Abigail Acton
Thank you very much. And that was an absolutely fascinating and very good questions. Thanks, guys. Okay, so now I'm turning to you Nico. Immune related diseases are on the rise and the typical Western diet might be to blame, but all theories need to be backed up. So the Diet-namic project wanted to know how short term dietary interventions can impact our health by modulating our immune systems.
00:15:12:21 - 00:15:19:03
Abigail Acton
Nicco How dynamic is the relationship between what we eat and the composition of our microbiome, and why does that matter?
00:15:19:05 - 00:15:48:01
Nicola Gagliani
So to show where is extremely dynamic, so the microbiome extremely rapidly responds to the diet. There are very clear studies in humans that just a couple of days of a very drastic change in your dietary habit dramatically impacts the composition of your intestinal microbiome. And then you ask me why this matters. And that was actually the question that we were trying to answer.
00:15:48:03 - 00:16:16:14
Nicola Gagliani
As Carmen alluded to, the microbiome can directly impact our health and different organs in our body, although we also found is that the microbiome is extremely connected with the immune system and being the microbiome. So dynamically change by the diet, you can infer that by changing our diet via the microbiome, you very rapidly also can change your immune system.
00:16:16:16 - 00:16:20:13
Nicola Gagliani
And that's what we have been studying in the last five and six years.
00:16:20:17 - 00:16:33:02
Abigail Acton
So can you tell me more about your findings regarding the impact of the microbiome that could be considered perhaps therapeutic? For example, I know that you're interested in studying its impact on chemotherapy and the efficacity of that process.
00:16:33:07 - 00:17:04:07
Nicola Gagliani
So what we found, I would say by serendipity in a way, is that patients affected by pancreatic cancer, they have different microbiome if they do or do not respond to chemotherapy. And that's where everything started. And we found that some bacteria that were highly abundant in those patients that responded to the chemotherapy were actually able to use an essential amino acid that as as it was ingested by a certain diet.
00:17:04:07 - 00:17:32:09
Nicola Gagliani
And we found indeed that these specific microbiome, specifically rich in responding patients was extremely efficient in producing a metabolites which is called 3-IAA, is a metabolite. The name is boring, but that's what it is. And these metabolites is very powerful in improving the efficacy of the standard care for these pancreatic patients.
00:17:32:11 - 00:17:43:05
Abigail Acton
That's absolutely fascinating. That's really, really fascinating. I mean, obviously you've published papers on this and you shared your findings. Are you getting any feedback from the medical community of interest on this or is it being picked up.
00:17:43:05 - 00:17:45:04
Nicola Gagliani
Too many!
00:17:45:06 - 00:17:49:21
Abigail Acton
Yes, I can imagine. But it's wonderful news. I mean, it's you know, such a natural way to.
00:17:49:23 - 00:18:16:11
Nicola Gagliani
This is obviously extremely in a way also risky. Right. So what we have provided to the scientific community is a proof of concept of the power of these metabolites. Now, to really move from the basic science to the clinic, much more needs to be done. This is obvious. We always say that, but especially in this case is extremely important because pancreatic cancer is extremely bad cancer.
00:18:16:11 - 00:18:26:22
Nicola Gagliani
A lot of people are suffering from this type of cancer, survival is not extremely high unfortunately, and that's why we need to not provide full hopes in the field.
00:18:26:22 - 00:18:45:09
Abigail Acton
Absolutely. No, no. It needs to be tested thoroughly to make sure it's completely robust. But it's an interesting concept that you found. Could you tell me a little bit more about the science? So you mentioned that you have studied the molecular mechanisms of T-cell adaptability. So in other words, your research has led to the discovery of a signaling pathway.
00:18:45:09 - 00:18:55:06
Abigail Acton
So you touched on that in your last answer. You were talking about the metabolites, but could you break that down a little bit more again, for a non-technical audience? But exactly what what is happening there, do you think?
00:18:55:08 - 00:19:18:24
Nicola Gagliani
So I need a little bit to step back. So there are those those were two a way independent findings. On one side, we found the impact of the diets on the efficacy of chemotherapy in pancreatic cancer patients. On the other side, we also found how T-cells dynamically respond to changes in the diet. And this is due to the fact that T-cells are perceived.
00:19:18:24 - 00:19:58:06
Nicola Gagliani
That's what we found even earlier are extremely plastic. So they can adapt to the changes in the environment. And within the environment there is also the diet and as I said before, the diet guide, the microbiota changes the immune system and among the cells of the immune system, T cells respond very rapidly to the changes in the diet because again, as the cancer cells alter T- cells respond to certain metabolites that are produced by the bacteria, their own cells of our body, and they all respond quickly and profoundly to these interaction between the diet and the microbiome.
00:19:58:11 - 00:20:17:16
Abigail Acton
Okay, that's fascinating. Thank you. Nico what attracted you to this area of research? There's for me, there's something very elegant about looking closely at a natural process and seeing the impact of of what we put enormous has further down the line in all sorts of ways. What attracted you specifically to this, though?
00:20:17:18 - 00:20:43:03
Nicola Gagliani
So I've always been interested in understanding how the immune system works. And so when we usually immunologists try to understand that by using classical immunological perturbations such as pathogens. But I thought that would have been also very interesting to understand how the immune system and the cells of the immune system respond to less classical immunological perturbations.
00:20:43:05 - 00:20:45:13
Abigail Acton
Something more natural, maybe just our environments.
00:20:45:15 - 00:20:54:13
Nicola Gagliani
Exactly. And I was always wondering, okay, now I go to eat something. Do I can I impact my mind system as rapidly as if I would take a pill?
00:20:54:15 - 00:20:59:20
Abigail Acton
Yeah. And in fact, you're finding that it's similar so far. What you're seeing so far is it's similar.
00:20:59:20 - 00:21:02:01
Nicola Gagliani
Yes. Yes. As very dynamic.
00:21:02:01 - 00:21:11:07
Abigail Acton
It's fantastic. That's good. That's good. Well, that's good to know. I've done that. Yeah, that's excellent. Okay, So do we have any questions for Nico please? Yes, Morten.
00:21:11:10 - 00:21:38:13
Morten Limborg
Thank you, Nick. That is quite fascinating. So I can see you have a strong focus on the food and the diet here. But I was just wondering, even though there's undoubtedly a huge effect of the diet, did you, by any chance observe any potential effect of their specific genes, a genotype of the different subjects? For instance, were there any variation of differences amongst subjects that got the same treatment in your experiment?
00:21:38:19 - 00:22:06:14
Nicola Gagliani
Really Morten, this is fantastic. So thanks for asking. Unfortunately, we cannot really answer those questions because as you know, to answer those questions, what you need is a huge amount of patients, in essence to really trace these genetic diversities and you know, in using mice, you are biased because mice are genetically identical. So you completely neglect that key aspect, but definitely will be fantastic to associate.
00:22:06:14 - 00:22:12:20
Nicola Gagliani
And I can tell you that definitely the genetics impacts the way you respond to the diet.
00:22:12:22 - 00:22:15:20
Abigail Acton
Excellent. Thank you. Carmen, you have a question.
00:22:15:24 - 00:22:31:03
Carmen Giordano
First of all, thank you very much. Very fascinating and very interesting. It might if a curiosity, what do you think could be the impact at long and short term of the diet of astronauts that are in a very particular situation?
00:22:31:05 - 00:22:34:01
Abigail Acton
Wonderful question, Carmen. It's such a lovely question.
00:22:34:06 - 00:22:57:18
Carmen Giordano
There is a reason Recently I read an article, very interesting article. They said that they are starting to understand if the life of these astronauts into space can impact their brain functionality, and they found something. So my question was, do you think that there is an impact also due to the diet they are forced to follow in space on their health in the long and short term?
00:22:57:23 - 00:22:59:11
Abigail Acton
Lovely question.
00:22:59:13 - 00:23:18:15
Nicola Gagliani
Of course. I mean, talk could be that that has it has an impact right. So I haven't tested but I think you're quite right if I can extend your question and I was thinking about that because a couple of weeks ago I was hiking, what about gravity as being, you know, gravity. Could that currently also, I think, impact the our immune system?
00:23:18:20 - 00:23:30:17
Nicola Gagliani
And I think we should find a way to dissect how gravity impacts directly our immune system and not via altering the way we eat because obviously that would be a very strong confounding factor.
00:23:30:19 - 00:23:39:05
Abigail Acton
Carmen I'm seeing your wonderful system, your wonderful tool being taken up into the space station to see what happens with the various organs you've got in the various worlds.
00:23:39:07 - 00:23:51:17
Carmen Giordano
Yeah, it's very interesting because I've read something about the impact of gravity also on brain functionality and the impact on gravity, on the interior of the brain and pathological.
00:23:51:17 - 00:24:11:21
Abigail Acton
It this sounds like this is a potentially another episode gravity. And then we could do all sorts of impacts here also underwater as well. Okay super. Thank you very much, guys. I'm going to turn to Morten. Mortne HoloFood consider the impact that feed has on the microbiomes of farmed animals. And also, I know that you're very interested in the genomic impact, too.
00:24:12:02 - 00:24:28:17
Abigail Acton
So excellent last question that you had. We've talked about humans, but the relationship between the health of any animal and its microbiome must be very close if we are what we eat as humans and presumably the same can be said for animals. How does that play out when it comes to feeding farmed animals? Morten?
00:24:28:19 - 00:24:53:15
Morten Limborg
Yeah, thanks for the question, Abigail. So and thanks for the excellent from Nico. So the main challenge when we when we look at production animals in order to to feed a growing population of humans there. The challenges if you look at the microbiome literature, it is extremely biased towards studies and human or lab mice with very little variation a snake alluded to.
00:24:53:15 - 00:25:15:10
Morten Limborg
Right, But if you look at the animal production today, there's a huge need for for replacing the current ingredients used in the feed. For instance, many animals are fed fish meals, but this come from wild populations where there are only so many fish in the sea. A lot of protein and fat comes from soy or other crops that necessitate deforestation in certain areas.
00:25:15:10 - 00:25:43:04
Morten Limborg
So we simply just need to replace this these ingredients in the animal seeds. And we don't really know what it does to the animal health. But here, obviously, we think the microbiome has that has has to play a role. And another example is that the biotech industry is already heavily marketing these so-called functional feeds where they add probiotics so basically a life culture of beneficial bacteria like we do in our own dairy products.
00:25:43:06 - 00:26:09:17
Morten Limborg
And often it's just like a one type fits all solution that you would feed the same probiotic strain to all chicken and the whole world for instance. Right. But I have in our team we have developed this new model that is more inspired by evolution in saying that even though the environment and the diet means a lot in shaping our microbiome, as Nico just told us the genotype 0f the host animal is
00:26:09:17 - 00:26:31:09
Morten Limborg
Important too. And so in our project and the HoloFood project, we set out to study some of the more pertinent challenges in either chicken production or salmon farming in aquaculture, because we believe in the future we can more intelligently tailor these feed solutions to the actual genotype of whatever food stock your farming in you are famining in your location.
00:26:31:11 - 00:26:43:09
Abigail Acton
So at this so much diversity across the same species, can you tell us something about species that are radically, radically different? So for example, your interest is fish. What's going on in a fish is microbiome.
00:26:43:11 - 00:27:05:06
Morten Limborg
Yeah, thanks for asking. So science, years ago when we started to study this topic on microbiomes and fish, I would say the same thing as in human in mice. And again, this goes back to the fact that the literature is so biased towards studies in humans or other warm blooded animals that has a constant body temperature and and which are nice, nicely warm.
00:27:05:08 - 00:27:31:24
Morten Limborg
So, so actually I can exemplify this through a series of students that I have had. So the first student Matisse was supposed to analyze the microbiome of hundreds of salmon, but he never, never ever managed to actually get microbial DNA out of the samples in the lab. That's what we thought. So actually, he ended up writing his whole thesis about comparing different methods to store the sample from the feed to the lab, because we thought we were doing something wrong.
00:27:32:01 - 00:27:51:12
Morten Limborg
And then another student, David, took over and and studied some microbes in some salmon we had where some were sick and some were healthy. And he was also getting deriving his expectations from the human literature. But when he, like, sorted out all the contaminants of the nonsense of the microbes, he only had two microbes left in the whole system.
00:27:51:12 - 00:28:16:05
Morten Limborg
And there were. But it was really interesting because there was one dominant microbe in the sick and one dominant in the healthy. So we can use it to to look at this. And then lastly, Jacopo did a whole phd, and he was supposed to sequence and study of the hundreds of microbes in salmon, and he ended up publishing five papers in just one specific bacteria that live and take the association with salmon.
00:28:16:05 - 00:28:22:21
Abigail Acton
So so that's really amazing. So we're talking about trillions and trillions in humans and you're talking but there's like a handful in the fish.
00:28:23:02 - 00:28:40:13
Morten Limborg
Exactly. I mean, and indeed, and the HoloFood project funded by the EU, we did what is called shotgun sequencing. So basically was sequenced all the DNA in more than 500 different salmon and after putting all of that data together we were able to assemble ten bacterial genomes.
00:28:40:15 - 00:28:41:13
Abigail Acton
Isn’t that fascinating?
00:28:41:19 - 00:29:01:02
Morten Limborg
There was all of the diversity. So coming from redoing our methods because we think we're doing something wrong, we have so now it took us five years to realize that this is just very, very different in salmon. Yeah, and remember, fish are exothermic, which means the body temperature inside the salmon actually ranges by 20 degrees over a season.
00:29:01:02 - 00:29:05:13
Morten Limborg
So that might be part of the explanation, but it's just very, very different.
00:29:05:15 - 00:29:12:08
Abigail Acton
It does beg the question why I mean, that seems to me to be the next question, the reason for these radical different numbers. No?
00:29:12:10 - 00:29:25:09
Morten Limborg
Yes. And I'm not saying that just because this is what it is in salmon, it might be different in other fish and salmon are carnivorous, so they may not eat meat as much microbial function compared to maybe so before.
00:29:25:11 - 00:29:29:10
Abigail Acton
Yeah, but I mean that would be the next place to look. Yeah.
00:29:29:12 - 00:29:30:12
Abigail Acton
Yeah, yeah, yeah, yeah.
00:29:30:12 - 00:29:36:11
Abigail Acton
Okay. Your background is in evolutionary biology, so how does that feature in your research? What insight does that bring to the table for you?
00:29:36:16 - 00:30:03:18
Morten Limborg
So yeah, just to elaborate a bit on the model I talked about in your first question. So our, our kind of different approach to this whole field is, is to look at the host organism and all of the microbes that live inside it as one single scaffold and part of the lectures referred to as a hollow by. So it means all of the life cells here and then and why we know the environment is really important in explaining to microbes.
00:30:03:18 - 00:30:24:06
Morten Limborg
It doesn't mean that these genes are not important. So if you think about us, we are all genetically different, right? When we look at each other and we also have a surface on the inside. So if you turned us inside out the epithelial surface in our stomach and intestines, also different environments, right? So you could actually think of the four of us
00:30:24:06 - 00:30:47:22
Morten Limborg
As four different types of brains of flypaper. And then imagine like a swarm of insects come flying through all of us, and then after the swarm is gone, it's a little bit different. What remains on our flypaper? So the same that happens even though we eat the same diet through intestinal tract, it's a little bit different. Which of those microbes actually are selected to stay in our environment and what not.
00:30:47:22 - 00:30:57:13
Morten Limborg
And that is where the host genotype comes into the equation of where this whole evolutionary angle actually can hopefully help do this in a slightly more precise way.
00:30:57:15 - 00:31:13:05
Abigail Acton
I think that's fascinating. I love it when you get kind of slightly impacts from cross-disciplinary backgrounds. You know, it's like a it shines a new light. It's a little bit like common as well, being a you know, with the engineering concept as well. That's excellent. Thank you so much. What do you hope the impact of your research will be?
00:31:14:02 - 00:31:48:07
Morten Limborg
What I hope is, first of all, that if we if we learn how the genotypes and the genes important, we would be able to actually in the future predict or even select four for healthy microbiomes in our production animals and eventually humans as well. But my main hope for the field in microbiome research is that we won't lose our humility when we get all these new data sets and have to interpret them in this complicated context, and then we don't get locked into our prior expectations about how it should be and how it should be.
00:31:48:07 - 00:32:16:06
Morten Limborg
Right? So so it's really, really key to maintain an open mind because the pace by which new huge datasets are generated is just so much faster than our theory and and bona fide models. Right. And I'm talking out of personal experience here. So I really think it's key to keep this open mind, even though we test hypothesis when we get these datasets and that we interpret them in a more holistic and evolutionary context.
00:32:16:06 - 00:32:27:08
Morten Limborg
But if we do that, I'm also super excited that this field, this microbiome research, will keep surprising us, but also enriching us and enable us to tackle our future societal challenges.
00:32:27:08 - 00:32:40:20
Abigail Acton
That's excellent. That's wonderful. Yeah, exactly. It's true. When you get a huge amount of information, you have an urge to just sort of classify it quick. No, not quickly, exactly. But you know, your preconceptions can step in coming. Any question? Yes. Carmen You have a question.
00:32:40:20 - 00:33:17:20
Carmen Giordano
I completely agree with your idea to lower down our expectation and see what the nature is telling us, because otherwise you can lose the pieces of the whole picture. So we have to see what is going on, what happens and what's the our experiments are giving back to us. So apart this my question is, do you think that your method can be applied to also other kind of animals in order to fine tune and help to fine tune the diets and the potential impact on our microbiota?
00:33:17:22 - 00:33:39:01
Morten Limborg
Yes, I think so. So I don't personally have a lot of experience from other animals, but within our our team, for instance, the whole evolutionary motivation comes from some previous studies on, for instance, the vampire bats. So they're like complicated mammals just like you and I, but they are adapted to live on a very specific and extreme diet.
00:33:39:01 - 00:34:00:24
Morten Limborg
They only get blood from other warm blooded animals. So there's a lot of essential vitamins, amino acids that are that they don't get through their diet. So it's only by actually looking beyond the pet's own genome, but also the microbes living inside it, how they see this. And then you might be able to relate studies like that to specific dietary diseases.
00:34:00:24 - 00:34:03:12
Morten Limborg
So metabolic diseases in humans.
00:34:03:14 - 00:34:13:10
Abigail Acton
Excellent. Thank you. Well, listen, I want to thank you all very, very much for your time today. And yeah, I think it's been a wonderful episode because it's all been so fascinating. Right?
00:34:13:12 - 00:34:14:21
Nicola Gagliani
I think it was very nice.
00:34:14:23 - 00:34:20:00
Carmen Giordano
Thank you very much.
00:34:20:02 - 00:34:44:12
Abigail Acton
If you've enjoyed this podcast and are interested in the latest scientific research coming out to the EU, have a listen to previous episodes. Follow us on Spotify and Apple Podcasts and check out the podcast homepage on the Cordis website. We've looked at apps designed to make finding missing children more effective. Trace the production of glass and related medieval trade routes and asked what it would take to make space exploration from the moon possible.
00:34:44:14 - 00:35:02:17
Abigail Acton
In our last 28 episodes, there will be something there to tweak your curiosity. So do have a listen. Perhaps you're curious about what other EU funded projects are doing in the area of microbiome research. The Cordis website will give you an insight into the results projects funded by Horizon 2020 and Horizon Europe that are working in this area.
00:35:02:19 - 00:35:22:18
Abigail Acton
The website has articles and interviews that explore the results of research being conducted in a very broad range of domains and subjects, from epigenetics to Epictetus. There is something there for you. Maybe you're involved in a project who would like to apply for funding? Take a look at what others are doing in your domain. So come and check out the research that's revealing what makes our world tick.
00:35:22:20 - 00:35:30:14
Abigail Acton
We're always happy to hear from you. Drop us a line. Editorial at CORDIS dot Europa Dot EU. Until next time.
Il microbioma è il nome dato a tutti i microrganismi che vivono dentro e fuori di noi, la maggior parte dei quali si trova nel nostro intestino. Essi sono del tutto unici per ognuno di noi e ne ospitiamo oltre 100 000 miliardi. Questa comunità di microbi interdipendenti ha un ampio impatto sulla nostra biologia e la ricerca si divide essenzialmente in due aree principali: la diversità tassonomica per identificare «chi» è presente e la metagenomica funzionale per capire il ruolo da essi svolto. Quindi come capire in tempo reale, quali segnali chimici vengono inviati dal microbioma ad altri organi? Questi segnali modificano il funzionamento del nostro cervello? Come interagisce il nostro sistema immunitario con i microbi che ospitiamo? Tutto ciò può avere un impatto sulla risposta di un individuo alla chemioterapia? E per quanto riguarda gli altri animali, in che modo il microbioma di un pesce differisce dal nostro e quali sono i punti in comune? I nostri tre ospiti esplorano queste e altre intriganti aree della più recente ricerca sul microbioma, finanziata dai programmi Orizzonte dell’UE. Carmen Giordano, coordinatrice del progetto MINERVA, è professoressa associata di bioingegneria presso il dipartimento di chimica, materiali e ingegneria chimica del Politecnico di Milano. È a capo di un team di ricercatori che sviluppano strumenti tecnologici innovativi per aiutare gli scienziati a conoscere meglio il funzionamento del sistema nervoso centrale. Nicola Gagliani dirige l’omonimo laboratorio che studia i meccanismi della biologia delle cellule T presso lo University Medical Center di Hamburg-Eppendorf, in Germania. Ha studiato l’interfaccia tra fattori ambientali e risposte immunitarie nel progetto Diet-namic. Il biologo molecolare ed evolutivo Morten Limborg è professore associato presso il Globe Institute di Copenhagen, in Danimarca. Attraverso il progetto HoloFood, Morten ha studiato come rendere l’acquacoltura più sostenibile utilizzando strumenti come il sequenziamento del metagenoma per potenziare i microbiomi sani dei pesci e di altri animali d’allevamento.
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Parole chiave
CORDIScovery, CORDIS, MINERVA, Diet-namic, HoloFood, microbioma, cellule T, sistemi immunitari, bioingegneria, acquacoltura