Gluten-Free January Survey Data, Part I: Demographics and Limitations

Thanks to Matt Lentzner for organizing Gluten-Free January, and everyone who participated and completed the survey, we have a nice data set illustrating what happens when a group of people stop eating gluten for a month. Janine Jagger, Matt and I have been busy analyzing the data, and I'm ready to begin sharing our findings.

GFJ had over 500 participants, 527 of which received the survey and 279 of which completed the survey at the end of the month. Of those who received the survey, 53 percent completed it. I think these are respectable numbers for a survey of this nature, and it reflects the conscientious nature of the people who participated in GFJ.

Demographics

Although respondents were primarily from the United States, I'm happy to say that the data represent 18 different nationalities:

Respondents represented a diversity of ages, the largest group being 30-39 years old, with similar numbers in the 20-29 and 40-49 year groups.
Respondents were just under 2/3 women.

Respondents represented a variety of weights, but the sample was biased toward lean people, in comparison with the general population. There were not many obese participants.
Overall, I was pleased to see that the demographics were quite diverse, particularly in the age and gender categories.

Limitations

There are a few caveats to keep in mind when interpreting the survey results:

1. GFJ participants do not represent a random cross-section of the population at large. They represent primarily health-conscious individuals who were motivated enough to make a substantial dietary change. In addition, many of the people who participated probably did so because they already suspected they had a problem with gluten.
   
2. The survey response rate was 53%. Although I think that's a reasonable number considering the circumstances, it leaves open the possibility that survey responders differ from non-responders. It's conceivable that participants with better adherence and better outcomes were more likely to complete the survey than those who did not adhere to the diet or had neutral or unfavorable outcomes, despite our efforts to encourage everyone to complete the survey regardless of adherence or outcome. So the results could be biased toward positive outcomes, meaning that we will need to see a strong effect for it to be believable.
   
3. This was a non-blinded diet trial without a control group. There's no way to know how much of the effect was due to avoiding gluten per se, how much was due to overall changes in diet patterns, and how much was a placebo effect.
   

With that in mind, what can we take from the survey data? I feel that we can use it to answer the following question: "what is likely to happen when a motivated, health-conscious person decides to avoid gluten for a month?" And I think we can also use it to generate (but not test) hypotheses about the effects of eating gluten on the general population.

Flu Season is Here

I've noticed everyone around me getting sick lately (I seem to have become mostly immune to colds and the flu in the last couple of years), so I took a look at Google Flu Trends. Lo and behold, the United States is currently near peak flu incidence for the 2010-2011 season. Here's a graph from Flu Trends. This year's trend is in dark blue:


Flu Trends also has data for individual US states and a number of other countries.

It's time to tighten up your diet and lifestyle if you want to avoid the flu this year. Personally, I feel that eating well, managing stress effectively, and taking 2,000 IU of vitamin D3 per day in winter have helped me avoid colds and the flu.

The China Study II: Fruit consumption and mortality

I ran several analyses on the effects of fruit consumption on mortality on the China Study II dataset using WarpPLS. For other China Study analyses, many using WarpPLS as well as HCE, click here.

The results are pretty clear – fruit consumption has no significant effect on mortality.

The bar charts figure below shows what seems to be a slight downward trend in mortality, in the 35-69 and 70-79 age ranges, apparently due to fruit consumption.

As it turns out, that slight trend may be due to something else: in the China Study II dataset, fruit consumption is positively associated with both animal protein and fat consumption. And, as we have seen from previous analyses (e.g., this one), the latter two seem to be protective.

So, if you like to eat fruit, maybe you should also make sure that you eat animal protein and fat as well.

Gluten-Free January Raffle Winners Selected!

Raffle winners have been selected and shirts are on their way. You know who you are. Thanks to everyone who participated and filled out the survey! For those who didn't, there's always next year.

Janine Jagger, Matt Lentzner and I are busy crunching the mountain of data we collected from the GFJ survey. We got 279 responses, which is remarkable for a survey of this nature.

Stay tuned for data!

Oltipraz

Oltipraz is a drug that was originally used to treat intestinal worms. It was later found to prevent a broad variety of cancers (1). This was attributed to its ability to upregulate cellular detoxification and repair mechanisms.

Researchers eventually discovered that oltipraz acts by activating Nrf2, the same transcription factor activated by ionizing radiation and polyphenols (2, 3, 4). Nrf2 activation mounts a broad cellular protective response that appears to reduce the risk of multiple health problems.

A recent paper in Diabetologia illustrates this (5). Investigators put mice on a long-term refined high-fat diet, with or without oltipraz. These carefully crafted diets are very unhealthy indeed, and when fed to rodents they rapidly induce fat gain and something that looks similar to human metabolic syndrome (insulin resistance, abdominal adiposity, blood lipid disturbances). Adding oltipraz to the diet prevented the fat gain, insulin resistance and inflammatory changes that occurred in the refined high-fat diet group.

The difference in fasting insulin was remarkable. The mice taking oltipraz had 1/7 the fasting insulin of the refined high-fat diet comparison group, and 1/3 the fasting insulin of the low-fat comparison group! Yet their glucose tolerance was normal, indicating that they were not low on insulin due to pancreatic damage. The low-fat diet they used in this study was also refined, which is why the two control groups (high-fat and low-fat) didn't diverge more in body fatness and other parameters. If they had used a group fed unrefined rodent chow as the comparator, the differences between groups would have been larger.

This shows that in addition to preventing cancer, Nrf2 activation can attenuate the metabolic damage caused by an unhealthy diet in rodents. Oltipraz illustrates the power of the cellular hormesis response. We can exploit this pathway naturally using polyphenols and other chemicals found in whole plant foods.

Vitamin D production from UV radiation: The effects of total cholesterol and skin pigmentation

Our body naturally produces as much as 10,000 IU of vitamin D based on a few minutes of sun exposure when the sun is high. Getting that much vitamin D from dietary sources is very difficult, even after “fortification”.

The above refers to pre-sunburn exposure. Sunburn is not associated with increased vitamin D production; it is associated with skin damage and cancer.

Solar ultraviolet (UV) radiation is generally divided into two main types: UVB (wavelength: 280–320 nm) and UVA (320–400 nm). Vitamin D is produced primarily based on UVB radiation. Nevertheless, UVA is much more abundant, amounting to about 90 percent of the sun’s UV radiation.

UVA seems to cause the most skin damage, although there is some debate on this. If this is correct, one would expect skin pigmentation to be our body’s defense primarily against UVA radiation, not UVB radiation. If so, one’s ability to produce vitamin D based on UVB should not go down significantly as one’s skin becomes darker.

Also, vitamin D and cholesterol seem to be closely linked. Some argue that one is produced based on the other; others that they have the same precursor substance(s). Whatever the case may be, if vitamin D and cholesterol are indeed closely linked, one would expect low cholesterol levels to be associated with low vitamin D production based on sunlight.

Bogh et al. (2010) recently published a very interesting study. The link to the study was provided by Ted Hutchinson in the comments sections of a previous post on vitamin D. (Thanks Ted!) The study was published in a refereed journal with a solid reputation, the Journal of Investigative Dermatology.

The study by Bogh et al. (2010) is particularly interesting because it investigates a few issues on which there is a lot of speculation. Among the issues investigated are the effects of total cholesterol and skin pigmentation on the production of vitamin D from UVB radiation.

The figure below depicts the relationship between total cholesterol and vitamin D production based on UVB radiation. Vitamin D production is referred to as “delta 25(OH)D”. The univariate correlation is a fairly high and significant 0.51.

25(OH)D is the abbreviation for calcidiol, a prehormone that is produced in the liver based on vitamin D3 (cholecalciferol), and then converted in the kidneys into calcitriol, which is usually abbreviated as 1,25-(OH)2D3. The latter is the active form of vitamin D.

The table below shows 9 columns; the most relevant ones are the last pair at the right. They are the delta 25(OH)D levels for individuals with dark and fair skin after exposure to the same amount of UVB radiation. The difference in vitamin D production between the two groups is statistically indistinguishable from zero.

So there you have it. According to this study, low total cholesterol seems to be associated with impaired ability to produce vitamin D from UVB radiation. And skin pigmentation appears to have little  effect on the amount of vitamin D produced.

I hope that there will be more research in the future investigating this study’s claims, as the study has a few weaknesses. For example, if you take a look at the second pair of columns from the right on the table above, you’ll notice that the baseline 25(OH)D is lower for individuals with dark skin. The difference was just short of being significant at the 0.05 level.

What is the problem with that? Well, one of the findings of the study was that lower baseline 25(OH)D levels were significantly associated with higher delta 25(OH)D levels. Still, the baseline difference does not seem to be large enough to fully explain the lack of difference in delta 25(OH)D levels for individuals with dark and fair skin.

A widely cited dermatology researcher, Antony Young, published an invited commentary on this study in the same journal issue (Young, 2010). The commentary points out some weaknesses in the study, but is generally favorable. The weaknesses include the use of small sub-samples.

References

Bogh, M.K.B., Schmedes, A.V., Philipsen, P.A., Thieden, E., & Wulf, H.C. (2010). Vitamin D production after UVB exposure depends on baseline vitamin D and total cholesterol but not on skin pigmentation. Journal of Investigative Dermatology, 130(2), 546–553.

Young, A.R. (2010). Some light on the photobiology of vitamin D. Journal of Investigative Dermatology, 130(2), 346–348.

Polyphenols, Hormesis and Disease: Part II

In the last post, I explained that the body treats polyphenols as potentially harmful foreign chemicals, or "xenobiotics". How can we reconcile this with the growing evidence that at least a subset of polyphenols have health benefits?

Clues from Ionizing Radiation

One of the more curious things that has been reported in the scientific literature is that although high-dose ionizing radiation (such as X-rays) is clearly harmful, leading to cancer, premature aging and other problems, under some conditions low-dose ionizing radiation can actually decrease cancer risk and increase resistance to other stressors (1, 2, 3, 4, 5). It does so by triggering a protective cellular response, increasing cellular defenses out of proportion to the minor threat posed by the radiation itself. The ability of mild stressors to increase stress resistance is called "hormesis." Exercise is a common example. I've written about this phenomenon in the past (6).

The Case of Resveratrol

Resveratrol is perhaps the most widely known polyphenol, available in supplement stores nationwide. It's seen a lot of hype, being hailed as a "calorie restriction mimetic" and the reason for the "French paradox."* But there is quite a large body of evidence suggesting that resveratrol functions in the same manner as low-dose ionizing radiation and other bioactive polyphenols: by acting as a mild toxin that triggers a hormetic response (7). Just as in the case of radiation, high doses of resveratrol are harmful rather than helpful. This has obvious implications for the supplementation of resveratrol and other polyphenols. A recent review article on polyphenols stated that while dietary polyphenols may be protective, "high-dose fortified foods or dietary supplements are of unproven efficacy and possibly harmful" (8).

The Cellular Response to Oxidants

Although it may not be obvious, radiation and polyphenols activate a cellular response that is similar in many ways. Both activate the transcription factor Nrf2, which activates genes that are involved in detoxification of chemicals and antioxidant defense**(9, 10, 11, 12). This is thought to be due to the fact that polyphenols, just like radiation, may temporarily increase the level of oxidative stress inside cells. Here's a quote from the polyphenol review article quoted above (13):

We have found that [polyphenols] are potentially far more than 'just antioxidants', but that they are probably insignificant players as 'conventional' antioxidants. They appear, under most circumstances, to be just the opposite, i.e. prooxidants, that nevertheless appear to contribute strongly to protection from oxidative stress by inducing cellular endogenous enzymic protective mechanisms. They appear to be able to regulate not only antioxidant gene transcription but also numerous aspects of intracellular signaling cascades involved in the regulation of cell growth, inflammation and many other processes.

It's worth noting that this is essentially the opposite of what you'll hear on the evening news, that polyphenols are direct antioxidants. The scientific cutting edge has largely discarded that hypothesis, but the mainstream has not yet caught on.

Nrf2 is one of the main pathways by which polyphenols increase stress resistance and antioxidant defenses, including the key cellular antioxidant glutathione (14). Nrf2 activity is correlated with longevity across species (15). Inducing Nrf2 activity via polyphenols or by other means substantially reduces the risk of common lifestyle disorders in animal models, including cardiovascular disease, diabetes and cancer (16, 17, 18), although Nrf2 isn't necessarily the only mechanism. The human evidence is broadly consistent with the studies in animals, although not as well developed.

One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin (19). Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals (20, 21).

Chris Masterjohn first introduced me to Nrf2 and the idea that polyphenols act through hormesis. Chris studies the effects of green tea on health, which seem to be mediated by polyphenols.

A Second Mechanism

There is a place in the body where polyphenols are concentrated enough to be direct antioxidants: in the digestive tract after consuming polyphenol-rich foods. Digestion is a chemically harsh process that readily oxidizes ingested substances such as polyunsaturated fats (22). Oxidized fat is neither healthy when it's formed in the deep fryer, nor when it's formed in the digestive tract (23, 24). Eating polyphenol-rich foods effectively prevents these fats from being oxidized during digestion (25). One consequence of this appears to be better absorption and assimilation of the exceptionally fragile omega-3 polyunsaturated fatty acids (26).

What does it all Mean?

I think that overall, the evidence suggests that polyphenol-rich foods are healthy in moderation, and eating them on a regular basis is generally a good idea. Certain other plant chemicals, such as suforaphane found in cruciferous vegetables, and allicin found in garlic, exhibit similar effects and may also act by hormesis (27). Some of the best-studied polyphenol-rich foods are tea (particularly green tea), blueberries, extra-virgin olive oil, red wine, citrus fruits, hibiscus tea, soy, dark chocolate, coffee, turmeric and other herbs and spices, and a number of traditional medicinal herbs. A good rule of thumb is to "eat the rainbow", choosing foods with a variety of colors.

Supplementing with polyphenols and other plant chemicals in amounts that would not be achievable by eating food is probably not a good idea.


* The "paradox" whereby the French eat a diet rich in saturated fat, yet have a low heart attack risk compared to other affluent Western nations.

** Genes containing an antioxidant response element (ARE) in the promoter region. ARE is also sometimes called the electrophile response element (EpRE).