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fermented food and immune health:

an interview with hannah wastyk

recorded september 2021
E: What is fermentation?  

H: Yeah I love this question because I used to hate it and now I have a response for it. Fermented foods are this mysterious thing that people just assume they know, but when you actually think about it deeper you’re actually like: “What is a fermented food?” 

The first time I googled it I found this definition that said “fermented foods are defined as foods and beverages produced through controlled microbial growth and the converstion of food components through enzymatic action.” I feel like you and I have talked about fermented foods at length, and get really excited about it. But I feel like this definition of fermented foods just didn’t capture the excitement and the magic that I felt when you talked about them or when we’ve had conversations about them.

So one of the ways I like to think about fermented foods comes from when we did that home ferment of kefir (Elisa and I work together in Sonnenburg Lab, and we were looking at a timecourse of kefir fermentation). That was one of the first times I’ve ever made kefir. It’s based off of milk, so you take a glass of milk, and you just set it out at room temperature, and you add a really greasy sticky clump of kefir grains. You just let it sit in a dark cabinet for, you know, three days. So I remember setting that up and thinking “This is really weird.” If I had just sat out a glass of milk in my cupboard and closed it and three days later opened it up it would smell rancid. I would probably have a gag reflex, and if I drank it I would get sick. But I’m doing this right now with kefir grains and the knowledge that it’s going to smell good, maybe a little cheesy, when I get it out and the research that you and I are working on is saying that it would actually make us healthier, reduce inflammation. And so that difference between spoiled glass of milk and a glass of kefir at room temperature is what I like to imprecisely define as what fermented foods are to me.

“that difference between spoiled glass of milk and a glass of kefir at room temperature is what I like to imprecisely define as what fermented foods are to me”

E: Cool! So you recently published a paper called “Gut Microbiota Targeted Diet Modulates Human Immune Status” that was published in Cell, which for those who don’t know, is a very prestigious science publication. I wanted to hear more about this paper. Can you explain what the background is, how you came to asking these questions and what the major takeaways are?

H: Sure, so that paper... My introduction to fermented foods came from an interest in wanting to study how the microbiome and immune system interact with each other. So I came to Stanford wanting to study these systems from a biochemical/molecular lens, because that was my experience previously. The tools to study the microbiome in high throughput even five years ago just didn’t exist.

The study that was ongoing when I ended up joining Sonnenburg lab was a different way of studying the axis of the microbiome and immune system by using human diet. This study in particular was the brain child of Justin Sonnenburg and Christopher Gardner at Stanford. Justin is a tenured professor at Stanford in the Microbiology and Immunology Department and Christopher is a professor in Preventative Medicine and really focuses on nutrition and diet.

The idea of this study was to study the diet-microbiome-immune axis with the hope of 1. making people healthier through a simple dietary shift with either high-fermented foods of high-fiber foods, and 2. study the interaction between the gut microbiome and the immune system. What I was getting at before was that the human gut microbiome is incredibly hard to study, in traditional (mouse) models because it is so complex. The immune system in mice is obviously very different than humans. When you add on the complexity and malleability of the gut microbiome, it is just very difficult to glean information between the two that is able to translate from mice to humans. On the other hand, we use mice so often in basic research because we can’t study drugs in humans for obvious safety reasons. So the idea behind this study was that we can go straight into humans by using an intervention that doesn’t need to be approved by the FDA.  

The microbiome is very malleable, like I said before, and so we are using diet as the method of change for the microbiome which by extension we hypothesize will change the immune system. So, from a personal standpoint I came into this study during my rotation back in Sonnenburg lab in 2018. For the most part all the samples had been collected, the study had been run, there was all of this data. It was my job, along with then post-doc Gabi Fragiadakis, to look at “How are we going to wrangle this data so that it is not just a data dump?” This is a really special study, we need to craft a narrative that is 1. biologically accurate and relevant, and 2. important to human studies and human microbiome and human immune system, and 3. innovative. How are we pushing the field? Because we really want to define how future studies will be run, both at a steady standpoint and as an analysis standpoint.

E: So what were the key takeaways?

H: That there have been previous work showing that diet has been able to reproducibly change the microbiome, in short term and long term ways. Occasionally they will have one or two measures of host health, whether that be glucose tolerance, weight gain, et cetera, et cetera, but there really hadn’t been a study prior to this that showed immune status, and deep profiling of how a dietary study is able to change the immune system, and a big reason for this is that people just didn’t this it would be able to happen. With grant funding, a lot of the narrative with dietary studies is that it’s too risky, that you won’t see anything, that people are human, and they are not going to eat the right things that you want them to, you won’t be able to measure any changes.

It was really the belief in diet on Christopher Gardner’s side and the belief in the microbiome on Justin’s side that we would be able to see these profound changes in the immune system. From there that it was getting the money, which was really philanthropic donations from people in the Bay Area that are very interested in this and honestly have deep pockets, and want to be able to pave this area of science through citizen science work. So it was funded by philanthopic donations, and then looked at not only one or two parameters of immune health, but over 100 different inflammatory markers that gave a really comprehensive look at what the immune system looks like and is it able to be perturbed by a dietary intervention and by extention the gut microbiome.

So that was one of them: the first study that was as comprehensive as this was. On the results side, we found that a diet high in fermented foods (in our study we had six servings or more during the highest levels of consumption) was able to a. increase microbiome diversity, so increase the number of unique species in your gut and then b. improve immune status by decreasing the number of different inflammatory markers. As I talked about before, we had measured a number of different inflammatory parameters. We wanted to see trends-- we didn’t want to rabbit hole ourselves into one or two markers of inflammation, because we don’t understand the immune system such that we can just measure one thing and and get a status of how healthy it is. So by having this comprehensive view, of all the immune parameters we were able to measure, we saw 19 decreased inflammatory proteins and 13 decreased immune cell signaling pathways. This is really significant because we do see these trends in people becoming healthier in terms of  an immune system that is lower in inflammation. So that was the big takeaway that everyone is talking about right now. It is the first time that someone was able to show fermented foods improve immune status.

A second takeway that I like to say even though this got literally no attention is that the high fiber diet. In our study we had 40g a day at the highest consumption and showed a mixed response. So in general, some participants did improve their immune status with lower levels of inflammation, but they had to have a high level of microbiome diversity to start with. The more microbes or unique ecosystem they had in their gut before the study started the better they seemed to respond, which  suggests that a hybrid between high fiber and high fermented food diet might have the best synergistic effects. They are looking into that now.

“The more microbes or unique ecosystem participants had in their gut before the study started the better they seemed to respond, which suggests that a hybrid between high fiber and high fermented food diet might have the best synergistic effects.”

E: Very very cool. Can you explain the different between an immunosupressive phenotype and decrease in markers of inflammation? Because immunosupression would not necessarily be good all the time. You were also looking at this in healthy individuals and not people with IBS or some sort of autoimmune disorder. So because this is a microbiome-immune paper, there might be people that interpret this as “Well these are good food for people with some sort of inflammatory disease because it led to a decrease in inflammation.” But that is not really the takeaway. Correct?

H: Yeah, that’s a really, really important point. Our study was only in healthy adults, and immune suppression and anti-inflammatory effects are very different. I mean, when you want inflammation is when you have infection or something. When you cut your arm, you eat some spoiled food, you want your immune system to respond to it, so you can get the pathogen out of there and clear the infection. The times that you don’t want inflammation is when you have chronic disease or chronic inflammation, and this is on the rise in industrialized countries like the United States. Pre-diabetes, obesity, make up 37% and 40% of US adults. These are the chronic diseases that we continue to see that continue to tick up not only in adults but in children as well, year after year. So what we are hoping is more of a preventative sense, where you can decrease these chronic inflammatory signals that you see in these luminal states of disease, then you can push the needle back towards health before more serious problems like diabetes, IBD, Crohn’s, and things like that develop. When you already have inflammation that’s indicative of Crohn’s disease, or UTI or whatnot, this study cannot be extrapolated to that for sure. That is a completely different patient cohort and honestly have different phenotypes. It’s a really important point to make.

E: If you were to continue this project, what next steps would you take?

H: I think the hybrid model between looking at the high-fiber and high-fermented food is a huge one, the study is just begging for it. If you prime your microbiome to increase the diversity to begin with, and then supplement fiber afterwards, can you see even lower levels of inflammation? Would that be the right model for someone who is in a more inflammatory IBS cohort? I think having IBS or IBD cohorts is insanely important, because shifting the focus from a preventative case to a treatment case is not outside the realm of what fermented foods can do.

We are not there yet, and that is either going to be through engineering fermented foods that are enriched in a particular microbe, microbial component, maybe it’s specific types of fermented foods like koji or tempeh instead of what is more popular in the US like yogurt, sauerkrauts and kimchi. The diversity of fermented foods is ginormous, so looking at the differences between them... is it the microbes that are in the fermented foods? Is it the metabolites or the small molecules that are being produced? Oh man, there is just endless numbers of questions you could go after.

E: Talking about the probiotics versus metabolites that are made in the fermented food, there is the idea that through fermentation you are changing the community (microbial community) of fermented food, you are changing the metabolites that are being produced, but you are also changing the bioavailability of different nutrients that are from the food itself. What do you think is having the greatest impact?

H: Yeah that’s a great question. I think it’s a combination of both, which is a cop-out answer. I think it would be naive to say that the probiotics component only are important because that assumes that they engraft in your gut, and I think you need to have the microbial  products in addition to the microbes themself to see the effects. Because the microbial products interact with the lining of your gut and enter systemic circulation, and that’s where they get a lot of their immune modulatory effects. So I don’t think the probiotics themselves are sufficient to see the immune modulation effects. On the other hand, is it only the metabolite or the products the microbes are producing? I think that is more likely the case because the’re a causal unit, right? So the microbes are chemical factories in your gut, and what they are  producing is actually causing the effects. I don’t know if you just had sterilized sauerkraut brine or cooked kimchi that you know, killed all the microbes, if that would have the same effect. I don’t know. But I don’t think the microbes themselves are sufficient given the increase in microbial diversity that we saw in the study in the fermented food cohort. The large large majority was not microbes that we actually ingested. It seemed to bloom a number of different commensals in the gut that were just lower than the level of detection that we had, and so they were able to create more niches. So whether or not you are able to see those effects with just the microbial products I don’t know. But I do think that will be a hot topic of research moving forward.

“The microbes are chemical factories in your gut, and what they are producing is actually causing the effects”

E: And have you changed your diet after working on this paper? Do you get around to eating six servings of fermented food a day?

H: I will admit that six is hard. I think I try to integrate it into what I already really enjoy eating, so I think the great thing about fermented foods is that they have a ton of flavor. So if you’re into sauerkraut or kimchi those are not just for eating on their own, but adding to sandwiches... they have the texture, they have the flavor component, so if I’m making sandwiches I always throw sauerkraut or kimchi on it. If I’m having a rice bowl or something like that I always throw kimchi or sauerkraut on the side. As far as my savory components I eat tempeh all the time. On the sweeter side like yogurts I try to have atleast one yogurt a day. There is Yokult, those little yogurts. I consider one of those a serving even though it’s probably not technically right. But those are really easy to just pound as well. I probably don’t eat six. Per day I’d say I eat three and four, but it has definetly changed the way I eat. I was very skeptical of dietary studies before joining the lab, and I would not have believed these results unless I’d have literally worked with the data with my own hands, and so I am definetly on the kimchi train, on the fermented foods train. I was FaceTiming my friend once, and she called me and I was literally in my bathrobe eating a tub of kimchi. She was like “Wow, you are a meme of yourself” and it’s very true...

E: That’s very funny. You’ve also gotten a few write ups, and there were some great ones in the New York Times. I noticed that in terms of the comments, you could break it down into maybe four categories. The first was praise and people sharing their favorite fermented foods. The second category was people commenting on the statistics, and they were saying you only had 36 participants (18 per group) and that sample size is just way too small. Then there were also people saying “Eating fermented foods is why I don’t have cancer anymore” or “It helped me treat x disease”.  And then my favorite group which was the people that were saying “Now I can drink as much wine/beer as I want because it’s a fermented food.” Could you respond to these last three: the statistics, the alternative treatment, and the alcohol. If you were to respond  to these people, what would you say?

H: Yes, I didn’t know if I should read the comments and then of course I read every single one and there was a rollercoaster of emotions [laughs]...

On the statistics side,  that was probably the most common that I saw that was like “Eighteen on each arm, this study doesn’t mean anything.” My response to that is you have to start somewhere. I know in an ideal world we would have a hundred participants across every single demographic and hundreds of samples. Trust me, I worked with n=18, and there is no one that wanted this study to be larger more than I wanted this study to be larger. But like I said before, this is a really nascenent area of research. The idea of a dietary intervention like this being in Cell is kind of mind blowing, so... in order to get the funding and grant money necessary for funding a study of hundreds of people you need to show that there is evidence that it would work. And because, again, mouse models are not a good proxy for seeing if this would translate to humans, starting in humans is no small ask. So 18 people that were able to adhere to a diet through, honestly, counseling of a nutritionist multile times a week, that’s a huge win for us. Longitudinal sampling of the stool samples for the microbiome processing, and the blood samples for the immune processing, you know... you don’t get twelve different samples from that many people you known. Each person was so incredibly expensive because they were so deeply studied that this type of analysis was really necessary to usher in a lot more studies of this design, and with much larger sample sets. So you have to start somewhere is my response to that. Everything was statistically significant that we reported, so even though it was a small sample set, if you’re talking statistics it still met the canonical p equals less than 0.05.

As far as alternative treatment, people swearing “This helped me,” n = 1 is really the basis of a lot of medicine to be honest. Like if you look at, you known, doctors going to conferences and presenting ground breaking research, it’s n=1. This happened in this one person, how can we scale this to help a lot more people. It’s really difficult of course to cast that into whether it will work for everyone and whether it’s possible and appropriate to do that. But I think that if people do find it works for them (some of it is going to be a placebo effect) but there really is some truth there, and so again, this is how science works. I know sometimes it can seem anecdotal, but a lot of really important discoveries and research has come out of people saying that something anecdotally has worked for them.

And finally the last one, as far as does beer or wine count as fermented foods, my official opinion on this is that the alcohol is probably counteracts any positive effects of the fermented food. So I think this is a way to not change your habits but just cast them as being healthier. So I don’t really give two thumbs up to that. I give a neutral eyebrow raise [laughs].

E: [laughs] But I guess part of that is that if the metabolites are important you would be getting some benefits too. But yeah, yeah sure.

H: Ok the metabolites are in the beer.... yeah. But also one of those metabolites is alcohol, which we do know has negative effects. So, you know, moderation, fun! Just do whatever you want, just don’t say that it is healthy because it is a fermented food. That is not, I think, a takeaway that should be had from this paper.

E: Yeah, that’s fair. I also wanted to add to your comment about the alternative treatment, that I think it is important to note that this shoudn’t be a substitute.If you are sick, go see a doctor, don’t just eat fermented foods as a cure.  

H: Yes, 100%. I’ve had a lot of people telling me that they hate fermented foods after this. And yes, I hear you, this is not a proxy for a prescription. If you’re having gut related problems or if you’re having inflammation related problems, this is, at its core, an academic paper and not a medical consultation, so definetly talk to your doctor if you’re having serious problems. It’s possible now that they will begin to recommend fermented foods, but that is kind of where this study lies. You know, health professionals and other academics will read this paper and other things will spin off of it.

E: So what are you working on now?

H: I recently graduated from Sonnenburg lab, and you are taking over fermented foods as the true fermented foods expert [laughs] so I am really excited about this interview and for you to get into the nitty-gritty about what makes fermented foods so special, not just from a health standpoint, but also from the cultural standpoint because it is such a rich area of tradition in so many different countries. I think from that standpoint I am really really interested in fermented foods from a number of different angles. I am not currently working on fermented foods other than just eating them in my home kitchen.  I started a company, Interface Biosciences, which is focusing more on the treatment side of things as opposed to the specific dietary intervention for preventative medicine idea. I am a little biased in saying the metabolites are what is important because my company is based on leveraging these metabolites for treatment of inflammatory disease. So this isn’t just eating kimchi, but finding the element of kimchi that is important and turning that into a traditional drug that will go through pharmaceutical pipelines, that will go through the FDA so that it can be used to treat people with IBS, IBD, and otherserious conditions. Because like you said before, a lot of people that have IBS and IBD eat fermented foods and it irritates their gut. There is something in fermented foods that decreases inflammation, we just need to understand the molecular mechanism of it more so that it can be used as a drug. And so that is what the company is focused on: leveraging the microbiome for treatment of inflammatory diseases through traditional pharmaceutical pipelines.

“ I am still very interested in fermented foods as a whole, I am very excited about the magic of it, where it is going to go....”

I am still very interested in fermented foods as a whole, I am very excited about the magic of it, where it is going to go.... the field is absolutely booming right now, so I am really hoping it doesn’t turn into a bougie boutique product that is only available to a subset of people that are financially well enough off to afford it. One of the great things about fermented foods is that they propagate themselves, so if you went through the sourdough pandemic phase of having a starter and giving it to friends, you can do that with kombucha, you can do that with kefir grains... I think the element of community inherent to fermented foods is what made them so popular throughout history. You know, you are able to use a mead stick throughout your family generations to create a ferment that goes through generations. And I think that is so incredible fascinating. So there is a lot to dive into it. I don’t know where the field is going to head, but the next five to ten years will really define who fermented foods are for, what they are used primarily for, and where the culture of it will go.

E: Great, I think we’ll leave it there! Thank you so much Hannah!

H: Yeah thanks for having me on. 


Hannah Wastyk
is a recent PhD graduate from Stanford University in Bioengineering. She has worked with Justin Sonnenburg to study the intersection of the microbiome and the immune system. She is currently the CEO and co-founder of Interface Biosciences, which is a biotech company that looks at the treatemt of inflammatory disease by leveraging the microbiome.

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