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-α 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.