Butyric Acid: an Ancient Controller of Metabolism, Inflammation and Stress Resistance

An Interesting Finding

Susceptible strains of rodents fed high-fat diets overeat, gain fat and become profoundly insulin resistant. Dr. Jianping Ye's group recently published a paper showing that the harmful metabolic effects of a high-fat diet (lard and soybean oil) on mice can be prevented, and even reversed, using a short-chain saturated fatty acid called butyric acid (hereafter, butyrate). Here's a graph of the percent body fat over time of the two groups:

The butyrate-fed mice remained lean and avoided metabolic problems. Butyrate increased their energy expenditure by increasing body heat production and modestly increasing physical activity. It also massively increased the function of their mitochondria, the tiny power plants of the cell.

Butyrate lowered their blood cholesterol by approximately 25 percent, and their triglycerides by nearly 50 percent. It lowered their fasting insulin by nearly 50 percent, and increased their insulin sensitivity by nearly 300 percent*. The investigators concluded:

Butyrate and its derivatives may have potential application in the prevention and treatment of metabolic syndrome in humans.

There's one caveat, however: the butyrate group at less food. Something about the butyrate treatment caused their food intake to decline after 3 weeks, dropping roughly 20% by 10 weeks. The investigators cleverly tried to hide this by normalizing food intake to body weight, making it look like the food intake of the comparison group was dropping as well (when actually it was staying the same as this group was gaining weight).

I found this study thought-provoking, so I looked into butyrate further.

Butyrate Suppresses Inflammation in the Gut and Other Tissues

In most animals, the highest concentration of butyrate is found in the gut. That's because it's produced by intestinal bacteria from carbohydrate that the host cannot digest, such as cellulose and pectin. Indigestible carbohydrate is the main form of dietary fiber.

It turns out, butyrate has been around in the mammalian gut for so long that the lining of our large intestine has evolved to use it as its primary source of energy. It does more than just feed the bowel, however. It also has potent anti-inflammatory and anti-cancer effects. So much so, that investigators are using oral butyrate supplements and butyrate enemas to treat inflammatory bowel diseases such as Crohn's and ulcerative colitis. Investigators are also suggesting that inflammatory bowel disorders may be caused or exacerbated by a deficiency of butyrate in the first place.

Butyrate, and other short-chain fatty acids produced by gut bacteria**, has a remarkable effect on intestinal permeability. In tissue culture and live rats, short-chain fatty acids cause a large and rapid decrease in intestinal permeability. Butyrate, or dietary fiber, prevents the loss of intestinal premeability in rat models of ulcerative colitis. This shows that short-chain fatty acids, including butyrate, play an important role in the maintenance of gut barrier integrity. Impaired gut barrier integrity is associated with many diseases, including fatty liver, heart failure and autoimmune diseases (thanks to Pedro Bastos for this information-- I'll be covering the topic in more detail later).

Butyrate's role doesn't end in the gut. It's absorbed into the circulation, and may exert effects on the rest of the body as well. In human blood immune cells, butyrate is potently anti-inflammatory***.

Butyrate Increases Resistance to Metabolic and Physical Stress

Certain types of fiber reduce atherosclerosis in animal models, and this effect may be due to butyrate production produced when the fiber is fermented. Fiber intake was associated with lower blood markers of inflammation in the Women's Health Initiative study, and has been repeatedly associated with lower heart attack risk and reduced progression of atherosclerosis in humans. Butyrate also sharply reduces the harmful effects of type 1 diabetes in rats, as does dietary fiber to a lesser extent.

Butyrate increases the function and survival of mice with certain neurodegenerative diseases. Polyglutamine diseases, which are the most common class of genetic neurodegenerative diseases, are delayed in mice treated with butyrate (1, 2, 3). Many of you have probably heard of Huntington's disease, which is the most common of the class. I did my thesis on a polyglutamine disease called SCA7, and this is the first suggestion I've seen that diet may be able to modify its course.

Yet another interesting finding in the first paper I discussed: mice treated with butyrate were more cold-resistant than the comparison group. When they were both placed in a cold room, body temperature dropped quite a bit in the comparison group, while it remained relatively stable in the butyrate group, despite the fact that the butyrate group was leaner****. This was due to increased heat production in the butyrate group.

Due to the potent effect butyrate has on a number of bodily processes, I believe it may be a fundamental controller of metabolism, stress resistance and the immune system in mammals, similar to omega-6:3 balance.

An Ancient Line of Communication Between Symbiotic Organisms

Why does butyrate have so much control over inflammation? Let's think about where it comes from. Bacteria in the gut produce it. It's a source of energy, so our bodies take it up readily. It's one of the main molecules that passes from the symbiotic (helpful) bacteria in the gut to the rest of the body. It's only logical that the body would receive butyrate as a signal that there's a thriving colony of symbiotic bacteria in the gut, and induce a tolerance to them. The body may alter its immune response (inflammation) in order to permit a mutually beneficial relationship between itself and its symbionts.

A Change of Heart

Butyrate has caused me to re-think my position on fiber-- which was formerly that it's irrelevant at best. I felt that fiber came along with nutrient-dense whole plant foods, but was not beneficial per se. I believed that the associations between fiber intake and a lower risk of a number of diseases were probably due to the fact that wealthier, more educated, healthier people tend to buy more whole grains, fruit and vegetables. In other words, I believed that fiber intake was associated with better health, but did not contribute to it. I now feel, based on further reading about fiber and short-chain fatty acids like butyrate, that the associations represent a true cause-and-effect relationship.

I also didn't fully appreciate the caloric contribution of fiber to the human diet. In industrialized countries, fiber may contribute 5 to 10 percent of total calorie intake, due to its conversion to short-chain fatty acids like butyrate in the large intestine (free full text). This figure is probably at least twice as high in cultures consuming high-fiber diets. It's interesting to think that "high-carbohydrate" cultures may be getting easily 15 percent of their calories from short-chain fats. Since that isn't recorded in dietary surveys, they may appear more dependent on carbohydrate than they actually are. The Kitavans may be getting more than 30 percent of their total calories from fat, despite the fact that their food is only 21 percent fat when it passes their lips. Their calorie intake may be underestimated as well.

Sources of Butyrate

There are two main ways to get butyrate and other short-chain fatty acids. The first is to eat fiber and let your intestinal bacteria do the rest. Whole plant foods such as sweet potatoes, properly prepared whole grains, beans, vegetables, fruit and nuts are good sources of fiber. Refined foods such as white flour, white rice and sugar are very low in fiber. Clinical trials have shown that increasing dietary fiber increases butyrate production, and decreasing fiber decreases it (free full text).

Butyrate also occurs in significant amounts in food. What foods contain butyrate? Hmm, I wonder where the name BUTYR-ate came from? Butter perhaps? Butter is 3-4 percent butyrate, the richest known source. But everyone knows butter is bad for you, right?

After thinking about it, I've decided that butyrate must have been a principal component of Dr. Weston Price's legendary butter oil. Price used this oil in conjunction with high-vitamin cod liver oil to heal tooth decay and a number of other ailments in his patients. The method he used to produce it would have concentrated fats with a low melting temperature, including butyrate, in addition to vitamin K2*****. Thus, the combination of high-vitamin cod liver oil and butter oil would have provided a potent cocktail of fat-soluble vitamins (A, D3, K2), omega-3 fatty acids and butyrate. It's no wonder it was so effective in his patients.


* According to insulin tolerance test.

** Acetate (acetic acid, the main acid in vinegar), propionate and butyrate are the primary three fatty acids produced by intestinal fermentation.

*** The lowest concentration used in this study, 30 micromolar, is probably higher than the concentration in peripheral serum under normal circumstances. Human serum butyrate is in the range of 4 micromolar in British adults, and 29 micromolar in the hepatic portal vein which brings fats from the digestive tract to the liver (ref). This would likely be at least two-fold higher in populations eating high-fiber diets.

**** Due to higher mitochondrial density in brown fat and more mitochondrial uncoupling.

***** Slow crystallization, which selectively concentrates triglycerides with a low melting point.

Krauss's New Article on Saturated Fat Intervention Trials

Dr. Ronald Krauss's group just published another article in the American Journal of Clinical Nutrition, this time on the intervention trials examining the effectiveness of reducing saturated fat and/or replacing it with other nutrients, particularly carbohydrate or polyunsaturated seed oils. I don't agree with everything in this article. For example, they cite the Finnish Mental Hospital trial. They openly acknowledge some contradictory data, although they left out the Sydney diet-heart study and the Rose et al. corn oil study, both of which showed greatly increased mortality from replacing animal fats with polyunsaturated seed oils. Nevertheless, they get it right in the end:

Particularly given the differential effects of dietary saturated fats and carbohydrates on concentrations of larger and smaller LDL particles, respectively, dietary efforts to improve the increasing burden of CVD risk associated with atherogenic dyslipidemia should primarily emphasize the limitation of refined carbohydrate intakes and a reduction in excess adiposity.

This is really cool. Krauss is channeling Weston Price. If this keeps up, I may have no reason to blog anymore!

Lindeberg on Obesity

I'm currently reading Dr. Staffan Lindeberg's magnum opus Food and Western Disease, recently published in English for the first time. Dr. Lindeberg is one of the world's leading experts on the health and diet of non-industrial cultures, particularly in Papua New Guinea. The book contains 2,034 references. It's also full of quotable statements. Here's what he has to say about obesity:

Middle-age spread is a normal phenomenon - assuming you live in the West. Few people are able to maintain their [youthful] waistline after age 50. The usual explanation - too little exercise and too much food - does not fully take into account the situation among traditional populations. Such people are usually not as physically active as you may think, and they usually eat large quantities of food.

Overweight has been extremely rare among hunter-gatherers and other traditional cultures [18 references]. This simple fact has been quickly apparent to all foreign visitors...

The Kitava study measured height, weight, waist circumference, subcutaneous fat thickness at the back of the upper arm (triceps skinfold) and upper arm circumference on 272 persons ages 4-86 years. Overweight and obesity were absent and average [body mass index] was low across all age groups. ...no one was larger around their waist than around their hips.

...The circumference of the upper arm [mostly indicating muscle mass] was only negligibly smaller on Kitava [compared with Sweden], which indicates that there was no malnutrition. It is obvious from our investigations that lack of food is an unknown concept, and that the surplus of fruits and vegetables regularly rots or is eaten by dogs.

The Population of Kitava occupies a unique position in the world in terms of the negligible effect that the Western lifestyle has had on the island.

The only obese Kitavans Dr. Lindeberg observed were two people who had spent several years off the island living a modern, urban lifestyle, and were back on Kitava for a visit.

I'd recommend this book to anyone who has a scholarly interest in health and nutrition, and somewhat of a background in science and medicine. It's extremely well referenced, which makes it much more valuable.

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Saturated Fat and Insulin Sensitivity

Insulin sensitivity is a measure of the tissue response to insulin. Typically, it refers to insulin's ability to cause tissues to absorb glucose from the blood. A loss of insulin sensitivity, also called insulin resistance, is a core part of the metabolic disorder that affects many people in industrial nations.

I don't know how many times I've seen the claim in journal articles and on the internet that saturated fat reduces insulin sensitivity. The idea is that saturated fat reduces the body's ability to handle glucose effectively, placing people on the road to diabetes, obesity and heart disease. Given the "selective citation disorder" that plagues the diet-health literature, perhaps this particular claim deserves a closer look.

The Evidence

I found a review article from 2008 that addressed this question (1). I like this review because it only includes high-quality trials that used reliable methods of determining insulin sensitivity*.

On to the meat of it. There were 5 studies in which non-diabetic people were fed diets rich in saturated fat, and compared with a group eating a diet rich in monounsaturated (like olive oil) or polyunsaturated (like corn oil) fat. They ranged in duration from one week to 3 months. Four of the five studies found that fat quality did not affect insulin sensitivity, including one of the 3-month studies.

The fifth study, which is the one that's nearly always cited in the diet-health literature, requires some discussion. This was the KANWU study (2). Over the course of three months, investigators fed 163 volunteers a diet rich in either saturated fat or monounsaturated fat.

The SAFA diet included butter and a table margarine containing a relatively high proportion of SAFAs. The MUFA diet included a spread and a margarine containing high proportions of oleic acid derived from high-oleic sunflower oil and negligible amounts of trans fatty acids and n-3 fatty acids and olive oil.

Yummy. After three months of these diets, there was no significant difference in insulin sensitivity between the saturated fat group and the monounsaturated fat group. Yes, you read that right. Even the study that's selectively cited as evidence that saturated fat causes insulin resistance found no significant difference between the diets. You might not get this by reading the misleading abstract. I'll be generous and acknowledge that the (small) difference was almost statistically significant (p = 0.053).

What the authors decided to focus on instead is the fact that insulin sensitivity declined slightly but significantly on the saturated fat diet compared with the pre-diet baseline. That's why this study is cited as evidence that saturated fat impairs insulin sensitivity. But anyone who has a basic science background will see where this reasoning is flawed (warning: nerd attack. skip the rest of the paragraph if you're not interested). You need a control group for comparison, to take into account normal fluctuations caused by such things as the season, eating mostly cafeteria food, and having a doctor hooking you up to machines. That control group was the group eating monounsaturated fat. The comparison between diet groups was the 'primary outcome', in statistics lingo. That's the comparison that matters, and it wasn't significant. To interpret the study otherwise is to ignore the basic conventions of statistics, which the authors were happy to do. There's a name for it: 'moving the goalpost'. The reviewers shouldn't have let this kind of shenanigans slide.

So we have five studies through 2008, none of which support the idea that saturated fat reduces insulin sensitivity in non-diabetics. Since the review paper was published, I know of one subsequent study that asked the same question (3). Susan J. van Dijk and colleagues fed volunteers with abdominal overweight (beer gut) a diet rich in either saturated fat or monounsaturated fat. I e-mailed the senior author and she said the saturated fat diet was "mostly butter". The specific fats used in the diets weren't mentioned anywhere in the paper, which is a major omission**. In any case, after 8 weeks, insulin sensitivity was virtually identical between the two groups. This study appeared well controlled and used the gold standard method for assessing insulin sensitivity, called the euglycemic-hyperinsulinemic clamp technique***.

The evidence from controlled trials is rather consistent that saturated fat has no appreciable effect on insulin sensitivity.

Why Are We so Focused on Saturated Fat?

Answer: because it's the nutrient everyone loves to hate. As an exercise in completeness, I'm going to mention three dietary factors that actually reduce insulin sensitivity, and get a lot less air time than saturated fat.

#1: Caffeine. That's right, controlled trials show that your favorite murky beverage reduces insulin sensitivity (4, 5). Is it actually relevant to real life? I doubt it. The doses used were large and the studies short-term.

#2: Magnesium deficiency. A low-magnesium diet reduced insulin sensitivity by 25% over the course of three weeks (6). I think this is probably relevant to long-term insulin sensitivity and overall health, although it would be good to have longer-term data. Magnesium deficiency is widespread in industrial nations, due to our over-reliance on refined foods such as sugar, white flour and oils.

#3: Sugar. Fructose reduces insulin sensitivity in humans, along with many other harmful effects (7).

As long as we continue to focus our energy on indicting saturated fat, it will continue distracting us from the real causes of disease.


* For the nerds: euglycemic-hyperinsulinemic clamp (the gold standard), insulin suppression test, or intravenous glucose tolerance test with Minimal Model. They didn't include studies that reported HOMA as their only measure, because it's not very accurate.

** There's this idea that pervades the diet-health literature that all saturated fats are roughly equivalent, all monounsaturated fats are equivalent, etc., therefore it doesn't matter what the source was. This is beyond absurd and reflects our cultural obsession with saturated fat. It really irks me that the reviewers didn't demand this information.

*** They did find that markers of inflammation in fat tissue were higher after the saturated fat diet.

Paleo is Going Mainstream

There was an article on the modern "Paleolithic" lifestyle in the New York Times today. I thought it was a pretty fair treatment of the subject, although it did paint it as more macho and carnivorous than it needs to be. It features three attractive NY cave people. It appeared in the styles section here. Paleo is going mainstream. We can expect media health authorities to start getting defensive about it any minute now.

Book Review: S.P.E.E.D.

This book was sent to me by Matt Schoeneberger, who co-authored it with Jeff Thiboutot. Both have master's degrees in exercise science and health promotion. S.P.E.E.D. stands for Sleep, Psychology, Exercise, Environment and Diet. The authors have attempted to create a concise, comprehensive weight loss strategy based on what they feel is the most compelling scientific evidence available. It's subtitled "The Only Weight Loss Book Worth Reading". Despite the subtitle that's impossible to live up to, it was an interesting and well-researched book. It was a very fast read at 205 large-print pages including 32 pages of appendices and index.

I really appreciate the abundant in-text references the authors provided. I have a hard time taking a health and nutrition book seriously that doesn't provide any basis to evaluate its statements. There are already way too many people flapping their lips out there, without providing any outside support for their statements, for me to tolerate that sort of thing. Even well-referenced books can be a pain if the references aren't in the text itself. Schoeneberger and Thiboutot provided appropriate, accessible references for nearly every major statement in the book.

Chapter one, "What is a Healthy Weight", discusses the evidence for an association between body weight and health. They note that both underweight and obesity are associated with poor health outcomes, whereas moderate overweight isn't. While I agree, I continue to maintain that being fairly lean and appropriately muscled (which doesn't necessarily mean muscular) is probably optimal. The reason that people with a body mass index (BMI) considered to be "ideal" aren't healthier on average than people who are moderately overweight may have to do with the fact that many people with an "ideal" BMI are skinny-fat, i.e. have low muscle mass and too much abdominal fat.

Chapter 2, "Sleep", discusses the importance of sleep in weight regulation and overall health. They reference some good studies and I think they make a compelling case that it's important. Chapter 3, "Psychology", details psychological strategies to motivate and plan for effective weight loss.

Chapter 4, "Exercise", provides an exercise plan for weight loss. The main message: do it! I think they give a fair overview of the different categories of exercise and their relative merits, including high-intensity intermittent training (HIIT). However, the exercise regimen they suggest is intense and will probably lead to overtraining in many people. They recommend resistance training major, multi-joint exercises, 1-3 sets to muscular failure 2-4 days a week. I've been at the higher end of that recommendation and it made my joints hurt, plus I was weaker than when I strength trained less frequently. I think the lower end of their recommendation, 1 set of each exercise to failure twice a week, is more than sufficient to meet the goal of maximizing improvements in body composition in most people. My current routine is one brief strength training session and one sprint session per week (in addition to my leisurely cycle commute), which works well for me on a cost-benefit level. However, I was stronger when I was strength training twice a week and never going to muscular failure (a la Pavel Tsatsouline).

Chapter 5, "Environment", is an interesting discussion of different factors that promote excessive calorie intake, such as the setting of the meal, the company or lack thereof, and food presentation. While they support their statements very well with evidence from scientific studies, I do have a lingering doubt about these types of studies: as far as I know, they're all based on short-term interventions. Science would be a lot easier if short-term always translated to long term, but unfortunately that's not the case. For example, studies lasting one or two weeks show that low glycemic index foods cause a reduction in calorie intake and greater feelings of fullness. However, this effect disappears in the long term, and numerous controlled trials show that low glycemic index diets have no effect on food intake, body weight or insulin sensitivity in the long term. I reviewed those studies here.

The body has homeostatic mechanisms (homeostatic = maintains the status quo) that regulate long-term energy balance. Whether short-term changes in calorie intake based on environmental cues would translate into sustained changes that would have a significant impact on body fat, I don't know. For example, if you eat a meal with your extended family at a restaurant that serves massive portions, you might eat twice as much as you would by yourself in your own home. But the question is, will your body factor that huge meal into your subsequent calorie intake and energy expenditure over the following days? The answer is clearly yes, but the degree of compensation is unclear. Since I'm not aware of any trials indicating that changing meal context can actually lead to long-term weight loss, I can't put much faith in this strategy (if you know otherwise, please link to the study in the comments).

Chapter 6, "Diet", is a very brief discussion of what to eat for weight loss. They basically recommend a low-calorie, low-carb diet focused on whole, natural foods. I think low-carbohydrate diets can be useful for some overweight people trying to lose weight, if for no other reason than the fact that they make it easier to control appetite. In addition, a subset of people respond very well to carbohydrate restriction in terms of body composition, health and well-being. The authors emphasize nutrient density, but don't really explain how to achieve it. It would have been nice to see a discussion of a few topics such as organ meats, leafy greens, dairy quality (pastured vs. conventional) and vitamin D. These may not help you lose weight, but they will help keep you healthy, particularly on a calorie-restricted diet. The authors also recommend a few energy bars, powders and supplements that I don't support. They state that they have no financial connection to the manufacturers of the products they recommend.

I'm wary of their recommendation to deliberately restrict calorie intake. Although it will clearly cause fat loss if you restrict calories enough, it's been shown to be ineffective for sustainable, long-term fat loss over and over again. The only exception is the rare person with an iron will who is able to withstand misery indefinitely. I'm going to keep an open mind on this question though. There may be a place for deliberate calorie restriction in the right context. But at this point I'm going to require some pretty solid evidence that it's effective, sustainable, and doesn't have unacceptable side effects.

The book contains a nice bonus, an appendix titled "What is Quality Evidence"? It's a brief discussion of common logical pitfalls when evaluating evidence, and I think many people could benefit from reading it.

Overall, S.P.E.E.D. was a worthwhile read, definitely superior to 95% of fat loss books. With some caveats mentioned above, I think it could be a useful resource for someone interested in fat loss.