Proof! Fiber Changes The Brain

In a post last week titled This is Your Brain On Fiber, we presented a mountain of evidence pointing to a very solid link between gut microbiota and brain functioning. And we did this in service of establishing a case between fermentable fiber intake and brain functioning. After all, if fermentable fiber intake is the primary modulator of gut microbiota, then the fiber –> brain link is just a hop, skip, and a jump away.

Well, it looks like that game of hopscotch has concluded.

Just three days after that post, a new study was released, and it’s just what I’ve been waiting for. A collaborative study by the Oxford University psychiatry department and prebiotic manufacturer Clasado has shown, for the first time, that consumption of prebiotic, fermentable fiber can significantly impact the brain by modulating gut microbiota.

The study fed rats either FOS (fructooligosaccharides) or GOS (galactooligosaccharides). And here’s what happened:

In both cases significant effects on the neuronal biochemistry of the rats were demonstrated. These effects are believed to have resulted from changes in the gut microbiota including an increase in bifidobacteria facilitated via the feeding of prebiotics. Brain Derived Neurotrophic Factor (BDNF), an important molecule involved in the development and maintenance of neural cells, increased in the brain after repeated ingestion of prebiotics, compared with rats that did not receive the prebiotics. Additionally, components of the N-methyl-D-aspartate (NMDA) receptor, which have a critical role in brain development, learning and memory, also increased in the rat brain after just two weeks of daily prebiotic feedings.

Those effects were the same ones that were presented in the last post, in studies where microbiota were manipulated through direct introduction of bacteria or through antimocrobial therapies. What was missing was using prebiotic, fermentable fiber as a precipitator of microbial changes. With this study, that is no longer missing. The news report notes that human clinical trials are also underway, and results of those will be released soon.

To those experimenting with high dose fermentable fiber and noticing changes & improvements in mood and cognition: you might not be so crazy after all. In fact, if this study holds true for humans, you may be less crazy than when you started.

With this in hand, we’ve got enough under our belts to confidently pick up where we left off. Stay tuned.

— Heisenbug

The Microbial Effects of Smoking: More Evidence

My original post on the microbial effects of smoking led to a line of inquiry that is still ongoing, and which I plan to return to shortly. But since that original post, I’ve come across quite a few pieces of data and supporting evidence for the broader smoking/microbial link, and I think it’s worth recording them.

Baby Colic

An NPR article last week reported that probotics — specifically Lactobacillus reuteri — have been found to greatly reduce the symptoms of colic in babies (a condition that results in excessive and uncontrollable crying in infants). It’s a condition that affects 8 to 15 percent of babies, and can take a major toll on families. Not only does the probiotic reduce the symptoms, but if given during the first few weeks of life, it can actually prevent colic.

I found this pretty intriguing, but I don’t know much about colic. So I read up on it. Guess what’s been shown to be strongly associated with colic? Smoking during pregnancy. According to a Danish epidemiological study in 2005, mothers who smoked 15 or more cigarettes a day were twice as likely to have babies with colic. Furthermore, studies have found that a) smoking leads to an increase of a hormone (motilin) secreted in the digestive tract; and b) baby colic is associated with an increase in this hormone, thus pointing to a mechanistic link.

According to that study, half of all women smokers continue to smoke during their pregnancies — 12% of all women who give birth.

Inflammatory Bowel Diseases

Crohn’s Disease and Ulcerative Colitis are the twin inflammatory bowel diseases — the first affects the small intestine, the second affects the large intestine. If any kind of disease has a strong microbial connection, it is inflammatory bowel disease. As I mentioned in this post, even animals with IBD present with the dysbiosis pattern found in humans.

What does this have to do with smoking? It’s well known in research circles and those afflicted with IBD that a strange paradox exists between smoking and these diseases. In Crohn’s sufferers, smoking exacerbates the disease. In Ulcerative Colitis sufferers, smoking ameliorates the disease.

The fact that smoking has such a profound effect on the course of two diseases with such a strong microbial connection — negative or positive — is further corroboration of the smoking/microbial link.

Cigarettes, Live Bacteria, Nicotine

Since the original post, I’ve gotten a few questions about how cigarettes may be inducing this effect, and what role nicotine plays in all of this. As I mentioned in that post, cigarette tobacco has been shown to contain gram-negative bacteria, and can introduce endotoxins directly into smokers. What I didn’t quite make clear is that cigarettes introduce live bacteria — and known human pathogens — into smokers:

The research team found 15 different classes of bacteria and a number of potentially pathogenic organisms. The most notorious organisms present were Acinetobacter, Bacillus, Burkholderia, Clostridium, Klebsiella, Pseudomonas aeruginosa, and Serratia. These bacteria were found in more than 90 percent of all cigarette samples tested. Also found in the samples were the pathogens Campylobacter, Enterococcus, Proteus, and Staphylococcus.

Apparently, it is the fermentation of tobacco leaves that creates extremely dense concentrations of bacteria. The bacteria, dead or alive, and the endotoxins they produce can lead to disease:

Even dead bacteria produce endotoxins that can activate cells that cause inflammation. He says there is some concern that the chemicals and bacteria might work together to speed up the malignancy of cancer cells.

This information would indicate that nicotine is not involved with the microbial effect. But more importantly, we also have evidence that nicotine is not involved in the broader smoking/heart disease correlation. Many like to explain smoking’s heart disease correlation by blaming nicotine’s inducement of abnormal heart rate (arrhythmia) and high blood pressure, which can lead to ischemia (insufficient blood flow to the heart). However:

— Heisenbug

L. Plantarum Cured My Eczema

I’ve got an exciting personal experiment to report on.

Some time in the past decade, I developed a very troubling case of hand eczema that is mostly triggered by cold, dry weather in the fall and winter. It can also flare up when I do a lot of cleaning — when my hands are exposed to a lot of water and soap, which are very drying. It results in patches of painful, red, itchy, inflamed, dry skin covering most of my hands. If you know anything about eczema — also referred to as atopic dermatitis — you know that it’s very different from your run of the mill “dry skin.” In fact it’s a completely different thing — it’s an inflammatory byproduct of an overactive/abnormal immune response. Like an allergy, but on your hands. In my case, I’ve determined that a certain level of dryness is required to trigger this response — hence the weather and cleaning triggers. The dryness allows something in the environment — things that should usually be benign like dust or pollen — to trigger the overactive response.

I initially treated this the same way most people do — go to a dermatologist and have them prescribe a steroid-based cream. But as I learned more about what eczema actually is, I decided this was an absurd way to treat it — essentially nuking your skin with steroids, which have nothing at all to do with the pathogenesis of eczema, to make it simply stop producing more skin. At best it treated the symptoms, and it had side effects that didn’t seem very worth it (is there anything creepier than “skin thinning”? It’s like out of a horror movie). Given that dermatologists have a monopoly on prescribing steroid creams, I figured they were probably more useful to them than they were to me. So I just lived with it.

But a funny thing happened. Over the past couple of years,  it stopped happening. But I didn’t actually realize it stopped happening until this fall, when it came back. It was quite a shock — I had completely forgotten about it. But as soon as the weather began to turn cold and dry, it hit hard. Nothing had significantly changed about my environment this year compared to the past few. So then I started to think about diet. But I had not made any dietary changes in the past year or two. And then it occurred to me — I actually did, and very recently. In September I decided to stop consuming a few staple fermented/probiotic foods that I have steadily consumed for the past couple of years — sauerkraut, kimchi, and kombucha. The kombucha was much less frequent — probably a few times a month. But sauerkraut or kimchi were consumed almost daily. I decided to stop them all to see if it made any real difference in how I felt. And for a while I didn’t notice anything. But then fall came, and so did the dry, cold weather. And then the eczema. And I also realized that the last time I had eczema was the winter right before I began regularly consuming these foods. Was there a connection?

I decided to focus on kimchi and sauerkraut, as I consumed them much more frequently than kombucha. And I already knew what the “active ingredient” in these foods would be — fermented vegetables like sauerkraut and kim chi are dominated by the bacterial species Lactobacillus plantarum. In addition to this, I knew that, unlike the commensal bacteria that take up residence in our gut, the primary mechanism of action that exogenous bacteria from fermented foods have in the human body is immune system modulation as they pass through. And again, eczema is a product of abnormal immune response. If sauerkraut & kimchi were responsible for the abatement in my eczema, then it was the L. plantarum and its immunomodulating effects.

Well, after multiple flares over the past few months, I finally got around to testing this hypothesis out.

I searched around and was able to find a probiotic supplement that was solely composed of isolated L. plantarum (it’s marketed as a digestive aid, but I ignored that). I then waited for my eczema to flare up again. As soon as it did, I began taking the L. plantarum. Within three days, the eczema had completely disappeared. This would usually be when the eczema actually gets worse. It usually has about a 2 week cycle before the active inflammation completely subsides. I’ve never seen it disappear like this. Usually at this point, hand washing would be painful and exacerbate it. Now I could hand wash with abandon. Even more amazing: I was able to walk around outside during a particularly cold spell without gloves, and did not have any exacerbation or return of the symptoms whatsoever. Being able to do these things three days into a flare up is unheard of. My hands now feel completely impervious to the triggers. Something has clearly interrupted the inflammatory response.

Following this discovery, I searched around and actually found a tiny handful of studies that support the effect of L. plantarum on eczema:

  • Two separate studies showed L. plantarum inhibiting house-dust-mite-induced eczema in mice.
  • Another study found a similar effect — L. plantarum inhibited allergic reaction and histamine-induced scratching (which is a hallmark symptom of eczema) in mice. It concluded that L. plantarum “may improve allergic diseases, such as anaphylaxis, atopic dermatitis, rhinitis, and pruritus…”
  • L. plantarum was successfully used as a vaccine against dust mite allergy in mice.
  • And based on the promising results in these mouse studies, a human study was done to see if L. plantarum had an effect. It did. The study looked at 118 children with eczema, and found that in the group given L. plantarum, the bacteria was seen to have a beneficial effect.

In all of these studies, L. plantarum led to inhibition of allergy & dermatitis through immunologic alteration. Exactly as I predicted would happen to me. I did not know these studies existed until after my own experiment. The fact that they corroborate my own experience is quite compelling.

If anyone else out there has this issue, consider giving this a try and reporting back. I’m really curious to see if it works for other people. I also think it must hold some potential for alleviating environmental allergies. I plan to post an update looking more deeply into how L. plantarum is having this effect, as I think there is a lot more to be learned from this.

And a final note. This all goes to show that probiotics/fermented foods certainly do have their place in gut health, but in a very different way than fermentable fiber consumption. Contrary to what many believe, probiotics and fermented foods will not significantly alter the bacterial composition of your microbiome. As these studies indicate, and my experience shows, the bacteria and their beneficial effects are undetected once consumption ceases.

Which makes sense.

As I said, the main mechanism of action for exogenous bacteria is through immune modulation as they pass through — a fundamental principle of the “Hygiene Hypothesis,” which contends that humans evolved to have regular exposure to bacteria from foods, soil, animals, and the environment to the extent that these bacteria became a fundamental part of our immune system. They don’t take up residence, they are merely tourists exploring a vast jungle. But like any deep pocketed traveler, they have beneficial effects as they pass through. A steady, constant exposure is the key.

In the case of our resident, commensal gut bacteria, it’s a very different ballgame. In this instance, we’re looking to modulate a rainforest teeming with flora numbering over 100 trillion. Do you really think parachuting in a few billion foreign flora, who don’t even consider this their home, is going to significantly affect this ecosystem? Or does it make more sense to, say, make it rain 50% more in a given month?

Want to alter your microbiome? Make it rain. Consume plant fiber.

But if you have an annoying case of eczema, you might want to host a few more jungle tours.

— Heisenbug

More Confirmation from American Gut + A Unifying Theory of Gut Health

In case you haven’t seen it yet, Jeff Leach of the American Gut Project finally got around to writing up his 10 day no-fiber experiment.

As you may remember, this experiment, which he initially posted on the American Gut Facebook page, was the topic of a previous post on this blog and a major piece of evidence for the case we’ve been building. Jeff’s experiment showed two things: 1) that the abundance of Firmicutes — specifically butyrate-producing clostridia — was driven by the consumption and fermentation of plant fiber; and 2) that the consumption of plant fiber led to the exact same microbiota shift as does the cessation of smoking. This combination is significant proof toward the microbial origin of heart disease hypothesis.

Now, Jeff has posted an extended explanation, and I’m happy to see that it is a confirmation of our own interpretation of the results. Specifically, Jeff notes:

Consequently, the relative abundance of the Family Ruminococcaceae took a hit along with the Family Lachnospiraceae and the Genus Ruminococcus. These three are known plant fermenters – that is, they metabolize dietary plant polysaccharides – that didn’t seem to compete very well as the fermentable substrates (fiber, resistant starch) dried up.

Those two families — Ruminococcaceae and Lachnospiraceae — are the butyrate-producing Clostridia clusters IV and XIVa we’ve been talking about, and the ones we assumed were to blame for the drop in Firmicutes.

Another useful bit of info from Jeff that we did not previously know: the diversity of his microbiota was halved during the no-fiber experiment. This lends a powerful piece of support to the notion that plant fiber consumption contributes to microbial diversity — something we also see in the cessation of smoking. (As I explained in the last post, microbial diversity also seemed to make mice smarter, but we’ll get back to that.)

Lastly, Jeff offers that the most likely explanation for the rise in Proteobacteria and Bacteroidetes was the rise in pH of his gut — it became less acidic. This also confirms the speculation we made about the nature of the Bacteroidetes-Firmicute relationship — that when Firmicutes dried up and stopped producing acidifying short-chain fatty acids, Bacteroidetes would opportunistically bloom as a result of a more favorable environment.

Of course, it still remains to be proven that this shift leads to adverse health consequences — that is a case we’ve been building here through the linking of different correlations. But I’m also happy to report that, in an exchange with Jeff, he informed me that he was also planning to measure health markers from blood serum and stool — including SCFAs and lipopolysaccharides (which are a byproduct of endotoxin-producing bacteria). So that may tell us a lot.

Lastly, reading Jeff’s post, I realized that there may be something that I haven’t touched on enough here and which may go a long way toward helping people understand the broader picture. And that’s the role of acidity and alkalinity in the gut. I think this concept can go a long way toward establishing a unifying theory of gut health.

In case you haven’t figured it out by now, acidity is a good thing. Acidity is a byproduct of fermentation in the gut — when plant fiber is consumed, it feeds specific groups of bacteria — Firmicutes, Actinobacteria (ie, Bifidobacteria) — that in turn produce short-chain fatty acids and other metabolites that make the colon more acidic. A very self-serving thing to do, as these bacteria thrive in a more acidic environment, and their competitors — Proteobacteria and Bacteroidetes — do not. Those groups prefer alkalinity. What’s the best way to boost their numbers? As Jeff showed: stop consuming plant fiber. No more SCFA production, less acidity.

But that’s not the only reason I consider this a useful concept. Take a look a probiotics and fermented foods — an aspect of gut health promotion that many people are much more familiar with. What bacteria predominate? The lactic acid producing bacteria (LABs) — Lactobacilli and Bifidobacteria. These are acid-loving bacteria. How else do you think these bacteria can survive the harsh conditions of your stomach and make it into your gut? And again, a real self-serving bunch, as lactic acid lowers pH like no one’s business. Good for you, good for them. It’s almost as if we co-evolved with these bacteria by consuming them for ages and ages.

But it goes even further than our friendly LABs. What about other traditional, fermented foods, like Kombucha? Kombucha is primarily made up of beneficial yeasts, and some bacteria. This can differ among types, but let’s take one of the more popular brands — GT Kombucha. The primary organisms: Saccharomyces boulardii and Bacillus coagulans. S. boulardii is a strain of yeast that is known to be highly resistant to acidic pH. And guess what makes Bacillus coagulans — perhaps the most common soil-based organism in probiotic products — extremely unique for a Bacillus genus bacteria? It produces lactic acid! In fact, it was called Lactobacillus sporogenes until the smart people in lab coats got their act together and realized they were dealing with something else.

And finally — guess what all that acid in your stomach does, besides break down all that food? It keeps the bad guys out — bad guys who can’t handle the heat. A major function of stomach acid is to protect your exposed gut from all of the pathogens with which you are in constant contact. (Something to consider the next time you pop that acid suppressing pill, maybe?) And if you were a bad gut bug hell bent on invading a human, what would you do? Develop acid resistance. Even pathogenic yeasts rely on a drop in acidity to overgrow.

It’s almost as if acidity tolerance + inducement is a defining requirement for commensalism.

Be good to the acid lovers, and they’ll be good to you. Keep it acidic, my friends.

69306382

— Heisenbug

This Is Your Brain On Fiber

Alright, the brain post. As promised. Please note, this is not a deviation from our central line of inquiry — we’re dot connecting, always. So hang tight! We’re going somewhere with all this…

~~~~~~~~~~~

One topic we haven’t covered here yet is the microbiome and the brain. But not for lack of interest. Quite the opposite — it’s too big, too important. I just haven’t been ready for it. Excitement overload, you might say. And the other reason is that the research in this area is more limited. But fear not, there is plenty enough to make for another episode of You Can’t Be Serious? Theater. I’ll start with a flurry of the more commonly cited studies involving experiments with isolated bacterial species, and then end with what I would consider to be the most compelling and authoritative study yet done on the gut-brain link — and what it all means for the case we’ve built so far.

Infection with C. jejuni & C. rodentium

Over the past decade, researchers have shown that introducing non-invasive strains of gram-negative bacteria into mice can alone stimulate anxiety, apart from any inflammatory or infectious effect of the pathogens. A series of three studies introduced the bacteria Campylobacter jejuni into mice to induce “sub-clinical” infections, which did not stimulate any immune response. The experiments showed that the pathogen induced an anxiety response in mice directly through neural pathways.

Similar studies were done with gram-negative bacteria Citrobacter rodentium. One study showed that mice infected with C. rodentium elicited anxious behavior without any signs of immune stimulation, showing the effect being transmitted directly from the gut to the brain. In another experiment, mice exposed to C. rodentium showed impaired learning and memory. Pre-treatment with probiotics prevented these effects. The study concluded: “The intestinal microbiota influences the ability to form memory.” The study also looked at germ-free mice (mice without a microbiota) and found that they lacked non-spatial and working memory altogether, regardless of infection, “indicating the requirement for a commensal gut microbiota in memory.

C. jejuni and C. rodentium belong to the Proteobacteria phylum. Proteobacteria go down when you eat plant fiber and stop smoking.

Probiotics: Lactobacilli and Bifidobacteria

There is a decent amount of research on specific strains of probiotic bacteria — specifically the lactic-acid producing bacterial groups Lactobacillus and Bifidobacterium. The vast majority of bacteria found in fermented foods and probiotic supplements belong to these groups. They are also normal commensal residents of the human gut.

In one study, supplementation with the probiotic bacteria Lactobacillus rhamnosus in mice was found to significantly reduce anxiety and depression. The effect was not found in mice whose vagus nerve was removed, proving a direct gut-to-brain mechanism. Another study found L. rhamnosus effective at attenuating Obsessive-Compulsive behavior in mice. The probiotic was found to be as effective as Fluoxetine (better known as Prozac, which is often used to treat OCD).

In a study using maternal separation as a standard inducement of depresson in mice, the administration of Bifidobacterium infantis was found to reverse depression and normalize motivation.

The combination of Lactobacillus helveticum and Bifidobacterium longum has shown anti-anxiety and anti-depression effects in mice, rats and humans. That same combination was shown to reduce post-myocardial infarction depression in rats.

And finally, a human study — perhaps the definitive one in this class of studies. 36 women with no gastrointestinal or psychiatric symptoms were split into three groups: one fed a fermented milk product (ie, yogurt with lots of lactobacilli and bifidobacteria), one fed a non-fermented milk product (no probiotic bacteria), and one with no product at all. Brain scans showed that in the women consuming the fermented yogurt, wide-ranging alterations in brain connectivity and regional stimulation were observed. They showed decreased reactivity in an emotional reactivity task (angry and frightened faces) and increased connections in cognition-associated areas of the prefrontal cortex.

Lactobacilli belong to the Firmicutes phylum. Bifidobacteria belong to the Actinobacteria phylum. Firmicutes and Actinobacteria go up when you eat plant fiber and stop smoking.

Diet, Microbial Diversity, Cognition

An interesting study. As opposed to the previous studies we just looked at, which tested the effect of introducing isolated species of bacteria into the microbiome, this study looked at the existing microbiome of mice as a whole — a lot more like the studies this blog has covered so far. Specifically, the researchers wanted to see if a diet-induced change in mice’s microbiota could have an effect on learning & memory. 

The researchers designed two diets with nearly identical nutrient ratios — calories, amino acids, fatty acids. One diet, however, included lean beef, which was known to have the ability to modulate mouse microbiota. Results: the study found that in lean beef fed mice, microbial diversity rose significantly. And so did learning & memory ability. A decrease in anxiety was also observed. It should be noted that while they went to great lengths to equalize the diets, they were not perfectly identical (specifically, the lean beef diet contained more taurine and double the fat). As such, microbial causation was not proven, but a correlation between microbial diversity and better learning & memory ability was firmly established.

Microbial diversity goes up when you eat plant fiber and stop smoking.

The Big One

Finally: the mouse study to rule them all. One reason I like this study is that, as in the previous study, it looks at the mouse microbiome as a whole. But the other is the methodology — germ-free controls and microbiota transplants galore. Solid isolation of microbial causation. As such, I’ve found it to be the most oft-cited study in gut-brain research.

The study had a familiar goal: to see if changes in the mouse microbiome had a direct, causal effect on mouse mood and behavior. To cause a shift in microbiota, researchers applied antimicrobials to one group of mice, but not to the control group. Also, just to be sure the antimicrobials weren’t having some other non-microbial effect, they also gave antimicrobials to germ-free mice — mice without a microbiota. Mice given the antimicrobials, but not the control or germ-free group, experienced a marked shift towards more exploratory behavior and less anxiety. The mice — which were a strain bred to be overly timid and shy — all of a sudden became “bold and adventurous,” in the words of one of the study’s authors. But that’s not all. Researchers then implanted the microbiota of the mice that were given antimicrobials into the germ-free mice. The germ-free mice, after the transplant, experienced the same shift toward more exploratory behavior and less anxiety. Thus, it was shown that the shift in microbiota was the cause for the change in mood and behavior.

Oh, and what exactly about this microbial shift caused this change? Let’s let the study speak for itself:

A 7-day course of ATM resulted in a significant increase in Firmicutes and Actinobacteria, and a decrease in γ-proteobacteria and Bacteroidetes. We believe that these changes in bacterial composition of the colon were responsible for the documented changes in brain BDNF levels and in behavior.

Ahem. Anxiety gone when Bacteroides and Proteobacteria go down, and Firmicutes and Actinobacteria go up. The same exact thing that happens when you eat plant fiber and stop smoking.

Once again, it’s our “golden ratio” of microbiota. But this time implicated in a completely different area of health — the brain. We now see that this exact same microbial shift can impact brain functioning. As I noted in my last post, the ability to show similar mechanisms in different factors of disease — or different areas of health, in this case — is a very good way to build a broader case. That we now see this microbial shift affecting both the brain and the heart further solidifies a link between it and general human health.

Neat, huh? Thanks for reading. See you next time…

Oh, wait. One more thing…

one-more-thing

The fact that we’ve established a firm case for a causal link between microbiota and heart disease, as well as the possibility for microbiota to influence brain functioning, puts us in a position to do something interesting: it allows us to to test that second brain/microbiota link for specific cases. We’re now in the position to use these two findings to put other specific brain-related factors/attributes under suspicion of having a microbial link. How? By using the microbial-heart link as our anchor.

~~~~~~~~~~~

Hypothesis!

Assuming an established microbial origin for heart disease, and assuming an established ability for microbiota to influence the brain, it is possible that a brain-related factor with a strong correlation to heart disease is, itself, strongly and independently influenced by microbiota.

~~~~~~~~~~~

Here’s what I mean.

In the case of plants and smoking, we’ve essentially created two separate 3-pointed triangles of causality.

Smoking             Plant-Fiber

These two separate triangles have the same  direction of causality. We can be confident of this direction because both factors have been shown to directly cause this microbial shift. And these two factors are separately correlated to heart disease. The fact that they are so different, yet both cause the same shift in microbiota, reinforces the microbiota -> heart disease causation theory.

Since we’ve now established the possibility that this microbial shift can also affect the brain, we can do something interesting: we can test for other brain/microbiota links by replacing plant fiber and smoking with a brain-related factor — but only one that has been shown to have a correlation with heart disease:

Brain-Factor

You’ll notice that there’s one thing different about this triangle: the direction of causality. That’s because, in this case, our data shows that microbes cause the brain change, rather than the other way around. In the case of plants and smoking, we have proof of the opposite: plants and smoking cause the microbial shift. But it also makes intuitive sense — it’s hard to see how microbiota could force you to smoke or eat plants. But in the case of the brain, it’s a little less clear cut. Yes, our studies above show a microbial -> brain change direction, so we know that’s possible. But we also know that things like stress may affect our microbiome — the gut-brain is a two-way street. But since we’re specifically interested right now in a microbial -> brain change effect, we’re going to structure our theoretical triangle this way and let our reasoning ability decide if the brain factor we find makes sense or not. If it does, it’s correlation with heart disease will mean it is a side effect of the microbial mechanism, rather than a root factor like plant fiber and smoking.

Which brings us to the final, crucial task: finding a good brain-related factor correlated to heart disease.

To really make this worth our while, we’d have to find some kind of brain-related factor that has a really high correlation with heart disease. Something strong enough that would lower the probability of it being just a side effect of, or a precondition for, some other stronger correlation. And as I said, it would also have to make intuitive sense in terms of direction of causation . But most of all, it has to be a pretty strong link — something that comes at least close to smoking’s place as the NUMBER ONE predictor of heart disease. In other words, we’d have to get pretty lucky. And I just don’t see that happening any time soo…

Report: Low IQ second-highest predictor of heart disease (after smoking)

Uh oh.

breaking_bad_hank

— Heisenbug

Animals, Gut Bugs, & Your Health: A More Serious Point

There were some pretty good reactions to the last post on animals and health care. But I wanted to do a slightly more serious follow up now on something I came across in the aftermath.

Following that post, this study arrived in my inbox (h/t Dr. BG of AnimalPharm), titled “COMPANION ANIMALS SYMPOSIUM: Microbes and gastrointestinal health of dogs and cats.”

It’s a broad overview of the microbial roots of inflammatory bowel disease in cats and dogs. Fascinating, I know. But I wanted to zero in on one bit of the study that I found pretty interesting:

Similarly to humans, a microbial dysbiosis has been identified in feline and canine IBD. Commonly observed microbial changes are increased Proteobacteria (i.e., Escherichia coli) with concurrent decreases in Firmicutes, especially a reduced diversity in Clostridium clusters XIVa and IV (i.e.,Lachnospiraceae, Ruminococcaceae, Faecalibacterium spp.). This would indicate that these bacterial groups, important short-chain fatty acid producers, may play an important role in promoting intestinal health.

In case you don’t know by now, that’s the microbiota pattern we’ve sort of been obsessing about. We see it everywhere. Call it the “golden ratio” of the microbiome and disease. So there’s that again!

But there’s also another thing we’ve been going on about lately, and that’s the power derived from being able to take two factors that are very different (like, say, plant fiber consumption and smoking) which are correlated to something similar (heart disease) in order to isolate a mechanism of action. In other words, a cause.

Here’s an example of what I mean:

Imagine I came to you and told you that both cigarette smoking and cigar smoking contribute to heart disease, and they do so because they both make your teeth yellow. You’d call me an idiot. Cigar smoking and cigarette smoking are very similar things, and have all sorts of similar effects because of that. So the probability of teeth yellowing being the explanation for their causing heart disease is quite low.

But what if both cigarette smoking and a diet low in plant fiber both made your teeth yellow? You’d probably be more willing to hear me out.

The more different the factors are, the more probable it is that the shared effect you’ve isolated is the cause you are looking for.

What are the chances that eating plant fiber and quitting smoking (or the inverse), very different actions which are both factors correlated to heart disease, are going to have the exact same (and previously unknown) effect in the human body, but that effect has nothing to do with the heart disease correlation? And given that effect (the microbial shift) has been already implicated not only in disease, but in metabolic disease — a class to which heart disease belongs — well haven’t we done something kind of notable?

I make this point because this study sort of does something similar. In this case, we find the “golden ratio” again, but in a completely different species of animal. That cats and dogs are so completely not human, yet experience disease as a result of this microbial pattern, is extremely corroborating information. It’s a pattern detected in human disease. It’s a pattern detected in human actions that are not only related to general healthfulness, but strongly correlated to those very diseases. And now we detect that pattern in diseases of a completely different species of animal. What are the chances that this information belongs in the file drawer labeled: Irrelevant?

Not sure? Let’s play the game again.

Let’s say I showed you a human being who ate a tennis ball and as a result could do highly complex physics equations without ever having studied physics. In order to convince you that this could be duplicated in ANY other human being, what would be more convincing to you: showing you the trick in another human being, or showing you a cat eating a tennis ball and then spouting off Einstein’s theory of relativity?

See?

I just wanted to make one other point, and this goes back to the point I made in the original post. Perhaps this is a small thing, and maybe only someone like me who consumes a lot of this kind of research would notice, but: the study quotation above is by far the clearest statement I have yet to see of the dysbiosis pattern that we have identified on this blog. And it’s in a study about dogs and cats. At this rate, we truly are going to solve chronic disease in our pets before we do in ourselves.

— Heisenbug

Plants & Smoking: An Important Dot I Forgot To Connect

Sometimes an insight comes through the most random of things.

In a discussion about mucilage following this post, reader Roelm brought up something I hadn’t heard before. Mucilage is a soluble, gel-forming fermentable fiber in the class of non-starch polysaccharides. A good one to have in the mix. Okra is rich in mucilage (it’s my favorite source of it), but it can also be found in flaxseed, psyllium, cacti, and chia seeds. Roelm writes:

My neighbor who has blood sugar level problems told me a while back that he consumes okra mucilage and that helps him control his blood sugar. He cuts in two a couple of okra fruits, puts them in a water container and he then drinks from the container throughout the day. Apparently he is not the only one to do this as he got the idea from the wife of a medical doctor. I can surmise that the mechanism is at least in part increased butyrate production like that with scFOS and resistant starch.

I had never heard of okra as a diabetes or blood sugar remedy before. But a search for “okra” + “diabetes” or “okra” + “blood sugar” turns up a lot of results. But nothing about how or why, save for a bunch of unsubstantiated conjecture about sugar metabolization and cholesterol (we’ll get to that in a moment).

As I said, the mucilage in okra is a prebiotic, fermentable fiber. And that’s confirmed in the research. Mucilage has a prebiotic effect and a significant effect on SCFA production — specifically propionate and butyrate:

Increased levels of the short-chain fatty acids (SCFA) were attained in the cultures at rates of 35 and 16% in response to MO and PO treatments, respectively. Propionic acid (propionate) and butanoic acid (butyrate) production increased at least 50% throughout MO and PO treatments.

And okra has specifically been found to improve metabolic disorder in mice and have an anti-diabetic effect, as well as counteract hyperlipidemia, which is also a contributing factor to cardiovascular disease.

But if you read these studies, you’ll find that they can’t make any real conclusions about why or how it has these effects.

And then it came back to me: fiber in general has had a long-standing correlation with less heart disease. And it, too, has never been shown why or how.

If you’ve been following along, you’ll know that one of the more exciting and interesting discoveries we’ve made thus far is that the cessation of smoking — which is the number one predictor of heart disease — seems to cause the exact same microbial shift as consuming plant fiber. And what I found to be notable was that these are two acts that are completely different yet both considered to be healthful. But it was much better than that! They are completely different acts that are not only generally healthful, but are specifically correlated with less heart disease. And they result in the same microbial shift.

Like I said, as we find in the specific case of okra, there have never been very good explanations for why fiber has this effect. All you will find is a lot of conjecture about cholesterol-binding and displacement of dietary fat consumption. But if you read closely, you’ll find these claims are always preceded by “may” and “is said to.” That’s because there’s no research backing any of that up. (I’ve found that the medical establishment invokes the “evidence-based” requirement rather selectively.) This is likely due to preconceived biases, ie, “cholesterol and fat are obviously bad and cause heart disease so it must have something to do with that.” (How evidence-based of them.) And a meta-analysis has in fact shown that cholesterol-lowering is not the mechanism, which remains undefined.

So to put it all together:

Smoking is the number one predictor of heart disease, and happens to cause a microbial shift when you stop. That microbial shift is the exact same shift caused when consuming fermentable plant fiber. And plant fiber is correlated with less heart disease. (Oh, and we’ve also shown that same microbial shift to be responsible for the insulin sensitization caused in human subjects who underwent fecal microbiota transplantation.)

Identifying factors that are completely different (plants & smoking), yet have the same effect (less heart disease), is a very good way to isolate a mechanism of action.

And, for that reason, in my next post we’re going to drill down even more deeply into this line of inquiry by completely departing from the land of metabolic disorder and venturing into an entirely different, but no less significant, area of health. I’ll let you guess as to what I might be referring to.

Ok, hint: Some say it’s the reason that tiny gut of yours is so bad at converting all of that plant cellulose into anything useful, but why you’re capable of reading this right now.

Alright, I need a break. I’m hungry and I’m mentally drained. You might say I have a gut-brain problem.

— Heisenbug