- The podcast episode features David Zebe, an author of the paper "Personalized Nutrition by Prediction of Glycemic Responses."
- The paper discusses how personalized diets, created with the help of accurate predictors of blood glucose response, can lower post-meal blood glucose and its long-term metabolic consequences.
- The prevalence of obesity and diabetes has significantly increased over the years, with 4 out of 10 US adults being obese and 1 out of 10 being diabetic.
- Nutrition is considered a major source of these diseases, and the paper aims to understand the changes in nutrition over the past few decades.
- Changes in nutrition include consuming less fat, replacing it with sugar, consuming more additives, and changes in meal times due to shifts and electric light.
- The study measures the effects of food intake by examining blood glucose responses, as spikes in blood glucose are associated with metabolic diseases, weight gain, and fat storage.
- Blood glucose responses are easy to measure using a continuous glucose monitor, providing accurate and high-resolution data.
- The study aims to reduce glucose responses and find the best diet for individuals, but it found that people's glucose responses can vary greatly even when consuming the same food.
- The factors that can affect glucose responses include genetics and lifestyle, which cannot be easily changed.

- The study identified three main factors that affect people's glucose responses: genetics, lifestyle, and the human microbiome.
- The study aimed to combine these factors to predict what foods are good for individuals to eat.
- The study standardized breakfast for participants and found that individuals had consistent responses to the same meal on different days, but there was a wide range of variability across the population.
- Different individuals responded differently to the same foods, indicating that there is no one-size-fits-all optimal diet.
- The study collected various data, including blood samples, questionnaires, continuous glucose monitoring, and stool samples to analyze the microbiome.
- The gut microbiome has a significant impact on health and can be changed, unlike genetics.
- The microbiome can be assessed through stool samples and can provide insights into an individual's health status and dietary habits.

- Gut microbiome can reflect and affect a person's health.
- A study by Jeff Gordon's group showed that transplanting the microbiomes of obese and lean twins into germ-free mice resulted in the mice becoming obese or remaining lean, respectively.
- The diversity of the microbiome is associated with a healthy host.
- There are various ways to exert an effect on the gut microbiome, such as antibiotics, probiotics, and prebiotics, but their full effects are not fully understood.
- Fecal transplants have been effective in treating Clostridium difficile infections, but may not work in individuals with a healthy microbiome.
- Postprandial glucose response is associated with weight changes, but long-term studies are needed to see significant differences.
- Day2 is a company that offers personalized food recommendations based on microbiome analysis.
- The research was conducted by a large group of scientists, including Dal Karem and Adina Weinberger.

- The speaker developed an algorithm based on people's metrics to predict their responses to different meals.
- The algorithm combined various signals such as BMI, glycated hemoglobin, gut microbes, nutrients, meal times, and blood parameters.
- The algorithm achieved a prediction accuracy (R-value) of 0.68, which is close to the theoretical upper bound of 0.7.
- The prediction was tested on an additional group of 100 people and achieved a similar accuracy of 0.7.
- The speaker mentioned that there are differences in types of foods between Israel and New York.
- The speaker stated that they chose not to make dietary suggestions because people are very different and universal recommendations would be suboptimal.
- The speaker discussed a study on bread consumption and its effects on the microbiome, noting that individual microbiomes remained mostly similar despite drastic changes in diet.
- A long-term study on the microbiome is being conducted by Aran Segel's group, following 200-300 people for 6 months to a year.
- The speaker mentioned that they are no longer afraid of dietary fats based on their research and reading of history.

- The video discusses the history of dietary fat consumption and its impact on health.
- The American Heart Association recommended reducing fat consumption in 1961, leading to the creation of the food pyramid.
- The decrease in fat consumption coincided with the rise in obesity and diabetes.
- The speaker stopped being afraid of dietary fats after studying the history and data.
- The speaker is now focusing on studying the ocean and soil microbiome and how it affects global health.
- The speaker is also working on a study that explores the role of the microbiome in human health, specifically looking at regions in the microbiome and their correlation with health metrics.
- One specific correlation found was that people with a certain region in their microbiome were 15 pounds thinner than those without it.
- This region is believed to be involved in the production of butyrate, a compound that has shown to have beneficial effects on metabolism and inflammation.
- The speaker suggests that having bacteria that metabolize fiber into butyrate may be more beneficial than directly consuming butyrate.
- The speaker is considering the possibility of supplementing people with this specific region in the future.

- The speaker plans to study microbiota in the ocean, specifically looking at genes that metabolize compounds found in oil refineries and plastic islands in the Pacific.
- They also mention adding data layers from NASA to explore basic questions about the ocean microbiome.
- The speaker hasn't noticed any changes in their personal microbiome since moving to a new country and being vegetarian.
- Changes in the microbiome can occur when traveling, but it tends to bounce back when returning to a familiar environment.
- Food poisoning can cause temporary changes in the microbiome, but it typically stabilizes over time.
- The speaker conducted a study with 26 participants to test predicted diets and their impact on blood glucose levels.
- The study found that certain foods had different effects on different individuals, with some experiencing significant glucose peaks during the "bad" diet and normalization during the "good" diet.
- The study also observed consistent changes in the microbiome following the good and bad diets, with beneficial bacteria increasing during the good diet and harmful bacteria increasing during the bad diet.
- The speaker suggests that individuals interested in conducting a similar study should either gather a large sample size or look for upcoming studies to participate in.

- The podcast episode discusses personalized nutrition and the paper "Personalized Nutrition by Prediction of Glycemic Responses" by David Zebe.
- The paper explores how personalized diets, based on accurate predictors of blood glucose response, can lower post-meal blood glucose and its long-term consequences.
- The prevalence of obesity and diabetes has increased, and nutrition plays a major role in these diseases.
- The study measures blood glucose responses to different foods and identifies genetics, lifestyle, and the human microbiome as factors that affect glucose responses.
- The gut microbiome has a significant impact on health and can be changed through various methods.
- Day2 is a company that offers personalized food recommendations based on microbiome analysis.
- An algorithm was developed to predict individuals' responses to different meals, achieving a high prediction accuracy.
- The speaker discusses the history of dietary fat consumption and its impact on health.
- The speaker is now focusing on studying the ocean and soil microbiome and its effects on global health.
- The speaker plans to study microbiota in the ocean and explore basic questions about the ocean microbiome with the help of NASA data.
- Changes in the microbiome can occur when traveling or experiencing food poisoning, but it tends to stabilize over time.
- The speaker conducted a study on predicted diets and their impact on blood glucose levels, finding individual variations in responses and changes in the microbiome.

David Zeevi - https://twitter.com/davezeevi - is a James S. McDonnell independent fellow at the Rockefeller University Center for Studies in Physics and Biology. He focuses on developing computational methods for studying microbial ecology in the human gut and in the marine environment, and its contribution to human and environmental health.

He was one of the authors on the paper Personalized Nutrition by Prediction of Glycemic Responses - https://www.ncbi.nlm.nih.gov/pubmed/26590418

The YC podcast is hosted by Craig Cannon - https://twitter.com/craigcannon

Read the transcript here - https://blog.ycombinator.com/david-zeevi-on-personalized-nutrition-based-on-your-gut-microbiome

***

Topics

00:40 - Why did David start working on personalized nutrition?

4:10 - How did the measure the effects of food in their study?

11:20 - How was the study standardized across people?

15:20 - How they measured an individual’s gut microbiome.

16:55 - What is the gut microbiome?

21:30 - Is there an ideal gut microbiome?

22:45 - How do you manipulate your gut microbiome?

24:15 - Fecal transplants.

26:20 - Elizabeth Iorns asks - Does post prandial glucose response regulation track with weight regulation? I.e. can they use their test to determine what individual people should eat or not eat to lose weight?

28:00 - Has this research been turned into a product?

29:00 - Who else worked on this research?

30:00 - How was their predictive algorithm made?

34:40 - Did they end up with any dietary suggestions?

35:40 - David’s bread study - https://www.cell.com/cell-metabolism/abstract/S1550-4131

38:20 - Has David changed his own diet?

38:50 - Why fat was vilified.

42:40 - David’s ocean microbiome and other research.

50:30 - Traveling and your microbiome.

56:00 - Trying this out yourself.

So today we have David Zebe on the podcast and you are an author on many papers, but the paper that I initially contacted you about is called Personalized Nutrition by Prediction of Glycemic Responses.

People eating identical meals present high variability in post-meal blood glucose response.

Personalized diets created with the help of an accurate predictor of blood glucose response that integrates parameters such as dietary habits, physical activity, and gut microbiota may successfully lower post-meal blood glucose and its long-term metabolic consequences.

So, we got to see the amazing statistics on metabolic disease in the world.

So right now, 4 out of 10 US adults are obese.

Mass index of over 30, which is actually not that bad, but it's still considered obese by the CDC.

Now it was about 1 out of 10 in the 1980s.

And this is based both on the World Health Organization and the CDC, the Centers for Disease Control.

1 out of 10 Americans are diabetic And this is an awful disease.

And it's a huge burden not only on people who have the disease, but also on healthcare systems.

And I told you before, it's like $250 billion spent on diabetes and its related costs in 2012.

And it's widely accepted that nutrition is a major source of these diseases.

Because diabetes was not nearly as prevalent in, for example, 1990.

Right, it was not nearly as prevalent in the 1990s, 1980s, 70s, It was not as prevalent, and neither was obesity.

And when we came to look at it, we just tried to figure out what are the changes, what are the major changes that were done to our nutrition over the last 30, 40, 50 years or so.

So first of all, we started consuming much less fat.

It was reduced from about 20% of our calories to about 15%.

We started, so having fat in your food is tasty.

And it's also very fulfilling and everything.

And if you want to give food a taste without fat, you usually add sugar.

So sugar mainly took the place of fat in our diet.

So there's a graph I sometimes show in lectures where you see the sugar consumption per capita per year since, I don't know, I think 1700 till today.

And the crazy fact is that the annual consumption in 1700 is the daily consumption today.

So we couldn't have evolved to undertake to treat this amount of sugar that's going into our system.

The other couple of things that have changed is that we consume much more additives with our food It's much less food and much more, you know industrialized.

And last thing is that Meal times changed we work in shifts.

Mm-hmm, And that changes when we eat and our daily routine in general.

And so then this study, how are you actually measuring the effects of food intake?

So this is also an interesting thing because, so we're thinking that if nutrition did cause this epidemic, what can restore healthy nutrition?

And when you try to ask what's healthy nutrition, you can look at popular Time Magazine covers, for example, and we looked at that.

And you can see that some of them say that saturated fats are bad for you.

Some say that fats are good for you, and some say that you should be vegetarian.

Some say that you should eat an Atkins diet.

And there's a famous 1, which I really like, from 1972 that says, eating may not be good for

But we thought as scientists that what you should eat is not a question of trend or fashion or whatever.

And we want to address it with scientific metrics.

So We had to choose a metric that was specifically good for this question.

We ended up choosing the blood glucose response.

The reason we chose this is that, well, when we eat, the carbohydrates in our food are broken down to sugars, which are then absorbed by our gut into our bloodstreams and that causes spikes in our blood glucose levels.

These spikes cause insulin secretion from the pancreas, which signals the body to store this glucose as fat or as other storage components.

Now, spikes in blood glucose are also associated with many other metabolic diseases, and of course with diabetes and obesity.

And it leads to weight gain because it is transferred to fat, right?

And it generally not just turns into fat, it also turns into, it gives a boost to the natural mechanism of storage.

And the last thing that was good about glucose responses was that it was very easy to measure.

So you just connect a small device, a continuous glucose monitor, it has a tiny needle or a tiny sensor that goes into your body.

I think it's like probably a quarter inch, something like that, and it goes into your body.

And that measures the glucose levels in your interstitial fluid.

It's highly correlated with the glucose in your blood, so you get a very accurate measurement of the glucose in your blood or a proxy for the glucose in your blood every 5 minutes.

So you have very high resolution of this metric.

If you now conduct a nutrition study, You can measure weight, for example.

It's affected by what you drink, what you eat that morning, the time of day that you Exercise, whatever.

And you can only measure it once in every long period of time, just because it's very noisy and because it changes very slowly.

So you can see the effect or the average effect of a diet over a week or 2 or a month or so.

Even though I know some people who get a step on the scale every day.

But it's usually recommended to look at it every week or

If you look at blood glucose, you can measure it for every meal.

So you can just see, get a fast feedback on each and every meal that you ate.

And That's what made this blood glucose such a great metric for us.

Since it was correlated with so many diseases such as cardiovascular disease, obesity, diabetes, and so on, we quickly realized that in order to maintain health or to restore that healthy phenotype, what you need to do is to probably reduce the glucose responses.

And that sounded easy, you know, okay, we just collect a few people and we look at their glucose responses and we find the foods that are good for everyone.

And you find the best diet in the world that would reduce glucose responses and that's it and we're done.

But biology and the world is more complicated.

What we found is that there were several, usually very small scale studies, that showed that people's glucose response can be very different from 1 person to another.

So 2 people eating the same loaf of white bread, 1 would really spike their glucose, and 1 would really stay flat.

And that's true even if you normalize the responses to the responses to glucose.

So you have just to see if, so even foods are not categorically good or bad, it also depends on the person.

So we said, OK, so let's think of what can affect these glucose measures.

And we came up with 3 main causes that can affect people's glucose responses or personal responses 1 is genetics, which unfortunately we can't really change we are what we're going with yeah for now I mean that's crisper is going to change all that The second is lifestyle which we all agree should be healthy, active, and so on.

And the third, 1 that was when we started sort of flying under the radar, was the human microbiome, which we found to be associated with many diseases, many disorders.

And if we have time, I can tell you a little bit about that.

And so we wanted to create a study that combines all these factors, nutrition as a target, genetics or a proxy for genetics, lifestyle, the microbiome, to predict what's good for people to eat.

And that's how we came up with this study.

And the study was standardized by giving them the same breakfast over the course of a week, right?

Well, there are a couple different breakfasts that you gave them.

Yeah, so the first thing we wanted to do in this study is to see, to try to recapitulate the variability that we saw in the small-scale studies.

And so as a controlled way to study variability in people's responses to food, we replaced their breakfast with a standardized meal that contained either bread, bread and butter, glucose or fructose, which had 50 grams of available carbohydrates each, and that was to be taken in the morning after the night's fast without exercising, without eating before that, only drinking, no exercising in the 2 hours after eating the meal because we wanted to get a clean response to the food.

And what we found is that 2 people eating the same meal in, sorry, 1 person eating the same meal on 2 different days was very similar to themselves.

So we had a correlation there of R of 0.7 to 0.77, which is very good, considering the noisiness of people.

But across people, across the population, the variability was huge.

So people, for any given food, covered the entire range of responses.

And they were very reproducible within themselves.

You can see a person eating the same loaf of white bread, having 2 very flat responses to glucose.

The glucose doesn't go up after the meal.

And other people who were not diabetics, who were not pre-diabetics or anything, had huge spikes to the exact same loaf of white bread.

And these people, you couldn't tell the difference otherwise.

And again, it's not just that 1 food is categorically worse than other foods.

Some people responded, had the highest response to glucose.

Some people had the highest response to bread, and a minority had the highest response to bread and butter.

Actually fewer people had a high response to bread and butter than to bread alone.

So the butter is, so the fat is somehow neutralizing it.

Right, and then interestingly, it's not, again, like in the pursuit of the optimal diet, it's not just that, oh, white bread has a lot of sugar, ice cream also has a lot of sugar.

This isn't good for you, you can't eat it.

So you'll have someone will respond in 1 way to bread and then differently to ice cream.

Yeah, we saw that exactly the exact same thing we saw with naturally occurring foods.

Some people have high response to rice, for example, and low response to ice cream.

And other people would be the other way around.

And that's with the exact same amount of carbohydrates in the food.

And so then, OK, so, oh, yeah, we should clarify.

Then they could eat whatever they wanted afterward.

We also gave them an app in which they recorded what and when they ate.

Maybe I should say a few things about what we collected in the study.

So We recruited people, about 800 people.

We had them go through a process in which they gave us blood.

They filled in questionnaires, both food frequency questionnaires and general medical questionnaires.

We had them connected to a continuous glucose monitor, as I told you before.

That measured their blood glucose every 5 minutes for the duration of a week.

And then this week, we also gave them an app which we developed in which they recorded when they ate, slept, exercised, and so on, and the exact amounts of every food in their diet.

So we also gave them weights to weigh their food when they go to eat at home.

And we gave them some leeway to eat at restaurants as well.

And did the stool sample element, was that in the original spec?

we also collected stool samples, which we analyzed to see the microbiome in various levels, both which microbes are in there, which genes of the microbes are in there.

And if I talk later about the microbiome, it's an amazing ecosystem with thousands of species, about as many cells as in the human body.

It weighs as much as your brain or a little bit more than your brain.

It's like People call it like a forgotten organ, not so forgotten now.

And these microbes have 150 times more genes than are in the human genome.

And this metabolic potential can be harnessed or can be accounted for when we're looking at what people are eating.

And this is very interesting because unlike genetics, the microbes can be changed.

So if we figure out a way to change the microbes that are affecting or have a deleterious effect on our health, we can maybe improve people's health altogether.

So you should both explain what this gut microbiome is actually for people, Because I think this word gets thrown around a lot, and then you're talking about changing it, and how would you even go about doing that?

So for context, let's give a proper definition for folks.

So the gap microbiome is the ecosystem of bacteria, archaea, which is also a type of unicellular creature, fungi, viruses, and small, I don't know, worms or whatever that we have in and around our body that are not of human origin.

And all of its associated genes and genetic material and so on and so forth.

So that's what usually people mean when they say microbiome.

There's a lot of cells, there's a lot of diversity there.

There are a lot of genes, and there are more and more related, More and more relations are found between this gut microbiome and many disorders and different outcomes.

So 1 of my favorite microbiome studies was done in Stanley Hazen's group in the Cleveland Clinic.

They looked at carnitine, which is a compound that is found in red meat.

This carnitine is metabolized by the microbiome to form TMA.

TMA is then oxidized in the liver to form TMAO.

And TMAO causes a reduce in reverse cholesterol transport and bile acid synthesis.

And these are long words, but what it eventually means is that it causes atherosclerosis.

These 2 processes, if they're reduced, it causes atherosclerosis.

And interestingly, if you remove these specific microbes that metabolize carnitine from the equation, the downstream effects are attenuated as well.

This was a major thing for us because this is the first time we saw that their microbiome can affect how each and every 1 of us responds to nutrition.

Another study, I think it was by Nan Qin and colleagues in 2014, I'm not sure, maybe it was published in Nature, but I'm not sure.

They show that you can accurately detect cirrhosis, liver disease, by only looking at your gut microbes.

And that showed us that the gut microbes can reflect our health status.

No, in monitoring what people are eating in their stool samples, you can kind of recompose what their gut microbiome is, right?

Well, I mean, you have to measure the gut microbiome as well, but you can, maybe you can get some idea on their health status and what they're eating from the gut microbiome.

And it's not only that microbes can affect your health or reflect your health, they can also, sorry, it's not only that microbes can reflect your health, they can also actively affect your health.

And There are a few very nice studies by Jeff Gordon's group at Washington University of St.

Especially 1 that I like the most from 2013, they took pairs of twins that were discordant for obesity.

And they transplanted their microbiome into germ-free mice.

Germ-free mice are mice that are born and raised in sterile conditions and they don't have a gut microbiome of their own.

And these mice were transplanted, these microbiomes of twins, 1 obese and 1 lean, many pairs of twins.

And interestingly, the mice that received the microbes of the obese twin became obese, and the mice that received the microbes of the lean twin remained lean after eating the same food and doing the same things.

And that also showed us that it's pretty...

And so kind of the, Maybe the logical extension in the sense that every human wants things to be black or white.

Where you often ask, like, okay, is there an ideal gut microbiome?

Because rather than the diet, maybe we just do the gut microbiome and then we do the transfer.

So I'm not sure if there's an answer or there's a clear answer.

I think people are trying to study the gut microbiome in health and disease.

The thing is that it's, and This is maybe just my opinion, it's so diverse that you need a huge sample to study what's good and what's bad in a microbiome.

So once you get to know the exact effect size of the microbiome on human health and whatever, maybe then you can start asking the question of what is healthy and what is not healthy.

We know right now that we know of some species that are healthier than others or are associated with better health.

Generally, a microbiome diversity, a high diversity of the microbiome, is associated with a healthy host.

So you want to let your kid eat dirt, I guess, or have a dog.

That's usually contributing to a healthy microbiome.

And so then, in the context of Jeff Gordon's group where they identify maybe a certain bacteria that's not ideal.

What is the process of trying to eliminate it?

So, I don't know if I have a good answer for that.

There are a lot of ways to effect, or to exert an effect on the gut microbiome.

You can take antibiotics or very specific antibiotics.

You can try and replace this microbe by ingesting some sort of probiotic or some sort of microbe that will occupy the same niche as this microbe just to push it out and take over.

You can take prebiotics, which is some sort of fiber, but I'm not sure that people have an idea of the full effects of each and every 1 of these things.

So there's still a lot of study to be done in this field.

I mean, I read a couple of studies before this podcast, and I read the book, I contain multitudes, but there are so many things out there between fecal transplants and the pills that you can digest where companies say, we have found the optimal probiotic or gut biome supplement.

In large part, have you found that stuff to be effective or is it just kind of bogus?

No, I'm not sure I can answer that with confidence.

Okay, because yeah, I guess specifically the fecal transplant stuff I think is the most eye-catching.

That's the dark side of microbiome science.

But it has been proven effective for some percentage of people, right?

So, fecal transplants have been used, their claim to fame is by treating Clostridium difficile infections.

That's a type of infection that takes over your gut.

It's a certain bacterium that takes over your gut.

Now when you try to treat it with antibiotics, it usually sporulates.

It creates spores and it resists the antibiotic.

The antibiotic kills everything else, and this thing just takes over all the gut spaces that were left by other bacteria.

Diff infection, it's predominantly the most abundant microbe in your gut.

And it causes extreme diarrhea and these sort of things.

Now when you treat these patients with antibiotics, I said, it's not working, so you want to treat them with something else.

You want to replace their healthy microbiome, and you indeed transplant stool into these people.

And that transplant works mainly because their microbiome is so depleted, and it's like, you know, cultivating an ecosystem in a place where there was none.

So if you take this ecosystem and you try to transplant it to a person with a healthy ecosystem, that's not necessarily going to work.

But people are making big money out of it.

I heard that a company is collecting stool out of professional athletes, NFL players, NBA players and so on to transplant to other people.

Yeah, I mean, however you wanna get paid, go

So we have a couple questions people submitted because they were very curious about this.

So Elizabeth Irons from Science Exchange had a couple questions, 1 of which was, does postprandial glucose response, which is the response that you're measuring with the glucose monitor, does it track with weight regulation?

I.e., can they use, can you guys use, their tests to determine what individual people should eat or not eat to lose weight?

So, theoretically, post-prandial glucose response is associated with changes in weight, just because of mechanism I told you about, that when we eat things that spike our blood glucose, we cause insulin secretion, which signals the body to store things as fat, among other things.

We haven't tried and tested it specifically.

Even the intervention that we did was a two-week intervention a good week and a bad week, we can get to that later.

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David Zeevi on Personalized Nutrition Based on Your Gut Microbiome