The future of research on human-associated microbiota

Anand Jagatia 0:04

What does the future hold for microbial research? In the past decade, there's been an explosion of interest in the trillions of microbes that live on us and in us, and the roles they may play in nutrition, in disease, in cancers, and even in brain development.

The goal of many scientists is to understand the microbiota better so that we can harness it to improve human health. But how we get there, and what will some of the challenges be? I'm Anand Jagatia, and joining me on the line to discuss these issues are three researchers on the cutting edge of the discipline.

Rochellys Heijtz 0:37

Hi, my name is Rochellys Heijtz, and I'm a data scientist, I work at the Karolinksa Institute. And we're particularly interested to understand the role of the human gut microbiota on early aspects of brain development and behaviour and in particular, neurobehavioral outcomes implicated in the pathophysiology of autism spectrum disorder.

Eran Elinav 0:59

Hi, my name is Eran Elinav. I'm a professor at the Weizmann Institute of Science in Israel. And we're trying to decode the alphabet that composes the language by which we and our internal microbes (commensal microbes) communicate in health, and to understand what happens when this language, when this crosstalk, is perturbed that leads to the development of a variety of common multifactorial diseases.

Jennifer Wargo 1:26

Hello, my name is Jennifer Wargo. I'm at the University of Texas MD Anderson Cancer Center. I'm a surgeon scientist and my group and I study the role of intertumoural bacteria as well as the role of the gut microbiota, in response to immunotherapy.

Anand Jagatia 1:41

So my first question is about moving from correlation to causation. There have been plenty of association studies over the years that have linked the composition of a microbiota to certain health outcomes. But what we really want to do is find out whether microbes actually causing or driving disease. So I wanted to ask you how we going to get there? Eran, should we start with you?

Eran Elinav 2:03

Well, I think that the nice thing about the microbiome field that in a decade of very intense and growing effort, it has started to produce very exciting tools. For example, germ-free mice, they enable us to transfer whole microbiome configurations, or distinct signatures of microbes, or even single microbe from humans suffering of a particular disease into mice that don't harbour any microbiome of their own. And then we can actually model the human disease in the reduced-mouse setting. And if we can recapitulate a human phenotype in these recipient mice, we can study them using many tools that are available in animal models, in order to reach insights about the causality by which a given microbe or group of microbes in the human body, contribute to disease.

Anand Jagatia 2:54

Okay, so germ-free mice are potentially going to continue to be really important tools. How else can we study causality?

Eran Elinav 3:02

The last two or three years, we've gathered more technologies that enable us to further prove causality or to probe into mechanisms. These include, for example, the development of what we call metabolomics, which allow us for the first time, to not only characterise the genomes of all the microbes that reside within different human microbiomes, but actually to characterise and quantify the 10s of thousands of potentially bioactive small molecules that different human microbiomes secrete or modify. So these small molecules we actually argue constitutes part of this elusive alphabet, by which we and our microbes communicate with each other.

Anand Jagatia 3:46

Right, so looking at these proteins, these metabolites means that we can not only say who these microbes are, also figure out what they're doing. Rochellys, is that something that your group has been looking into?

Rochellys Heijtz 3:55

I certainly agree, I will only add one thing, we have taken the same approach, looking at the metabolites, trying to identify also, those active products that actually can cross the blood–brain barrier. And we actually going now into using CSF sample, cerebral spinal fluid, to see if we can also detect in humans as well.

Anand Jagatia 4:18

And Eran, you mentioned that these microbes could potentially be producing 10s of thousands of bioactive molecules that we might want to study. So how on Earth do you go about analysing that much data?

Eran Elinav 4:29

That's a great question, because its actually includes not only the thousands of metabolites that the human microbiome can generate or modify, but also a huge chunk of genomic data that represents the genomic code of the different microbial elements within the microbiome. So the way that we choose to try and simplify this really multi factor equation is to develop new computational pipelines. And using this computational machine learning and AI approaches, we are able to narrow down the list of potential drivers of disease coming from the microbiome in order to actually study their potential function.

Anand Jagatia 5:10

Jennifer, can I bring you in here?

Jennifer Wargo 5:12

Yeah, I just wanted to echo now what we're trying to do is go beyond this, again, this taxonomy to look more at function, to do metabolic profiling within these patients, and also to do more work in the mouse models. So we work a lot with the germ-free mouse models. We're also looking at other factors that impact these gut microbes and how they may influence response to cancer treatment and overall immunity, such as the role of diet. In cancer patients, we find that if patients have a high-fibre diet, they they actually have a more diverse microbiome and are much more likely to respond to immunotherapy. And in addition, we've looked at the use of over-the-counter probiotics, which has a… an interesting impact on the microbiota in our patients, and also in our germ-free mouse model.

Anand 6:00

What are going to be some of the difficulties then in teasing out some of those relationships?

Jennifer Wargo 6:05

So I think, you know, a common question now is, what is the optimal consortia of microbes that can actually enhance responses enhance overall immunity first, and then enhanced responses to cancer immunotherapy. And I think we don't know the answer yet. And certainly, there's a lot of trials underway, including trials using faecal transplant from complete responder patients being transplanted into patients who were going on to immunotherapy. And we have such a trial underway. I mean, I think we do need to standardise approaches for collection, for sequencing, and then, ideally, to develop databases that could be shared, and so that we can learn, you know, really, from these global cohorts

Anand Jagatia 6:48

What I was wondering was whether now each of you could paint a picture of the future. So looking forward ahead, you know, decades in the future: What kinds of things do we want to be able to do with this research and this knowledge? Rochellys why don't we start with you? What do you what are your hopes for the future?

Rochellys Heijtz 7:05

Well, in terms of my own research, we recently discovered that components of the bacterial cell wall, they're able to translocate from the gut and cross the blood–brain barrier. So we are very much focusing on identifying those motifs. And what we would like to have in the future is like a microarray. And then we can actually screen infants once we identify, once we know, the mechanisms. Then we need to have tools for the clinicians to screen large populations. And then we can actually go into personalised medicine.

Anand Jagatia 7:42

And Eran, I know that your personalised medicine and personalised nutrition, they're both things that you know you're really interested in as well.

Eran Elinav 7:49

Yeah, we have found that the microbiome can represent a unique signature, which is unique to each individual, which can explain different traits of different individuals in health. We've recently proven this to be the case, with personalised nutrition, in which we deeply examine the large cohort of human individuals, and found that we can use data acquired from the microbiome together with other clinical data, in order to accurately predict an individualised, unique responses to any given food, which opens up the prospect of personalising dietary approaches, in contrast to the one-size-fits-all dietary modalities, which we know have not worked very well, in 50 years of fighting the metabolic syndrome.

The microbiome represents an extra genome, which, in contrast to our human genome, is not only important, but is amenable to change and manipulation, we can use it diagnostically in order to personalise treatment into personalised diagnostic. And we can try to find therapeutic targets in it. And this concept of personalisation and the utilisation of the microbiome, I think would constitute a growing and exciting aspect of microbiome research in years to come.

Anand Jagatia 9:10

Yeah, certainly, I mean, that, that that idea of being able to, you know, re-engineer or restore or kind of reconstitute somebody's microbiome so that it kind of to make them healthier is really exciting. I mean, what we're going to be some of the challenges that we need to kind of deal with now and in the coming years, so that we can get to that stage one day.

Eran Elinav 9:28

I think that there are several challenges which we need to face, we need to improve our clinical trial capacities to larger trials, and to include much more data collection, and advanced technologies that would enable to analyze this big data such as AI and machine learning. And this is a big challenge that we as a field need to face in terms of development of new experimental and computational techniques that will enable us to probe and to differentiate between the causative signals and the many noisy secondary signals, which are of less importance.

Anand Jagatia 10:02

And Jennifer, finally, what do you think that the future could hold with relation to cancer? And what's kind of stopping us from from getting there one day?

Jennifer Wargo 10:10

Yeah, no, definitely. I think one challenge in the field is I think we don't know what is the perfect microbiome unit to either treat cancer to prevent cancer. In addition to that, I think there is kind of an urgent need to really develop tools to be able to profile the microbiome, and for patients with cancer, relatively quickly, but that are reliable, and that can be tested in large cohorts of patients. And then from a therapeutic aspect, again, I think, you know, Eran hit the nail on the head, I think we need to do better trials, I think we need to be rational about the different ways that we are manipulating the microbiome, and use a scientific and rational approach to designing strategies to manipulate the microbiome. And then also to do this in larger cohorts in a collaborative way to collect large numbers of bio specimens, so that these can be analysed, and if we know if/why a patient responded or didn't respond. You know, and then I think another big question in the field is, is an optimal microbiome optimal for overall health and protection against all kinds of diseases, not only inflammatory bowel disease and neurodegenerative disease? But is there a, you know, the perfect microbiome out there that could really restore optimal health? And, you know, I think that's a big question that, you know, if I were to think ahead and say, what is the future, you know, what could we look for in the future? So could you one day have an app on your smartphone or on your smartwatch that could actually tell you what your metabolic profile is, and which would be a reflection of your gut microbes and could actually send you an alert to eat more fibre or modify your diet? Wouldn't that be interesting?

Anand Jagatia 11:50

That sounds like a really incredible idea. And microbiota research in general, and what it could offer us is something that's really captured the public's imagination, but there is also a lot of hype. And so I wanted to ask you what may be some of the limitations of this research are? What are some of the things that it won't be able to do? Or what are some of the areas where we should be more cautious?

Jennifer Wargo 12:08

One area of hype is that the microbiome is really been embraced by really everyone is now something that's modifiable that you could change that could actually improve overall health. And so there are large efforts to do that. But they're not always, rationally thought out. And so I think that there are a lot of people who want to go out there and change their own microbiome and do so by either buying over-the-counter probiotics or changing their diet in a drastic way. And they might actually be harming the microbes in their gut and actually negatively impacting their own health. Another aspect of the hype is that now there are all these trials looking at different ways to manipulate the microbes in order to treat disease. And I think, you know, we will see negative trials in this because not all of these trials are going to be perfect right off the bat. We don't know the answers yet. And I think the important thing is that we need to learn from those trials, not just when these negative trials start to get published or not published and presented, not just throw up our hands and say, it was all hype, this can't work.

Anand Jagatia 13:16

Thanks Jennifer. Eran, Rochellys, have you got anything to comment on in terms of hype?

Eran Elinav 13:20

I think that some of the hyper hype is caused by irrational expectations of the microbiome hearing are changing everything in human physiology. And we need to realise with with the slow maturation of the field, that the microbiome or components in the microbiome would probably be a beneficial and will probably be found to regulate many important human body processes. But the microbiome is not going to do it all and, and the human genome is extremely important. And and really to get at the true potential of the microbiome. And to get over this overhype, we need to transform the field from many aspects of what I call hand waving into data driven, science driven and mechanism driven studies that would actually identify how components of the microbiome do what we think they're doing.

Anand Jagatia 14:11

Yeah. And Rochellys, how about you, have you got anything that you wanted to say?

Rochellys Heijtz 14:14

Another point of view is that I get many phone calls from parents out there that they want, you know, the perfect probiotic for their kids that they have ADHD or autism, or even other patients with anxiety disorders. And I think that is one thing that we need to be aware that there is no going to be the probiotic or the perfect solution. For all the psychiatric disorders, we have to take into consideration aspects like developmental changes that are going to take place, gender differences, the impact of diet, and so forth. So… so when we're thinking about therapeutics, it's not a trivial issue. And this is where I think we need to have our expectations more realistic that this process will take more time than just three or five years, in my opinion, at least.

Anand Jagatia 15:08

Could each of you maybe give me like one trend that really excites you? And something that, you know, our listeners should kind of like keep an eye on? And, Jennifer, why don't we start with you?

Jennifer Wargo 15:17

Yeah, I think well, one area that really excites me is the role of the tumour microbiome. And, and I think early studies focused on bacteria, but now we know that viruses can play a major role in carcinogenesis, and even response to therapy. And so I, I would keep my eye out for the, the microbiome in tumours as well. And could we develop vaccine strategies based on that information to actually prevent cancer?

Eran Elinav 15:39

One point that probably would become more and more prominent in the microbiome field in years to come, which is the study of microbiomes other than the gut microbiome, the gut microbiome has been extensively studied. But there are other microbiomes that are equally interesting, such as the skin microbiome, the urogenital microbiome, the respiratory system microbes. In each these localities, the microbes have evolved to provide critical activities and functions to the relevant organ. And I think we will learn much more about these other microbiomes and their contribution to human health in years to come. And as well, we will learn about the contribution of microorganisms in these different microbiomes that are different than bacteria, the virome the mycome, the parasites in the microbiome are probably very important and central, but are much understudied, as compared to bacteria. And I expect that we will learn much more about the contribution of these other kingdoms, to this really intriguing ecosystem in years to come.

Anand Jagatia 16:41

Thanks, Eran. And Rochellys, how about you? What are some things that we should look out for?

Rochellys Heijtz 16:45

Something that excites me at the moment is actually the impact of diet because there we can, we can actually help and guide the patients. Another thing is that I think we need to make a global consortium and effort, really, perhaps, is an organisation more at… at international level, to join these efforts and to really critically guide new clinical studies and translational studies into the field that that would be something that I would like to to see.

Anand Jagatia 17:16

Fantastic. Well, it's been an absolute pleasure talking to all of you all the remains for me now to do is to thank each of you: Rochellys Heijtz, Eran Elinav and Jennifer Wargo, I've been Anand Jagatia, thank you so much for speaking with us.