Thursday, May 25, 2017

Microbe/Host Genetic Interactions

Nuclear Receptor

Here's a brand new paper out of Duke University that shows for the first time how gut microbes directly can effect host cells which could lead to human disease. This strengthens my notion that we must maintain a healthy gut flora and avoid upsets that can lead to colonization by pathogenic microbes.

Microbiota regulate intestinal epithelial gene expression by suppressing  the transcription 1 factor  Hepatocyte nuclear factor 4 alpha (Davison et al., 2017).

Sure to get a collective *yawn* from most readers, and even researchers, this paper explores a phenomenon that many seem to ignore:
...the roles of nuclear receptors  in host responses remain poorly understood, and no previous study has defined the impact of microbiota on nuclear receptor DNA binding. Nuclear receptors are a metazoan innovation.

Until recently, it was not believed that microbes could interact with their host more than superficially. A top cancer researcher once told me, "microbes are ubiquitous in nature...there's no way they can cause cancer." This Duke paper maybe proves him wrong! My contention has been all along that if microbes do interact with us on a cellular and genetic (DNA) level, then we must have also evolved ways to regulate this interaction so that we can live in harmony with the trillions of bacteria that inhabit us.

There's been evidence for decades that bacteria and fungi ("microbes") can cause cellular damage and genetic defects leading to disease, but little is known about the mechanisms involved. 

Nuclear Receptors

Nuclear receptors are an interesting area of molecular biology. Not many study them, it seems. And never before in the context of microbe/host interaction.

From Wikipedia:
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.
If a hacker was looking for a way past an animal's firewall, it need look no further than the nuclear receptors. From here, you could control nearly every aspect of its host's life. The picture at the top shows a diagram of a nuclear's a protein that binds to DNA and causes genetic changes. To go much deeper would entirely tax my day (and brain), but this is all the basis for what you hear described as "epigentics" and requires terms like "ligand" and "transcription factors." I'll spare us both the agony of a lesson.

The Duke Paper

This research demonstrates that certain host genes, in this case HNF4A of the Zebrafish, interact with genes of a microbe in the fish's intestine. If the researchers took away the HNF4A, the fish developed intestinal dysbiosis similar to that seen in human's with inflammatory bowel diseases.

The genes here are not important. The Zebrafish is not important. What is important is that here they are showing a direct mechanism whereby microbes interact with a host's DNA and cause alterations. It also shows that animals have developed defenses against these attacks.

Between the Lines

Reading between the lines, we do not see the names of any specific gut microbe named. We do not even see a differentiation between "bacteria" and "fungi" in the descriptions of gut microbes. These researchers have not identified the microbe that interacts with the host to cause disease. It's possible that there are many.

Another paper recently showed that human inflammatory bowel disease was more likely caused by the lack of gut bacteria responsible for digesting human bile. If this proves to be the case, it means we have been looking completely in the wrong direction for a probiotic treatment for certain bowel disorders. Instead of increasing bifidobacteria or whatever, we should be increasing the gut microbes that degrade bile, though there are virtually no papers describing these microbes.


We do not know everything there is to know about gut microbes and how they effect our health. I think it's safe to say that we are up against a formidable enemy, these fungi and bacteria that inhabit us. But we are equipped with ways of dealing with them, making them work for us, even.  Until everything is known, I believe our best bet is to eat a diet filled with lots of plant fiber and whole foods. We should avoid unnecessary antibiotics and drugs. Live a healthy lifestyle. Let our food and our biology take care of us the way nature intended.

How do you know if its working?  What's your gut tell you?  Is it constantly upset?  Do you have a hard time "going?" Are you on meds for gut problems?  Do you have other health problems?  If you can answer "no" to these questions, then you are on the right track. If you answered "yes," then you have some work to do.

And keep in mind...this is not just a "gut thing." It's also about autoimmune diseases, cancer, and brain disorders. Most of the pharmaceuticals being developed for human diseases like these target the host immune system. You can do the same at home by eating right and exercising. But once these diseases get hold in you, all bets are off. So pay particular attention to what your gut is telling you, and keep your firewall updated!



  1. Very interesting, such a great blog, and FYI my local vitamin store now sell all sorts of resistant starches! things are going mainstream.

    1. I suspect you will start seeing more and more, and the choices will get confusing as manufacturers start making outlandish claims. Keep it simple, eat most of your fiber as real food. No supplement can compete with real food. Use supplements to increase overall fiber, especially on those days when you don't eat so good.

  2. Very interesting. I wish we understood more - specifically how to influence these interactions further. Even though I consider myself to eat a high polyphenol diet, I've started supplementing some - Circumin, pomegranate extract etc. Whilst I couldn't have managed this earlier in my healing journey, I do think they're having a positive effect. I've never dreamt so much!!
    I do still think prebiotics are essential, but when these or these plus prebiotics aren't enough - other possible protocols for people to consider could be extremely helpful. Just my 2 cents

    1. I think they are getting closer to understanding, but the people with the money to study this are looking for ways to make drugs. If people would just give up junk, processed, and fast foods it would put the drug companies out of business. As it stands now, there are so many people with messed up guts and poor health from eating badly that drugs are the easiest route. It amazes me how people refuse to start eating better, and doctors, even nutritionists, give such bad advice on what makes a diet healthy. I want to scream every time I hear someone say that their doctor told them to avoid fiber.

    2. I sometimes go lower fibre - mainly if experimenting. And when I say low - I bet its still 30g (100g of chocolate for a start!). Tbh I usually get what I associate as yeast flare up. Today I had quite a flare so I had 3 very green bananas and 3 slices sourdough Rye bread. Guts now feel much calmer thank God!

      Been to a social family gathering and the sheer amount of shite others eat I also find bewildering. But as usual I'm just the wierd one!

      I'm much much better than years ago and can pretty much eat what I want, though like I say lower fibre especially if coupled with something like excess cheese and I pay the price.

      Further interventions to get truly 100% would be great. Hopefully further developments come out over the coming years. Though like you say above I won't hold my breath for my doctor to come forward with the info. The full extent of their nutritional advice to me was eat more carrots!

  3. But you've said real food alone - unless one makes a huge effort - cannot provide enough resistant starch. So what's wrong with the powders?


    1. The plan should be to make real foods a bigger and bigger part of the diet, but I'll admit that it's hard to get much more than 20g if you are counting. All the experts point towards 35g or more per day, even up to 50, 100, or more for full benefits.

      For instance, today I had bacon, eggs, and hashbrowned (pre-cooked and cooled) potatoes, and a half a dried plantain. The potatoes had maybe 5g of fiber, but the plantain slices had 25-30g. Later I'll have a smoothie with fresh strawberries, blueberries, dark chocolate, chia seeds, pea protein powder, and some Hi-Maize or PS.

      I pretty much end every day with 50g or more without relying mostly on starch/fiber powders.

      I think that using an isolated starch, ie. potato, Hi-Maize, or green banana flour is a far cry better than what is sold as "fiber" at the supermarket.

      Amazon's #1 fiber is FiberCon (yes, really!). It contains:
      Calcium Polycarbophil (625 Mg Equivalent to 500 Mg Polycarbophil). Inactive Ingredients: Caramel, Crospovidone, Hypromellose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Silicon Dioxide, Sodium Lauryl Sulfate.

  4. The wife was reading the recent "news" that as little as one drink per day increases breast cancer risk. I misinterpreted her comments as concern, when in fact I learned later that she she was skeptical. In the interim, I delved deeper into the mainstream media's BS. There are lots of problems in what was reported. But the most damning bit of information was in the original report cited by the MSM. The report speculates about the mechanism between alcohol intake and breast cancer. It seems to conclude that women who imbibe in alcohol are well-documented to have diets low in folate, which plays a role in cellular regeneration. In other words, women who imbibe in alcohol don't eat as many green leafy vegetables, beans, etc. that women who don't imbibe. Which grabs the media's attention more? "As little as one drink per day significantly increases breast cancer risk" or "Eating a good diet reduces breast cancer risk"? It's shameful.

    Here is a good discussion of the role of the gut microbiome and it's metabolites on epigenetics, cancer, and disease.

    Of course, Tim's post indicates there is much to be learned. But the advice to eat Whole Foods is solid.

  5. Quoted from Beatrice Trum Hunter, Processed foods, she wrote early in her career, “may appear brighter and may last longer, but the people who eat them don’t.”

    1. I like that - I may use it!!

    2. I like it too. I saw another one I liked by Cava restaurants (awesome for quality healthy food): "Eat like there's a tomorrow."

  6. "I believe our best bet is to eat a diet filled with lots of plant fiber and whole foods."

    Hi Tim,

    Great post as usual. I've also followed the extensive work you've done at Potato Hack. I have a couple of questions.

    1. What are your thoughts on this article that conclude that increased fiber intake / bowel move may actually be associated with increased risk of diverticulosis? (

    2. There's also conflicting opinions / debate on the importance (or lack thereof) of fiber in our diet, in terms of being a health benefit. Many in the LC / Keto community say there's no direct evidence that fiber has any health benefits? Are they wrong?


    1. Hi Shameer -

      I'm not Tim, but I've researched your questions for a few years. A friend has diverticulitis, and I looked into this for him. My impression is that early studies (like the one you post from 2012) are anti-fiber. But more recent studies have muddied the waters a bit by being pro-fiber. Here's Webmd's take on diverticulosis.

      It explains why fiber might be good.

      Are you familiar with PubMed run by NIH? You can enter search times like "fiber diverticulosis" and it will bring up studies published about them. Here's one concluding fiber decreases diverticulitis risk from 2017.

      Like I said, I think there's a dividing line somewhere about early 2016 questioning the common wisdom that fiber exacerbates diverticulosis. As an anecdote, I can say that I've seen no issues myself (I'm > 100 g/ day fo 3.5 years). I have no issues with straining on the toilet. After years of straining with IBS-D. Sounds contradictory, but there it is.

      Regarding your question 2: Again PubMed is a great site. Everyone has different ailments. Mine was cardiovascular disease. Enter "cardiovascular disease fiber" and studies pop up. Read the studies. Some studies say that fiber doesn't improve lipid levels. Look at what fibers they use. Keep searching. Discover that a study compares different types of fibers for lipid levels, and the ones that are nonfermentable yet form gels (psyllium and guar gum) seem to work very well, but resistant starches and inulin do not. Have autoimmune issues? Look them up. You'll find lots of studies showing health benefits.

      In my opinion, I think the biggest danger is following someone else's dogma. You are intelligent. You know that an all Twinkie diet is not good. You know that a 100% fat diet is not good. You know there's nothing nutritious about regular pasta. But you know broccoli is good for you. Collard greens are good. Blueberries are good.

      Is fatty meat good for you? Well, humans are certainly designed to eat some fatty meat, and it's a whole food. Decide for yourself. I go through periods where I eat lardo and other pure fats. But still with lots of fiber. Note that studies of high fat diets never have a high(ish) fat diet with high fiber always high fat, zero fiber.

      After all my research, I've arrived at a diet that's unlike anyone else's as far as I know. Most importantly, I've not followed anyone. I've been influenced by Tim and others, and I'm grateful for their influence. But I've called BS on many, and yet have taken the good. And as far as I know, no one has duplicated me. How? For me, it's an intuitive/gut feeling model that changes hour-by-hour.

      Finally, I think it was Jeff Leach who said (paraphrased) "A study shows no benefits of fiber? Look closely, they forgot to give them fiber." 35g/day is not high fiber. 120g/day might be!

    2. Shameer

      read carefully what Wilbu wrote. You cannnot get a smarter answer than this.

      "Many in the LC / Keto community say there's no direct evidence that fiber has any health benefits? Are they wrong?"

      They are dumb.

  7. Thanks Wilbur and on as usual.

    The study that Shameer cited, "A high-fiber diet does not protect against asymptomatic diverticulosis," has a couple of important distinctions. "Asymptomatic" means this type of diverticulosis does not cause problems. Some theorize that nearly everyone (up to 60%), regardless of diet, develop diverticules, and only a certain percentage (10-40%) have problems, ie. diverticulitis, fistulas, etc. The study was designed to look at people found to have diverticules incident to other routine care.

    When they discovered these diverticules, they asked the patient to recall what their diet was like. They only asked about diet for the past 12 months. the researchers noted:

    "We cannot exclude the possibility that people with
    diverticulosis had symptoms and changed their diet as a

    It is very likely that these folks, mostly 50-60yo, had been experiencing gut dysbiosis symptoms for many years and had changed their diet to include more fiber as everyone advises.

    As to your LC/keto questions...I think that these people are deluding themselves if they think they can eat mostly meat and remain healthy into old age. Especially if much of the meat is cured (bacon/sausage) like these people are always talking about. Low carb is a powerful tool for weight loss, but then you need to transition to a higher carb, higher fiber, real-food diet. This was the original Atkin's Diet plan, but everyone has forgotten his LC phase was a short part of the overall program.

    I've been showing people for years that you can just as easily lose weight on a nearly 100% carb diet (The Potato Hack). But just because a diet is good for weight loss does not mean it is suitable forever.

    Thanks for the questions! I hope we answered them satisfactorily.

  8. Here is a great 2017 review (full text):

    "Detrimental Impact of Microbiota-Accessible Carbohydrate-Deprived Diet on Gut and Immune Homeostasis: An Overview"

    The conclusion: [MAC is fiber]

    "Food processing has significantly decreased the amount of MAC content in the Western diet, when compared to the contents of the ancestral hominin diet (7). As discussed above, low-MAC consumption not only has detrimental impacts on gut microbiota in particular but also on the host as a whole. It favors the development of diseases and increases mortality, as shown in preclinical and clinical studies (5, 9, 52). Low consumption of MACs over generations leads to the complete disappearance of beneficial bacterial strains in a preclinical study (26). While such study has not been carried out in humans, it is known that, similar to mice, the consumption of a diet low in MACs decreases bacterial diversity. This seems to suggest that long-term-reduced MAC consumption over generations will likely also have detrimental effects in humans. The only treatment able to correct this “scarred microbiota” was combined dietary and probiotic interventions. This might explain the low efficacy of probiotic-exclusive treatments in humans, as probiotics may not grow in a dysbiotic environment. Thus, dietary interventions alongside administration of beneficial bacterial strains could be a cost effective treatment to manage most non-communicable Western lifestyle diseases. Extensive research still needs to be done to determine (1) what types of MACs are most efficient at diversifying the microbiota and promoting production of SCFAs and (2) how much MACs should be consumed to optimize maintenance of health, or to treat different types of inflammatory diseases."

  9. Very interesting stuff. I think until you've experimented yourself, you're never really quite sure who to trust/ believe.

    I do listen to the Bulletproof podcasts and have been swayed in the past by focusing more on mitochondrial health. In Bulletproof world - fat is the king, and why wouldn't it be? Mitochondria burn ketones much more effectively than glucose creating much less ROS.
    However for me at least since experimenting with higher fats (and hence lower carbs) - guts have gradually gotten worse. I've stopped it recently when ibs d came back. Upping the complex carbs has already begun to move things back to how they should be.

    Some people may just be able to get away with less Fibre? Mark Sisson looks very well for his age and yet he seems lower carb? Then again Jimmy Moore...

    I suppose the last point is how many LCs have managed to correct a broken gut? I'm not talking manage symptoms by avoidance but actually correct it the way Wilbur has? I haven't come across any and I read up quite a bit!

  10. Mark Sisson is much more open-minded than most of the LC gurus. He eats wheat, sugar, and other paleo no-nos from time-to-time, but then again, has been a life-long athlete and takes testosterone injections.

    LC, VLC, keto are the go-to diet for the obese. Most never uncover the root problems of their obesity. You rarely see healthy, lean, athletic people talking about LC unless they are a paid spokesman. They don't need it. In fact, the athletes of the world mostly warn against LC diets. But, these diets can be helpful to turn around obesity. Just no magic bullet for long-term weight maintenance.

    On another note, I just heard that Dr. Perlmutter or Grain Brain fame has started recommending resistant starch to those on his grain-free, LC diet. Smart move.

  11. I do think people are starting to see LC/ Keto etc. aren't the cure all they were touted as. 2 recent episodes on bulletproof were interesting. Dr William Davis was recommending lentils for the microbiome and John Mackey was much stronger in his recommendations of whole foods including grains (though not gluten) to support overall health and the biome.

    Even Mr bulletproof himself appears quite open to others points of view and doesn't try to dissuade them if they differ from his high fat perspective.

    Inspired by comments on here and reading an old resistant starch thread on I decided to push things a little further. As plantains have become more locally available I've been eating 1 raw per day along with a green banana and a raw potato or 2. Things are changing - mind and energy levels feel sharper. I hope it continues!


      I find, too, that soft cheeses like brie and Camembert, cottage cheese, or yogurt are very complimentary to the changes that occur when you start increasing RS. The bacteria that make these cheeses so good also like to feed on RS and help to make a better environment in the gut.

      If you can eat dairy, that is.

  12. 1st time I've heard that song - I'm a little young for it!

    Thanks for the tip - I've bought some brie to test!

  13. I keep seeing on the Keto platform people who have drastically cut their carbs to under 20 grams start complaining about increasing constipation!! They DON'T ask how can that be, so that they could proper advice: increase your fiber. Most of them are first time dieters and they think it is the bee's knees. I am sure a few years down the line we will see a shift from keto to solve the problems of constipation.

    Jo tB