Saccharin Induces Diabetes By Messing With Your Microbes. And it’s in my toothpaste.

Uh oh.

Many of you are probably already aware of the big study from the past week — the one showing that artificial sweeteners impair glucose tolerance by modifying your gut bacteria. If you aren’t, read up. I’ll have more to say about this study — some deeper questions and some dot connecting — soon.

But right now I want to alert people to something a little more practical.

Earlier today, I was reading this post on the blog of microbiologist Jonathan Eisen. In the post he calls attention to the fact that triclosan, an antibacterial agent, is in his toothpaste. He takes toothpaste makers to task for downplaying and minimizing the risk, and he’s right. A study recently came out showing that triclosan promotes nasal colonization of Staphylococcus aureus. Major source of infections.

Triclosan is the active ingredient in antibacterial soaps and lots of other products. More and more research is showing that it’s bad stuff, and many people are catching on. But as Jonathan’s post shows, many people aren’t aware of just how many things it’s in.

I myself have known about triclosan in toothpaste for a while, and so I’ve made it a point to avoid it. But since I hadn’t really paid attention in a while, I decided to go and check my current tube of Crest toothpaste just to make sure. Luckily, no triclosan.

But then I noticed something else.

Buried in the ingredients list, I found this:




You just can’t win, can you?

Now, I have no idea if the amount of saccharin in toothpaste is clinically significant. And I know, you aren’t swallowing a ton of toothpaste. But multiple brushings a day, every day, over decades? And what about the oral microbial impact?

Honestly, I don’t care. I’m buying new toothpaste tomorrow.

Oh, and I love this Q&A on Crest’s website:


Saccharin in Crest Toothpaste?


We use saccharin as a sweetener in Crest for a variety of reasons. Saccharin offers better stability both during manufacture and while on store shelves or in your medicine cabinet. Saccharin does not contribute to the development of cavities.

We’re confident our use of saccharin is completely safe for our customers, or we would not use it. Consumers regularly ingest higher levels of saccharin in more frequently used foods and beverages than we would ever expect them to ingest by using Crest. And, of course, our use of saccharin is permitted by the Food and Drug Administration (FDA).

Oh good. I’m sure the FDA is up on the latest microbiome research. I bet they’re issuing a warning as we speak.

By the way, saccharin was banned as a carcinogen by the U.S. and Canada in the 1970s. Those bans have since been lifted because, as far as I can tell, saccharin isn’t quite cancer-y enough and it’s more important to allow food manufacturers to make money from people dying, or something.

Moral of the story: Microbiome research makes everything outdated, and puts everything under suspicion.

That is all.

— Heisenbug

Clostridia & Food Allergies: Excellent News, Silly Conclusions

For those of you who are vigilant microbiome news junkies, you may have already come across this one last week: researchers found that inserting a major class of human gut bacteria — Clostridia — into mice with peanut allergies eliminated the allergy. And they found that inserting the other major class of human gut bacteria — Bacteroides — did nothing to alleviate the allergy.


If you’ve been following this blog for a while, you know that this is the class of bacteria, more than any other, that we like to obsess over around here.

Clostridia are the bacteria that make up the majority of people’s “Firmicutes” in gut reports. That’s why I’ve tended to use them a bit interchangeably in the past (though I should probably stop that). They are usually broken into two clusters: Ruminococcaceae and Lachnospiraceae (also often called Cluster XIVa and IV). And those are the exact clusters that were found to ameliorate the allergies. And Bacteroides are the other side of the coin — they tend to make up majority of the other major gut phylum, Bacteroidetes.

The most important, and longest running argument on this blog, has been about Clostridia/Firmicutes: they grow on fermentable fiber from plants and are the main beneficiaries of resistant starch intake, they are the ones that produce the majority of short-chain fatty acids like butyrate, and they seem to be universally correlated with health promotion. Lower Clostridia? Almost never good. And the other dominant, and related argument on this blog has been this: that these effects are due to their interaction with the immune system. Remember, it is said that 70% of our immune system is in our gastrointestinal system. All these people experiencing sleeping/dreaming effects with resistant starch? Probably the Clostridia, and their SCFAs, modulating the immune system.

And the general theory I put forward in this post, about what exactly makes Clostridia so special, was this: that from the little research I could dig up, Clostridia seem to be the adherent bacteria in the human gut. That they are the ones residing in the mucosal layer, acting as a defensive barrier, providing SCFAs to the epithelium, and thus directly communicating with our immune system. The other bacteria, like Bacteroides, seem to inhabit the luminal space — the hollow cavity of the intestine.


So…was that right? The researchers who conducted this recent peanut allergy study sure seem to be saying exactly that:

“These bacteria are very abundant and they reside very close to the epithelial lining, so they’re in intimate contact with the immune system,” Nagler says.

In one quote, we get significant support for two major lines of argument from this blog: that Clostridia are a special and important class of gut bacteria in the human gut because they are the mucosal-adherent bacteria, and because they modulate the immune system.

In case you were interested in the nitty gritty of this particular study, it looks like the Clostridia eliminated the allergies through regulation of an immune modulating cytokine, just like we talked about in the sleeping & dreaming post:

To identify this protective mechanism, the researchers studied immune responses to bacteria in the gut. Genetic analysis revealed that Clostridia caused innate immune cells to produce high levels of interleukin-22 (IL-22), a signaling molecule known to decrease the permeability of the intestinal lining. Children with food allergies are know to have greater permeability in their guts when they eat problem foods.

In a second part of the experiment, the antibiotic-treated mice were either given IL-22 or were colonized with Clostridia. When exposed to peanut allergens, mice in both groups showed reduced allergen levels in their blood compared to controls. Allergen levels significantly increased, however, after the mice were given antibodies that neutralized IL-22, indicating that Clostridia-induced IL-22 prevents food allergens from entering the bloodstream.

As for how, exactly, Clostridia modulates this immune signal, the researchers stayed pretty general. As you know, we’ve focused on short chain fatty acids as the likely mechanism (but have certainly kept the door open to other possibilities):

“They are always signaling to our bodies, but we’re not usually making a response to them. We found they generate particular signals that promote the production of mucous and natural antibiotics the body makes to reinforce the barrier [of the intestinal lining] and prevent those food allergens from getting past the epithelial barrier and into our blood,” said Nagler.

Alright, enough of this victory lap stuff. Time to vent some frustration.

While this study is a really great one to see, the ultimate conclusions drawn by the researchers, both in the study and the media reports, is disappointing, to say the least. Why? Because both in the study itself and in the many news reports about it, what the researchers say essentially amounts to this: “We need to put Clostridia in a pill.” 

Exhibit A:

Nagler and her university have filed for a patent application on the new findings. The ultimate goal is to “interrupt [the allergy] process by manipulating the microbiota,” she says—a probiotic consisting of Clostridia could be a new allergy therapy, for example. Nagler knows of none on the market yet, and they would need testing in people before becoming a treatment of choice.

Exhibit B:

“The exciting implication for consumers is this gives us a way to intervene and see if we can now use modulation of the bacteria in our gut as a way to prevent or treat food allergies,” Nagler said. “We could use the Clostridia to develop a novel, new treatment we can give to people with food allergies, or to protect people before they get food allergies, to elicit this barrier protective response. This is a totally new probiotic.

Nagler said that several companies are already working to develop this new probiotic. “In fact,” she added, “we are working with one company. Clostridia are very difficult to work with because they can’t be exposed to oxygen. The good thing about them is they form very stable spores that can live under very extreme conditions. We can potentially collect spores of Clostridia and create them as a pill.”

Exhibit C:

Clostridia bacteria are common in humans and represent a clear target for potential therapeutics that prevent or treat food allergies. Nagler and her team are working to develop and test compositions that could be used for probiotic therapy and have filed a provisional patent.

Sigh. Big, big sigh.

First things first: I find it pretty disturbing that the first thing health research labs do, once they make an important discovery about human health, is to immediately file a patent. Furthermore, it’s one thing to patent some kind of novel, synthetic, chemical drug, and another to patent something that’s essentially a part of and produced by the human body. These are native human gut bacteria. You’re patenting the idea of putting them in a pill? What’s next, a patent on Vitamin C chewables?

Which brings us to the real reason I find this so frustrating: everything about this study, and everything we know about Clostridia in the human gut, points to the fact that probiotics are not the answer.

As I just said, these are native human gut bacteria. They live and grow inside of you. They can’t survive outside of a human. They exist because you exist. They need you, you need them. Heck, the researchers said it themselves!

“Then we tried to find out which bacterial population it was, and in a whole series of experiments, we settled on Clostridia, which are oxygen-sensitive bacteria,” Nagler said. “They can’t live outside of an environment that is oxygen free. Deep inside your body, deep inside your intestines, there’s no oxygen, and that’s where this kind of bacteria live.

In other words: you don’t need to “seed” or “infect” yourself with these bacteria, as if they are some exotic, hard to acquire bug. Don’t believe me? Here’s the proof: EVERY SINGLE INDIVIDUAL GUT REPORT I HAVE EVER SEEN CONTAINS THESE BACTERIA. I have never seen a report showing no Clostridia. Not one. If you are a human, then you almost assuredly have Clostridia in you.

What DOES differ, from person to person, is the amount. In some, they are the predominant bacteria. In others, a tiny fraction. And what do you think accounts for that? Do some people have access to a magical Clostridia tree? Is there a secret, members-only Clostridia CSA you need to join?


From everything we’ve gathered here on this blog, it’s quite clear that the quantity of these bacteria aren’t related to some type of external exposure. Rather, they respond to the intestinal environment and the inputs into that environment. Clostridia grow when you feed them plant fibers, and they thrive in an acidic intestinal environment — one where a lot of fiber fermentation is taking place, which itself drives down the intestinal pH. Which means that not only a lot of fermentable plant fiber, but also a diversity of fermentable plant fiber, is a pretty good bet.

In other words: if a rainforest is dying because it isn’t raining enough, you don’t plant more trees. You make it rain more. Get it?

As for the question of why this fact isn’t abundantly clear to, or promoted by, the researchers who conducted this study, I think that’s patently obvious. Don’t you?

— Heisenbug

The Truth About “Lactose Intolerance”

I’ve wanted to address this one for a while.

I consider lactose intolerance to be one of the most universally mischaracterized and misunderstood concepts in all of nutrition and health. The most astounding thing is how deeply misunderstood it is by health experts, like doctors and nutritionists. It’s quite shocking how pervasive it is. So my aim is to take the basic principles of gut microbiome physiology that we regularly discuss on this blog, and use them to cut through what I consider to be a sort of mass delusion.

There’s a reason I put lactose intolerance in scare quotes in the title of this post. To me, there are really two concepts of lactose intolerance. I’ll start with the first one, which I call technical lactose intolerance.

Technical lactose intolerance is genetic. It means that your body, once it is past infancy, ceases to produce the lactase enzyme, which is required for breaking down and digesting the sugar carbohydrates in dairy (lactose) in the small intestine. But here’s the funny thing: what this really means is that you are a standard, run-of-the-mill human being. You see, technical lactose intolerance is actually the norm. It’s estimated that nearly 70 percent of the world’s population does not produce the lactase enzyme, making them technically lactose intolerant. Which makes the term lactose intolerance very strange. We usually reserve the word “intolerance” for something that should be tolerated but isn’t, like an allergy. It’s the lactose tolerant people — those who have the genetic mutation that allows them to produce lactase into adulthood and therefore digest lactose — who are the real oddities. Lucky duckies, they are.

Technically lactose intolerant populations, historically, tend not to consume much fresh milk. That we know. But notice I said “fresh milk” and not “dairy.” That’s because dairy consumption, in the form of cheese, yogurt and other fermented dairy products, is insanely prevalent throughout the world among technically lactose intolerant populations. It has been for ages. In fact, these dairy products were invented by ancestral populations who were assuredly lactose intolerant themselves.

Now hold that thought for a moment.

Let’s move on to the second type of lactose intolerance, what I like to call “lactose intolerance.” This is the kind of lactose intolerance that we most often hear about and discuss socially — at a dinner party, PTA meeting, with your doctor, in the news, etc. It’s the mainstream understanding of lactose intolerance: that your digestive system just isn’t equipped to handle dairy. Eat some cheese or yogurt (don’t even think about milk), and GI discomfort is bound to strike. You just aren’t built to handle it because of those crappy genes of yours. Nowadays, whenever you come across people who declare themselves to be lactose intolerant, they are almost undoubtedly referring to this type of lactose intolerance. And most doctors seem to accept and even propagate this understanding of lactose intolerance.

So what explains this dichotomy? Simple: the second type isn’t lactose intolerance at all. It’s dysbiosis.

If you remember, we have a pretty simple definition of what fiber is. It’s any carbohydrate that isn’t absorbed by your small intestine, and instead passes into your large intestine to be broken down and fermented by bacteria. Gee, isn’t that exactly what lactose is in a person who doesn’t digest lactose? Why yes, yes it is! Lactose, in people who don’t produce the lactase enzyme, is treated as prebiotic, fermentable fiber. You don’t digest it, so your gut bacteria do. Simple as that. In fact, lactose is known to be the preferential fiber for a pretty important class of gut bacteria.

And that’s what explains why lactose intolerant populations don’t generally consume much fresh milk, but plenty of fermented dairy products. That’s because a glass of fresh milk is quite a large bolus of lactose. A tall glass of milk might contain around 20 grams. For someone who produces lactase, that’s fine — it’s just sugar that will be digested. But for a non lactase-persistent person, that’s a lot of fermentable fiber. Which means it’s a limiting factor for how much milk you can consume in a sitting. But that’s the case with any kind of fiber intake, right? At a certain point, it will get uncomfortable, no matter how bulletproof your gut situation is. But yogurt, on the other hand, might contain around 7 grams of lactose per serving. Cheese? Even less. That’s because lactose is exactly what lactic acid-producing probiotic bacteria (ie, lactobacillus) consume in order to ferment these products. They drastically reduce the amount of lactose in them, which means you can comfortably consume much more of it without any discomfort. And that was probably pretty handy in the days when calories were a little harder to come by than they are today.

7 grams of lactose or less? Easy peasy. That’s a pretty decent prebiotic gut snack. Provided your gut isn’t a barren wasteland, that is! And yours truly is living proof: I am a technically lactose intolerant person. My body does not produce the lactase enzyme, confirmed by genetic testing (23andme). But guess what? I consume the hell out of dairy. Cheese and yogurt are daily staples. But that’s not all. Sometimes, I go ahead and do something crazy: I drink a glass of milk. If it’s a small one, not much happens at all. If it’s a tall one? Maybe I shouldn’t be too social that evening. And that’s exactly what technical lactose intolerance is: it’s just a limitation on how much lactose you can consume before things get less than comfy. Like anything else with a lot of fermentable fiber.

Which brings us to our modern “lactose intolerant” epidemic. You see, these people aren’t really lactose intolerant. They are fermentable fiber intolerant. Dairy gives them problems not because they lack a digestive enzyme, but because they lack their other 90 percent. Their gut bacteria just don’t seem to be able to handle even a small dose of lactose fiber.

Without doing too much research on this, I very strongly suspect that the entire concept of “lactose intolerance” is quite new and modern, relatively speaking. A hundred years ago, I don’t think anyone identified as “lactose intolerant.” Most people consumed dairy just fine. A subset of them — lactase producers — regularly drank fresh milk. But most people didn’t because they just weren’t culturally accustomed to doing so, and they probably knew it would make them kind of gassy and bloated if they drank a lot. And that’s that.

But probably right around the time we figured out how to royally screw up our guts and invite all manner of chronic ailments into our lives, a lot of people started to notice that dairy gave them problems in their tum-tum. But instead of figuring out why, we decided to just give it a name, blame genetics, and pretend like it existed since the beginning of time. Gee, does that sound like anything else?

Which leads me to believe that, just maybe, a gut rehab protocol could potentially cure this modern “lactose intolerance” epidemic sweeping the globe. If I had a problem digesting any amount of dairy, I would definitely try out a fiber adaptation regimen. It may be just the ticket to joining the ranks of us lactose intolerant, milk-drinking hermits.

— Heisenbug

Should you have your gut bacteria sequenced? Update on uBiome and American Gut

A couple of months ago, I called attention to a concerning matter: a science writer, Tina Saey, reported on Twitter that she received dramatically different results from the two major microbiome sequencing services available, uBiome and American Gut. And what was most concerning was that the two tests were done using the same sample. So any sort of external factors like diet, or simply the passage of time, could not account for the difference. Tina later posted a lengthier rundown and analysis of her experience.

Shortly thereafter, another science writer undertook a similar experiment, but with a twist: like Tina, she sent the same sample to both uBiome and American Gut, but she also sent an extra sample to American Gut that was taken from the same — but a different section of — her stool (sorry, I try my best to avoid the inevitable ick factor). Interestingly, in her case both uBiome and American Gut matched up well. But her two American Gut samples, taken from different parts of her stool, did not. There were a couple of fairly significant discrepancies.

Well, I think it’s time to close the loop on this matter as best we can, as I’ve been getting questions about the usefulness of testing.

A couple of weeks after sounding the alarm here on this blog, uBiome co-founder Zac Apte left a comment here directing people to an informative blog post at uBiome addressing this issue. The main thrust of it is that uBiome believes the discrepancy to likely be due to the fact that they and American Gut use two differing “extraction” techniques, which are known to result in different outcomes. Fortunately, the way these techniques produce different outcomes is well-understood and can be quantified, and so Zac and his team were able to run an analysis to see if Tina’s results matched when corrected using the “extraction bias” information. And they did seem to come quite close:


Furthermore, I queried Zac recently on the case of that second writer and her experiment on intra-stool variation. And his answer was that this is not much of a surprise — intra-stool variation is expected, and that is why these services have specific collection instructions (swabbing toilet paper), so that the same area is sampled every time. So it seems that directly sampling stool, and in two different areas, circumvents the procedure that’s specifically designed to avoid this problem.

So where does this all leave us?

Well, we’re certainly still left with the question of which technique — and thus which service — provides a more useful and “accurate” accounting of your gut microbiota. Ideally, I’d like to see a dialogue between American Gut and uBiome so that we can get a better understanding of all this and get at what’s really going on. A comparison study might also reveal that perhaps something other than the extraction technique is creating the discrepancy, such as differences in transport or collection methods.

But regardless of all that, I think there are two strong reasons to do one of these tests if you are so inclined.

Detecting Extremes

In my opinion, this is the clearest and best reason to plunk down the money for these tests: the chance that you will find something weird and out of the ordinary. Who knows what you might find? That’s really the usefulness of a test that is largely based on comparative data to a broad population. And it seems to me that both services are still capable of surfacing this kind of thing. What do I mean by something weird? Something like an overgrowth of a specific class of bacteria, the presence of something very rare, or bacterial ratios that are significantly outside the distribution of the population to which you belong.

Detection of any of these things are helpful clues that may get you closer to figuring something out. If you suffer from some sort of health issue and suspect a gut bacteria-related connection, and you can afford the cost, then this may very well be a good reason to do this kind of testing.

Detecting Trends

Trending — seeing how your gut bacteria change over time in response to different stimuli and interventions (drugs, diet, etc.) — is the other very good reason to consider testing. Assuming you stick with one company for your testing, you should be able to get a pretty reliable view of how your gut is changing over the course of several tests. Trending might also be useful for trying to connect the improvement or deterioration of a specific health condition to a specific change in your gut bacteria. Also, while we don’t have a ton of clear and widely established bacterial health markers, the research definitely does point to some (and if you’ve been following along, you should know who they are). Which means there are some clear targets for anyone trying to hack their gut.

The one piece of advice I would give in this regard is to always try to make a prediction before testing, instead of trying to make connections in hindsight. It’s very easy to make all sorts of connections and explanations after the fact, but if a prediction made before receiving results turns out to be true, it’s much more likely to be relevant (because it’s so unlikely for it to actually come true).

And on that final note: I’m going to have some pretty interesting stuff to share very shortly. Stay tuned.

— Heisenbug

Why Resistant Starch & Prebiotic Fiber Improve Sleep and Dreaming

Hey folks. I know, it’s been a while. To make up for it, I’ve decided to take a request from the audience.

A while back, reader Daz made a request: to look into the mounting anecdotal connection between prebiotic fiber — and specifically resistant starch in the form of potato starch — and improved sleeping & dreaming. One of the most prevalent reports from people who begin a high resistant starch regimen is the report of improved sleep and more intense, vivid dreaming. And I’ve found the dreaming part to be especially important, because it’s so specific and so peculiar. That something like that can be experienced so widely must mean something quite specific is going on.

Well, at the time I decided to pass. One reason was that it was just not something I planned to look into at that very moment. But the main reason was that, for quite some time, I had been harboring a hunch about the mechanism in the back of my mind, and I was really hoping it was right, because it would explain a lot and would fit in perfectly with everything we’ve discussed here. And I knew that if I did actually look into it, I would likely be disappointed. I’d probably come up with no supporting evidence, and maybe even something contradictory. Ignorance is bliss. So I put it off.

And then Daz asked again.

Well, I admire persistence, so I bit the bullet and prepared to be disappointed. But I wasn’t. I hit the jackpot.

But first, a refresher.

One of the central premises of this blog, if not the most central, is that our our gut microbiota produce byproducts when they ferment fiber from plant foods — short-chain fatty acids (SCFAs) like butyrate, acetate, and propionate. And these metabolites are known to be used locally and directly by the intestinal tissue as an energy source. They are also metabolized by other adjacent bacterial populations, in what is known as cross-feeding. None of this is controversial. It is well supported and documented, much like the evidence we have for your liver producing bile, and your heart pumping blood. As such, it’s a pretty decent premise to have for a blog about gut microbiota.

Where we begin to drift away from established fact, and more into the land of argumentation, is when we start to explore how important these metabolites are, and why they are important. But we don’t stray too far, as there is quite a bit of research supporting our argument here as well. What’s that argument? That these metabolites are very important, mostly because they regulate our immune system. (Note: they, along with the bacteria themselves, are probably important for quite a few other reasons. But the metabolite/immune theory is what we’re focusing on right now, and also the one we probably give most of our attention to on this blog).

Well, in researching this, it struck me that we may have taken this theory for granted a little too much around here. Some time away is good for some perspective, I guess. So it’s worth supporting this assertion with some actual data. Ready?

Quick primer: cytokines are proteins produced by human cells for important signalling processes, and two types of cytokines –the interleukins (IL) and tumor necrosis factor (TNF) — are immune signalling proteins, meaning they regulate the immune response. Also known as: inflammation. Some are pro-inflammatory, and some are anti-inflammatory. Depends on which ones are released.

There is a large body of research and data showing that short-chain fatty acids produced by human gut microbiota are powerful modulators of those two classes of cytokines.

Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E2 and cytokines:

SCFAs have long been known to modulate the immune response. Acetate, propionate and butyrate represent the most often described SCFAs that are capable of immune activation. SCFAs affect neutrophil function and migration[12-15], and inhibit tumor necrosis factor-α (TNF-α) or interleukin-1 (IL-1)

TNF and IL-1 are pro-inflammatory cytokines. Inhibiting them has an anti-inflammatory effect. The study concludes:

SCFAs can have distinct antiinflammatory activities due to their regulation of PGE2, cytokine and chemokine release from human immune cells.

In Regulation of Inflammation by Short Chain Fatty Acids, we find:

These fatty acids have been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of GPCRs (GPR41 and GPR43) and inhibiton of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions including production of cytokines (TNF-α, IL-2, IL-6 and IL-10), eicosanoids and chemokines (e.g., MCP-1 and CINC-2).


Macrophages are the major source of inflammatory mediators involved in insulin resistance, atherosclerosis, rheumatoid arthritis and neurodegenerative diseases. Once activated, macrophages produce large amounts of TNF-α, IL-1 and IL-6…

SCFAs modulate the production of inflammatory mediators by macrophages as shown in Table 1. SCFAs, mainly butyrate, suppress the LPS- and cytokine-stimulated production of pro-inflammatory mediators including TNF-α, IL-6 and NO. Butyrate also enhances the release of the anti-inflammatory cytokine IL-10.

Insulin resistance, atherosclerosis, rheumatoid arthritis, neurodegenerative diseases? Someone should write a blog about how maybe this stuff might be connected.

So SCFAs not only lower pro-inflammatory cytokines, but also increase anti-inflammatory cytokines like IL-10. So that’s nice.


The production of prostaglandin E2 (PGE2) is also modified by SCFAs….PGE2 has been considered an anti-inflammatory prostanoid due to its ability to attenuate the production of IL-1 and TNF by macrophages and Th1 differentiation.

So again, SCFAs decrease IL-1 and TNF.

And from this study — Butyrate and other short-chain fatty acids as modulators of immunity — we find that cytokine modulation by SCFAs does impact systemic inflammation:

Taken together, these results indicate a clear inhibition of TNF-a and IL-1b-stimulated VCAM-1 expres- sion by SCFA in HUVEC.


By preventing chemotaxis and cell adhesion, SCFAs might prevent infiltration of immune cells in peripheral tissues and can have a protective effect against systemic inflammation.

And it concludes by blowing a passionate kiss to butyrate, specifically:

Overall, SCFAs, especially butyrate, seem to exert broad anti-inflammatory activities by affecting immune cell migration, adhesion, cytokine expression as well as affecting cellular processes such as proliferation, activation, and apoptosis.

In a study of healthy elderly who supplemented with galactooligosaccharide fermentable fiber, this was exactly the effect observed:

Significant increases in phagocytosis, NK cell activity, and the production of antiinflammatory cytokine interleukin-10 (IL-10) and significant reduction in the production of proinflammatory cytokines (IL-6, IL-1beta, and tumor necrosis factor-alpha) were also observed.

And to round it all out: this study found all three SCFAs to reduce pro-inflammatory cytokines TNF, IL-1, and IL-6. This one found both butyrate and propionate equally anti-inflammatory, with acetate slightly less so. And this one found acetate and propionate less modulatory than butyrate, but they did increase the anti-inflammatory IL-10, which butyrate did not. It concluded:

A combination of the three SCFA causes a shift in the T helper lymphocyte phenotype towards a more anti-inflammatory phenotype and this might explain the protective effects of fiber.

Alright, that should do it. Gut bacteria produce SCFAs. These SCFAs modulate our immune system and inflammation. Solid ground.

So, what does this have to do with sleeping and dreaming? Apparently, a lot — every bit as much as I hoped and suspected.

It’s pretty common wisdom that the quality of our sleep has a lot to do with our immune system. But that wisdom tends to go in just one direction: that adequate sleep is essential for maintaining a strong, healthy immune system. And that’s almost undoubtedly true. But as I’ve suspected for a while now, that is only half the story. I believe, and a decent body of research supports the idea, that our immune system has a tremendous impact on the quality and structure of our sleep.

But before we get into the research, I think a simple look at the human experience pretty clearly supports this suspicion. I don’t think I’m alone when I say that when I’m sick — a cold, flu, whatever — my sleep suffers. And if there is any time when the human body is experiencing a higher than normal amount of inflammation, it’s when it is fighting some sort of infection. To me, being sick with an infection is probably the clearest cause I can think of for impaired sleep (other than some sort of acute pain). What would come second? In my mind, that would clearly be stress, anxiety, or depression — mental states that have also been clearly connected to higher states of systemic inflammation.

But as I said, that’s all experiential, anecdotal stuff. Does any actual research support this idea? It does. It turns out those cytokines I just went on and on about are in fact the masters of our sleep. And it seems that none other than IL-1 and TNF are the chief cytokines that have been indentified as sleep regulators:

Much data demonstrate that at least two cytokines, IL-1b (hereafter referred to as IL-1) and TNFa (hereafter referred to as TNF) are involved in the regulation of sleep. These two cytokines may be considered as sleep regulatory because data derived from electrophysiological, biochemical and molecular genetic studies demonstrate specific effects on sleep-wake behavior.

Well now. That alone provides quite a solid link — a strong case for the hypothesis that SCFA modulation of cytokines explains its effects on sleep. But it gets better. Oh so much better. Do you remember how I said that it was the vivid dreaming part that was especially interesting, because of its specificity? The thing is, sleep quality is a pretty general, subjective effect. Which is to say, it could be explained in many ways and be the result of many factors. But vivid dreaming? That’s pretty darn specific. And that’s why it’s so useful — it narrows the pool of factors and mechanisms sharply. If we find a connection between “vivid dreaming” and SCFA modulation of cytokines, now that would be something. Fat chance, right?

Fat chance indeed:

Interleukin-1 beta (IL1) and tumor necrosis factor alpha (TNF) promote non-rapid eye movement sleep under physiological and inflammatory conditions.

Ya don’t say. Please, go on:

IL-1 and TNF at effective doses increase NREM sleep of mice, rats, rabbits, cats, and sheep (human subjects on IL-1 therapy complain of fatigue and sleepiness). These cytokine-induced increases in NREM sleep occur irrespective of whether they are administered centrally or peripherally.

Uh huh. And:

Low doses of IL-1 or TNF need not affect REM sleep, but most concentrations that consistently increase NREM sleep also suppress REM sleep, irrespective of timing of administration.

I wonder if that other cytokine that SCFAs seem to reduce — IL-6 — has a similar effect?

Sleep deprivation of human volunteers increases IL-6 in plasma, and subcutaneous injection of IL-6 increases slow wave sleep and reduces REM sleep of humans.

Yeah, ok, but what would really convince me is if you took mice and…oh, you did that, eh:

Mice lacking functional signal- ing receptors for IL-1 or TNF spend less time in spontaneous NREM sleep in the absence of immune challenge. Substances that increase IL-1 and/or TNF also increase NREM sleep, whereas substances that interfere with the synthesis or secretion of these cytokines reduce NREM sleep. Collectively, results of numerous studies indicate that activation of the IL-1 and/or TNF systems increases NREM sleep, whereas inhibition of these systems decreases spontaneous NREM sleep.

Fine. But what about those other cytokines, the anti-inflammatory ones SCFAs increase. If you could show me that…oh, ok, I’ll just shut up now:

The majority of these cytokines and chemokines when injected into laboratory animals increase NREM sleep. The exceptions are IL-4, IL-10, and IL-13, which reduce NREM sleep. In this respect, IL-4 and IL-10 are of particular interest because they inhibit the synthesis of IL-1 and TNF.

Alright. I think you know where this is headed now. In case you don’t have the old wikipedia handy on the bookshelf, I’ll lay it out right here. What is NREM sleep?

Non-rapid eye movement sleep, or NREM, is, collectively, sleep stages 1–3, previously known as stages 1–4. Rapid eye movement sleep (REM) is not included. There are distinct electroencephalographic and other characteristics seen in each stage. Unlike REM sleep, there is usually little or no eye movement during this stage. Dreaming is rare during NREM sleep, and muscles are not paralyzed as in REM sleep.

And what is REM sleep?!?!?!

REM sleep is physiologically different from the other phases of sleep, which are collectively referred to as non-REM sleep (NREM sleep). Subjects’ vividly recalled dreams mostly occur during REM sleep.

Come. The hell. On. SCFAs downregulate cytokines that increase NREM sleep and decrease REM sleep. And they upregulate cytokines that do the reverse. More REM, less NREM. Not much dreaming in NREM. All the vivid dreaming in REM. That’s it. That’s really it? Just like I dreamt about, no doubt after I hit the potato starch too hard one night? Speechless.

Ok, time to take a step back. What have we done here? Well, yeah, we came up with a pretty good answer for why people are experiencing these effects on a high fermentable fiber regimen. And that’s cool. Explanations are good. But I think it goes much further than that.

What we’ve done is added a monumentally significant data point toward the broader theory that fermentable fiber consumption, through increased intestinal SCFA production, is hacking the immune system. In other words, the resistant starch / sleeping & dreaming connection is now a major piece of proof for the broader and much more important theory that gut bacteria, through SCFA production, profoundly modulate the human immune system and result in a systemic anti-inflammatory effect.

And that’s amazing. And on top of that, we’ve also now been handed an immensely useful biomarker for gut/immune hacking: if you’re trying out a high fermentable fiber regimen and experience these sleeping and dreaming side effects, I’d say that’s some pretty good evidence that you are achieving an anti-inflammatory effect. In other words, it’s proof that you are in fact achieving the desired effect. Your immune system has been hacked. Achievement unlocked. 1000 points for you.

Ok, that’s all for now.

Oh, and thanks, Daz, for the kick in the pants.

— Heisenbug


Heisenbug lives.

Hi all.

Just wanted to let you know that regularly scheduled programming will return shortly. Apologies for the blackout — got swallowed up by some consuming projects over the past couple of months. But rest assured, Heisenbug lives.

Seth Roberts

It is with a very heavy heart that I share the news of Seth Roberts’s passing.

As many of you probably know, Seth was an early champion of this blog and was very encouraging of the ideas contained in it. Had it not been for Seth, I might not have continued past the first few posts. In fact I sometimes found myself writing posts imagining Seth to be the entire audience.

I only got to know Seth personally at the beginning of this year, but we struck up a friendship by email and Skype very quickly. We emailed frequently, often daily, and were deep into a writing project together. Sadly that won’t reach completion now.

We never met in person, but planned to soon given that we both had roots in California. I’m very sad that we won’t be able to. You’d think that only knowing someone via the Internet and not having met in person makes it easier to deal with their passing, but in reality it’s quite difficult, because there’s no one else to share the sadness and grief with.

The deep sense of loss I feel is one for the world. Seth had an extremely unique perspective on very big and important ideas. He said things no one else was saying, and understood things in a way no one else did. The commonality we found on ideas about human health, personal science, innovation, and societal progress is one that I’m not sure I will find again. The phrase “Yes, I agree with that” was probably a part of every exchange we had. Losing the only person who you feel understood certain ideas is very difficult, and the importance of keeping those ideas alive is now felt very acutely.

Learning about his passing late last night made for a horrible night of sleep — one that none of Seth’s discoveries could have made better. Rest in peace, Seth. I will do my best to advance the ideas we found so much agreement on, in some small way.

— Shant