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.

https://2.bp.blogspot.com/-Dte69_5xIQ0/XNMEy8PW6PI/AAAAAAAAILQ/-nGHh1EgWh8H42ItV-uGXuu-vvh8CkRLgCLcBGAs/s640/african-vs-american%2Bdiets.png

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
[2]

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

https://2.bp.blogspot.com/-7H8SF9U_zI4/XNLu7hpBgNI/AAAAAAAAILE/21nyHxlM2AcRIeSB4nXjECI2dDDqxZtSACLcBGAs/s600/new-definition-of-dietary-fibre.png

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.

[3]

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, justmeat.co) 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 Ketotic.org 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.

Collagen?

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.

Carnitine

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.

References

[Alb2017]

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, https://doi.org/10.3945/jn.117.256404

"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."

[Dan2015]

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. https://doi.org/10.1080/10408398.2015.1038377.

"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."

[Eva2003]

Evans, Allan M, and Gianfranco Fornasini. “Pharmacokinetics of L-Carnitine:” Clinical Pharmacokinetics 42, no. 11 (2003): 941–67. https://doi.org/10.2165/00003088-200342110-00002.

"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%."

[Góm2011]

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. https://doi.org/10.1016/j.foodhyd.2011.02.007.

"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."

[Gre1959]

Green, N. M., and D. A. Lowther. “Formation of Collagen Hydroxyproline in Vitro.” Biochemical Journal 71, no. 1 (January 1959): 55–66. https://doi.org/10.1042/bj0710055.

"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."

[Hug1981]

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 http://www.mv.helsinki.fi/home/hemila/concepts/Hughes_1981.pdf

"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."

[Hug1988]

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."

[Iwa2005]

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. https://doi.org/10.1021/jf050206p.

"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."

[Liu2009]

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. https://doi.org/10.1271/bbb.90050.

"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."

[Oes1999]

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. https://doi.org/10.1093/jn/129.10.1891.

"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."

[Pea1960]

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. https://doi.org/10.3181/00379727-105-26117.

"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. "

[Ste1949]

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."

[Str2010]

Strijbis, Karin, Frédéric M. Vaz, and Ben Distel. “Enzymology of the Carnitine Biosynthesis Pathway.” IUBMB Life 62, no. 5 (2010): 357–62. https://doi.org/10.1002/iub.323.

"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."

[Wat2010]

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. https://doi.org/10.1021/jf9031487.

"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."