Tuesday, January 27, 2015

Hot Shit!

I'm just reading an article from the May 2014 journal Cell Death and Differentiation, titled "Gut microbiome and anticancer immune response: really hot Sh*t!." (hattip Gemma, who also helped me write this!)

I read lots and lots of scientific papers, too many, in fact.  But this one has really captured my attention.  It kind of cuts through a lot of the BS and narrows into what is really important when it comes to gut health.

Importance of Butyrate


One area we lose sight of too easily is the importance of butyrate production by gut microbes. Everyone has the gut bacteria in-place to produce butyrate. Many different species can turn food we eat into butyrate, these species are mainly in the Clostridium family. I've yet to see a gut test from anyone that doesn't have lots of butyrate producing microbes.

Measuring butyrate is a whole 'nother issue. I had a butyrate test last summer, and it showed that my butyrate level was in the highest percentile. The low acceptable range was way, way lower than my test. In all of the many papers I've read on the importance of butyrate, none have ever given a specific amount required for gut health.

My Butyrate was 27mM/g.  Normal is "above 3.9"


A problem encountered in butyrate measurement is that the amount seen in feces can be misleading. If we have a gut that is starved of butyrate, the cells that use butyrate will be weakened and less butyrate will be utilized, showing up instead in your feces. The accurate way to measure butyrate would be to install a permanent tap on the portal vein and measure the butyrate as it enters your bloodstream. Several studies have done exactly this on pigs and rats, but not humans. A study in the '80's measured blood butyrate as found in human victims of tragic accidents, but unless the autopsy was performed within an hour or so, the results were not conclusive.

As we have no way of accurately accessing the butyrate required to produce beautifully healthy guts, and in turn, a robust immune system, all we can do is eat foods that are known to produce butyrate when fermented by out gut bugs.

From the "Hot Sh*t" paper:

Prebiotics refer to indigestible food ingredients that selectively promote the colonization of healthy commensals such as the dietary fiber inulin that promotes Bifidobacteria growth. More specifically, cancer-preventive antioxidants include dietary polyphenols (flavonoids, phenolic acids, lignins present in tea, wine, nuts, fruits, and so on, and ellagic acid metabolized by colonic microbiota into urolithins exhibiting antiestrogenic and anti-COX2 activities). Another polyphenol called ‘daidzein’, a soy isoflavone metabolized by gut microbiota into equol and only detected in a fraction of individuals (harboring sulfate-reducing bacteria), may protect against breast and prostate cancer, mostly in Asia. The fiber has been involved in the prevention of colorectal cancers and butyrate, one of the most abundant short-chain fatty acids resulting from the bacterial fermentation of fibers and selectively transported into the colon epithelium is the most compelling tumor-suppressive molecule. Butyrate has both cell autonomous and cell extrinsic antitumor effects. It decreases proliferation and promotes apoptosis of tumor cells, ameliorates inflammation associated with colitis and favor expansion of peripheral Treg. Most of these effects result from epigenetic regulation, butyrate acting as an endogenous HDAC inhibitor.


Lots of words, and in an article on prevention of cancer, not on "fiber" or gut health, specifically. It says butyrate acts as an HDAC inhibitor (HDI). HDAC inhibition is kind of the 'holy grail' in many health problems. Man-made HDIs are used as mood stabilizers and in epileptic treatments as well as cancer and treating auto-immune diseases. HDI's are a huge industry...yet if we eat right, we can simply make our own!

Also, did you notice the author singled out inulin as a prebiotic, and mentioned its promotion of Bifidobacteria. Had they looked a bit harder they would have also discovered RS, pectin, glucomannan and all the other fibers that act similarly to inulin. It was nice to see them also mention the polyphenols found in foods that are also associated with good gut health and anti-cancer activities. This fits in nicely with what we have been saying all along:  Try to eat lots of fiber, but also important are the compounds found in real foods and not available as a supplement.

Here's a bit more from the paper on butyrate from our gut bugs:

Moreover, the intestinal microbiota can also influence systemic immune responses. A recent work highlighted the role of certain metabolites (short-chain fatty acid butyrate and to a lesser extent propionate) produced by commensal bacteria in dictating the extrathymic differentiation of periph- eral regulatory T cells. Butyrate acts within T cells to enhance acetylation of the Foxp3 locus and protein, as well as DCs to decrease their proinflammatory NF- k B-dependent cytokine secretion profile through an HDAC inhibitory activity.


Did you get that?  Yes, you probably need a doctorate degree in biology to understand what they are saying, but bottom-line, they are saying that butyrate from our gut bacteria is needed to ensure a healthy immune system. "Butyrate acts within T cells to enhance acetylation of the Foxp3 locus and protein," without going into a lot of detail, this says that butyrate is the fuel that runs our immune system.

Leaky Gut, Chemotherapy, and Fiber


This "Hot Sh*t" paper is not about butyrate or fiber, it's about a new theory on how chemotherapy works in cancer treatments. This theory revolves around chemotherapy agents creating a "leaky gut" situation which allows certain beneficial bacteria from our small intestines to leak into our bloodstream where it is seen as harmful and our own immune system is called into action.

Gram-positive commensal bacteria translocate during chemotherapy and prime pathogenic Th17 (pTh17) cells contributing to the tumoricidal activity of cytotoxic compounds.


To further this theory, they show that chemotherapy is not effective on animals that have been given large doses of antibiotics. With germ-free animals, there is no bacteria left to leak into the blood to evoke the immune stimulating response.

The skewed gut microbial communities and the leaky gut barrier leads to a generalized activation of self-reactive B and T cells and production of autoantibodies. Therefore, we surmise that any compound compromising the intestinal barrier integrity and/or the innate mucosal immunity and/or directly the gut microbiota will affect the functional equilibrium of this compartment and cause symptoms, as well as distant immunological perturbations.


They are saying here that they believe the effectiveness in disrupting the gut's barrier results in boosting of the immune system. This makes me believe that all of this talk of "leaky gut" is possibly nature's way of boosting our immune system. Unfortunately, when we are eating total crap food, ie. artificial colors, flavors, chemicals, and processed oils, and also having guts that have been destroyed by antibiotics, there is no telling what will leak into our body and what the consequences will be.

First, we observed that certain bacterial species of the SI can selectively and efficiently translocate within 24–48 h after exposure to an alkylating agent, [chemotherapy], yet administered at a metronomic regimen only reducing B-cell numbers. Second, at these early time points, the permeability of the intestinal barrier was readily increased, whereas the number of Th17 cells and CD103รพ DCs accumulating in the LP significantly decreased, setting the stage for bacterial translocation.

Possibly when eating as humans are meant to eat (omnivores eating real food) then this leakiness is a natural function to restore immune system health.

Oncologists have been using "platinum salts" for many years in chemotherapy with some good success. One standard explanation is that plantinum salts "trigger apoptosis" or cause the cancer cells to self-destruct. The "Hot Sh*t" paper proposes that platinum salts work by causing gut leakiness and a resulting immune response. The side effects of platinum salts are many: nausea, vomiting, kidney damage, nerve damage, among a long list.

Gut Enterotypes


Just as people can be genetically thin, fat, or of medium build, it seems that our gut flora also tends to gravitate towards three types:

Recently, an interesting but still controversial notion has emerged as to the existence of ‘enterotypes’ characterized by dominant genera ( Bacteroides , Prevotella and Ruminococcus ) and their co-occurring phylogenetic traits that could be associated with long-term dietary habits.
  • The Bacteroides enterotype was associated with animal protein and saturated fats,
  • The Prevotella enterotype was predominantly observed with high fiber/plant-based nutrition and high carbohydrates (low meat and dairy consumption). 
  • The  Ruminococcus enterotype often merged with the Bacteroides one.

I am simply amazed at how hard these cancer researchers looked into the contributions of the gut when writing this paper!

These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host–microbe mutualism.

It appears the gut is no longer being overlooked by cancer researchers!  Let's hope this trend continues.

The microbiome present in the distal gut performs myriad functions protecting the host against pathologies. Indeed, the host–microbiota symbiosis has evolved in three directions.
  • First, colonization by commensal microorganisms is key to immune development. 
  • Second, the commensal community keeps in check invading pathogens and prevents them from expressing virulence. 
  • Third, the intestinal microbiota appears to digest glycans and regulate fat storage in mice and potentially in humans. Exemplifying the host–microbe mutualism, the microbial genome is highly enriched in hundred families of glycoside hydrolases and in more than 20 families of polysaccharide lyases, whereas the human genome is relatively devoid of these carbohydrate-metabolizing enzymes. 

Implications for cancer


I think it has been well-established that a healthy immune system is the first line of defense against diseases like cancer. But how, exactly, to get a healthy immune system has eluded us. Here we see these researchers recognizing the gut microflora as a key contributor to the immune system:

Recently, we and others reported that gut microbiota is indispensable for the immunomodulatory and antitumor effects of certain anticancer therapeutics including chemotherapy and platinum salts.

If anyone reading this has cancer, or knows someone who has cancer, maybe this advice will help:

Future prospects for a better management of cancer patients aim at:
  • (i) diagnosing patients dysbiosis (metagenomics, metatranscriptomics, epidemiology on diet, medications and exercise, and so on), 
  • (ii) compensating dysbiosis by appropriate ‘immunogenic probiotics’
  • (iii) prebiotics synergizing with probiotics to set the stage for a healthy intestine that has been compromised by DNA-damaging agents, 
  • (iv) monitoring the immune responses raised against the relevant commensals to establish a correlation with longterm benefit and immune fitness.

In other words: No cancer treatment should proceed without consideration of prebiotics, probiotics, and testing to ensure there are healthy levels of "good" microbes in the gut!

 Conclusion


My thoughts are that if you want to avoid a date with platinum salts, just keep your immune system in top-notch condition at all times!  This simply involves eating foods that produce butyrate (prebiotic fibers) and a wide range of colorful fruits and veggies, nuts, and other healthy foods every day. Fermented foods and probiotics are also important! 

As of now, we don't know exactly what the "perfect" microbiome looks like, how much butyrate we need exactly, and which fibers are required for immune system perfection. Might as well just eat the foods we know are good for all this and avoid the ones that we know cause harm. A fiber supplement on top of a healthy diet will help to ensure enough butyrate!

77 comments:

  1. I would figure not finding much butyrate in high fibred faeces can indicate great uptake by colonocytes. Probably best from whole foods as opposed to purified fibre because it takes longer to process by the body.

    Sort of like iron absorption. Since there's only a 4 inch length of small intestine where iron is absorbed (Dr. Fasano), pill could just fly past but liver doesn't. So I query the application of large volumes of various purified fibres to accomplish the task effectively. They reduce transit time and thus decrease the amount of time that microbial digestion can act on substrate such that colonocytes get their 'meal'.

    Maybe this is good reason (combined probably with progesterone) that women's transit time is slower. The digestive tract can extract more butyrate and other FFAs.

    I think there's a sweet spot on fibre and it's individual. You don't want transit time too fast. What about absorbing minerals and vitamins like B12? Anyone checked this with fibre bombs?

    Very interesting about leaky gut.

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    1. I wish it wasn't so hard to pin down a requirement for butyrate, then we'd know precisely what we need to eat.

      I feel strongly that we need a substantial amount of fermentable fibers to produce all we need. The 2-10g found in SAD diets just does not provide the "miles-per-gallon" or "BTUs" needed to produce enough butyrate.

      I agree on the real foods, but have no problem with supplementing to get my fiber count higher.

      At least papers like this show that the right people are looking into the requirements.

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  2. hi tim
    "This makes me believe that all of this talk of "leaky gut" is possibly nature's way of boosting our immune system"
    so maybe sealing your gut is a distraction?
    better to fill your gut with the right stuff, and it wont leak?
    but hope it leaks when you need it to boost the immune system?
    or im over stating it?

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    1. Nope. I think you are right on.

      Here's what has always made me leery...persorption of starch granules. It's a normal and natural reaction. If you eat any type of starch or any plant that contains polyphenols or storage carbohydrates, these minute particles get sucked into your bloodstream. 100% of the time. Every person. Can't be a 'mistake.'

      What this paper shows is that not only plant matter gets persorbed, but also bacteria that line the small intestine.

      I think that with a healthy immune system, all this leakiness is no problem, and in fact, helps boost the immune system.

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    2. At the risk of asking for something that's been explained elsewhere...do you have a way to clarify what differentiates this normal leaking from leaking that creates more and more allergies?

      During the worst/most reactive times I've had with food sensitivities, any food I ate in quantity for any length of time would start causing reactions. Clearly the mechanisms were malfunctioning there - the constant inflammation, bad bugs, gut permeability....something :D But if leaking is to be considered a normal thing (and are we sure about their control subjects? leaky gut is doubtless epidemic in american guts!)....then what's the difference between a healthy mechanism and a mechanism that allows more and more immune responses to run amok?

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    3. "...do you have a way to clarify what differentiates this normal leaking from leaking that creates more and more allergies?"

      Nope.

      That seems to be the million dollar question at this point. It probably has to do with the immune system, though, don't you think? The gut is probably just doing what it is supposed to do, and the immune system can't keep up.

      How to get from 'broken' to 'healed' is the hard part. Wish I had the answer! It's tough to eat right when so many foods cause problems.

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    4. Fascinating! I'm sure the answer is just around the corner, you know? A further refinement differentiating between aspects of mechanisms that we currently look at in a bloc, but that should be understood to be unique and/or in concert with others, for specific purpose.

      It cannot be a coincidence that people with lots of food intolerances almost universally have crap immune systems in every other way. They catch every cold, colds last 3x as long or are much more severe, their immune systems attack healthy tissues etc. So in some people, this leaking is creating a strong immune response that heals, in others it's a chronic problem leading to poorer and poorer health. There's something there we're not yet seeing.

      On the subject though! Something really cool! Our whole family just had the flu. In our town, people are getting knocked on their asses by this thing - 3 weeks of bronchitis etc. We've been doing potato starch for a while, have been on Prescript Assist (a question about that in another post, actually)...and while we all did get sick, none of us got THAT sick. I was the sickest in a GI way, but even so it wasn't awful. My youngest was sickest in a respiratory way, but he charged right through it with a powerful immune response and got better FAST.

      Long story short - we got the flu, but it didn't get us. It just couldn't get in very deep. WAY cool :D

      At the same time? Food allergy responses are WAY down in the house. My youngest has a very aggressive reaction to corn - yet the best cough/expectorant med I could find is based in corn syrup. He had to take that med for the better part of a week and do you know how much he reacted to the corn?

      ZERO. NOTHING. NO REACTION WHAT-SO-EVER. Corn used to make this kid look dysphoric-mania with ticcing....now nothing?

      HOLY CRAP.

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    5. My thinking was microbial dysbiosis or lack of SCFA or pathogens or whatever causes the gut to leak bacteria which stimulates the immune system when there may not be a need to be stimulated. If you can herd the cats by correcting the issue with the colon, maybe improper autoimmune responses can be reduced. Million dollar question indeed.

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    6. maybe....if dysbiosis is already in place, the foods you eat feed the critters you don't want (or don't want nearly as much of), *they* cross over (where you'd prefer to have different critters crossing over) and reaction then ensues. In that case, the gut is doing what it is designed to do (leak, namely) but the wrong bugs/mix of bugs is crossing into the blood stream.

      What we think of as 'food reactions' may in fact be 'bug reactions' ? That may explain why so many sensitivities come in sets though - if gluten and casein feed the same group of undesirable bugs (or pathological bugs that take root in some people)....then you'd usually have these allergies paired, and in fact this is the case more often than not.

      I dunno man, this crystal ball is reeeeally murky!

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  3. Hi Tim, Back from Mexico so soon?

    Is it as tricky to measure the ph of the colon accurately as it is to measure butyrate? I had a great plains stool test done and the levels of my fatty acids were good but in particular butyrate was a bit low. However, my ph was something like 6.6, I think that is a bit high from what I have read. Can the ph be quantified properly and is that a good indication that your butyrate level is good? Or do all the fatty acids lower ph?

    sl

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    1. I have been searching for a way to measure fecal pH for over a year. I've ended up with a $400 lab-quality pH meter and more questions than answers.

      I think that pH is probably the best indicator of a healthy gut, and the contents of the colon should be "slightly acidic" meaning in the range of 5 to 6.5. Outside this range, pathogens can grow uncontrollably. To get a pH inside this range, one must eat lots of fiber and hopefully have the gut bacteria to ferment the fiber to SCFA.

      The Short Chain Fatty ACIDs are what determines the pH. Certain microbes produce butyrate and others produce lactic acid. There's also propionate and acetate and some others.

      What I have found with my handy-dandy pH meter, and this will sound pretty gross, so try not to form a visual.

      The pH of a 'fresh' sample of mine after eating lots of fiber is 5.5. A few minutes later, that same sample reads 6.8. Later still, 7.2.

      Also, a fresh sample, tested at multiple sites, ranged from 5.5 to 6.5, and a few minutes later from 6.8 to 7.2.

      Here's the problem, I believe: Short chain fatty acids used to be referred to (more appropriately maybe) as VOLATILE fatty acids. "Volatile" meaning "readily evaporates."

      So if these SCFAs evaporate quickly, fecal pH would require some special steps to accurately test.

      There are some studies on colonic pH that used a special electronic pill that transmits the pH of the intestines as it moves through the digestive tract. The graphs produced are pretty cool, and show exactly what is happening. You can see the acidity rise at it gets closer to 'freedom' as the SCFAs are being used up by the cells in the colon.

      This problem with pH is also a problem with measuring butyrate. If it is evaporating quickly, how can you hope to accurately measure it with a small sample of feces unless there was some way to prevent the 'volatile' nature?

      When I did the sample that I sent off to Genova Labs, a small collection of poop was dropped into a bottle containing some type of liquid and sealed. Maybe this preserves the butyrate and other SCFAs for an accurate measurement, but if your sample sat around for a couple minutes before being sealed in the sample jar, the reading is most likely wrong.

      This would make a great blog post when I get time and some more data!

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    2. Correction: "You can see the acidity rise at it gets closer to 'freedom' as the SCFAs are being used up by the cells in the colon."

      Should say: "You can see the pH rise..."

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    3. Just putting this here for future reference. From Art Ayer's on the volotility of SCFA and measuring fecal pH:

      "Volatility of SCFA: Check the boiling points. All are well above water. A key point is what is buffering the pH? All of the SCFAs buffer the pH at around 4-5. The rest of the feces also has strong buffering at closer to 7. I would suspect that your readings may be influenced by the fact that you aren’t using a solution, so you get lots of artifacts. You may also be getting some big effects going from anaerobic to aerobic conditions and their will be a lot of bacterial death. It would be more accurate to make a quick slurry and then filter or spin to remove the bacteria, and measure the pH of the solution; or just quickly take a reading of the slurry for comparison. I don’t think that the pH is not actually a reflection of the SCFA composition, which won’t quickly change, since they don’t evaporate or get altered by the bacteria, since the bacteria are suspended and separate from the solution that is read by the pH meter."

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  4. Holy Shit, Tim! Amazing stuff!

    (Terra, back from the dead, er, the flu :P)

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  5. (having returned from the flu, Terra has saved up comment-energy apparently :D)

    I have an off-topic (for the article) question, if I may. Has anyone started up the RS protocol in combination with Prescript Assist....and had significant irritability or anxiety flare up for a time?

    Initially, we were all taking Probiotic 3 - peaceful relaxed family. In the interest of bug-replacement variety, we're now doing a stretch of Prescript Assist....intense family! Irritability, anxiety, very brief flares of temper. My anxiety is noticeably worsened considerably. Strangely, though I have flares of anxiety I cannot *stay* anxious. And though my spouse has flares of irritability, he cannot *stay* irritable.

    It's such a *specific* response, that I thought I'd ask about it, see if anyone else had noticed this same pattern when first using PA.

    I just hope that the anxiety/irritability fade as the good bugs take hold and the bag ones die off. I have faith that this will be so - Prescript Assist cannot be formulated of the 29 gut bugs that happen to cause idiopathic anxiety, when the whole point of a balanced gut is a balanced mind and body! LOL!

    Any similar stories? Thoughts?

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    1. @Terra
      My story is a bad, bad acne flare on my chin. I was taking Primal Defense, and also introducing higher amounts of fermentable fibers. Also, Beet Kvass. And, a new face cream.

      Too many variables! I dropped the Primal Defense and I'm trying to do a better job of tracking what I'm taking.

      An alternative-minded doctor told me once that it's good to take probiotics and eat fermented foods, but keep in mind they don't always get along.

      I didn't know what that meant at the time, but I'm wondering if dramatic shifts in the populations are causing some of these symptoms.

      Welcome back from the flu!

      Michelle

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    2. I also experience (noticebly) increased irritability on Prescript Assist. I resolved myself to finish out the bottle I had and not order another one. The way I combated this was by taking them before bed.

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    3. TY for the welcome, @Michelle :D

      YES acne! And acne + rashes I've never seen before, even with years battling candida. I'm actually excited about it - evidence of die-off of dysbiosis is something I'm really happy about even if I'm currently scratching my skin off LOL I know it will subside from years of experience...so I'm patient with it and eagerly awaiting the positive outcomes. (oh candida, how much did you teach me? oh, that's right. far more than I wanted to know :P)

      Tracking multiple variables is enough to make you crazy, tho - slowing down was a good plan :D When you re-introduce PA, I'm very curious to hear any effects you notice!

      Thanks for you note, Anon :) If my N=1 is any help, the anxiety is decreasing and my soooooothed potato-starch-chill gut/brain seems to be getting back to business. It's very slow, but it's happening. Not at all surprisingly, as the acne & rashes + less-deep sleep slowly die down, the anxiety is dying down, too. Chalk up a hashmark in the "this was a die-off thing, thank goodness!" column. Now waiting to see if the anxiety dies back down to baseline (since I'd JUST gotten the damn thing under control this past fall, this is very very important to me - anxiety is better at completely screwing up your life than depression or bipolar, that's for damn sure).

      Within the family we have 2 'irritables' 1 'anxious' and 1 'chill you guys, what's the problem?' reactions to the shift PA in bringing on. :P The chilled out kid is the one with the strongest digestive system (no reflux, no heart burn, strong stomach acid), so I'm not surprised. He's also the one with the unbelievably good reaction in the allergy category - no longer reacting to corn. Last night he ate a pile of cheese - I'll be quizzing him about all his eliminatory functions today :D Aaah, the things that become normal when you've spent your whole life dealing with gut ill-health :P

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    4. I suspect fluctuating (erratic) sex hormones may be a confounding variable re: acne & mood. I'm 51. My cycles are irregular and periods light.

      I wish I had a tricorder! (Star Trek for you non-nerds).

      Michelle

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    5. I'm definitely having big hormonal changes from PS and the big changes in probiotics. I'm off progesterone completely (it was a must-have or 2 weeks of PMS previously) and everything else about my cycle is acting both healthier and slightly peri-menopausal. (the acne isn't anything cycle-related though, it's whacked out crazy rash stuff :P)

      The hormonal changes were really unexpected - very happy with that particular improvement in health!

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    6. @Terra

      Here an article (on breast cancer mainly) presenting a research showing that more diverse microbiome can influence the way the body processes estrogen (in a good way).

      Diverse gut bacteria associated with favorable ratio of estrogen metabolites (2014)

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    7. Amazing. The whole hormone connection continues to impress me! Insulin resistance, estrogen dominance, PCOS, hormone mediated cancers... - if all of these things are at least partially treatable by fixing the gut, what an amazing advance that will be :)

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  6. What is a relation of this to Jack Kruzes theories about leaky gut being an adaptation in humans?

    http://jackkruse.com/brain-gut-3-look-in-the-past-to-see-your-prologue/

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    1. I'll use Jack's own words, from where you linked:

      "All evolutionary theories are equally true and false, depending upon how you use them. If they service you and your own thoughts they are not helping mankind. If they serve the path to finding the truth buried within our species, to better our understanding, then they are in service to scientific truth. Can a blog post filled with words reveal a scientific truth? Can a truth be put into words?"

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    2. Just messin' with ya. Jack's a smart guy. Just a little wordy.

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    3. @TomR

      From your link:

      "Humans are the only mammal on the planet that can get an autoimmune disease easily. . Primates do not get them easily because they do not have zonulin. Humans have zonulin and primates do not."

      "“leaky gut by design“

      Is this true? I need to research this a bit.

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    4. Jack Kruze lives on a different planet.

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    5. For lack of a better link here one to the Wheat Belly on the zonulin/haptoglobin issue:

      What do you have that chimps don’t have? (2012)

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    6. If gut leakyness is a function, then perhaps sealing it with Akkermansia is not a good idea?

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    7. @tomR

      High Akkermansia (supposing the fecal sample report reflects its real number which is questionable) may show just anything, starting with the effect of a very eccentric, laxative diet in a highly stressed individual (think elite Irish rugby players), or a hibernating animal, or a patient with cancer. Go figure.
      I have stopped reading Grace's blog because the level of cherry picking and wild conjectures presented as facts exceeded my tolerance limit.

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  7. re: I am simply amazed at how hard these cancer researchers looked into the contributions of the gut when writing this paper!

    It may be becoming apparent to cancer researchers that the somatic (gene) theory is at a dead end, nicely summarized at:
    http://robbwolf.com/2013/09/19/origin-cancer/

    Coincidentally, Seyfried, in 2012, breathed new life into the long-ignored Warburg metabolic theory, and made it at least clear that digging almost anywhere else is apt to be more productive. I suspect that's what afoot here.

    I've read Seyfried's book, and while it scores some key points (like: stop overdosing on cancer food {glucose}), a restricted calorie ketogenic diet is not 100% sure fire cure. This gut connection is probably a big part of the puzzle.

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    1. @Boundless

      Ketones and ketogenic diet are not a cure. Just look at one of the latest papers by Dr. Seyfried, where they implanted mice with aggressive tumours, and fed them ketones. The survival increased, yes, but how much? The mean survival for controls was 31 days, the group supplemented with 1,3-butanediol (BD) or a ketone ester (KE) survived 47 and 52 days, respectively.

      There was less glucose and more ketones, sure, but the tumour adapted and found something else to eat, it did not take that long.

      The title sounds oh-so-promising...

      Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer

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    2. re: Ketones and ketogenic diet are not a cure.

      Just to be clear, I didn't say they were. I read Seyfried's book when it was first published, and figured that if it were the magic bullet, it would be clear in a couple of years. It's clear now that it's not a reliable cure, but is nonetheless being used by people who decline to be impoverished and made miserable by the SoC, such as:
      http://greymadder.net/

      re: The mean survival for controls was 31 days, the group supplemented with 1,3-butanediol (BD) or a ketone ester (KE) survived 47 and 52 days, respectively.

      That's 152% and 168%. What life expectancy extension does the SoC for this cancer offer? (and I don't know the answer to that)

      re: There was less glucose and more ketones, sure, but the tumour adapted and found something else to eat, it did not take that long.

      Prevention is probably the bet with the biggest payoff today, and I'm betting that an LCHF, low-inflammatory (including grain-free) diet, plus optimized skin and gut biome, are a huge part of that, along with reducing exposure to triggers (and that's a really long list).

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    3. "Prevention is probably the bet with the biggest payoff today, and I'm betting that an LCHF, low-inflammatory (including grain-free) diet, plus optimized skin and gut biome, are a huge part of that, along with reducing exposure to triggers (and that's a really long list)."

      Nice observations! I'm thinking too that cancer doesn't stand a chance when the immune system is working as it should.

      Your use of the term LCHF will raise some hackles, but it's all relative. Low carb compared to SAD, yes! High fat compared to the low-fat diet fads, yes!

      I'm starting to get a sense that 'high' anything, in a chronic state, is not so smart. I think LC Paleo did not deliver as expected, and a re-tooling is happening now involving added fibers.

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    4. True. I don't want to get too far off topic here, but it might be interesting to see a discussion on how fats and proteins (plant v animal) impact the gut bacteria in a LCHF diet. We discuss plants and fibers often, but these other two pieces affect the microbiome, ph, etc. too.

      B.

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    5. Funny, I was just reading this on Medical Express from today:

      Gut bacteria byproduct linked to chronic kidney disease for the first time

      Cleveland Clinic researchers have, for the first time, linked trimethylamine N-oxide (TMAO) - a gut metabolite formed during the digestion of egg-, red meat- or dairy-derived nutrients choline and carnitine - to chronic kidney disease.

      TMAO has been linked to heart disease already, with blood levels shown to be a powerful tool for predicting future heart attacks, stroke and death. TMAO forms in the gut during digestion of choline and carnitine, nutrients that are abundant in animal products such as red meat and liver. Choline is also abundant in egg yolk and high-fat dairy products.

      The research team was led by Stanley Hazen, M.D., Ph.D., Chair of the Department of Cellular & Molecular Medicine for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart and Vascular Institute at Cleveland Clinic, and W.H. Wilson Tang, M.D., Department of Cardiovascular Medicine in the Miller Family Heart and Vascular Institute and Lerner Research Institute. The research will be published online on January 29th and in the January 30th print edition of Circulation Research .

      According to the Centers for Disease Control and Prevention, more that 20 million Americans are estimated to have chronic kidney disease, many of whom are undiagnosed. It is caused by a gradual loss of kidney function over time. As the disease worsens, waste products can accumulate in the blood and can be fatal without interventions. It has long been known that patients with chronic kidney disease are at an increased risk for cardiovascular disease, but the exact mechanisms linking the two diseases are not known. This newly discovered TMAO link offers further insight into the relationship between cardiovascular disease and chronic kidney disease.

      "It's a triple whammy" said Dr Hazen. "Elevated plasma TMAO levels in subjects are linked to future cardiac risks, and in subjects with normal renal function, elevated levels predict long-term future risk for development of chronic kidney disease; animal model studies show that long-term exposure to higher levels of TMAO promotes renal functional impairment and atherosclerosis; and as the kidneys lose function, TMAO isn't eliminated as easily, and levels further rise, increasing cardiovascular and kidney disease risks further."

      Drs. Hazen and Tang measured fasting TMAO levels in 521 patients with chronic kidney disease and in 3,166 subjects without chronic kidney disease, following all subjects over five years. They found that TMAO levels were higher in patients with chronic kidney disease, and elevated TMAO levels were associated with greater mortality risk in both subject groups. In animal models, the researchers also found that chronic dietary exposures to choline and TMAO were associated with development and progression of chronic kidney disease. Further studies are needed to determine if dietary interventions can delay disease progression of both chronic kidney disease and associated cardiovascular disease.

      "Our studies raise the exciting prospects of nutritional interventions to help retard development and progression of chronic kidney disease. Regrettably, very little is known about diet and renal disease progression," said Dr. Tang.

      This research strongly implies the need to focus preventive efforts on dietary interventions and therapeutic targeting of gut microbiota-dependent TMAO pathways, potentially to halt development and progression of chronic kidney disease, as well as cardiovascular disease risks

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    6. Link to above: http://medicalxpress.com/news/2015-01-gut-bacteria-byproduct-linked-chronic.html

      And for the record, reading that doesn't make me want to change anything I do, or think anyone should change. It is just a new paper. I think one day we will be able to use information like this to tailor our diets to our genetics and gut microbiome. Until then, it's just interesting in a 'hmmmmm...' sort of way!

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    7. Haha. Yes, need that as a standard qualification now. I need to start looking more at studies on plant proteins. The science is so interesting and exciting, but often contradictory. I will read the text, but wouldn't it be nice to see a microbiome test required for all diet tests like these. Could reveal more about causes or correlations.

      B.


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    8. Notice that choline helps brain performance. So does keto. And both are apparently incompatible with the gut?

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    9. And gut bacteria spews dozens of neurotransmitters...

      I get what you are saying, and I think ketosis is great. Especially at night when I sleep and if I get stranded in my car for 24 hours during a blizzard.

      I just can't see any scenario that would make me want to eat a diet that would put me in perpetual ketosis. I don't care if people want to take this route, it's certainly better than SAD/Metabolic Syndrome, especially in the short term. But a long-term diet that produces continual ketones has to be methodically planned and executed, not too much meat, hardly any carbs, and low fiber by default unless supplementing.

      I'd like to see a few gut reports of people who have been doing a keto diet for some length of time. Maybe we'd be surprised. But until then, I prefer to use ketosis as a back-up plan for when I need it, naturally.

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    10. Okay, I haven't read all of this thread, but mealie meal (grain, corn) appeared to reduce the rate of CRC among black South Africans (who have other issues....) I don't buy the no grain argument. One of the best stimulators (as I've discovered) is whole oat groats. Based on the amount of mucous and whatnot produced by the colon, and speed of excretion Bristol Stool Scale 4, oat groats are 'awesome'. Again, a grain.

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    11. I was taught that choline is an essential nutrient...........maybe this study is chicken and the egg? sorry. What came first? The kidney disease or the choline? I don't buy this at all.

      Delete
  8. Maybe leaky gut is like stress. You need some, but chronic, unremitting stress is bad.

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    1. Kate - it's kind of like the chicken and the egg, eh? Which came first...leaky gut or a weakened immune system? From a paper we were just looking at:

      "Fink and colleagues reported that epithelial tight junctions are compromised in critical illness, leading to increased permeability and persistent activation of systemic inflammation. Even social-disruption stress can increase the translocation of gastrointestinal microbiota to secondary lymphoid organs."

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    2. You can 'do keto' with vegetable fibres. Lots of vegetables are low glucose. Sauerkraut is for sure compatible with a keto diet.

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    3. Any aspect of physiology that has to go into over drive during stress is probably not one we want to see active all the time. Our modern lives induce levels of stress that kill experimental animals, it's insane!

      (and whenever I look at a study, I always ponder whether the 'control' subjects create a meaningful 'control' in any way. I mean, if you're asking your control subjects to eat SAD to prove or disprove something about dietary health...? ridiculous :P) /soapbox

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    4. It's a good soapbox to be on. I get disappointed in the science, too, that's why I'm trying to learn as much as I can and crowd-sourcing the knowledge so we can all share real-life experiences.

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    5. I love it, Tim! You're providing not only great synthesis of info, but a platform for all the self experimenters to compare notes. It's invaluable stuff. The best health changes I've made in my life have been under these same circumstances, in the age of the internet :)

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  9. Is it a ridiculous to think that you could induce gut permeability via exercise/gluten(in some) or similar and then add "good and/or targeted bacteria" just afterwards in an attempt to combat previously translocated systemic pathogens/infections?

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    Replies
    1. It's not a ridiculous thought at all. Researchers have been using a similar method to deliver drugs and chemotherapy agents into the intestines and blood using nanoparticle carriers.

      I'm not sure if one could intentionally use the phenomenon of 'leaky gut' in any meaningful way as you describe, but it's maybe a good reason to eat those fermented foods we always talk about.

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  10. Hi Tim!

    Very interesting paper you found, I'm glad to see that cancer research is now starting to focus on gut flora!

    Personally I think that my three year LCHF diet was a huge contributor to me developing Crohn's disease as the gut flora seems to be severely weakened by a high fat, high protein diet. Anyway, I'm now starting to improve following a modified version of SCD including more prebiotic,l and probiotic foods. I've just recently starting to experiment with fibers as well. My Genova Diagnostics test showed a very low diversity, my questions is: have you seen any studies that indicate that increasing fiber intake also increases diversity? Most of the studies I've seen only focus on certain strains of bacteria and doesn't include the big picture.

    I'm doing before and after FMT testing from both Genova and Ubiome to see any changes. Will be travelling to the UK to do 2 weeks of FMT at the Taymount clinic in June. Will be interesting to see the results. One rather interesting effect they mentioned when doing FMT was that the patients who had the best outcome often had the worst response to the FMT. This would include joint pains, abdominal pain, gases etc. this would subside over the two weeks, and they believe it was because the immune system was activated thanks to the influx and colonisation of the new flora. Just wanted to put that out the for those of you who might be feeling worse for a while when introducing probiotics or fibers! It might actually be a good sign!

    Best,
    Bo

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    1. Wow, Bo, that's great! I hope it works for you. I sure would love to see you treat your new microbiome right! I have this feeling that if people just eat a normal crappy diet after FMT, they will lose their new friends.

      Hey, keep good notes and get back with me when it's all over and we'll write up your story for the blog if you like. I'd love to hear all the dirty details of how they prep you, how it feels, and what the gut reports look like.

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    2. I will make sure to take notes of the experience and do my best to keep my new biome happy!

      Have you ever seen any studies where they discuss total microbial diversity increasing from increased fiber intake? Would be interesting to know if it's possible to go from low to high diversity by increasing fiber intake.

      Thanks, Bo

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    3. Alpha vs Beta diversity. Seems like unless you are adding new bacteria through either the FMT, bacteria on the food itself (fermenting) or the environment, alpha might go down on any major shift in diet. The Leach article discussed a little of this and showed a decrease, then a little rebound which is interesting.

      B.

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    4. Great, thanks for the links! Will have a read through and get back to you.

      Had a quick read of the last one. Really interesting. When they mention microbial network units, are they talking about basically putting together a "probiotic" mix of the most relevant microbes for that particular patient? Seems like we're not quite there yet, but hopefully soon!

      Thanks
      Bo

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    5. I think they are getting close. Have you seen this paper?

      re-POOP-ulating the Gut

      Rather than hit-or-miss with feces, they isolated some 20 strains and used those with good success.

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    6. I hadn't seen that paper, thanks! Interesting, and I do believe that individualised treatment of microbial transplants is the way forward. At Taymount they actually try and match your donor's biome so that it complements your own, which is a quite simple but potentially effective way of doing it.

      In the paper on prebiotics, FMT and microbial network units they state:
      "A new, more accurate definition for a prebiotic compound may be ‘an indigestible food compound that stimulates the ecological biodiversity in the human gut microbiome’. Indeed, a recent study using a novel molecular tool with high-phylogenetic resolution indicated that prebiotic compounds such as inulin (IN) and long-chain arabinoxylans (LC-AX) both increase the abundance of specific primary degraders. Despite the very different structure of IN and LC-AX, both compounds also increased a similar spectrum of secondary degraders that benefit through cross-feeding with the primary degrader (Table 1) (Van den Abbeele et al., 2011). Such microbes that increased in both treatments mostly belonged to relatives from the Clostridium clusters IV and XIVa. Although primary degraders are essential to initiate the breakdown of the specific polysaccharides, the stimulation of these microbial networks/meanders increases the microbial diversity and may be more beneficial than the increase of a specific primary degrader."

      I do agree with this and believe more focus should be put on diversity as looking at increase of only certain species. Secondary degraders needs to come into more focus and should be explored further. In the paper they mention long-chain arabinoxylans as a potent prebiotic. Do you know in what foods this is found? Is there supplement? I did a google search but came up quite empty, perhaps I'm looking at it the wrong way!

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    7. "In the paper they mention long-chain arabinoxylans as a potent prebiotic. Do you know in what foods this is found? Is there supplement?"

      These LC AX's are found in whole grains, it doesn't look like there is a supplement available, but I found a patent application for producing a LC-AX supplement, it is very informative, have a read through!

      As to the efficacy of LC-AX and 'do you need it?' It does seem like a very good stimulator of beneficial bacteria, even when compared to inulin. Some really good discussion of how it acts on gut microbes can be found here.

      However, keep in mind, this is a 'franken-rat' study, but still very interesting.

      I wrote a post a while back "Pigs love Potatoes" and in it, they also used AX with great success.

      So, until we have a supplement, looks like you are stuck with whole grains! Maybe a good reason for those steel-cut oats for breakfast. I really don't have a list of AX-rich foods, when you look it up, you see they are just "found in wood and whole grains, among other plant sources.

      "Arabinoxylan is a hemicellulose found in both the primary and secondary cell walls of plants, including woods and cereal grains,[1] consisting of copolymers of two pentose sugars – arabinose and xylose."



      Make this a link

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    8. Well, apparently there is an LC-AX product called NAXUS made by a company called BioActor:

      But I can't find it for sale anywhere, probably lost inside the bowels of the food industry!

      "BIOACTOR has already a long-chain Arabinoxylan ingredient derived from wheat endosperm in its portfolio, NAXUS, which recently obtained a positive EFSA Opinion for glycaemic control, and for which promising scientific evidence was recently obtained towards other health endpoints. Hans van der Saag, BIOACTOR’s managing director comments; “The addition of short-chain Arabinoxylans which are derived from the same raw material source as our long chain Arabinoxylans-ingredient, further strengthens our portfolio of patented specialty fibers with clinically proven health effects”.

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    9. Many thanks for looking into LC-AX! Seems like we're indeed stuck with whole grains for now. Unfortunate for me since I try to avoid most grains except the occasional oats and rice!

      Delete
  11. I just want to put out there that my energy levels have skyrocketed after consuming fermented vegetable JUICE regularly. Prior to that I was eating fermented vegetables and other vegetables, including starchy, and PS. It was the juice that made this difference. I haven't felt this well for as long as I can remember. Does anyone have any idea why the juice would have such an impact? Thanks for an excellent post, Tim!

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    1. The increased salt intake.

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    2. Not the original anonymous here. I wonder about salt too. I crave salt and really enjoy the juice. Dr. Ayers speculated on another reason in the comments of this post "Gut Microbiome 2014: Diet, Inflammation, Disease, and Repair"

      B.

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    3. Dr. Ayers speaks about increased count of bacteria in the juice, in his comment linked above.

      I think it might relate to special forms of microbes called "viable non culturable" as well.

      We have seen the paper on honey before - they are there too, in a very dangerous environment, trying to survive in some way.

      And I think that is part of the story, as these special forms are still alive, and can perform some magic :-) when they get a chance.

      They are also found in vinegar, so I guess in the fermentation juice as well.

      They are also found in wine, here a paper:
      The viable but non-culturable state of wine micro-organisms during storage. (2000)

      "Colony counting and DEFT did not give the same results when wine micro-organisms were enumerated. Both methods were used to monitor the population of acetic acid bacteria (AAB) and lactic acid bacteria (LAB) during wine storage. Results suggest that part of the populations had reached a viable but non-culturable (VBNC) state. These cells were unable to produce colonies but could hydrolyse fluorescent esters and could be counted by DEFT. For AAB, O2 deprivation quickly induced this state. Recovery from this state was very rapid as soon as O2 was available. The response was not so clear for LAB during wine storage. However, a similar state was induced by sulfiting. Moreover, filtration of wine stored in barrels and contaminated by Brettanomyces, AAB and LAB demonstrated that cell size was not homogeneous. Cells which remained in wine after several weeks could pass through a 0.45-microm membrane. However, when they re-entered a growing phase, they were again retained by membrane filtration. During and after the decline phase, wine micro-organisms might survive as smaller cells in a VBNC state."

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    4. SALT - I've been craving salt like crazy since starting PS, and I cannot tie it to anything yet. Nothing I've tried helps (in food variety, adding high quality mineral supplements etc.). I've been using Himalayan pink salt as freely as my body is interested in eating it, but it's just so odd. Very curious about *why* though.

      @Gemma - drinking vinagre with the 'mother' still in (the clump of culture) has been around as a 'digestive cure' for a long time in health food circles...very cool to see this!

      Hey - are we saying that one cause for improved life expectancy in the many French wine-drinking studies might be the viable non-culturable bugs? If that's so, I have to say I find it quite hilarious :D IT'S NOT THE WINE, IT'S THE BUGS just doesn't read nearly as well as well for a soundbyte, yk? :D

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    5. I read someplace that one of the surprising results of the American Gut Project to date is that drinkers have more diverse gut populations. Perhaps this is the explanation.

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    6. hi
      fermented vegetable JUICE how do you make it?
      what kind?

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    7. I call the liquid from the fermented vegetables the juice. Sometimes, large scale fermenters will have excess liquid, bottle it and sell it as a "juice". You don't really need to make it special. Don't throw away the liquid after you've finished eating all of the pickles or kraut and enjoy :)

      B.

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    8. Yeah, but I need MORE than just the "leftover" juice from the vegetables. I'd be drowning in veggies if I make enough to drink all the juice I want. But I guess that's what I have to do.

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  12. Just wondering, how much juice do you drink per day? I like the juice part too, but limit myself to a tablespoon or so.

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  13. Much more than a tablespoon. I kind of just chug in out of the bottle. It's hard to say how much - maybe 6 ounces per day? And I am still somewhat constipated.

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    Replies
    1. What kind of fermented vege juice, may I ask? Something a bit like beet kvass?
      Funny about the salt, I've been craving salt too. Put great big piles of celtic sea salt on everything. Feel like I can barely taste it. I'm sure it is a good sign, isn't sea salt in particular supposed to have the same minerals as blood? I guess somehow the body is finally able to re-mineralise or something. Dunno.

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    2. It's the juice from the veggies. Check out Wise Choice Market. I've been drinking all them, including beet.

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  14. I wrote a longer post earlier and some how lost it.... but some people, when they are on a low insulin diet, their bodies can't hold onto salt. Also, some people just sweat out a lot of salt with no way to control it. People of northern European decent can sweat out more than 100x the salt of some people of African decent. (Of course, there is a bell curve to every population.) When it is hot out and I am exercising even a moderate amount, I have to supplement salt (I make my own salt pills). Before figuring this out, I actually passed out a couple of times while exercising. I take one to two teaspoons a day at night, with dinner depending on how I feel when it is hot out. For a while I experimented with adding potassium to it, but that made me feel pretty bad.

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    Replies
    1. I've skirted the edges of metabolic syndrome for years - my insulin is probably better regulated now than it has been since my teens - between gut bugs and intermittent fasting, the change has got to be huge. My next round of blood tests promise to be interesting :) Better insulin control--> want more salt might be a cause that fits.

      Like the poster above, I want mineral laden salt - celtic, himalayan, etc. Straight salt doesn't satisfy me nearly enough. Once again...starting this process kicks off so many other healing processes automatically, and that's immensely heartening :)

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  15. http://hahasforhoohas.com/the-fart-that-almost-altered-my-destiny

    Just had to share this for some laughs here since we are familiar with similar results in our efforts to improve out health...

    gina

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