Wednesday, May 8, 2019

"High-Fiber Diet Might", a translation

In this month's JAMA Network Open we have an opinion piece [1] that struck a chord with me — a discordant, grating, and tuneless chord. I thought I'd share with you what I heard, when I read it, just to do my part in spreading the pain.

Italics for the author's word, bold for my translation, and footnotes for further commentary.

High-Fiber Diet Might Protect Against Range of Conditions

The popularity of low-carb diets, such as Atkins and keto, have helped give the macronutrient a bad name, and in part, it’s deserved.

We concede that carbohydrates are contributing to health problems, but we weren't wrong. We never meant all carbohydrates were good, just the good ones!

“Have carbs got a bad reputation? Certainly…for a very understandable reason,” said Jim Mann, MB, ChB, PhD, a professor in human nutrition and medicine at the University of Otago in New Zealand. “They are highly refined, and, in many countries, sugar intake is high.”

But just as there are “bad” fats and “good” fats, there are also bad carbs and good carbs. “We showed very clearly in our work in diabetes that the benefits of carbs came from the good carbs, and the good carbs are not high in sugar,” Mann said. “They are high in fiber.”

In fact, we've shown that the benefit from carbs come from those carb foods that are low carb.

Mann, who spent years helping to hammer out the World Health Organization’s definition of fiber, recently coauthored a series of systematic reviews and meta-analyses that showed intake of fiber and whole grains—probably due to their high fiber content—but not foods with a low glycemic index was associated with significant reductions in mortality and chronic illnesses. (Breakfast cereals and other manufactured whole grain products are more highly processed today, so they provide less fiber and, likely, fewer health benefits, the authors noted.)

Mann spent years trying to help the WHO find a definition of fiber that would only include those fibers that had the properties they wanted to claim for it. (see image below from the cited paper [2] and further ironies). He recently coauthored a series of papers trying to retroactively support recommendations for high fibre intake. (Also, please don't mistake our recommendation of whole grains to mean we're recommending actual breakfast cereals or products that say "whole grains" on them).

Observational data suggested a 15% to 30% decrease in all-cause and cardiovascular-related mortality and incidence of coronary heart disease, stroke, type 2 diabetes, and colorectal cancer in people who consumed the most dietary fiber relative to those who consumed the least, the authors found. In addition, clinical trials showed that compared with low intake, high dietary fiber intake lowers body weight, systolic blood pressure, and total cholesterol. Given that the findings from prospective observational studies and clinical trials were complementary and that there was evidence of a striking dose response, the relationship between a high-fiber diet and lower disease risk could be causal, the authors concluded.

The meta-study (see quotes from it in the notes [3]) suggests that our recommendations might have had some basis, especially when we play the mind-game of expressing the weak-looking relative risks in absolute terms instead.

Although high-fiber intake is associated with lower weight, which in turn reduces the risk of diabetes, cardiovascular disease, and many cancers, dietary fiber appears to have benefits independent of its effect on weight, Mann said.

These findings and others suggest that virtually anyone who wants to lower their risk of a variety of ailments—including cardiovascular disease and multiple types of cancer, such as ovarian, pancreatic, and liver as well as colorectal—should consume more, not fewer, carbs, as long as they’re good carbs, ie, fiber-rich whole grains, legumes, fruits, and vegetables.

When we adjust for weight loss associated with these lower-carb carbs, much of the already small correlation goes away. Therefore it makes sense that this recommendation to eat higher fibre should be applied to anyone who doesn't want to die a horrible death.

However, in westernized countries, few people consume anywhere near the recommended amounts of dietary fiber. In the United States, the average dietary fiber intake by adult men and women is 18 g and 15 g, respectively, based on the 2013-2014 National Health and Nutrition Examination Survey (NHANES) data. And yet, the 2015-2020 Dietary Guidelines for Americans recommends a daily minimum intake of 33.6 g per day for men and 28 g for women 19 to 30 years of age, and only slightly decreasing amounts as people get older.

No one is paying attention to our guidelines. Even though our results are weak and there has been no causal link established, we recommend a fibre intake with a precision to the tenth of a gram to help convey our confidence.

And what about people who swear by a low-carb diet and, as a result, consume relatively little dietary fiber?

“In the short-term, if a person has a very high body mass index, almost anything that would cause weight loss would be beneficial,” said Edward Giovannucci, MD, ScD, a professor of nutrition and epidemiology at the Harvard T.H. Chan School of Public Health. “In the long-term, it’s a different story,” Giovannucci said, noting a lack of long-term studies of low-carb diets.

Please don't confuse your actual results with the power of our statistical model. We don't have enough data on what you're doing to show if the benefit you're experiencing in practice works in theory. Nor have we bothered to learn enough about it to realise it can be implemented with or without high fibre.

Figuring Out Fiber

An early theory for why dietary fiber was inversely related to colon cancer risk was mechanical: Fiber quickens the transit time of stool by bulking it up. There might be some truth to that explanation for why fiber intake and colon cancer risk are inversely related, said Giovannucci, who served on the American Institute of Cancer Research panel that produced a recent report on the relationship between diet, nutrition, and physical activity and colon cancer. “Certainly, you would think fiber would be more relevant to the diseases of the colon,” he said.

We've had this intuitive theory that fibre might be protective of colon cancer for a long time, since it goes through the colon when you eat it.

Indeed, “the lack of fiber is particularly pertinent to the remarkably high incidence rates of colon cancer in westernized societies,” Stephen O’Keefe, MBBS, MD, FRCP, wrote in a recent article. “In stark contrast, colon cancer is rarely seen in rural African communities consuming their traditional high-fiber (≈50 g/d), low-meat, and low-fat diets.”

Westerners have higher rates of colon cancer than non-westerners, including those that eat higher fibre diets low in meat and fat, (and those that eat lower fibre diets high in meat and fat, but we don't talk about that).

In 2015, O’Keefe coauthored a widely cited study in which 20 African Americans and 20 rural Africans swapped their regular diets for 2 weeks. The researchers prepared high-fiber (50 g/d), low-fat African-style meals for the African Americans and high-fat, low-fiber meals for the rural Africans.

The brief diet swap was long enough for the scientists to observe reciprocal changes in participants’ gut microbiota and metabolome, which were associated with changes in mucosal biomarkers of cancer risk. The authors emphasized that changes in animal protein or digestible carbohydrate intake associated with changes in dietary fiber consumption could also have contributed to the observed mucosal alterations. They concluded that their results raise the hope that increasing fiber consumption, along with moderating fat intake, could reduce African Americans’ disproportionately high incidence of colon cancer.

Since we can't do a trial for long enough to to measure what we care about, we are trying to find other support for the idea that fibre is protective of colon cancer. For example we can compare intestinal bacterial effects of traditional foods from rural South Africa, to a diet of french fries and burgers with ketchup, and see if any of the microbiome responses correspond to another body of epidemiological associations that might be more predictive than the ones we already have [4]. As you can see in the photo, lack of fibre is the clear difference in this study.

Dietary fiber appears to be protective even after a diagnosis of colorectal cancer, Giovannucci and his coauthors suggested in a recent JAMA Oncology article. Using data from the Nurses’ Health Study and the Health Professionals Follow-up Study, they found that higher fiber intake after a diagnosis of nonmetastatic colorectal cancer was associated with a lower risk of death from that disease and all causes.

“Higher intake of fiber, especially cereal fiber, has been linked to improved insulin sensitivity, lipid profile, endothelial function, and reduced inflammation,” and evidence is just beginning to suggest that hyperinsulinemia and markers of insulin resistance and inflammation predict worse survival in patients with colorectal cancer, Giovannucci and his coauthors note.

Although we don't have trials supporting high fibre diets in those diagnosed with colon cancer, we have some more weak associations that suggest it would [5]. The associations for fruit and vegetable fibres are particularly weak, even by our standards, so we won't mention them specifically. This association might in turn be just a reflection of the association between higher fibre intake and metabolic syndrome symptoms, which is independently predictive, but instead of suggesting that we take measures to reduce metabolic syndrome, we'll continue to recommend the fibre itself.

In other words, the explanation for why a high-fiber diet appears to be protective goes far beyond speeding stool’s conveyance through the colon. And, it turns out, fiber’s health benefits extend beyond the colon as well.

So, never mind about the initial explanation we tried to use to justify our hypothesis. Let's move on to something even less intuitive.

For example, a recent study involving participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial found an inverse association between dietary fiber intake and head and neck cancer, particularly oral cavity and pharyngeal tumors.

“We have found the inverse association between dietary fiber and head and neck cancer risk not only among smokers and drinkers but also among never smokers and never drinkers,” said coauthor Daisuke Kawakita, MD, PhD, of the Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences in Japan.

The late British surgeon Denis Burkitt, FRS,—aka the “Fiber Man”—popularized the notion a half-century ago that dietary fiber protected against a host of diseases, but not until recently have scientists begun to explain “the whole biochemistry of how fiber can have distal effects all around the body,” said O’Keefe, a University of Pittsburgh gastroenterologist.

In order to try to confirm our hypothesis about the association between fibre intake and cancer, we'll divide and conquer. By retroactively dividing the set of diseases into different classes, we can manipulate the size of the associations by choosing which sets to report on. We can revisit the same data set over and over again with different hypotheses until one of them statistically pans out. This is often called "data dredging" or "p-hacking", but those words have unpleasant connotations.

O’Keefe and others posit that fiber’s effect on gut microbiota may explain its health benefits for the colon and beyond. “The metabolites of fiber, particularly butyrate, can prevent cancer in any part of the body,” he said.

Butyrate, a short chain fatty acid that serves as a fuel source for the cells that line the colon, facilitates apoptosis of colonic cancer cells and reduces gut inflammation, note the authors of a 2017 review article about butyrate in the colon and peripheral tissues. As the authors write, research has shown that increased fiber consumption or oral butyrate supplementation has been shown to decrease adiposity and improve insulin sensitivity.

The most promising current potential mechanism to lend plausibility to the fibre hypothesis is that fibre is broken down into butyrate by gut bacteria. Butyrate, (which can come from other sources besides dietary fibre), has been shown to have benefit in the colon, (probably because it breaks down into the ketone body beta-hydroxybutyrate [6]). As per the paper we cite, [7] butyrate from fibre that makes it into the bloodstream is captured by the liver and metabolised. So butyrate doesn't actually reach peripheral tissues. However, if we supplement butyrate so that it does reach them, it can improve insulin resistance. Glossing over these details, we can then make it sound like butyrate from dietary fibre has benefits across the body.

But are the apparent health benefits from consuming foods naturally high in fiber due to fiber itself or to other nutrients that accompany it?

The correct answer is both, O’Keefe said. Dietary fiber is a marker for other nutrients in naturally fiber-rich foods, particularly phytochemicals, and at the same time it is also a biomolecule, he said. Plus, O’Keefe said, “People who eat fiber-rich foods are health conscious as well. Their lifestyle is better.”

Can't all this association be explained by the other things people who eat fibre eat and do? Yes. It could totally be from the health-conscious nature of people who eat fibre, but we really think it's about the plants, and we're doing our best to come up with theories about how that could be true. For example, we're branching out our search for a benefit from plants into other non-nutritive chemicals they contain. Fibre is still a biomolecule, it's got to have a positive effect.

Fiber in a Pill?

These days, it’s possible to find high-fiber brownies and high-fiber ice cream in many supermarkets. Of course, the only reason they’re high in fiber is because synthetic or isolated fiber was added to them.

Besides flour or milk, their labels list such ingredients as soluble corn fiber—“produced from corn through enzymatic hydrolysis of corn starch,” according to an industry website—or sugarcane fiber, also used to make plates and bowls.

“They do seem to be able to lower cholesterol a bit, but we do not know whether those synthetic or extracted fibers have the same long-term benefits,” said Mann, who, to illustrate this point in lectures, uses a slide of a high-fiber English muffin sold in the United States. A check of the ingredients of high-fiber English muffins is likely to reveal that their fiber comes from an additive such as cellulose, not whole wheat flour.

As Giovannucci said, “In most of the observational studies that are the basis of most of the data and recommendations, what we really studied are the whole foods.”

It's really important to understand that the proposed benefit we're attributing to fibre isn't attributable to fibre, but to foods that contain fibre. It's not really about the fibre. Fibre is used for making plates! So just eat whole foods with lots of fibre. Ok?

Still, when the US Food and Drug Administration (FDA) in 2016 finalized its Nutrition Facts and Supplement Facts Label, with the agency’s first-ever definition for dietary fiber, it included 7 isolated or synthetic nondigestible carbohydrates, such as cellulose and guar gum, as well as “intrinsic and intact” fibers in plants.

Based on small, short-term clinical trials, the agency said, the isolated or synthetic carbohydrates had “physiological effects that are beneficial to human health,” such as lowering blood glucose or cholesterol or increasing the frequency of bowel movements.

Well maybe it is about the fibre. Anyway, how else could you lower your blood sugar? As a bonus you get lower cholesterol and you get to poop more. These have both been equally shown to improve health, as I'm sure we don't have to explain.

In June, the FDA released a scientific review of 8 more added nondigestible carbohydrates it plans to include in its definition of dietary fiber. However, none of the research cited by the FDA looked at the long-term impact, namely disease risk, of the 15 added nondigestible carbohydrates. In late March, the FDA announced plans to propose that manufacturers be allowed to identify a 16th nondigestible carbohydrate as dietary fiber on food labels.

Added fiber is better than no fiber, O’Keefe said, but “we’re designed to eat a balanced diet, and a balanced diet comes from what’s available naturally.”

So, we know fibre is good for you based on weak long-term associations that in all likelihood have to do with other components of the diet or behaviour of the subjects. That doesn't change our conviction that it is still better to get fibre from other sources than not at all, especially since now we can use these food additives to put health claims on labels. When you get your fibre this way and are still unhealthy, we can remind you that we never said that isolated fibre had health benefits.

Feasting on Fiber

Mann said he typically consumes at least 40 g of fiber a day, which might seem daunting to most people in westernized countries. “It does require a bit more preparation,” Mann noted. “If people are not well off, it’s cheaper to go and buy a Big Mac.”

Indeed, the NHANES data found that higher income was associated with higher fiber intake, although there are other explanations for that relationship besides the cost of high-fiber foods.

Basically, the reason we're finding this association is that rich people tend to be healthier and they also eat more fibre whereas poor people tend to be unhealthier and they also eat more Big Macs.

Increasing dietary fiber intake doesn’t have to be expensive. Mann, O’Keefe, and Giovannucci all pointed to legumes, which include beans, chickpeas, and lentils. A good source of protein as well as fiber, legumes are “a particularly underutilized food,” Giovannucci said.

You, too, can have the health of the wealthy if you'd just spend more time cooking these evidently undesirable and unappealing foods. Poor people have more time than rich people. It's not like time is money.

Experts emphasize the need for public health messages about the value of consuming more dietary fiber and how to do it.

“We need a population push, just a bit like the lung cancer story,” O’Keefe said, referring to the worldwide decline in smoking rates. “The information’s got to get out to the population to understand the clear significance and strong relationship between fiber intake and various kinds of cancer and westernized diseases.”

If we get the narrative right, we can make people believe that hazard ratios of 1.2 or 1.3 are as meaningful as hazard ratios of 20. We just have to push people more.

That's the state of the art, folks.

References and Notes

[1]Medical News & Perspectives, April 17, 2019, High-Fiber Diet Might Protect Against Range of Conditions, Rita Rubin, MA, JAMA. 2019;321(17):1653-1655. doi:10.1001/jama.2019.2539

Cummings, Jh, Ji Mann, C Nishida, and Hh Vorster. “Dietary Fibre: An Agreed Definition.” The Lancet 373, no. 9661 (January 2009): 365–66.

In this paper Mann and his colleagues also make clear that although even the epidemiological evidence fails to show benefit, whatever substances they can support as beneficial with experiments using extracts from food should not get the label when they are sold as extractions, but only when sold to match the epidemiological data.

"[B]ecause long-term epidemiological evidence of health benefit is lacking, the definition requires generally accepted scientific evidence to be presented to competent authorities before such polymers can be labelled as fibre...

"Calling [oligosaccharides] fibre is potentially misleading for consumers. For example, bottled water with some of these substances added could be sold as a source of fibre. Consumers might then be tempted to obtain the recommended fibre intake from such products rather than from fruit, vegetables, and wholegrain cereals."

In the end it gets the desired label, though.


Reynolds, Andrew, Jim Mann, John Cummings, Nicola Winter, Evelyn Mete, and Lisa Te Morenga. “Carbohydrate Quality and Human Health: A Series of Systematic Reviews and Meta-Analyses.” The Lancet 393, no. 10170 (February 2019): 434–45.

"Quantitative recommendations relating to dietary fibre do not have a strong evidence base."

"Findings from prospective studies and clinical trials associated with relatively high intakes of dietary fibre and whole grains were complementary, and striking dose-response evidence indicates that the relationships to several non-communicable diseases could be causal. Implementation of recommendations to increase dietary fibre intake and to replace refined grains with whole grains is expected to benefit human health."

The "striking" observed correlations combined to an all-cause mortality relative risk RR 0·85 (0·79 to 0·91), which the authors consider to be "moderate" evidence. I consider this rather generous.

[4]O’Keefe, Stephen J. D., Jia V. Li, Leo Lahti, Junhai Ou, Franck Carbonero, Khaled Mohammed, Joram M. Posma, et al. “Fat, Fibre and Cancer Risk in African Americans and Rural Africans.”. Nature Communications 6 (April 28, 2015): 6342.
[5]Song, Mingyang, Kana Wu, Jeffrey A. Meyerhardt, Shuji Ogino, Molin Wang, Charles S. Fuchs, Edward L. Giovannucci, and Andrew T. Chan. “Fiber Intake and Survival After Colorectal Cancer Diagnosis.”. JAMA Oncology 4, no. 1 (January 1, 2018): 71.
[6]Does a ketogenic diet confer the benefits of butyrate without the fibre?
[7]McNabney, Sean M., and Tara M. Henagan. “Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance.”. Nutrients 9, no. 12 (December 2017): 1348.

Saturday, May 4, 2019

Who is a Carnivore? problems of names, identity, community

Who gets to decide what the Carnivore Diet means?

Let me start by contrasting the relatively easy question of how to define a diet, with a deeply difficult question.

In my early twenties, I was studying Judaism. I was preparing to convert before marrying my Jewish then-boyfriend. There was no pressure from my boyfriend or his family to convert, it was just something I wanted to do as a way of embracing the family and community. Besides, I found the Jewish approach to life, as exemplified by that family, the community at the university, and the writings I read, as practical, wise, and rich with beauty and meaning.

If you know much about Judaism, you know that Jews are not missionaries. The last thing they want is an influx of people calling themselves Jews who don't exemplify Jewish values. So the process of converting is long and complex. None of it rests on holding any particular belief. As an atheist, this was both a relief and a source of anxiety for me. I felt certain that at no point in the process would I be asked to profess a belief in God, although I was never quite certain whether it was really OK not to. My own boyfriend considered belief in God a private, off-the-table question, even between lovers, as inappropriate as asking whom he voted for, or what his passwords were. The one time I asked him, he made his signature impish grin and told me to never mind. I knew many self-proclaimed atheist Jews, but they were Jewish by birth and upbringing. It seemed they had a right to choose their Judaism in a way that a convert arguably might not.

Still, if you can be Jewish and not believe in God, is this not a slippery slope? Where does it end? Who is a Jew? Like all Deep Questions, there is no set of sufficient and necessary conditions that will define once and for all who gets to call himself a Jew. The best answer I gleaned was that if you are accepted as Jewish by other Jews, then that was definitive.

Whether or not you are a Carnivore is not a Deep Question, but trying to make it one is a source of mass confusion. There are always going to be border cases where lack of definition will make it hard to decide, but there are also many cases that are clearly yes or no. Let's look at some.

"Carnivore" in this context is a diet, not a biological label

The question of whether or to what degree humans are carnivores is an interesting question, even a Deep Question. I have an entire chapter (not yet published) in my book Facultative Carnivore devoted to answering this theoretical question, because it is relevant to the more practical question of whether or not the Carnivore Diet is a healthy one.

What it is not relevant to is whether someone is or is not following the Carnivore Diet, because the Carnivore Diet isn't defined as "the diet biological carnivores eat." For one thing, there is no such single diet. What diet should get to have the label "Carnivore" can't be answered by that line of inquiry, any more than what a Jew is can be answered by reading the bible. I delve into the biological questions more in the book.

There are not gradations or levels of the Carnivore Diet

If you eat X% the Carnivore Diet, you are not following the Carnivore Diet. Sorry, but no. This idea has a long history of causing unpleasant emotions. Let me exemplify with a story from ZC history.

The Carnivore Diet is a rebranding of a diet that was originally called "ZC" for "Zero Carb". Some still use that name. I and some others started calling it "Carnivore" several years ago, on the naive hope that it would be less confusing than ZC, since the diet contains items that have non-zero carbohydrate, and there are foods that have no carbohydrates that are not allowed on the diet.

ZC was defined by a small group of people who gathered on a forum called "Zeroing in on Health", founded by Charles Washington, and heavily influenced by the writings of Vilhjalmur Stefansson and Owsley "the Bear" Stanley (For copies of some of these writings, please visit Michael Goldstein's website, I was an early member of this group, joining in December 2008.

The diet that was being followed there was a plant-free diet. The strictest version of the diet excluded all plant foods, but some of us drank coffee or tea. These were considered acceptable empirically. That is, through observation, the benefits of removing plants didn't seem to be hindered by that, and so while it was not encouraged, it was still considered acceptable as part of the diet.

However, there were other people on the forum who were eating a small amount of plant foods regularly. These people were welcome to observe and participate, but they were not considered to be following the diet. Partly the justification was because those of us who got benefit from plant abstinence, often would have return of unwanted symptoms when even small amounts of plants were consumed. So, while there is probably some degree of arbitrariness to the definition, the definition was clear.

Some people took offense to this exclusion. My interpretation is that they felt judged. They wanted to be viewed as one of the "cool", "bad-ass", "hard-core" ZCers, but were excluded due to what felt like a minor infraction. These folk started accusing the stricter folk of being "purists" and zealots, which really has nothing to do with it. If you strictly avoid plants because even a small amount brings back your arthritic pain, your motive is not moral, it's practical! Nonetheless, this accusation was bantered about, and the ones who were either able to eat some plants without ill consequence, or who were simply not choosing to eat a strictly plant-food-free diet for whatever reason, began calling themselves "Dirty Carnivores".

Eventually, a prominent Dirty Carnivore, whom I'll call "S" had a falling out with the ZIOH admins and decided to start her own forum by that name. I was a member of both fora for at least several months. However, over time, S and others began to ostracise those of us who didn't eat plants, including a Carnivore I'll call "R". We were accused of being puritanical just because of the way we ate. None of us ever tried to impose our own diets on other members, but our mere steadiness in our own decision made others uncomfortable. After we left that forum, S even started attacking R on yet a third forum, calling her a fraud, because she had previously reported eating a handful of nuts in a moment of weakness (which, by the way, led to arthritic pain). This "transgression" meant R wasn't a "real" Carnivore, according to S.

I'm not the Carnivore Police

The main reason I bring up this story is because it illustrates some problems with the X% carnivore terminology. I am not trying to "call out" any individual, or shame anyone who has used these phrases, or who decides to continue to use them. I am not claiming any exclusive right to define a word; I'm a linguist, for Goodness' sake! I'm just telling you from my experience what kinds of problems these terms have led to in the past.

If you thrive on a diet that is mostly meat with some plants, I think that's fantastic. I do not consider it a badge of honour to eat the way I do. Eating this way by choice may well be uniquely health-supporting for many individuals, but I don't do it by "choice" exactly. I consider it a disability that I need to eat as strictly as I currently do.

However, if you eat a low plant diet and call yourself X% Carnivore, then I think you might be missing the point of the Carnivore Diet, which is that some people get therapeutic benefit from a very specific way of eating that isn't about percents.

I personally like the term "Carnivore Adjacent". I think it was coined by Amy Berger or Ted Naiman in a Twitter thread. (I don't remember precisely.)

The second reason I am telling this story is that, hopefully, you can see that there is a meaningful difference between someone following a Carnivore Diet who uncharacteristically eats some plants sometimes and someone who routinely eats some plants, even though there will never be a uniformly agreed upon definition of how often is too often to fit the label.

Regardless, I think using a fairly strict definition of the term Carnivore has value. Keep in mind:

  • Carnivores are not trying to be an exclusive club.
  • Carnivores are not making unimportant distinctions by drawing arbitrary lines on the plate — these distinctions matter for us.
  • Carnivores are not doing this to be pure or morally superior.

Who is a Carnivore?

Frankly, I think the best answer to the question of whether you are following a Carnivore Diet is whether the people in the Carnivore Diet community think you are. This is not because the Carnivore Diet is like a religion, but because it was defined by a community. If the community changes, the definition will change. If splinter groups break off, new names will follow. With any luck, they'll be less confusing than this name has turned out to be.

Tuesday, January 15, 2019

Not the Collagen, but the Carnitine?

Note that I'm using the tradition Zooko and I developed on of end-to-end citations, so check the references for supporting statements, not merely links.

In trying to understand why meat cures scurvy, and why long term carnivores don't develop it, I've previously written about how I discovered that the USDA database misleadingly lists beef as containing no vitamin C, which is inaccurate. Beef contains enough vitamin C that carnivore-diet-level intakes should provide just enough vitamin C to stave off scurvy, provided the meat isn't overcooked. I've also written about my hypothesis that less vitamin C is needed on a low carb diet due to increased endogenous antioxidants and less competition from glucose. The availability of vitamin C in meat, combined with the hypothetical lower requirement, could explain the observations.


However, these explanations have always seemed just barely adequate to me, and to others. Some have suggested meat supplies us with pre-formed collagen, and that this would relieve the burden of vitamin C to synthesise it. However, as far as I can tell, the collagen in meat would not be digested intact but rather broken down into its precursor amino acids during digestion.

It's not immediately obvious that this wouldn't still work, because those amino acid precursors include hydroxyproline, the very form that vitamin C is needed to create, by hydroxylating proline. However, the problem is that when collagen is formed, the hydroxylation is the last step, a post-translational step, after assembling the rest of the protein into procollagen out of mainly glycine and proline [Alb2017]. So collagen creation doesn't actually use hydroxyproline, it uses proline. This is borne out in studies. In vitro, preformed hydroxyproline isn't used to make collagen [Gre1959]. In vivo studies in rats and guinea pigs show that not only is labelled dietary hydroxproline not incorporated into tissues [Ste1949], but injected hydroxyproline doesn't help with wound healing in animals made deficient in vitamin C [Pea1960].

Collagen hydrolysate

Collagen / gelatin hydrolysate is a recent industrial by-product innovation [Góm2011]. Controlled enzymatic hydrolysis of collagen or gelatin is used to create bioactive peptides (chains of amino acids with biochemical activity) that contain hydroxyproline . The peptides appear to have better absorption than food-derived peptides [Iwa2005], [Liu2009] and even seem to be incorporated into animal tissues, at least in some studies [Oes1999], [Wat2010]. It is difficult to evaluate the claims, because the papers all appear to be motivated by product development, and may be overstated.

The product is marketed as useful due to the charge that aging animals, including humans, apparently lose the ability to synthesise collagen well, because of impairments in post-translational modifications to the proteins [Dan2015]. This is said to account for weakened joints and wrinkles.

The general assumption is that most actual food is broken down into amino acids during digestion and so these products are considered to be different from food, in that they are broken down into peptides that are small enough to be absorbed and somehow escape being further broken down before they are absorbed.

Therefore, while this is interesting from a pharmacological, supplement perspective, it doesn't seem to indicate that a meat-based diet would have this effect. To the contrary, if it were known that collagen peptides from meat provided these peptides, then the product would not be innovative and the process would be unnecessary! I've yet to see a direct comparison, though. Moreover, since none of these experiments involved vitamin C depletion, it's also unclear whether the proposed incorporation of the peptides is itself vitamin C dependent.

For these reasons, I conclude that the potential therapeutic value of collagen hydrolysate does not support collagen from meat as a significant way to spare vitamin C, and more likely contributes to refuting it.


Nonetheless, there is a second aspect of scurvy that eating meat does seem able to help with: carnitine. Vitamin C is not only needed to synthesise collagen, but to synthesise carnitine [Str2010]. Some of the symptoms of scurvy, including fatigue, which is the first sign of it [Hug1988], likely come from a deficiency of carnitine. Guinea pigs deprived of vitamin C live longer when given carnitine [Hug1981].

Unlike collagen, significant levels of carnitine do make it through the digestive system [Eva2003]. Therefore it stands to reason that eating meat spares vitamin C that would normally be used for carnitine synthesis, and then more of the vitamin C it provides can be used for collagen. I don't know how much of the 6-10 mg/day of vitamin C that's believed to be needed to prevent scurvy is accounted for by carnitine synthesis, but it could well be enough to tip the balance from barely adequate to easily adequate.



Vance L Albaugh, Kaushik Mukherjee, Adrian Barbul; Proline Precursors and Collagen Synthesis: Biochemical Challenges of Nutrient Supplementation and Wound Healing, The Journal of Nutrition, Volume 147, Issue 11, 1 November 2017, Pages 2011–2017,

"Although the most straightforward approach to improve wound strength is to provide additional proline in the diet, neither proline nor hydroxyproline increase wound breaking strength (31). Ingested hydroxyproline is readily degraded and synthesis of hydroxyproline occurs only posttranslationally—not de novo—once proline has already been incorporated into collagen."


Daneault, Audrey, Véronique Coxam, and Yohann Wittrant. “Biological Effect of Hydrolyzed Collagen on Bone Metabolism.” Critical Reviews in Food Science and Nutrition, May 15, 2015, 00–00.

"Regarding the mechanisms involved in ageing, Knott et al. highlighted an increase in the overall metabolism of collagen which may account for impaired post-translational modifications, leading to severe dysfunctions in the collagen network and a more fragile bone matrix (Knott & Bailey, 1998). Altered post-translational modifications hamper the formation of cross-links between collagen molecules based on aldehyde formation from specific telopeptide hydroxylysine or lysine residues (Knott & Bailey, 1998) and include an abnormal increase in lysyl hydroxylation or glycosylation, which are key to sustain the structural and mechanical integrity of the collagen network (M. Saito & Marumo, 2010; Yeowell & Pinnell, 1993 . These alterations lead to thinner fibrils and higher bone fragility."


Evans, Allan M, and Gianfranco Fornasini. “Pharmacokinetics of L-Carnitine:” Clinical Pharmacokinetics 42, no. 11 (2003): 941–67.

"By comparing the amount of carnitine ingested per day with the amount recovered in urine and feces, it was found that subjects on a low-carnitine diet excreted more L-carnitine than they ingested, while those on the high-carnitine diet excreted less than they ingested. The results with the latter group suggested that humans do not absorb all of the L-carnitine that they consume.[99] In the same study, subjects on a low-carnitine diet excreted about 25% of an oral tracer of L-[methyl-3H]carnitine as metabolites of the compound (mainly trimethylamine-N-oxide and γ-butryobetaine, which appear to be formed within the gastrointestinal tract prior to absorption; see section 3.3). If it is assumed that there was negligible excretion of the tracer via expired air, the extent of absorption in the subjects fed the low-carnitine diet may have been as high as 75%, on average.[99] In those subjects on a high-carnitine diet, 37% of the dose could be accounted for as excreted metabolites, meaning that the extent of absorption might have been about 63%. Importantly, the results suggest that the efficiency of absorption tends to diminish as the carnitine content of the diet increases,[91,99] reflecting the involvement of specific transporters that can be saturated even with normal dietary intake. As described below (section 3.1), the bioavailability of supplemental or medicinal oral doses of L-carnitine tends to be even lower, at 5–18%."


Gómez-Guillén, M.C., B. Giménez, M.E. López-Caballero, and M.P. Montero. “Functional and Bioactive Properties of Collagen and Gelatin from Alternative Sources: A Review.” Food Hydrocolloids 25, no. 8 (December 2011): 1813–27.

"Scientific literature about different alternative sources and new functionalities of collagen and gelatin has experienced a boom in the last 10e15 years, in part due to the growing interest in the economical valorisation of industrial by-products (from the meat and fish industry), the environmental friendly management of industrial wastes, and the search for innovative processing conditions as well as potential novel applications."


Green, N. M., and D. A. Lowther. “Formation of Collagen Hydroxyproline in Vitro.” Biochemical Journal 71, no. 1 (January 1959): 55–66.

"3. The addition of unlabelled L-hydroxyprohne to the incubation medium in the presence of L-[14C]proline had no effect on the ratio of the specific activities of collagen hydroxyproline and proline although the total radioactivity incorporated was reduced.

"4. Incubation of the tissue with L-[14C]hydroxyproline did not result in a significant incorporation of radioactivity into collagen.

"5. Radioactive free hydroxyproline was isolated from the slices and medium after incubation with L-[14C]proline but its specific activity was only half that of the neutral-salt-soluble collagen hydroxyproline and the total counts present were not increased when unlabelled hydroxyproline was present as a trapping agent.

"6. It is concluded that free hydroxyproline is not an intermediate in the formation of the hydroxyproline of collagen.

"7. Both proline and hydroxyproline added to the medium were found to be concentrated intracellularly about 2-5 times. The lack of incorporation of free hydroxyproline cannot therefore be due to the impermeability of the cells towards hydroxyproline."


Hughes, “Recommended Daily Amounts and Biochemical Roles—The Vitamin C, Carnitine, Fatigue Relationship.” in Vitamin C (ascorbic acid) J. N. Counsell, D. H. Hornig. 1981 ISBN 0853341095, 9780853341093

"Our studies have indicated that in guinea pigs such a relationship does in fact exist. By dietary means we produced tissue ascorbic acid concentrations of 12 % and 100 % saturation respectively in two groups of male guinea pigs. In the 'low ascorbic acid' group the mean concentration of skeletal muscle carnitine after 20 days was 0.5 ȝ g/g tissue and in the 'ascorbic-acid-sufficient' group it was l.15 ȝ g/g tissue. There was no concomitant emergence during this period of any of the symptoms customarily regarded as presaging the emergence of scurvy in guinea pigs— such as growth depression and kidney hypertrophy [38] (Table 1)."

"In a further study it was shown that administration of carnitine (10 mg per animal daily) prolonged significantly the life span of male guinea pigs given a scorbutogenic diet (Fig. 5). This could imply that carnitine may replace ascorbic acid in certain of its functions—a biochemically unlikely explanation. It is more likely that carnitine prolongs the life span by significantly 'sparing' ascorbic acid which would otherwise be used in the formation of endogenous carnitine."

"It would therefore appear that the involvement of ascorbic acid in carnitine biosynthesis is a nutritionally significant happening and that muscle carnitine is a highly sensitive indicator of ascorbic acid status."


Hughes, RE Ascorbic acid, carnitine and fatigue. Med. Sci..Res., 1988; 15, 721-723

"References to the early emergence in scurvy of fatigue and lassitude were ìnvariable features of the earliest clinical descriptions of the disease [23]. Eugalenus in 1658 spoke of "spontaneous debility" [24], Lister, in 1696, wrote of "weakness of limbs and considerable fatigue" [25] and Sydenham in 1742 of "spontaneous lassitude and difficulty of breathing after exercise" [26]. Naval surgeons with first hand experience of scurvy were equally clear in their descriptions: "The signes of the Scurvie are many, namely a general lazinesse ... shortnesse and difficultie of breathing, especially when they moove themselves" commented Woodall in 1639 [27] and Lind, over a century later, wrote: "... this lassitude, with a breathlessness upon motion, are observed to be among the most common concomitants of the distemper" [28]. Practising 'land physicians' in the last century made similar observations. Shapter, a careful clinical observer, describing an outbreak ofscurvy in Exeter in 1847, perhaps put the matter most clearly: "... the spongy and swollen gum appears to me to have been erroneously estimated as amongst the primary and most obvious manifestations of the scurvy ... I am inclined to say there is a class of well-marked symptoms preceding this... The first or initiatory stage ... has appeared to me to be characterised by ... debility ... weakness, listlessness and a disinclination to exercise" [29].

"More recent cases of scurvy have also underlined the early emergence of fatigue. In 1952 it was noted in a case history that the patient had, during the year before admission, "become increasingly weak and easily fatigued" [30] and reports of experimentally induced scurvy in human volunteers similarly drew attention to the early emergence of fatigue [3]-33]. Crandon, who placed himself on a scorbutogenic dief, commented that a feeling of fatigue developed from the beginning of the 3rd month of deficiency, a full 6 to 8 weeks before the emergence of the traditional 'overt' signs of scurvy such as perifollicular hyperkeratotic papules, petechiae, poor wound healing and softening of the gums [34].

"It will be noted that the fatigue of scurvy, like the fall in muscle carnitine in hypovitaminotic C guinea-pigs [7], evidences itself before the traditional overt signs of scurvy and it has been suggested that it reflects an impairment of the endogenous biosynthesis of camitine in the absence of adequate ascorbic acid [23]. The pathological features customarily associated with scurvy are all, theoretically, amenable to reductionist treatment in terms of the hydroxylation of lysyl and prolyl residues in the formation of collagen. Fatigue bears no identihable relationship to collagen formation, and this is possibly the reason why this fêature of incipient scurvy has been generally ignored by students ofthe disease."


Iwai, Koji, Takanori Hasegawa, Yasuki Taguchi, Fumiki Morimatsu, Kenji Sato, Yasushi Nakamura, Akane Higashi, Yasuhiro Kido, Yukihiro Nakabo, and Kozo Ohtsuki. “Identification of Food-Derived Collagen Peptides in Human Blood after Oral Ingestion of Gelatin Hydrolysates.” Journal of Agricultural and Food Chemistry 53, no. 16 (August 2005): 6531–36.

"In the present study, we isolated and identified some food-derived collagen peptides in human serum and plasma as show in Table 2 . Among them, Pro-Hyp, which has been demonstrated to be present in urine ( 15 ), is a major constituent in any case. In the case of the oral ingestion of chicken type II gelatin hydrolysates, a significant amount of Pro-Hyp-Gly was detected in human plasma. This motif is also abundantly present in type I and II collagens. However, only a less amount of Pro-Hyp-Gly was observed in the blood from those who ingested type I gelatin hydrolysates. The chicken type II gelatin hydrolysate preparation contained a significant amount of mucopolysaccharide ( Table 1 ), which might affect digestion and absorption of collagen peptides. Another tripeptide, such as Gly-Pro-Hyp, could not be detected in all cases. Some dipeptides consisting of hydrophobic amino acids (Ile, Leu, and Phe) and Hyp are contained in human blood as minor constituents after loading of the gelatin hydrolysates. So far up to now, biological activities of them have not been described."


Liu, Chinfang, Kazuko Sugita, Ken-ichi Nihei, Koichi Yoneyama, and Hideyuki Tanaka. “Absorption of Hydroxyproline-Containing Peptides in Vascularly Perfused Rat Small Intestine in Situ.” Bioscience, Biotechnology, and Biochemistry 73, no. 8 (August 23, 2009): 1741–47.

"It is generally assumed that, during absorption, proteins derived from foodstuffs are hydrolyzed, generating small peptides and amino acids in the lumen. These small peptides are then hydrolyzed by intracellular peptidases, leading to the appearance of digestive products, mainly as free amino acids, in the portal vein. In contrast, there is some evidence that the intestinal transport of peptides or macromolecules may give, to a small but significant extent, antigens or biologically active substances."


Oesser, S., M. Adam, W. Babel, and J. Seifert. “Oral Administration of (14)C Labeled Gelatin Hydrolysate Leads to an Accumulation of Radioactivity in Cartilage of Mice (C57/BL).” The Journal of Nutrition 129, no. 10 (October 1999): 1891–95.

"Several investigations showed a positive influence of orally administered gelatin on degenerative diseases of the musculo-skeletal system. Both the therapeutic mechanism and the absorption dynamics, however, remain unclear. Therefore, this study investigated the time course of gelatin hydrolysate absorption and its subsequent distribution in various tissues in mice (C57/BL). Absorption of (14)C labeled gelatin hydrolysate was compared to control mice administered (14)C labeled proline following intragastric application. Plasma and tissue radioactivity was measured over 192 h. Additional "gut sac" experiments were conducted to quantify the MW distribution of the absorbed gelatin using SDS-electrophoresis and HPLC. Ninety-five percent of enterally applied gelatin hydrolysate was absorbed within the first 12 h. The distribution of the labeled gelatin in the various tissues was similar to that of labeled proline with the exception of cartilage, where a pronounced and long-lasting accumulation of gelatin hydrolysate was observed. In cartilage, measured radioactivity was more than twice as high following gelatin administration compared to the control group. The absorption of gelatin hydrolysate in its high molecular form, with peptides of 2.5-15kD, was detected following intestinal passage. These results demonstrate intestinal absorption and cartilage tissue accumulation of gelatin hydrolysate and suggest a potential mechanism for previously observed clinical benefits of orally administered gelatin."


Peacock, E. E. “Effect of Dietary Proline and Hydroxyproline on Tensile Strength of Healing Wounds.” Experimental Biology and Medicine 105, no. 2 (November 1, 1960): 380–83.

"In normal animals there is very little incorporation of dietary hydrosyproline in the general protein pool; nearly all of N15 labeled hydroxyproline can be recovered in the urine and stools (Stetten(9)) However, there is an extremely low turnover of the amino acids in a normal animal's collagen (Neuberger and Slack (8) ) , therefore Stetten's experiments do not necessarily mean that an animal which was actively at tempting to synthesize new collagen under the handicap of protein or scorbutic acid deficiency would not be able to by-pass the hydroxylation of proline and utilize free hydroxyproline for collagen synthesis.

"Green and Lowther (3) investigated the possibility of incorporating free Nl" labeled hydroxyproline into collagen which was being formed by an in vitro tissue slice from a carrageenin granuloma. Their results showed that practically all of the hydroxyproline was produced by hydroxylation of bound proline and that almost none of the free labeled hydroxyproline was incorporated in the saline extractable or new collagen fraction. They showed, however, that fibrolblasts' cell membranes were freely permeable to hydroxyproline, therefore we still wondered if free hydroxyproline could be utilized by fibroblasts in healing wounds."

"Protein depleted rats were given dietary supplements of .5% synthetic d-1 hydroxyproline and 1% synthetic d-1 proline. Guinea pigs on an ascorbic acid deficient diet were given a dietary supplement of 5% d-1 hydroxyproline. The animals were wounded by a standard technic and the tensile strength of their healing wounds was tested at 48-hour intervals between the 6th and 21st postoperative days. Neither hydroxyproline nor proline exerted a significant effect upon the rate of gain of tensile strength in the wounds of protein deficient rats or scorbutic guinea pigs."

"Depletion and ascorbic acid deficiency reveal that the results of Stetten and Green also apply to the wounded animal, and that impaired wound healing in pathological states cannot be overcome by administration of dietary hydroxyproline. "


Stetten, Marjorie R. “Some Aspects of the Metabolism of Hydroxyproline, Studied with the Aid of Isotopic Nitrogen.” Journal of Biological Chemistry 181, no. 1 (November 1, 1949): 31–37.

"Some of the isotope was found in the body proteins. The very low isotope concentration of the hydroxyproline isolated from the body proteins indicated that less than 0.1 percent of the hydroxyproline in these rats had been derived from the dietary hydroxyproline in 3 days. A higher concentration of N15 was found in the glutamic acid, aspartic acid, and arginine of the proteins and probably came indirectly from degradation products of the hydroxyproline.

"The body proline contained only traces of N16, indicating that little if any of the proline of the body is derived from dietary hydroxyproline.

"The hydroxyproline of the proteins is not derived to any appreciable extent from dietary hydroxyproline but rather from the oxidation of proline which is already bound, presumably in peptide linkage."


Strijbis, Karin, Frédéric M. Vaz, and Ben Distel. “Enzymology of the Carnitine Biosynthesis Pathway.” IUBMB Life 62, no. 5 (2010): 357–62.

"The first enzyme of the carnitine biosynthesis pathway is TML dioxygenase (TMLD), which hydroxylates TML to yield 3‐hydroxy‐TML (HTML)."


"In addition to these cofactors, TMLD also requires the presence of ascorbate (vitamin C) for enzymatic activity, presumably to maintain the iron in the ferrous state."


Watanabe-Kamiyama, Mari, Muneshige Shimizu, Shin Kamiyama, Yasuki Taguchi, Hideyuki Sone, Fumiki Morimatsu, Hitoshi Shirakawa, Yuji Furukawa, and Michio Komai. “Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats.” Journal of Agricultural and Food Chemistry 58, no. 2 (January 27, 2010): 835–41.

"Collagen, a major extracellular matrix macromolecule, is widely used for biomedical purposes. We investigated the absorption mechanism of low molecular weight collagen hydrolysate (LMW-CH) and its effects on osteoporosis in rats. When administered to Wistar rats with either [14C]proline (Pro group) or glycyl-[14C]prolyl-hydroxyproline (CTp group), LMW-CH rapidly increased plasma radioactivity. LMW-CH was absorbed into the blood of Wistar rats in the peptide form. Glycyl-prolyl-hydroxyproline tripeptide remained in the plasma and accumulated in the kidney. In both groups, radioactivity was retained at a high level in the skin until 14 days after administration."

Thursday, December 13, 2018

Misaligned Virtue

On eating your vegetables, non-compliers, and food reward.

I have always loved food. I was encouraged to love food, and vegetables especially. It was a point of pride to eat them, and more than that, to like them. Why? Because they are presumed good for you, and while doing something good for you is virtuous, liking something good for you is even more virtuous! It is one thing to be willing to suffer for an end, but to want something intrinsically that has a good result — that means you are a naturally good person. That means your instincts are well formed. This is the essence of feeling right for the world, competent, belonging.

Food is one of the first things we are aware of. It's a daily interaction. To parents who want their children to thrive, which, I think, is the usual way of things, seeing a child "naturally" gravitate to actions that will cause them to thrive puts their mind at ease. If you want to please your parents, showing signs that you are naturaly predisposed to take actions that make you healthy works. This is more so the more health-conscious your parents.

And yet this particular example is odd. Consider the effort we go to to "encourage" children to eat vegetables. There are multiple research intiatives and campaigns going on to try to "get" children to eat vegetables [1]. This is because we believe vegetables are health-giving, but at the same time there is a widespread resistance by children against eating them. How could such a trait have possibly evolved?

One reason many children struggle against this adult-imposed mandate to eat vegetables is that it competes in many cases with something more rewarding. It is generally considered healthy for a child to run and play. Do we have to tell children to chase each other, to skip and jump and dance? No. In fact children are notoriously active. It is a challenge to keep them still! However, if they have access to a captivating book, movie, or video game, then they may be less inclined to go outside. Likewise, one reason children may be eating lower quantities of vegetables could be that the alternatives available are more appealing. If those alternatives are sugar or even starch (presugar) or meat, i.e. high quality protein or energy sources, then it stands to reason that children would choose those alternatives instead.

We are wired to seek energy and nutrition in the form of protein. Sugar, starch, and fat are all dense sources of energy which we need. Meat is an excellent source of amino acids which we also need. We are driven to eat these. Vegetables, on the other hand, are relatively nutrient poor. Yes, you read that right. I know that we are lambasted with propaganda telling us how important colourful vegetables are for nutrients, but this is misguided. For one thing, most plant sourced nutrients are less bioavailable than animal sourced alternatives. Individual types of plants are always nutritionally incomplete, and many essential nutrients simply aren't available in the necessary amounts in any normal consumption of plant foods. For another, non-starchy vegetables are poor sources of energy. A vegetable is constructed of carbohydrates. These carbohydrates are either merely "structural", which means made of fibre, and hence indigestible, or they are digestible, meaning they are sugars or starches. If a plant (fruit or vegetable) is high in sugar or starch, it is not usually a challenge to get children to eat them. However, the kinds of vegetables we've been taught to eat for vitamins aren't typically energy dense.

Besides children, there is another relevant class of people. We tend to think of them as people who have never grown up. They're stereotypically men, but of course not always. These people eat what they feel like even when it's not thought to be good for them. They often engage in other activities known to be unhealthy in the long term, such as drinking alcohol to excess, or partaking in other drugs, engaging in risky behaviours such as promiscuous sex or thrill seeking, smoking, and just generally behaving in ways that aren't recommended by health advocates. Why do they do this? Because it feels good! It is gratifying.

We have a reverence for the ability to delay gratification. It stands to reason. The ability to defer or even reject an activity that gives pleasure now in order to get more pleasure later pays off, at least when the calculation is correct. We presume that this ability to delay gratification develops over time as part of "growing up", but we recognise that some individuals never seem to attain much of that ability.

Where this reasoning goes wrong however, is when we erroneously assume we know the long term consequences of a decision. We can be reasonably sure, for example, that not smoking will improve health when accumulated over decades, but not all presumed long-term behaviours are so certain in their effects. The longer the outcome takes to have an effect, the harder it is to learn from one's own experience. In the case of some health behaviours, it takes trust and discipline.

The personality type that tends to gratify now tells us about our brain's pleasure and reward system. Only something that gives us pleasure now would cause us to act in a way that we believe would be detrimental later. These non-compliers don't tend to eat their vegetables. Why? Because vegetables don't give us much pleasure! In fact, they often taste downright bitter and unpleasant unless drenched in a sugar sauce or melted fat. Unlike coffee or beer, this bitterness is not compensated for by desired psychological effects. There is no measurable upside. You can learn to like it, just as you can learn to like coffee or beer, but there is no intrinisic reward. The available rewards are social, or a self perception of virtue. If children don't like vegetables, it is usually because the vegetable is bland or bitter, and it provides no physiological reward because your body is getting little out of it. This fact can be used to form hypotheses about behaviours we evolved to do through the pleasure / reward mechanism.

It is true that many vegetable have vitamins in them, but with very few exceptions (e.g. salt), we do not seem to be driven by micronutrient needs much, in the way we are for protein and energy [2]. In contrast to foods high in energy, which activate brain reward systems, or high in protein, which satisfy hunger, an item like broccoli doesn't seem to even register as food, even when hungry [3]. While you may have heard stories about cravings for chocolate indicating magnesium deficiency, the one study that I know of that tested that refuted it [4]. Explaining chocolate cravings with a need for magnesium seems like the worst kind of self-delusional rationalisation. It's ok to just give yourself permission to eat chocolate, if that's what you want.

That we aren't driven to seek micronutrients is important. It suggests that the foods we evolved on that fulfilled energy and protein needs also provided all necessary nutrients at the same time. Otherwise we simply would not have survived. What foods present during the majority of our evolution that most of us want to eat from a young age without prodding simultaneously contained protein, energy, and necessary micronutrients? Why are we advocating diets so notoriously difficult to balance and so far from our natural inclinations that we actually have to campaign people to get them to eat it?



As reported in

Stephen J. Simpson, David G. Le Couteur, David Raubenheimer,
Putting the Balance Back in Diet,
Cell, Volume 161, Issue 1, 2015, Pages 18-23, ISSN 0092-8674,

"Similar types of experimental design have been used to show that organisms from acellular slime molds all the way to primates possess nutrient-specific appetite systems for macronutrients, such as proteins, carbohydrates, and fats, as well as for at least two micronutrients, sodium and calcium (Simpson and Raubenheimer, 2012). However, most micronutrients do not seem to be specifically regulated; rather, their intakes are maintained within healthy limits by a combination of correlation in foods with other regulated nutrients and non-specific mechanisms such as learned aversion to foods associated with development of a micronutrient deficiency, coupled with heightened attraction to novel foods (Simpson and Raubenheimer, 2012)."


As presented by Stephan Guyenet at the Ancestral Health Symposium 2017. Not yet elsewhere published to my knowledge. See experimental evidence at 13m00 (single subject).


Michener, Willa, and Paul Rozin. “Pharmacological versus Sensory Factors in the Satiation of Chocolate Craving.” Physiology & Behavior 56, no. 3 (September 1994): 419–22.

"Chocolate craving has been attributed to rewarding effects of phenylethylamine (13) or magnesium (1,2,29). It is clear that chocolate can have neurologic effects because it will induce migraine in susceptible individuals, as will phenylethylamine (23). However, claims for a physiological basis for the causation or satiation of chocolate craving have been criticized on the ground that they are not adequately supported by evidence (31)."


"This is the first experimental study directed at differentiating between physiological or sensory accounts of the satiation of nondrug cravings, using chocolate craving, the most common craving in North America. At the onset of craving, chocolate cravers consumed a chocolate bar, the caloric equivalent in "white chocolate" (containing none of the pharmacological components of chocolate), the pharmacological equivalent in cocoa capsules, placebo capsules, nothing, or white chocolate plus cocoa capsules. Chocolate reduced self-rated craving. The cocoa capsules, placebo, and no treatment conditions had virtually no effect. White chocolate produced partial abatement, unchanged by the addition of all the pharmacological factors in cocoa. This result indicates no role for pharmacological effects in the satisfaction of chocolate craving. It also suggests a role for aroma independent of sweetness, texture, and calories."

Friday, October 5, 2018

Thirteen days of near-carnivory fails to impress

Alan Levinovitz is an author and scholar of religious studies who has written about diet and science. He recently wrote an article criticising the carnivore diet: The Carnivore Diet Is the Latest Fad to Ignore That Food Does More Than Just Feed Us. It is this article that got me talking with Alan on Twitter about his suggestion in the article that the anecdotal effects are psychological. I was delighted that he took me up on a long form debate about this, and have posted that separately. I admire and applaud Alan for his cordial manner on social media, which is a precious rarity.

Here I want to object to a couple of points in his article that have to do with keto-adaptation, not carnivory in particular, and not the whole muddy question of potential disease modification. I absolutely agree with his cautions that we need more study, that proposed mechanisms are routinely falsified, and that the baseline Western diet combined with a wretched medical system incentivises junk science cures. However, I don't see how his 13-day trial sheds light on the biology, and I think he should have done just a little more research.

His article doesn't stand alone. It is consistent with prevalent and justified attitudes that nutritional science is mostly bunk. Unfortunately, this often results in a base level of hostility and refusal to even consider a scientific perspective on a topic viewed with suspicion. This is exemplified by a Twitter interaction I had in which someone tweeted Alan Levinovitz's article, saying that she was worried about the effects of ketosis on the brain. I was eager to share some of my research, because if there is anything the science shows, it's that ketosis is healthy for the brain! Fetuses and breastfed babies are in mild ketosis during brain growth, neurological diseases and cognitive decline are sometimes reversed by ketosis. It is our brains that probably account for the fact that we alone as species can stay in ketosis without caloric or protein restriction. When I invited her to read my presentation on this from earlier this year, she acted as if I were a salesperson approaching her on the street. "Not interested. Have a nice day."

It turns out that ketogenic diets are drastically different from other diets, because they directly affect metabolism. As I've explained in one of my first posts on the topic, ketogenic diets are recognized as being at least as powerful as drugs in at least two major clinical condition, and there is reason to believe they are useful against others. In the noise of weak dietary therapies, it's harder to see a signal. This difference, though, doesn't happen all at once. Keto-adaptation accounts for the two phenomena Alan described that I want to address.

Since we're already on a tangent looking at that tweet, let's just talk about colon cancer and fibre for a moment. I won't delve into it deeply here. You can read my article about the misapplication of science about butyrate from plant fibre to colon health, if you're interested in that angle. Note also, though, that associations between fibre intake and colorectal cancers, which is confounded by the healthy user profile among other things, show minimally reduced relative risk—far above 0.33 [Mur2012] which is considered by some a minimal threshold for even suspecting causation (see e.g. [War2012]). It is understandable to "worry" about colon cancer, given the hype about it, but you would think that someone in the medical profession would want to dig a little deeper and not just parrot headlines.

Bullshit pounds lost

Alan explains his experience of losing 7 pounds while carnivorous, but gaining back 5 after resuming his high carb diet, as follows: "Those were the bullshit pounds that low-carb diets use to hook their marks, like a con man giving away the first jackpot in a street hustle... If you stop eating low-carb, or “zero-carb,” the early loss—up to 12 pounds!—returns instantly because it’s not fat you’ve lost, just water released as your body burns through its glycogen stores."

Indeed, as I described in the second link above, much of the first few pounds lost when you stop stuffing your liver with carbs in the form of glycogen are from water required to store it. You lose carb weight before your fat loss will accelerate on a ketogenic diet. Your body disposes of excess carbs before excess fat just as it does in the bloodstream when your blood sugar is sufficiently high. However, that hardly impacts the fact that you lose excess fat on a ketogenic diet. People like me, who have lost over 60 pounds, or others who have lost even more, did not lose just water, and it would be ludicrous to suggest that. Total weight lost will only be mostly water if you stick to the diet for a bullshit timeframe, like 13 days. This isn't just a quick-fix, 13-day, fit-into-your-wedding-gown hack.

In any case, you could make the same argument about fat! Fat is stored with about equal parts water. When you lose a pound of fat, that's actually half water [Mel1942], twice as much as what carbs are stored with. [Edit 2019-05-14 This is INCORRECT. I was conflating water stored with fat with water that results from the chemical breakdown of fat. My bad!] What a scam, right? Granted, Alan is right that it's only carbs and the necessary water that pack back on so fast. Apparently he lost 2 fat pounds in 2 weeks not counting the glycogen-water, presumably eating as much as he liked, and he doesn't appear to be particularly overweight, so one wouldn't expect more true loss than that, especially in such a short time frame.

I think this criticism is only fair if you've been misinformed about the diet in the first place. Understanding the basic physiology of how the diet works would seem to me to be the onus of the dieter. Writers advocating the diet tend to clarify this. For example, in the most recent Atkins Diet book from Westman, Phinney, and Volek: "As with any weight loss program, some of the initial weight loss you'll experience is water weight... So if you drop 10-15 pounds in the first few weeks, you'll be saying good-bye to some unnecessary water weight along with the initial fat pounds. But once that excess water is gone, you'll be losing primarily body fat." From yours truly: "Another noticeable effect in the first days is water loss. One of the inefficiencies of glycogen storage is that it needs to be stored with water. It takes about 3 or 4 grams of water to store a gram of glycogen [ref] . This means that as you deplete your glycogen stores you could lose up to 2 kg of water! Not only that, but high circulating insulin levels cause water retention by inhibiting sodium excretion (see e.g. [ref]). The keto diet lowers insulin levels and increases insulin sensitivity, allowing excess fluid to be released. These combined effects are the origin of the claim that the weight lost on keto diets is due to water loss. In the very beginning, this is true, but subsequently, of course, it is not." Where is the hustling here?

Athletic performance

Alan suffered from keto-adaptation, and though he appeared to know about it, citing Phinney, he still complained about his athletic performance, which is known to take 4-6 weeks to resolve in professional athletes. He didn't plan to do the diet for that length of time, so it seems disingenuous to bring this up as an issue.

Give it more time and have a good reason

As I've outlined in my post about how to try a carnivorous diet (Eat meat. Not too little. Mostly Fat), It takes about 30 days to see appreciable differences from this diet (and often more), compared to a merely ketogenic one. Those differences are really only possible if you've tried a ketogenic diet and didn't get everything you hoped for, and if those hopes were within certain categories none of which seem to apply to Alan. I don't advocate eating a carnivorous diet for no reason at all, and even the "unparalleled fuck you" Alan describes is only fun for a little while compared to the fun you could be having by eating whatever you please. It speaks to the power of the intervention that any of us are doing this more than 13 days at all.

End-to-end citations


Mellanby, Kenneth. “Metabolic Water and Desiccation.” Nature 150, no. 3792 (July 1942): 21.

"The utilization by the body of ingested food substances and of tissue reserves yields among other things quantities of metabolic water. As the complete combustion of 100 gm. of fat produces about 110 gm. of metabolic water, whereas 100 gm. of carbohydrate yields only 55 gm. of water, fat reserves and fatty foods are believed to be particularly valuable as a protection against desiccation. This contention would appear to be supported by the fact that many animals which exist in deserts have large reserves of fat."


Murphy, Neil, Teresa Norat, Pietro Ferrari, Mazda Jenab, Bas Bueno-de-Mesquita, Guri Skeie, Christina C. Dahm, et al. “Dietary Fibre Intake and Risks of Cancers of the Colon and Rectum in the European Prospective Investigation into Cancer and Nutrition (EPIC).” PLoS ONE 7, no. 6 (June 22, 2012).

"After a mean follow-up of 11.0 years, 4,517 incident cases of colorectal cancer were documented. Total, cereal, fruit, and vegetable fibre intakes were estimated from dietary questionnaires at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models stratified by age, sex, and centre, and adjusted for total energy intake, body mass index, physical activity, smoking, education, menopausal status, hormone replacement therapy, oral contraceptive use, and intakes of alcohol, folate, red and processed meats, and calcium. After multivariable adjustments, total dietary fibre was inversely associated with colorectal cancer (HR per 10 g/day increase in fibre 0.87, 95% CI: 0.79–0.96). Similar linear associations were observed for colon and rectal cancers. The association between total dietary fibre and risk of colorectal cancer risk did not differ by age, sex, or anthropometric, lifestyle, and dietary variables. Fibre from cereals and fibre from fruit and vegetables were similarly associated with colon cancer; but for rectal cancer, the inverse association was only evident for fibre from cereals."


Warren, John B, Simon Day, and Peter Feldschreiber. “Symmetrical Analysis of Risk–Benefit.” British Journal of Clinical Pharmacology 74, no. 5 (November 2012): 757–61.

[See graphic]

An Open Dialogue with Alan Levinovitz on Miracle Cures

Introduction for outside readers

Twitter can be a wonderful way to learn from others, but as a medium for in-depth, multifaceted discussion it is painfully difficult. Recently I attempted to start a sincere dicussion with Alan Levinovitz, an author and journalist with expertise in religious studies, who has also written extensively about diet and science.

I have not yet read Alan's book, The Gluten Lie, and so I'm gleaning the following from reviews. I trust he will correct my interpretation of his position as needed, but roughly: In the book he argues that eating gluten is rarely a legitimate problem, but the gluten-free movement is instead reflective of a widespread tendency to project notions of good and evil onto food, thus making dietary prescriptions operate more like religious rituals than like scientific therapies. Adding to that the notion that faith is extremely powerful — so powerful that it can emulate "real" treatments — brings him to the conclusion that many people are unnecessarily restricting their diets, because the cure they think they have found is a trick of psychology. Given the potential downsides to food restriction, from nutrient deprivation to social exclusion and missed enjoyment, he aims to dispel myths of this type.

I have great sympathy for many of these ideas. The authors he criticises in his book, for example, William Davis and David Perlmutter, are authors whose reasoning I likewise have found fault with, even though I agree with some of their conclusions despite that reasoning. I also perceive much of the plant-based rhetoric, not just from vegans, but even within the Paleo community, to be largely driven by notions of purity, rather than scientifically based. This has been beautifully articulated by Nick Mailer in his lecture on Paleo Puritanism from AHS16. If you haven't watched it, you're in for a treat. Moreover, though I rarely talk about it here, I've been fascinated with religion, philosophy, psychology, and cognitive neuroscience for decades, much moreso than any of this nutrition stuff. While I am an atheist, I harbour extreme skepticism of certain assumptions often made about the nature of causality and knowledge.

I became aware of Alan's work, because he recently wrote an article criticising the carnivore diet: The Carnivore Diet Is the Latest Fad to Ignore That Food Does More Than Just Feed Us. It is this article that got me talking with Alan on Twitter. After a few rounds of (remarkably respectful) dialogue, he accepted my invitation to an epistolary discussion in particular of the following idea:

(When) does contesting a solution to a chronic disease entail contesting the presence of the disease itself?

So the purpose of this article is to summarise the brief points we already touched on and to invite Alan to discuss these ideas more fully so that we can come to a mutual understanding of where we differ, or a realisation that we don't. I appreciate the opportunity! It is my intention to make the best good faith argument I can, because I sincerely want to understand this phenomenon. That means I'm going to give the most cogent representation of my understanding of the arguments I'm not yet persuaded by, and seek to avoid even subtly diminishing them in order to make them less persuasive.

For reference, here is a link to the beginning of our discussion on Twitter. I admit to a little testiness in that initial contact, but we got over it. In true Twitter form, the discussion immediately subdivided into multiple threads involving different subsets of commenters, and high potential for sidetracking and confusion.

I also have two objections to the article that don't pertain to this focal question, They both have to do with the keto-adaptation phase of ketogeic diets, not carnivory in particular. I have put them in a separate article so as not to disrupt the dialogue here.

(When) does contesting a solution to a chronic disease entail contesting the presence of the disease itself?

Consider a chronic debilitating disease, such as rheumatoid arthritis. RA is problematic because it has the following properties:

  • Incurable according to conventional medicine, i.e. there is no scientifically accepted cure

    This is a problem because it can be taken as an indication that the probability there is any cure at all is low. Our confidence will be modified by our confidence in medical science generally, and our conception of the possible causes of the disease.

    On the other hand, insofar as the disease is considered incurable, it should elevate the importance of any new findings of people curing it.

  • Can go into remission "spontaneously" (but see below)

    This is a problem because it makes it hard to tell when a therapy just happened to coincide with the remission that was going to occur anyway.

  • Involves difficult to measure, subjective symptoms of pain

    Without good measurement, it's difficult to evaluate the extent of an effect. Moreover, pain is known to be more subject to perceptual manipulation than visible symptoms, and is considered to be more responsive to placebo effect.

  • There are various claims of very different "alternative" therapies curing it, including veganism, carnivory, and homeopathy

    This calls into question plausible mechanisms, and in the case of the mechanism-implausible homeopathy, additionally adds evidence to the susceptibility of the disease in question to modification by faith alone.

    As Alan points out, in this case, the possible consistent interpretations of this situation are:

    • At least some people swearing by the proposals are either lying or mistaken
    • RA has multiple etiologies amenable to different solutions depending on which
    • A common factor or effect in plausible proposals is responsible for the remission, making each vastly unnecessarily restrictive

I want to focus on the possibility that people are mistaken, because I think most of the meat of the problem is here. The way to contest the solution but not the disease is to claim that the solution is spurious. There are two main ways one could make such a mistake. The mistake could be a matter of real remission that is only coincidentally related to the therapy, or the mistake could be due to a psychosomatic effect. Let's consider each in isolation first, with the assumption that it is the only one in operation.

Spontaneous remission

Alan pointed out in his article that RA can go into spontaneous remission. However, my literature search indicates that this is constrained with respect to the course of the disease, and the duration, as well as the initiating context. In the paper he cites [Sha2010], the authors describe how a small minority of RA patients go into "drug-free" remissions. By this phrase, they do not mean remission without drugs! Drug-free remission here means that after successful drug treatment, some patients stay in remission after withdrawal of the drug. In almost half the disease returns. Spontaneous remission without a drug is quite rare, happens only in very early stages of the disease, i.e. within a few months of diagnosis, and lasts only for a few months [Val2008]. It is considered imperative to do whatever it takes to get remission by drug treatment early to prevent ongoing damage, and exactly because later stage disease doesn't typically have such periods of relief.

This gives us a way to quantify the probability that the alternative treatment in question was responsible for the remission, by looking at the mean and variance of the time since diagnosis, and duration of remission. I do not have actual statistics on this for RA, but consider this as a thought experiment. If spontaneous remission rates start, say, at 10% in the first month, fall to 1% after 4 years, and after 8 it's unheard of, then someone going into remission at 4 years after diagnosis is already extraordinarily unlikely, and at 15 it's astronomically so. Similarly, if that kind of remission lasts on average 6 months, with a standard deviation of 4, then a remission of 2 years due to any intervention should be considered highly likely to have something to do with the intervention. No drug study would ever be doubted at that level. Granted, a drug study will have multiple people, and will track everyone who tries it, not just those who succeed. Nonetheless, to ignore a statistical anomaly of that magnitude smacks of strong, and possibly irrational bias against the intervention.

I further offer the idea that multiple trials off and on the intervention can narrow down the uncertainty. If the patient can replicate the effect over and over by stopping and starting the intervention, then it uncouples the potential for coincidence. All of this assumes, of course, that the mechanism of action of the therapy is not placebo or faith. So let's move on to that possibility.

What are the limits of placebo and faith healing?


Where I think Alan and I might differ the most is in our belief about how much effect can possibly be attributed to belief. (Don't think about that last sentence too hard!) One type of effect that is considered to reflect this kind of mind power is the placebo in a controlled trial. However, placebo effects are so limited that several people have questioned their extent or even existence, noting that the level of variance that can be achieved in practice and that is normally attributed to placebo, can be mostly or completely explained by regression to the mean [McD1983], [Hró2001], [Sen2009], [Col2015].

Regression to the mean describes the tendency of measurements that have some variability, when taken multiple times, to stay close to the average. In particular, if you get a measurement that is extreme (far from average), there is a high probability that a second measurement later will be less extreme. For example, suppose that I have a particularly bad flare up of RA symptoms this month. It's highly likely that next month my symptoms will be less severe even if I do nothing. This scenario is of clinical relevance because patients in trials are likely to have been enrolled because they are suffering more than others. See [Yud1996] for a discussion of the problem and how to account for it.

In meta-analysis, placebo effects have mostly not been found clinically significant [Hró2011], . An important potential exception that is relevant here is pain, which along with nausea has varied enough to reach significance, though arguably accountable through biased reporting [Hró2011]. I'd also conjecture that pain, like other sensations, is not perceived by people in a linear fashion (see e.g. Weber's and Fechner's laws for perception of light and sound intensity). This may make it difficult to scale based on people's reports when asked to rate pain.

What the statisticians who deny that the placebo effect is psychosomatic are saying is that you don't need a psychological explanation to account for the fact that people in the control group also get better! The statistical properties of the situation already anticipate this effect. Critically, though, this kind of statistical effect can only happen within mathematically definable limitations. If the average measurement is 100, and the standard deviation is 5, then regression to the mean wouldn't account for a drop to 50.


Besides the placebo effect, the idea came up in our Twitter discussion that "stress" can cause psychosomatic symptoms. My issue with this idea is simply this: emotions are physiological. Feeling stress can be a symptom of physiological disturbance. It may appear quickly, relative to other bodily symptoms, but just because it comes first doesn't mean that it caused the bodily symptoms. I see no way to systematically distinguish between a case where a food caused, for example (and I don't mean to suggest this pathway is definitive), an immune response which results in inflammation of the brain which influences affect in the form of increased feelings of stress, followed by a rash, pain, or gastrointestinal distress. To claim that the bodily symptom was caused by stress is making an unwarranted assumption.

In my own personal experience of psychiatric disease (I have latent type 2 bipolar disorder that went into remission following a dietary change), I have suffered life situations far more stressful since my dietary changes than during the worst years of the disease: divorce, psychological abuse in a subsequent long-term relationship, two moves, a new job followed by leaving the job to work for myself (two career changes), oldest child left home, drastic changes in financial position, and taking on a mortgage for the first time. These are considered to be among the most stressful events a person can experience. Yet, my mental and physical health have continued to be superior to the prior 5 years when my bipolar disorder was at its peak and my life was stable. I think the diet has made me more resilient to stress and more physically healthy. Someone else might argue that it made me more resilient to stress and consequently more healthy. What it didn't do was simply reflect the environmental stress in my life.


Is it possible for a person to cure a disease simply by believing in it strongly enough? My first experience with this idea was in my first year at university. I was studying mathematics, and there was an extremely mathematically intelligent, stereotypically nerdy young woman in my classes. We sometimes studied together, and later, while my life was falling apart due to my first depressive episodes, she was going on to become a talented cryptographer. One of the things she told me was that she found Jesus as a child and that He cured her epilepsy. I did and do find this astounding, and I've never forgotten it. At the time, I absolutely believed that her experience was real, and that it was a testament to the power of the mind.

What makes this not scientifically palatable? Moreover, why isn't everyone falling over themselves to get in His good graces? I think the only reason this kind of effect is dismissed is because of numbers. I'm not really familiar with the literature, but as far as I understand, this kind of result simply hasn't been reproducible at scale. Religious believers, as far as I'm aware, are not better off generally than non-believers in their rate of suffering disease. The only studies I've seen in which prayer made any difference were, again, interestingly, in pain, but they were weak. For example, Matthews found that when patients with RA (no less) were prayed for, there was a (barely) statistically significant effect on 2 of 10 measures of symptoms after 6 months [Mat2000]. This effect was not replicated when patients were prayed for at a distance without their knowledge. Similarly, there was a study showing some relief of migraine pain from prayer [Taj2017]. The effect was significant, but modest, in that the participants were still in a lot of pain at the end. This was not a cure, by any means. Moreover, the baseline differences between groups increased the likelihood in regression to mean effects in the treatment group, compared to the control.

When people pray for their own health, the main effect seems to be on one's ability to cope with the problems, not the issues themselves. Hollywell et al. did a meta analysis finding that there was a correlation between prayer and better mood, but also a correlation between chronic disease and prayer [Hol2008]. While there is an obvious explanation for the increased prayer in that situation, it also suggests it isn't helping much. In a similar study, Anderson also found that prayer appears to help with coping with chronic disease, but had no effect on outcomes [And2016].

This lack of replicability doesn't mean that faith healing doesn't happen in individuals, but it does raise questions about what is so difficult to replicate that only a select few can manage to do it. I would think that if you believed in this kind of power you would be searching for any way to replicate it possible.

The point of a controlled trial, and particularly blinding, is to distinguish between the effects that come from a treatment and the effects that come from expectation of being healed. If we are going to chalk up the effects of the carnivore diet to a strong expectation, then we have to explain at least the following things.

First, back when the population of people trying this diet was much smaller than it is now, no one had heard of it curing psychiatric or autoimmune disorders. People came to "Zero Carb" for weight loss. Then people started sharing stories about other health issues surprisingly resolving. When my mood disorder appeared to vanish, no one was more surprised than I was. This effect could not have happened due to my faith in the ability of the diet to have that effect. It wasn't on my radar of possibilities. I didn't even necessarily think it was a particularly healthy diet! I thought of it as a temporary weight loss manoeuver. Here I think the only way that we can argue that the current collection of autoimmune and psychiatric effects of a carnivore diet are due to faith is to do some kind of bootstrapping. We must argue that these initial first examples were mistakes of the chance type that started to influence newcomers, gathering their own momentum, and shaping subsequent expectations in a feedback loop.

Second, the people who now come to try a carnivore diet are for the most part people for whom traditional medical solutions didn't work. How do we explain the fact that these people couldn't muster the required faith in a traditional medicine, but could muster it with diet? To use my own story as an example again, I was practically overjoyed when my depressive disorder was rediagnosed as bipolar disorder, because I was sure that now, finally, I would have access to the right medicine to help me. It didn't help me; not even a little bit. My bipolar disorder was progressing.

So to return to the orginal subject: I think Alan is saying that he can question a solution to a disease without questioning the presence of the disease, by saying that either the disease wasn't cured by the treatment, it just happened to remit at the same time, or it was cured by faith, which has nothing to do with the purported biological mechanisms of the therapy. Moreover, the specifics of the therapy are arbitrary, and need only meet certain requirements that make us able enact the faith healing mechanism. I would like to learn from Alan what he thinks these requirements are.

Plausible mechanisms and prior probabilities

It's not enough for the supposed mechanisms to be wrong for a therapy to be discounted. Observations hold whether we understand them or not. This is the scientific process: recognise patterns in observations and figure out what accounts for them. If you have to overturn a prior held belief to explain the facts then so be it. If you later find out that your belief in why a therapy works isn't scientifically tenable, it doesn't negate the observations.

However, I agree with Alan that if there are no plausible mechanisms for a therapy, then it is implausible. For example, I cannot fathom any mechanism by which homeopathy would work. If it were the case that many people were testifying that homeopathy reduced their RA symptoms to nothing, rather than a regression to the mean result of small reductions in pain for short periods, then I would have to concede that either there is something that homeopathy is doing that we physically don't yet understand, or that homeopathy dials in to the requirements of faith healing in a way that even prayer cannot. However, I don't think we're in that situation as far as homeopathy goes.

On the other hand, there are plausible mechanisms for a carnivore diet to heal RA, related to intestinal permeability. Some plant compounds are known to increase intestinal permeability (See e.g. [Mil2011], [Shi2013]). At the same time an important function of the intestinal barrier is to prevent the absorption of toxic plant secondary metabolites [Fin2010]. Autoimmune conditions are associated with intestinal barrier dysfunction [Smi1985], [Jul2016] which some argue is causal [Arr2006], though others attribute this to the treatment of NSAIDs (e.g. [Bja1984]). Celiac disease, also connected to intestinal permeability, is associated with RA [Vol2006], [Ler2015], [War2015]. So intestinal permeability may on the one hand be worsened by the intake of certain plants, and simultaneously such intake may worsen the autoimmune condition itself because of toxic exposure in a way that it couldn't in someone with an intact barrier. Not all plant compounds are implicated equally, and the criticism that carnivory may often overshoot what is necessary in an individual case is a valid one. Nonetheless, I think this knowledge should give us a higher prior probability when considering the possibility that this is a "real" solution than we would give homeopathy.

My perception is that the vehement criticism against the carnivore diet, not necessarily by Alan, but in general, is that most people have a strong prior belief that plant foods are not only harmless, but in fact beneficial. This position does not stand up to scientific scrutiny. There has never been benefit demonstrated in a study that was not either epidemiological, or based on extrapolation from drug-like effects in concentrated isolates. In neither case was there a comparison between humans eating only animal based foods, and those eating animal based foods with the addition of plants.

Plants are toxic to their predators as a biological strategy. It is pure fantasy to imagine that we developed in happy symbiosis. To the contrary, it is an arms race. Our resistance to such toxins is well honed, but limited, and it is reasonable to expect that even the plants of lowest toxicy which we selectively bred for our own use could result in harm if our resistance were lowered.

What I have been seeing for nearly a decade since I started on this diet is a dismissal of carnivory based on it sounding implausible to people because of their prior convictions about plants. That is, the objections don't come because they've looked at the difference between a diet with and without plants, and conclude that there is no discernible metabolic or biological effect of the difference, in the way that there is no discernible effect between a homeopathic remedy and a vial of water. To the contrary, all kinds of things must be happening differently. Rather, most people assume that there are differences, but that these differences have to be detrimental, and couldn't possibly be therapeutic. This is a double standard.

What's the difference?

It seems to me that when you characterise what someone offers as the explanation for their recovery from a chronic disease as a mistake, you are either claiming that they are a careless or unscientific thinker (because they do not understand the statistics around recovery from their disease), or that they are fooling themselves in a profound way. I concede that this is not the same as questioning the existence of the disease, but it does entail a claim that the disease was in their own power all along. I find it hard to distinguish the claim that I have the power to stop my chronic disease by evoking the right state of mind, and that I am creating my disease by not thereby stopping it. In other words, the disease is a product of my lack of belief. It's "in my head".


I hope I have generated something of interest for Alan to respond to. I could never have done this on Twitter! I am looking forward to hearing from him.


End-to-end citations


Anderson, James W., and Paige A. Nunnelley. “Private Prayer Associations with Depression, Anxiety and Other Health Conditions: An Analytical Review of Clinical Studies.” Postgraduate Medicine 128, no. 7 (October 2, 2016): 635–41.

"This analytical review evaluated research studies examining the association between private prayer and health conditions. Private prayer was defined as praying for one’s own health. Forty-one articles reported relationships between prayer and health. Studies were assigned prayer frequency scores from 1 to 8 depending on the specificity and frequency of private prayer. Prayer frequency scores ranged from 8 (high specificity of prayer and frequency) to 1 (low specificity of prayer or unstated frequency). Twenty-one studies with prayer scores from 5 to 8 were evaluated in detail. Frequent private prayer was associated with a significantly lower prevalence of depression (P <0.01);higherlevelsof optimism or coping (P < 0.01); and higher levels of mental health (P < 0.01). No significant associations were reported between private prayer and physical heal th or blood pressure. Prospective controlled clinical trials are required to more critically asses the associations between private prayer and health conditions."


Arrieta, M C. “Alterations in Intestinal Permeability.” Gut 55, no. 10 (October 1, 2006): 1512–20.

"For decades a variety of pathological states have been associated with abnormal permeability. Many of these are a consequence of intestinal epithelial damage that is associated with disease but not involved in a causal manner in the genesis of disease. However, in several autoimmune conditions it appears that increased permeability is a constant and early feature of the disease process. Furthermore, it is becoming increasingly apparent that in some conditions increased permeability is critical to the development of disease as if it is abrogated the disease does not develop. This is particularly true in type 1 diabetes. In other diseases such as Crohn’s disease or coeliac disease, a similar pattern of findings are apparent but the experiment to try and prevent disease by preventing the increase in permeability has not been performed."


Bjarnason, Ingvar, Alex So, A.Jonathan Levi, TimothyJ. Peters, Peter Williams, GiuseppeD. Zanelli, J.Michael Gumpel, and Barbara Ansell. “INTESTINAL PERMEABILITY AND INFLAMMATION IN RHEUMATOID ARTHRITIS: EFFECTS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS.” The Lancet 324, no. 8413 (November 1984): 1171–74.

"The suggestion that the intestinal mucosa may be abnormally permeable and a site of absorption of antigens in rheumatoid arthritis was tested by the use of a 51Cr-EDTA (edetic acid) absorption test. 24 patients with rheumatoid arthritis excreted significantly more 51Cr-EDTA than did 34 controls. Intestinal permeability was normal in untreated patients but almost invariably abnormal in patients treated with non-steroidal anti-inflammatory drugs. Studies in patients with osteoarthritis showed that the permeability abnormalities were due to an effect of NSAIDs on both the proximal and the distal intestine and that the effect was systemically mediated. Indium-111-labelled leucocyte scans showed ileocaecal inflammation in 6 of 9 patients on or recently on NSAIDs. Although increased intestinal permeability does not seem to be important in the pathogenesis of rheumatoid arthritis, the administration of NSAIDs may lead to loss of intestinal integrity, thus facilitating antigenic absorption and perhaps contributing to persistence of the disease."


Colquhoun, David. “Placebo Effects Are Weak: Regression to the Mean Is the Main Reason Ineffective Treatments Appear to Work.” DC’s Improbable Science, December 11, 2015.

"[T]he placebo effect, though a real phenomenon, seems to be quite small. In most cases it is so small that it would be barely perceptible to most patients. Most of the reason why so many people think that medicines work when they don’t isn’t a result of the placebo response, but it’s the result of a statistical artefact.

"Regression to the mean is a potent source of deception

"The get-better-anyway effect has a technical name, regression to the mean. It has been understood since Francis Galton described it in 1886 (see Senn, 2011 for the history). It is a statistical phenomenon, and it can be treated mathematically (see references, below). But when you think about it, it’s simply common sense."


Fasano, Alessio. “Leaky Gut and Autoimmune Diseases.” Clinical Reviews in Allergy & Immunology 42, no. 1 (February 2012): 71–78.

"Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/ immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoim- mune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases."


Fink-Gremmels, Johanna. “Defense Mechanisms against Toxic Phytochemicals in the Diet of Domestic Animals.” Molecular Nutrition & Food Research 54, no. 2 (February 2010): 249–58.

"or many decades, the epithelial cell layer, closely connected by tight junction proteins, has been described as the barrier system of the intestines, preventing the absorption of many [Plant Secondary Metabolites], as well as biocides and drugs. This assumption was supported by the identification of specific transporters that facilitate the absorption of polar nutrients, such as amino acids and sugars (soluble ligand carriers previously denoted as organic anion transporters, glucose transporters, and others) [50]."


Hollywell, Claire, and Jan Walker. “Private Prayer as a Suitable Intervention for Hospitalised Patients: A Critical Review of the Literature.” Journal of Clinical Nursing, November 2008.

"Summary of key findings

  • Prayer, measured by frequency, is usually associated with lower levels of depression and anxiety. (a) But most of the studies that show positive associations between prayer and wellbeing were located in areas that have strong Christian traditions and involved samples that report relatively high levels of religiosity, church attendance and use of prayer.
  • Church attenders, older people, women, those who are poor, less well educated and have chronic health problems make more frequent use of prayer. (a) It may be that the weak and vulnerable in society are more likely to turn to the church and to prayer in times of difficulty.
  • Prayer is a coping action that mediates between religious faith and wellbeing.
  • Prayer takes different forms, some beneficial, others possibly not: (a) Devotional prayers that take the form of an intimate dialogue with a supportive God are associated with improved optimism, wellbeing and function. (b) Prayers that involve only pleas for help in extremis may, in the absence of a pre-existing faith, be associ- ated with increased distress and possibly poorer function"

Hróbjartsson, Asbjørn, and Peter C. Gøtzsche. “Is the Placebo Powerless?” New England Journal of Medicine 344, no. 21 (May 24, 2001): 1594–1602.

"We found little evidence in general that placebos had powerful clinical effects. Although placebos had no significant effects on objective or binary outcomes, they had possible small benefits in studies with continuous subjective outcomes and for the treatment of pain. Outside the setting of clinical trials, there is no justification for the use of placebos."


"Placebos have been reported to improve subjective and objective outcomes in up to 30 to 40 percent of patients with a wide range of clinical conditions, such as pain, asthma, high blood pressure, and even myocardial infarction.1-3 In his 1955 article “The Powerful Placebo,” Beecher concluded, “It is evident that placebos have a high degree of therapeutic effectiveness in treating subjective responses, decided improvement, interpreted under the unknowns technique as a real therapeutic effect, being produced in 35.2±2.2% of cases.[1]”

"Beecher's article and the 35 percent figure are often cited as evidence that a placebo can be an important medical treatment. The vast majority of reports on placebos, including Beecher's article, have estimated the effect of placebo as the difference from base line in the condition of patients in the placebo group of a randomized trial after treatment. With this approach, the effect of placebo cannot be distinguished from the natural course of the disease, regression to the mean, and the effects of other factors.4-6 The reported large effects of placebo could therefore, at least in part, be artifacts of inadequate research methods."

[Hró2011](1, 2)

Hróbjartsson, Asbjørn, and Peter C. Gøtzsche. “Placebo Interventions for All Clinical Conditions.” The Cochrane Database of Systematic Reviews, no. 1 (January 20, 2010): CD003974.

"We did not find that placebo interventions have important clinical effects in general. However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea, though it is difficult to distinguish patient-reported effects of placebo from biased reporting. The effect on pain varied, even among trials with low risk of bias, from negligible to clinically important. Variations in the effect of placebo were partly explained by variations in how trials were conducted and how patients were informed."


Julio-Pieper, M., and J.A. Bravo. “Intestinal Barrier and Behavior.” In International Review of Neurobiology, 131:127–41. Elsevier, 2016.

"The intestinal barrier function contributes to gut homeostasis by modulating absorption of water, electrolytes, and nutrients from the lumen into the circulation while restricting the passage of noxious luminal substances and microorganisms. Chronic conditions such as rheumatoid arthritis, inflammatory bowel disease, and celiac disease are associated to intestinal barrier dysfunction. Here, the hypothesis is that a leaky intestinal wall allowing for indiscriminate passage of intraluminal compounds to the vascular compartment could in turn lead to systemic inflammation. An increasing number of studies are now investigating the association between gut permeability and CNS disorders, under the premise that translocation of intestinal luminal contents could affect CNS function, either directly or indirectly. Still, it is unknown whether disruption of intestinal barrier is a causative agent or a consequence in these situations. Here, we discuss the latest evidence pointing to an association between increased gut permeability and disrupted behavioral responses."


Lerner, Aaron, and Torsten Matthias. “Rheumatoid Arthritis–Celiac Disease Relationship: Joints Get That Gut Feeling.” Autoimmunity Reviews 14, no. 11 (November 2015): 1038–47.

"Rheumatoid arthritis (RA) and celiac disease (CD) belong to the autoimmune disease family. Despite being separate entities they share multiple aspects. Epidemiologically they share comparable incidence environmental influences, associated antibodies and a recent incidental surge. They differ in their HLA pre-dispositions and specific predictive and diagnostic biomarkers. At the clinical level, celiac disease exhibits extra-intestinal rheumatic manifestations and RA gastrointestinal ones. Small bowel pathology exists in rheumatic patients. A trend towards responsiveness to a gluten free diet has been observed, ameliorating celiac rheumatic manifestations, whereas dietary interventions for rheumatoid arthritis remain controversial. Pathophysiologically, both diseases are mediated by endogenous enzymes in the target organs. The infectious, dysbiotic and increased intestinal permeability theories, as drivers of the autoimmune cascade, apply to both diseases. Contrary to their specific HLA pre-disposition, the diseases share multiple non-HLA loci. Those genes are crucial for activation and regulation of adaptive and innate immunity. Recently, light was shed on the interaction between host genetics and microbiota composition in relation to CD and RA susceptibility, connecting bugs and us and autoimmunity. A better understanding of the above mentioned similarities in the gut-joint inter-relationship, may elucidate additional facets in the mosaic of autoimmunity, relating CD to RA."


Matthews, DA. “Effects of Intercessory Prayer on Patients with Rheumatoid Arthritis. - PubMed - NCBI.” Accessed October 2, 2018.

"Multivariate analysis showed significant overall improvement in the 10 outcome variables over a 6-month postintervention follow-up period for group 1 (n=26) when compared with a 6-month preintervention follow-up period for the waiting-list control group (group2 n=14) (P > .0001). Univariate analysis (Table 3) showed a greate reduction over the 6-month follow-up period for group 1 versus group 2 in the mean number of temder joints (differences of -7.1 vs 0.5, P = .016) and for MHAQ scores (differnces of -3.6 vs 1.5, P= 0.4)"


McDonald, Clement J., Steven A. Mazzuca, and George P. McCabe. “How Much of the Placebo ‘Effect’ Is Really Statistical Regression?” Statistics in Medicine 2, no. 4 (October 1983): 417–27.

"Statistical regression to the mean predicts that patients selected for abnormalcy will, on the average, tend to improve. We argue that most improvements attributed to the placebo effect are actually instances of statistical regression. First, whereas older clinical trials susceptible to regression resulted in a marked improvement in placebo-treated patients, in a modern'series of clinical trials whose design tended to protect against regression, we found no significant improvement (median change 0.3 percent, p > 0.05) in placebo-treated patients."


Milner, Sinead Eileen, Nigel Patrick Brunton, Peter Wyn Jones, Nora Mary O’ Brien, Stuart Gerard Collins, and Anita Rose Maguire. “Bioactivities of Glycoalkaloids and Their Aglycones from Solanum Species.” Journal of Agricultural and Food Chemistry 59, no. 8 (April 27, 2011): 3454–84.

"Glycoalkaloids, a class of nitrogen-containing steroidal glycosides, are biologically active secondary plant metabolites and are commonly found in plants of the Solanum genus. These include many common vital agricultural plants including potato ( Solanum tuberosum ), tomato ( Solanum lycopersicum ), and aubergine ( Solanum melongena )."

"The toxicity of glyoalkaloids in humans is well documented, with “ solanine ” poisoning from blighted, green, or sprouted potatoes being reported as early as 1980. 14 - 16,27 - 29 Accordingly, current safety regulations limit their content in the edible tuber to 20 mg/100 g fresh weight (fw). 30,31 The mechanism of toxicity induced by glycoalkaloids is associated with their membrane-disruptive properties 32 - 34 and their inhibition of acetylcholinesterase activity. 35 - 39 Bioactivity of glycoalkaloids is not limited to their toxicity; they have been reported to possess anticancer, anticholesterol, and anti-inflammatory properties, for example, and some of these e ff ects have been reviewed. 1,14,16,30,40 - 47 Although there have been multiple reviews of individual glycoalkaloids in the literature, including separate reviews of potato 45 or tomato 1 glycoalkaloids, this is the fi rst review to examine and compare the bioactivities, toxicities, and synergisms of action of the principal Solanum glycoalkaloids. Furthermore, the mechanisms of action are discussed, and the relationship between molecular structure and bioactivity profile is presented."


Senn, Stephen. “Three Things That Every Medical Writer Should Know about Statistics” 18, no. 3 (2009): 5.

"Regression to the mean is the tendency for members of a population who have been selected because they are extreme to be less extreme when measured again [4, 5]. Because entry into clinical trials is usually only allowed if patients have extreme values (diastolic blood pressure above 95 mmHg, Hamilton depression score greater than or equal to 22, forced expiratory volume in one second less than 75% of predicted etc.), regression to the mean is a phenomenon that is likely to affect many clinical trials. We can expect that patients will appear to improve even if the treatment is ineffective. Regression to the mean is a plausible explanation, for example, for the ‘placebo effect’ which then becomes, as I hope to explain, a purely statistical rather than psychological phenomenon."


Shammas, Rania M., Veena K. Ranganath, and Harold E. Paulus. “Remission in Rheumatoid Arthritis.” Current Rheumatology Reports 12, no. 5 (October 2010): 355–62.

"Spontaneous remission is not uncommon in patients who present with very early arthritis, some of whom may meet criteria for RA over less than a few months. Spontaneous remission is thought of as a “natural remission,” in which disease activity essentially disappears, and medications are no longer required. Spontaneous remission may be seen in 13% to 55% of individuals presenting with undifferentiated arthritis, probably as a result of different underlying etiologies, such as a transient viral infection [32]. About one third of patients with undifferentiated arthritis go on to develop RA."


Shiobara, Tomoko, Takeo Usui, Junkyu Han, Hiroko Isoda, and Yoko Nagumo. “The Reversible Increase in Tight Junction Permeability Induced by Capsaicin Is Mediated via Cofilin-Actin Cytoskeletal Dynamics and Decreased Level of Occludin.” PLOS ONE 8, no. 11 (November 18, 2013): e79954.

"Previous results demonstrated that capsaicin induces the reversible tight junctions (TJ) opening via cofilin activation. The present study investigated the mechanisms underlying the reversible TJ opening and compared the effect to the irreversible opening induced by actin inhibitors. Capsaicin treatment induced the F-actin alteration unique to capsaicin compared to actin-interacting agents such as latrunculin A, which opens TJ irreversibly. Along with TJ opening, capsaicin decreased the level of F-actin at bicellular junctions but increased it at tricellular junctions accompanied with its concentration on the apical side of the lateral membrane. No change in TJ protein localization was observed upon exposure to capsaicin, but the amount of occludin was decreased significantly. In addition, cosedimentation analyses suggested a decrease in the interactions forming TJ, thereby weakening TJ tightness. Introduction of cofilin, LIMK and occludin into the cell monolayers confirmed their contribution to the transepithelial electrical resistance decrease. Finally, exposure of monolayers to capsaicin augmented the paracellular passage of both charged and uncharged compounds, as well as of insulin, indicating that capsaicin can be employed to modulate epithelial permeability. Our results demonstrate that capsaicin induces TJ opening through a unique mechanism, and suggest that it is a new type of paracellular permeability enhancer."


Smith, M. D., R. A. Gibson, and P. M. Brooks. “Abnormal Bowel Permeability in Ankylosing Spondylitis and Rheumatoid Arthritis.” The Journal of Rheumatology 12, no. 2 (April 1985): 299–305.

"Intestinal permeability was measured using a low molecular weight polyethylene glycol as a permeability marker in patients with osteoarthritis, ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Patients with AS showed a significant increase in bowel permeability when compared to controls. Intestinal permeability was also increased in patients with active RA but was less than the control group in RA patients who did not have active joint disease."


Tajadini, Haleh, Nasser Zangiabadi, Kouros Divsalar, Hossein Safizadeh, Zahra Esmaili, and Hossein Rafiei. “Effect of Prayer on Intensity of Migraine Headache.” Journal of Evidence-Based Complementary & Alternative Medicine 22, no. 1 (January 2017): 37–40.

"At the beginning of study and before intervention, the mean score of pain in patients in groups A and B were 5.7 ± 1.6 and 6.5 ± 1.9, respectively. According to results of independent t test, mean score of pain intensity at the beginning of study were similar between patients in 2 groups (P > .05). Three month after intervention, mean score of pain intensity decreased in patients in both groups. At this time, the mean scores of pain intensity were 5.4 ± 1.1 and 4.2 ± 2.3 in patients in groups A and B, respectively. This difference between groups was statistically significant (P < .001)."


Valesini, Guido, Manuela Di Franco, Francesca Romana Spinelli, and Rossana Scrivo. “Induction of Remission in Rheumatoid Arthritis: Criteria and Opportunities.” Rheumatology International 29, no. 2 (December 2008): 131–39.

"[R]emission represents the primary objective of treatment in rheumatoid arthritis (RA). In the last two decades, rheumatologists have realized that complete (or almost complete) control of th e disease is essential to prevent long-term joint damage and remission in RA is now more feasible than in the past, thanks to the introduction of biologic disease modifying anti-rheumatic drugs (DMARDs) in RA therapy."

"[P]eople with RA may undergo spontaneous remissions in the early phases of the disease, generally only for a few months."


Volta, U, G Deangelis, A Granito, N Petrolini, E Fiorini, M Guidi, P Muratori, and F Bianchi. “Autoimmune Enteropathy and Rheumatoid Arthritis: A New Association in the Field of Autoimmunity.” Digestive and Liver Disease 38, no. 12 (December 2006): 926–29.

"We report the case of a 35-year-old woman with a diagnosis of coeliac disease at the age of 32 due to a severe malabsorption and flat mucosa without endomysial and tissue transglutaminase antibodies. The lack of clinical and histological improvement after 1 year of a gluten-free diet led to a diagnosis of refractory sprue. She had a good clinical response to steroids that were stopped after 3 months when she became pregnant. After delivery, she again started to complain of malabsorption with arthritis. Positivity for enterocyte autoantibodies together with a flat mucosa persistence allowed to identify a condition of autoimmune enteropathy; moreover, a rheumatological assessment gave evidence of an associated rheumatoid arthritis. Treatment by steroids and methotrexate brought to the remission of intestinal and articular symptoms together with an improvement of duodenal histology. This is the first description of an autoimmune enteropathy associated with rheumatoid arthritis. Autoimmune enteropathy should be always ruled out in patients with a villous atrophy unresponsive to a gluten-free diet, autoimmune manifestations and negativity of coeliac disease markers."


Warjri, Synrang Batngen, Tony Ete, Taso Beyong, Bhupen Barman, Kyrshanlang G. Lynrah, Hage Nobin, and Obang Perme. “Coeliac Disease With Rheumatoid Arthritis: An Unusual Association.” Gastroenterology Research 8, no. 1 (February 2015): 167–68.

"Coeliac disease has a significant association with many autoimmune disorders. It shares many common genetic and immunological features with other autoimmune diseases. Gluten, a gut-derived antigen, is the driver of the autoimmunity seen in coeliac disease. The altered intestinal permeability found in coeliac patients, coupled with a genetic predisposition and altered immunological response, may result in a systemic immune response that is directed against sites other than the gut. Gut-derived antigens may have a role in the pathogenesis of other autoimmune disorders including rheumatoid arthritis. Here we report a case of adult coeliac disease associated with rheumatoid arthritis."


Yudkin, P.L., and I.M. Stratton. “How to Deal with Regression to the Mean in Intervention Studies.” The Lancet 347, no. 8996 (January 1996): 241–43.

"RTM is, in essence, a chance finding masquerading as a real one. Despite the name, it is not confined to regression analysis but turns up in several different situations[2]. This paper is concerned with intervention studies. Such studies often target individuals who have unusually high values of a risk variable, such as cholesterol. In a group of such individuals, the mean cholesterol level will, on remeasurement, be lower than the starting mean, even without any intervention or treatment[3-6]. This is the RTM effect. In a group selected on the basis of unusually low values of a variable RTM works in the other direction. RTM occurs with any variable that fluctuates within an individual, either genuinely or due to measurement error[7]. Examples are cholesterol, blood pressure, and plasma glucose. A single measurement may be higher or lower than the individual’s long-term average (or "true") value, but individuals selected because they have a single high measurement will include a disproportionate number whose measurement was by chance higher than their true value. This can be better understood from the figure. The population distribution of the measurement in question consists of numerous individual distributions, with the peak of each representing the individual’s true value. Above any high cut-off point (the vertical line at L) there will be more individuals like A (with their long-term average below the line) than like B (with their long-term average above it). On remeasurement, the values recorded for these individuals will tend to revert towards their long- term average, so that the mean measurement of the group as a whole will fall. In this paper we illustrate the magnitude of the RTM effect in a group of individuals with high cholesterol concentrations, selected from a population with repeated cholesterol measurements and no intervention. We then describe two methods for estimating the RTM effect in an intervention study, and go on to show how intervention studies can be designed specifically to limit the RTM problem."