Justin Sonnenburg | The Gut Microbiome is a Key Lever on Human Health

Hello everyone, welcome to the sponsor of the

health

and biotechnology outreach group, Bahamas plus Capital. I'm very excited to have Justin Southern Bronk here and before we get going, I want to remind people that if you're interested in joining us, Vision Weekend is taking place in San Francisco on the 2nd. and December 4 and at Home in France from November 18 to 20. I'll leave the link here to the weekend in the chat, but it's basically an opportunity for all of you to meet people in this group and in other groups, we have a really exciting longevity and biotech track, but we also have molecular machines, a space of tags newest, Computing and other tracks, so if you're interested in exploring a little what progress might look like. different domains, I think it's good to go there, there is an application form, which means that people come into this group, you know, who are researchers, scientists, etc., they can apply for subsidized tickets and then get to that and so on in the final application review so just a reminder if you want to join and now is a good time to apply.

I also want to say that the biotechnology and longevity report is now available and so are our workshop videos. so if you want to check it out, do that too and there's also the longest price that you can still apply, which I'll share a little bit more about in the chat, so that's all from me for now. I'm very excited to see it. welcome Justin is at work, we have taken into account all your respective requests and nominations, very seriously, we present talks, which I will also share again here in the chat, but this is just to say that you know we trust this group the most. is growing in nominations from all of you guys nominating wonderful people who should give a talk and I think Justin, you've been nominated not just by one but by several different people so congratulations on that so we take you seriously and uh, here you are, thank you so much for joining us to discuss the conscious biome.

I'll be in the chat. I'll be monitoring after your presentation, we'll get to the q a um, as always, time gets very short at the end, so if I want to make sure your question is heard, leave it in the chat so we know we'll get to that from the beginning and for now I'm very excited to have you here. I think thank you very much for coming. Thank you all for joining and I'm very excited about the presentation thank you okay awesome thank you so much for that great introduction let me make sure I share the right information.

Okay, it's wonderful to be here, yes, thank you for the nomination and the invitation. Today I wanted to cover the basics of the gut

microbiome

, but what I also see is a great opportunity. I think a lot of people are thinking about the gut

microbiome

as this interesting component of our biology and

health

and they're thinking about it in a very traditional way in terms of how it can be harnessed and um in biomedicine um I think it's a little flawed um or al less no uh comprehensive and I think the biggest opportunity is to think about the microbiome in a completely new way um um I uh think that um I see there's an admission that comes up, I don't know if it's anyone else, that's the thing as a co-host, you and I see it when people try to come together and I understood it.

I'm not sure if I'm the only wonderful guardian, no, no, I'm here, okay, so I think there's a huge opportunity to potentially correct the deterioration of the microbiome in the industrialized world. and that could reverse the trends of many Western diseases, and I'll get into that in more detail, so I like to start with this cross section of the gut microbiome in situ. This is just a cross section of colon the microbes that live in the lumen of the intestine or on the top left here each little colorful stick there is a different bacterial cell and then on the bottom right the blue area is the host tissue those are clonocytes and um and you can see how close the microbes have to host the tissue, just separated by this thin green mucous layer that we secrete to keep the microbes in the right place, so we're still making an amazing interface for information exchange biological.

We need to work hard to map. all of this, but we have learned some great principles over the last 10 to 15 years studying this community, so we know that our

human

s are outnumbered by the microbial cells that live in and on our bodies. by number of cells, we are actually more microbial than

human

, there is enormous coding potential in the composite genome of our microbiome, most of these genes we still do not understand what they do and of course there is an important step to understand not only what microbes are in our gut, but understanding what these microbes are doing, how they integrate with our biology, we've known for a long time, or gut microbes are important for gut health, they're important in helping us digest food, but There really is an important role of the gut microbiome in tuning much of our biology, from metabolism to immune function and things like neurodegeneration, mood behavior, so this little diagram here captures the microbes. as if they are upstream or in control of much of our biology. but I think a better way to think about it is that our microbes are part of the integrated system that is our body.

What's special about our gut microbiome is that it's malleable, so we can change it, and it's also individualized, so that gives us a huge opportunity, you know, once we understand how to manipulate this community and how those changes will ripple throughout our biology at a tremendous level to change our health in various scenarios, and I really think the microbiome is going to be an incredibly important part of Precision Health in the future, but I think the same characteristic of Malleability also leads to a vulnerability that our microbiome can deteriorate and, in fact, since we have not paid attention to it for the last decades.

Of the tremendous lifestyle changes in terms of processed foods, use of antibiotics, many of you are aware of the health measures that during industrialization and particularly during recent industrialization, our gut microbiome has changed quite drastically and what the implications are for foreign human health, so an important question has arisen. To what extent can we manipulate our own biology through the microbiota? Can we generate a knowledge base rather than tools to rationally manipulate these microbes? There are many different approaches to doing this, but one of the most important things that you will see if I look in the field and certainly throughout my talk is that diet is the main tool we have to manipulate our gut microbes in terms of composition and function and therefore what components of the diet are important, it's actually dietary fiber and I think that You know, dietary fiber has become a kind of inert, boring substance in our diet, but it really plays a role amazing at feeding our gut microbiota and in particular what we like to call microbiota accessible carbohydrates, the complex carbohydrates that are metabolically accessible to our gut microbiota and this scheme just lays out the logic of why these components of our diet are disproportionately important for gut microbes if we eat a Western diet full of fat, starch, protein, you know, simple sugar, a lot of that is digested in our little one.

The intestine is absorbed into our bloodstream and our microbes starve. If we eat a plant-based diet that's high in dietary fiber, we can't actually digest these complex carbohydrates, they end up getting into the distal guide, which is then microbes. can ferment these complex carbohydrates producing short-chain fatty acids and other metabolites that enter our circulation, so there really is a huge metabolic difference between simply eating a Western diet and eating a high-fiber plant-based diet if we don't feed our microbes with food. fiber, we know that our microbes start to eat us, these microbes can use that green mucus layer as a backup food source, it is also made of carbohydrates and we know that a low fiber diet results in mucin bloom using microbes and also a thinning of the mucous layer and in mouse models that we and others have tested, so one of the most important changes in our thinking has occurred in the last 10 years in my laboratory, just thinking about the asymmetric plasticity of the microbiota to over evolutionary time, eh, in comparison. to our human genome, so we have these two components of our microbial and human biology that need to work together for us to function properly, but they can adapt at very different rates, so if you take antibiotics, you eat a Western diet for a period very short.

Over a period of time, you can change your microbiome, while your Human Genome, of course, whether as an individual or as a society over a generation, remains relatively static, leading to the possibility that there may be an incompatibility between our genome human and our microbiome, so we're really interested in mapping common features of the microbiome as humans expanded across the planet. Can we learn about the functions and species that may have shaped our human genome over the past hundred thousand years and perhaps longer? Has the microbiome changed recently with lifestyle? We spend a lot of time thinking about these questions.

We have been studying non-industrialized populations in different parts of the world. This was a study we published in 2017 focused on Hadza hunter-gatherers, but putting their microbiome data together with a lot of other microbiome data that's been collected in other studies, our data is right along the line here that says Tanzania, all these populations, their microbiome data is represented in this primary coordinate graph that simply separates the composition of the microbiome based on the variability in that composition versus other populations and it's basically the grouping of the populations on this x-axis, it's significant here and You can see that non-industrialized populations are on one side, industrialized populations are on the other side of the axis, suggesting or illustrating that there has been a state. a change in lifestyle, this separation is not just a general loss of biodiversity in the gut, it is actually a loss of specific families of microbes, so these graphs at the bottom show a fractional representation of different groups of bacteria that live in the intestine and, um, yeah. how their fractional population is represented on the same axis: the spirochetes succinivibrio and previtella, all very abundant and non-industrialized populations, but rare or absent in industrialized populations, and the opposite occurs with Veruca microbial blooms in industrialized populations, but very rare in non-industrialized populations. and it just so happens that Veruca microbes are mucin-loving bacteria and therefore the same data that we see in mouse models with a proliferation of mucin-loving bacteria within the intestine on a low fiber diet we can see in hundreds of individuals in populations that eat a low fiber diet one of the detractors of this data is that all of this data comes from different studies, uh, people with different human genetics living in different geographies, so Ashish Jaw was a postdoc in my laboratory and is now a professor at New York University in Abu Dhabi.

He returned to his native Nepal and surveyed four populations that live along a lifestyle gradient but have very similar human genetics and live in similar geography. He quantified the differences in his lifestyle using a correspondence analysis of an extensive survey questionnaire that confirms what was basically known. About these populations that the chip hangs or runs through, the Raji and the router are transitional populations settled in the 1980s, they feed a little, but they mainly cultivate and the Taru only cultivate, so they were established 250 years ago, for What Ashish was interested in was how their microbiomes compare to the microbiomes of Americans and we see that the microbiome composition in the bar graph on the left reflects lifestyle, so the foragers are on the far left, the Americans on the far right and then transitional communities are in the middle, so the extent to which populations have moved away from a foraging lifestyle determines the extent to which their microbiome has changed.

He can see that in more detail if he looks at the different taxa and the abundance in these different populations, these are the taxa that explain the separation in thedata, so the individuals in the chi Peng um group are shown on the left here, each column is the microbiome of a different person. If we simply compare the Peng chi to the Americans, we actually see very similar differences to what we saw when we looked at the Hadza versus the Americans, but now with these transition communities we can again capture the intermediate states of the microbiome transition.

The degree to which populations have stopped foraging determines the degree to which their microbiome has changed. Very similar patterns are seen. Acromanzia mucinophila Very low abundance in traditional communities Very abundant in the For Americans, this is a muse and a loving bacteria. The opposite is true for these species that we call missing taxa, so these are our species or families that are volatile and negatively associated with industrialized human societies, so these are the microbes that are disappearing in industrialized societies. Gut and Ashish in this additional paper that we published proposed this model of um disappearance and appearance of different microbes along this lifestyle gradient.

I've mentioned the taxa of disappearance, we also know the taxa of flowers, these are taxes that um Bloom are selected in societies of urbanization and modernization and um she noticed these different patterns of disappearance and appearance and um you know, we think of these populations as populations moderns who live different lifestyles, all equally evolved, but another way to interpret this data is the change in human lifestyle over time for industrialized populations, which is why we were all foraging for food at one point, a few years ago. Ten thousand years ago, we switched to agriculture and now, in the last one to 200 years, we have become more and more industrialized. and now our lifestyle is spreading around the world changing the microbiome as it spreads, so it's all compositional data.

What about functions? We now have metagenomic data that confirms many of these trends that have composition and then give us great detail in terms of function. The graph only shows functions that are enriched in the hunter-gatherers versus enriched in the industrialized gut, there are important differences and this tells us that these changes in composition are not just changes in um that result in redundant functionality with different species doing what same. functions we actually have a functionally different intestine than we had, probably a few hundred years ago and again with the same human genome. What is surprising about this data is the number of oxidative stress genes that are represented in the industrialized intestine and this is a pattern. that suggests that there is a latent inflammation or at least a different metabolic state within our epithelium and colonic tissue, so really, an interesting trend, okay, that's consistent with or supports the spread of things like inflammatory bowel disease in the Western world, and so, this change in the gut microbiome can be observed in real time.

This is a beautiful study by the Dan Knights group published a few years ago in which they followed immigrants from Southeast Asia to the United States and what they saw is that in a few months the microbiome of these people would change to look more American the longer they were people in the United States, the more diversity they would lose they would lose Privateella species, which is a hallmark of industrialization, they would lose fiber-degrading bacteria, so again with a low-fiber diet you lose a fiber-degrading species. more strains of bacteroides and then the pattern becomes more severe over generations, so children of second-generation immigrants born in the US have an even more industrialized gut microbiome, so again, This is everything you know about modern populations happening in real time, a beautiful Harvard study by Alex. costix group Sequence Paleophysis North American individuals who lived one to two thousand years ago determined microbiome composition based on that sequencing data and then overlaid the Paleo feces in the orange spots here on top of other modern ones Microbiome composition data from industrialized populations and not industrialized.

We see that Paleo stools are very similar to non-industrialized microbiomes in terms of microbial composition, supporting that the industrialized microbiome is a recently derived state and that non-industrialized populations have microbiomes. which are similar to the microbiomes of and our ancestors, so we have changed our microbiome recently, our microbial identity has changed, we know that our gut microbes can change our immune status, we also know that chronic inflammatory diseases are increasing, whether you are looking ulcerative colitis or other autoimmune diseases, you know, food allergies, there are a lot of diseases driven by immune dysregulation that have increasing rates at an earlier age of onset and spread is our lifestyle, so The question is, could this strange microbiome? inside our intestines our immune system is being deregulated and you know we have an approach that we have inherited from the air of infectious diseases of being a reactive medicine of waiting for chronic diseases to arise and then basically trying to treat the symptoms. of this inflammation by turning off the immune system, which has a lot of negative consequences, but you know, tons of drugs try to turn off the immune system or aspects of it, an inflammatory disease, so it's like we're trimming the branches of these diseases to as they arise and instead, you know an important question is: can we think about this differently?

Do you know the current approach? I like this cartoon. The sailor tells good news. Captain, he can inform the passengers that we have reduced the rate of sinking. And instead of stopping the rise of diseases, I think the question is: can we stop them in their tracks? What are the root causes of these trends? Know? We have dozens of these inflammatory diseases. Are there really dozens of inflammatory diseases? different causes or there could be just a small handful of causes and then the disease that you develop is determined by other environmental factors or maybe elements in your human genome that determine that you will have heart disease and I will let you know cancer, but Um, but basically it's inflammation that's really sending us on this trajectory, so you know, could the microbiome and the microbiome and diet really be at the center of this?

Is there a unifying theory? So we really started to think about whether we can repair it. our gut microbiota and improve our health or at least proof that health can be improved by changing the microbiota and we started the human microbiome study center at Stanford with a large group of partners and the goal is to really develop humans like experimental model to study. the gut microbiome um I think I worked closely with my wife Erica, we were raised in the era of thinking about the molecular mechanism working through animal models and then trying to make a translational leap to humans that typically fails um and I think probably has a higher failure rate when it comes to the microbiota just because of the divergence of animal models to humans because we are studying the diet because the diet is safe we ​​think well why can't we start doing experiments in humans with use omics data of diet map the interactions and then translate them back to animal models, knowing that we would be studying something that is relevant to human biology and also gain direct information about what works and what does not work to change aspects of human biology through of the microbiome. nutrition axis, so I just want we've done a ton of studies in close collaboration with Christopher Gardner's group.

I wanted to give just one example of this. This is a study we call the E5 enemy study, where we feed people fermented foods. or high fiber stuck over the course of several weeks to see how that would affect your microbiome and immune status. We published this in Cell last year, it was covered in the New York Times if you want a quick read of the overview of the study, but basically I'll just give you a little bit of the highlights here, focusing on the group that ate highly fermented foods. , so, these are people who eat, you know, kimchi, yogurt, kefir, sauerkraut, kombucha, things like that, they could be foods with live microbes that have been fermented.

I got people to eat differently with the help of Dalia Perlman, who is an amazing diet educator at Stanford, who works with people to actually get living, free humans to eat differently, which is not so easy and then the project was really boosted. by three um fantastic trainees Maddie Hannah and Gabby um and Gabby are now professors at UCSF um so this is a quick overview of the data um we got people to increase their fermented fruit foods from um base to the maintenance phase, like this Here we enroll people for three weeks, monitor blood and stool over the course of the study, take them through a ramp phase, a maintenance phase for six weeks, and then a washout phase four weeks later.

During the maintenance phase, we gave people up to more than six servings of fermented. meals a day started with about zero servings of fermented foods a day, so we saw a huge increase over the course of this increase, a huge increase in the diversity of their microbiota. This seems complicated, but in the context of human studies this is really remarkable. increase in diversity that frankly is not commonly seen with dietary interventions and people over this kind of time period, ask on that slide, ask on that boxplot, yes please, that looks pretty messy and I'm curious , what is the least squares linear fit to the medians or what are we looking at there yeah, no, you're going to have to do it.

I don't remember what the setting was, um, I can, I can send the document and make it available, um, correctly, the data that I'm not including here the high fiber data and then a lot of other data from human studies where the line it's completely flat despite the intervention happening over and over and over again, so we see significance from baseline at several of these, um, later time points, okay, quick follow-up question, yeah, so The whole fiber thing is really iffy. In my opinion, I did my limited look and am wondering if they are separating the fiber like this, it says fermented fiber foods. like there are two things, there are fermented things and then there is fiber, there are separate problems, they are not totally and what I am not showing here is the high fiber arm, so we had another arm that ate legumes, whole grains, vegetables, fruits increased. dietary fiber from 20 grams baseline to over 40 grams of dietary fiber for six weeks during the maintenance phase, so I'm not showing that data, just for the sake of time, but interestingly enough in that study in that arm of the study uh there was no increase in microbiome diversity and I'll show you in a second here um for the fermented foods arm there were major changes in I'm just showing four here there were over two dozen inflammatory markers that decreased as these people were increasing. the diversity of your microbiome by consuming fermented foods, we didn't see changes like that with a dietary fiber, so we had two separate arms.

I'm just showing the highly fermented foods here and that was six weeks long, that was fine, so these graphs show. The time course decreases as the study progresses, but the main endpoints of the study are from what we call 10 weeks, but it is six weeks of maintenance plus a four-week ramp period to allow the intestines of the people balance on the diet, so we're comparing the endpoint to the baseline, so the microbiota diversity definitely crashed in the industrialized gut, it's probably happened progressively over a long period of time as We change our lifestyle, we can talk more about the dietary fiber intervention and why it failed in that short period of time.

I think this is probably due to the fact that we don't have the right fiber-degrading microbes, as that study on immigrants showed. You lose fiber-degrading microbes in the industrialized microbiome and if you just get the dietary fiber back, there's a good chance it will shoot right through you, um, unfermented, and it's actually the short-chain fatty acids that are produced by fermenting fiber which are immune modulators, so it is notamazing. that an industrialized guts in a short period of time without providing fiber degrading microbes, we are not seeing a significant change, we may need to reintroduce fiber degrading species to really see an effect in a short period of time, is it possible What 10 weeks were just?

It's not enough time for a small number of your species to evolve in dollars in numbers, yeah, exactly, I think that's when you combine a short period of time for an intervention and, um and uh, you know, a style of sanitized life where we don't have much access to get microbes in a short period of time, so you're stuck in this industrialized gut that we monitored carbohydrates in feces and saw a lot of what should be fermentable hemicellulose carbohydrates in these feces, suggesting that, in fact, more than In this short period of time you simply see these fibers running through people.

I think if you implemented a high fiber diet for months and years, you would gradually acquire those high fiber microbes. Actually, the next one I was just going to pass a Some slides talk about synthetic biology. I'll take that into account before moving on to the next topic, but you said 20 to 40 grams in that high-fiber intervention and you know that if you eat only unprocessed, unrefined whole plant foods, that diet provides 60 to 80 grams of fiber per day, so even 40 is a low number compared to what can be achieved. I totally agree and if you go to Hudson hunter-gatherers, they eat over 100 grams of dietary fiber per day, so you know.

I think the 40 grams were above the recommended guidelines for most diets, they are based on how much dietary fiber per calorie you consume, but I generally think that even for you, 2500 calories is less than 40 grams per day, most of that is. Based on heart health data and I think more fiber is probably healthier and more in most cases, anyway, I agree with your comment, but the second part on synthetic biology actually sheds light on the idea of acquire microbes that can degrade. fiber, although it focuses more on the technology of using it to graft microbes into the gut microbiome to perform specific tasks, so you know, I've mentioned that the gut microbiome is an important component of our biology, but we can also think of it as a technological platform um these microbes are rich in sensors, they can detect all the nuances in the intestinal environment because their survival requires it.

If we can learn about those sensors and rewire them, we can have microbes that respond to specific conditions in the desired way, um and so on. We've been working on this, just so most of you are probably familiar with synthetic biology, but the idea is simply to generate a list of parts that can be genetically connected and that will give you the desired predictable outcome, so we focused on the bacteroids. the most abundant genus in the American gut as a form of um as a chassis for designing the gutmicrobiome and I should say it was on the opening slide um uh uh The two scientists Wes and Liz who were on that first slide went off and founded this company Novo and biotechnologies um which I am a co-founder of and They are now in phase two of the trials and I will tell you more about the technology that they are developing.

So, you know, synthetic biology allows you to do things like, create gut bacteria that express different fluorescent proteins. here we're looking at six different species of bacteroids inside the gut of a mouse living inside the cell wall of a plant, so that's the purple area. Here you can see that different species have different colors, different types of clonal populations, but also well-mixed populations. Um, using the cell is actually a small space and potentially degrading cell wall fibers there, so one of the main barriers to using microbes in the gut as a therapeutic is the barriers to engraftment, it's been well studied and It is well described that if you put a gut microbe in a number of different people and track it, it will do very different things in those different people and this was demonstrated very well with the species Bifidobacterium pulmonarum which was fed to people for 14 days and this just shows the density of that species. these different individuals, so each line is the density of B longum from a different individual over time after finishing treatment, about two-thirds of people eliminated B longum, but about one-third of people who They kept belonging to them inside their intestines and shed them.

According to the sisters they belong to and were grafted to, it turns out that the people who grafted them lacked a similar strain of Baseline B. Lungum was lost from individuals who had a similar strain of Baseline membership, so it is consistent with the idea that if you have a strain in your gut, the second arrival of that same strain will be lost and will not have a place to graft in the gut, so this is a big problem if you want to develop a microbial therapy, so Wes and Liz took care of this. First they wanted to demonstrate that variability.

They took a surrogate therapeutic microbe that we could track and put it into three different groups of mice. One harbored a mouse microbiota and the other two harbored two different human microbiotas. They simply tracked the density of that microbe during the first one. week you can see very different dynamics, high levels and decreasing and decreasing average levels below the level of detection, very different dynamics depending on the background microbiota that this microbe encounters, in reality we isolate this microbe for its ability to degrade a very specific to seaweed. known as porphyrin, so this seaweed polysaccharide, because it is not commonly consumed by Westerners or mice, there is no background competition and when seaweed is provided in the diet of these mice, it is actually providing a privileged niche specifically for this microbe without any background competition, so on day seven we started feeding the mice with algae and here we see what happens with the density of the microbe in the three cases and in the three groups of mice we achieved high levels of reproducible density during the seeding of the algae extract and, in addition, Impressive was that Liz decided to titrate the porphyrin in different groups of mice using a ten-fold dilution, so one percent point one percent point zero one percent porphyrin We see that the density achieved during that feeding shows a direct linear relationship with that dose of porphyrin, so the log decreases.

In the density achieved, I am suggesting that you can actually tune the abundance of this single microbe at the bottom of a microbiota. complex and that is shown in the images here where our microbe is labeled in green, in the background the microbiota in pink has low doses and porphyrin in high doses, so you can actually modulate the abundance of a single microbe within the intestine using this privileged niche strategy and that's why novum has taken this to human trials now, this is human data that they recently published again using a variety of doses of porphyrin giving the therapeutic microbe without porphyrin, they don't see the graft and then they see the graft at the level that corresponds to the dose and when they remove the porphyrin, the microbe, the therapeutic microbe, is lost from these individuals, so this is now a system in which other systems can be designed to achieve the desired functionality in the gut microbiome and this is what they're using as a therapeutic chassis and it makes available a lot of possibilities for gut targeted therapies and so just to finish uh thank you to my group wonderful collaborators uh funders my wife and I have written a book if you're interested in learning more about the microbiome and looking forward to the wonderful discussion thank you very much okay this is something I think uh Carl has already applauded you as the first in this chat for making a book available as an audiobook too, you are getting a lot of applause here, okay, let's move on to the questions.

I know we already had some of them. registered completely early and this is also to say that if you want to just raise your hand and not drop the whole question in the chat, you can do that too and I'll get back to you as well, but I think maybe starting with me. I think it was first up to the top like Steve's question, well Cosmo, Cosmo was even before maybe it's Cosmo, do it if you can unmute otherwise I can ask the question if you asked me or Cosmo , uh, yeah, Cosmo, go. first and then Steve doesn't have a microphone, okay Mike, I should text it.

Yeah, any ideas on why the Aquamans here are beneficial to health, especially given their preference for feeding on mucous membranes? Yes, it's a great question and I think it's one of the great mischiefs you can have. It may have to do with the dosage, it may have to do with a difference in strains, it may have to do with the fact that a lot of what people suffer from and where acromancy seems to show an effect is in, you know, I I think acromancy is showing positive effects of metabolic syndrome, perhaps strengthening the intestinal barrier and um in um potentially boosting the immune system in um uh cancer immunotherapy with checkpoint blockade in those cases, it may be that acromancy in is actually driving the immune system to um do things that maybe aren't the best for us for longevity, but Amelia, you know it's like the ketogenic diet does great things for um and I don't want to get into a whole debate about the ketogenic diet here, but my opinion on The ketogenic diet is that it can improve many metabolic dysfunctions and problems with our high carbohydrate diet, but it is probably not healthy in the long term, so my feeling for Ackermans is similar to the same.

Wonderful, we have Steve next. I'm really interested in the clinical questions surrounding this type of potential therapy and would like to know if it's how the technology is developing or the science around the issues of considering pathologies of microbiome composition as different from, say deterioration of the mucous layer or failure of the type of junction gaps of, say, inflammation-induced zinc deficiency yes, they are great questions and I think one of the big problems that the field is experiencing is all the feedback loops that are present where they end up with a microbiota that reinforces physiologies that they may not have started because of the microbiota, so I think a good example of this is the OB mice that we know for lack of satiety peptide, they just eat a lot and end up obese with a different microbiota if If that microbiota is transferred to lean wild-type mice, those mice will actually gain weight more quickly than mice that receive a normal microbiota.

We know that that microbiota did not initiate obesity in the original case, but rather it was the genetic deficiency of the peptide. satiety and just eat it, but you end up with this microbiota that enhances that metabolic characteristic, so I think that in the case of an alteration of the barrier and, you know, an altered microbiota, you can suffer from these diseases, see altered microbiota, that microbiota In many cases they probably reinforce a disease that enhances whether it is causal in terms of onset. I think it's still an important question, but I guess I actually have a slight advantage that may clarify this a bit.

I framed this in terms of the Max short-chain fatty acids and Mac dietary diet consume microbes, but I think this kind of captures, you know, an industrialized microbiota that doesn't produce a lot of short-chain fatty acids. We know that short-chain fatty acids reinforce the barrier that this microbiota consumes. the mucus ends up with this eroded mucosal layer all kinds of inflammation occur the host reacts with reactive oxygen species increased oxygen tension in the intestine you end up with more facultative anaerobes here less anaerobic microbiota which then powers a cycle and the opposite is true for a healthy microbiota where you can produce short chain fatty acids, you have a healthy mucous layer and you maintain low oxygen levels in the gut, so I think you can end up in these cycles and then figure out where to intervene or how many nodes you have.

Needing to intervene to have an effect is an important question for the field right now. Okay, I'm collecting questions as we go and we have a ton, so let's have a rare professional fire over here. I'm sure we'll add more as we go. Let's get to the next question we have from Micah and Micah, do you have a microphone? Ask yourself the opposite, great, so if we can sequence the microbiota of paleo fecal matter, then we can synthesize that same basic cocktail and then choose it as a transplant. cocktail basically and give it to people and at any recruiting base to tryto get people back to what we think is at least what we're involved in, and if so, do you think that would be helpful?

Yes, I think it's a great question. Know? I think we've probably lost species and functions that are important to our health. It is debatable whether all of them are, probably not, so determining which ones we should and should not recover and what characteristics of our current microbiome. fit our current environment versus those that are harmful or important questions. I will point out that, you know, there are cases of people getting fecal transplants from Hadza hunter-gatherers, which is similar to the experiment you're suggesting that you can read blog posts about that, um, but the one thing to quickly note about novoam here, they've actually engineered this microbe to break down dietary oxalate to prevent kidney stones, um, because if you have kidney stones, they're likely to come back, most kidney stones occur. of calcium oxalate um and doctors will just tell you to avoid foods that contain oxalate, but it turns out if you look there, we used to have a microbe in our gut called oxalobacter strange that could break down oxalates, that's one of these that goes away.

People in the taxa that have it are protected from developing kidney stones and yet we know that they will most likely go away over time, so Novoam is bringing this back not because they are interested in reconstructing the gut microbiome, but because they're interested in it's therapeutic, but essentially they're carrying out a functional complementation of an important function that we've lost, so you can do this function by function and maybe come up with this answer, but it's a good point for any of the microbiome testing companies. try that specific uh and you know one that we've lost to see you know what people you know could people tell if they have it or not?

Yeah, you know, I don't know and I don't know the level that um it needs to be at for it to be functional so it's a good question and I'm actually not aware of what the testing companies are doing because, You know, there are many and the quality of the data varies from what I do. I've heard that anyways buyer beware but if you see oxalobacter for mitchies in your report that means you have this microbe that can degrade dietary oxalate or yeah cool GMO next up hello can you hear me ? Yes, oh, yes, yes, actually It kind of partially answers my question, but I was curious about, in general, what are the types of therapeutic uses of your artificial bacteria that you were talking about, like noble being developed.

I mean, you just gave an example right now, but I was curious about something like that. the variety of things you could address with this, yes, no, you know, there are very good examples, you can come back. There's a scientific paper in 2000 where people engineered lactococcus lactus to secrete interleukin 10 to treat inflammatory bowel disease and that was, you know? I went into the clinic and I think it was a question of dosage and it ended up failing, but you know there are examples of administration of cytokines and you can imagine maybe in cretins with metabolic diseases, so I think there are a wide variety of possibilities for the administration of um. from Therapeutics from the gut and you know of course gpcrs that are being mapped right now where you can imagine microbes secreting metabolites that would also trigger them okay wonderful next is Johnny yeah you partially mentioned this too but um .

I was wondering what other experience you've had with analyzing an individual person's microbiome and then creating a custom probiotic blend and in the chat I came in with my experience with floret, some genomics, so I'm wondering if you had any thoughts on that? , first they analyzed your microbiome, then they created a personalized pill that you take every morning and then in a couple of months you monitor, so I'm about to reabulize mine. I'll probably send the sample, yeah, cool. Well, yeah, so go ahead, my opinion is that all of that is bullshit and no, I don't mean, I don't mean literal bullshit, I mean figurative bullshit, um, yeah, I think that, um, The ability to customizing probiotics to the gut microbiome is totally premature and Half Baked um, uh, you know, I don't know that company, except for things that I've heard, I'll hear say, um, it supports my theory, um, you know, I will.

I say, the real opportunity here, from an impact standpoint, not a money-making standpoint, is to think about population-level interventions that can, because you know, what's happened to our microbiome with this deterioration, what's happening in industrialized populations as our lifestyle spreads. is affecting hundreds of millions of people to the point where the Gates Foundation is becoming more interested in metabolic diseases than infectious diseases over time because this is affecting all these nations that are starting to eat processed foods and have access to antibiotics, etc. If you want to have an impact in this field, you should think not about personalization, but about population-level interventions that can fix the microbiome of hundreds of millions of people.

Thanks and I'll probably end up going back to moments and other diet diets. thank you, yes, wonderful, close to your next fantastic and thank you, I'm enjoying, I've enjoyed your science, but I'm really really enjoying your wisdom, so I'm going to make two statements to provoke you, uh, tell me. If I'm wrong, we're very interested in aging and as far as I've read the literature, the microbiome doesn't change with age, either cross-sectionally or individually, although I still wouldn't say we have 0 to 100. but um and even If you are given antibiotics, it returns to its original state within a year or probably less time, so we are interested in aging.

I just wanted to know if you picked some that don't mean the microbiome is good individually, but do you think it changes with aging and secondly, a gerotherapy drug like metformin? There are several studies that say it changed the microbiome and even suggested that it is a mechanism of action. Know? Do you think of drugs as? As you know, changing the microbiomes, yeah, yeah, it's very interesting, so the first point, you know, I think it's very clear that the microbiome changes very dramatically during the first two years of life, so you know we're born without a microbiome and you.

I know it's like an ocean, an island that rises out of the ocean, this new ecosystem or gut, you know, it's rapidly colonized, there's definitely a pattern of succession and in fact, recently, this year, we published a scientific paper that looks at the development of the infant microbiome in um uh non-industrialized versus industrialized populations and that succession pattern of microbiome assembly is very different in industrialized versus non-industrialized populations with a notable microbifidobacterium infantis which is the canonical degrader of human milk oligosaccharides that is lost in industrialized populations even in babies who are exclusively breastfed, so this is like a population-wide loss of a very important gut microbe for babies, so in that part of life there are definitely changes.

I agree that over the course of most of life it is very stable, resistant to perturbations or even in some cases, and um. and then, you know, towards the end of life there can be different trajectories, there can be, you know, loss of diversity, this is usually, um, I think the model right now is that this is due to a change in the dietary habits as people progress, particularly in care facilities as they age and this corresponds to immunosenescence and inflammation and things like that, but I think there is the question of knowing the stability of the gut microbiome throughout life and what What this means for an individual.

Um, you know, and particularly thinking about interrupting that or rescheduling that, so that's a very good question. Your second question means changing microbes, so I don't know much about the format except that it can act as an um uh. an antioxidant and reducer of the intestine and this leads us to my model that we are in a redox state, that is, it has too much oxidative stress for the intestinal microbiota to be healthy, so it may be that metformin helps to return it to a state less oxidative, but there could be other modes of action, there is no doubt that drugs can have a massive impact on the gut microbiome and this can be beneficial in some cases, it can be areas of elimination in other cases, but it can also provide a powerful

lever

to reprogram the gut microbiome in various ways in the future so yeah I think they have a role to play thank you wonderful Kyle so I have kind of a general question and then the specific instantiation is. um and the specific justification is that you showed several slides at the beginning comparing various populations um first in the four different populations of Nepal with the modern type of Western and then the actual type of paleo that you know versus uh newer, you know. versus you know anyway um so I would love to see it.

I'm wondering if there is data available that adds anything extra. Plant-based diet like I'd love to see where they fall relative to the US compared to those four different people from Nepal, uh, people that you know that might help answer that question of do you know how much of the modern changes are compensatory adversities that you know are problematic? And it could be the high level, you know, so I'm curious to know that the data is readily available somewhere and then the high level question, of course, is you know you're the expert here, but I know you're a researcher, from what I understand.

You're not following the kind of information available now directly to consumer type testing companies and things like that, but you know who we turn to to help us have the most expert opinion on what to do next and I know you have some of this in your book and of course there's only four recent books called fiber driven by another gastroenterologist who you know has some experience and there's some good advice in those books but yeah you know that's the high level question you know to who to go to get the Best thing we can do now while the investigation continues, yes, that's a good question.

I think, you know, I love, I love the idea of ​​going to people who are eating a super healthy high fiber diet for a long period of time. seeing if your microbiome is different in your metabolic state and immune system and there are people who do this well, I mean there's a whole calorie restriction group and people like Luigi Fontana have done other studies on them but they haven't sequenced the microbiomes that I know. Many of you know people like Dean Pomelu and I, you know we have an intake of 70 grams of fiber per day or more, for example, yes, yes, totally, no.

I would love for you to know that one of the incredible limitations in this area is funding. I mean all the dietary intervention works, in fact, that study with fermented fiber that we're doing now in pregnant mothers to see if we can change the microbiota that they pass on to their babies and if that changes the immune status of the babies. We propose to do this also in children with food allergies at the moment, as well as with fermented foods and fermented foods to write products that we can translate into medical foods to infiltrate the clinic, but I think the biggest challenge here is funding because it is national.

The Institutes of Health have a small allocation for nutrition studies, very difficult, we have had many grants rejected even with preliminary data from a cell article, so I would love to do studies like this if you have funds to do those types of studies or or could you take me to those people, it would be a study that I would be interested in doing. I think you know in terms of where you should go to optimize your gut microbiome. You know, I think if you're trying. with something like um uh, you know, metabolic syndrome or prediabetes or something like that, there are companies like Date Two that are very scientifically sound and that are using machine learning based on microbiome profiling to recommend what people should eat to maintain .

I know that blood glucose increases after brandially, but I think in terms of the concept of maintaining health, you know, and that's really, I think where the money is here if we can figure out how to get ahead of these diseases and tell you to the people. what they should eat or the microbes they need to increase their microbiome to prevent inflammatory diseases. I think that's really the direction things need to go and there's no one who can do that right now, well we've got two more minutes. I want to get to the last question and I know you've already touched on this a little bit, but I just want to expand on it.

You can link it openly, which is the question of if the people here in this group are excited about this work, which I think they are, then what's the best way for them to do it?can you support this? Basically, what are collaboration requests? You know, funding requests and I know you've already mentioned some of it, but they can be. more like this is kind of a Shameless plug moment, yeah, give it to us, how can people help, yeah, fantastic, thanks Allison, um, you know, I think, um, the main issue here comes back to, um, goes back to funding, I think you know at At Stanford with Christopher Gardner's group we have a Human Immune Monitoring Center where we can monitor the immune system in great detail to see how people's inflammatory status changes and then we have a variety of other technologies that we're using, so we have like all the technology infrastructure components in place and what we're missing is basically funding, so, you know, populations definitely help with enrollment.

You know, if we can accelerate that for several studies that we have funding for, that will lower the cost of the study, but what we really need is data, because you know, as Carl was mentioning, people want to know what you should know if you should follow a Mediterranean diet, what are the different microbes that are important for that, what do we need. What you need to do is generate a lot of data where we can map diet to the microbiome of different elements of health, including different components of the immune system. If we have that map now, we can start modifying various microbes to get specific responses, for example, if you are going to receive immunotherapy, you may want a very different immune state than if you were fighting an autoimmune disease and have a map How to modulate specific immune components based on access to the dietary microbiome would be incredibly powerful, so I think we need more studies, more data and then we can take profiles and tell people where they are going and what they need to do to fix it. .

Wonderful, thank you, that was loud and clear. I think we really heard you, thank you very much for joining us and presenting. I think so, people are very excited about your work, thank you very much, now there is definitely a lot to discover, a lot to discover. Really very interesting, thank you very much for joining and for everyone present. I just shared in the chat the nomination form for future topics, so again, if you want your voice to be heard by nominating future topics, then that's the best way to do it. Also always email me, a lot of you have been doing that, thanks for all that, I really appreciate it, thank you so much for joining in and Justin.

I hope it's not the last time we toast you here and I look forward to seeing you all. Have a great time, a great rest of your day and see you very soon for the next seminar, thank you all, thank you very much, take care of yourselves.