Category Archives: Advanced nutrition

Research studies, hypotheses, data, etc.

Non-celiac gluten sensitivity

Gluten is protein, not carbs.  A gluten-free diet is frequently low-carb, because most dietary gluten comes in the form of bread (and wheaty foods).  But believe it or not, bread is an incredibly complex food… many different proteins, carbohydrates, and nutrients that could be problematic for some people (more on this later).

Gluten is not a FODMAP, but most gluten-containing foods are.  Gluten is actually very rich in the amino acid glutamine.  Gluten, not bread.

So we have three studies on purified “gluten,” asking if it’s the gluten, FODMAPs, or something else in wheaty food that is problematic.

Study #1. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of FODMAPs (Biesiekierski et al., 2013)

Strong study design; patient population was people who thought they were gluten sensitive (but definitely not celiac).

This is the study which led journalists to claim non-celiac gluten sensitivity doesn’t exist, and it’s really sensitivity to FODMAPs, in part, because of this:

 

 

low FODMAPs and gluten free

 

 

Baseline = low gluten diet
Run-in = low gluten and low FODMAPs

 

Here’s the fly in the ointment:

 

symptoms returned in all participants

 

After the run-in period, subjects still followed their gluten-free diets but also received either 16g relatively pure gluten/d (High gluten), 2g gluten + 14g whey protein (Low gluten), or 16g whey protein (placebo).  GI symptoms returned in all participants.  So, low FODMAPs worked for about a week, but then symptoms returned regardless of whether they were eating gluten or not.  In other words, neither low FODMAPs nor low/no gluten worked very well in this study.

But this study may have introduced a brilliant new confounder: food intake was strictly controlled — the experimental diets were different from their normal diets.  Restricting gluten and FODMAPs may have provided some transient benefit, but if the new experimental diet introduced something else that caused problems, then that may explain the gradual return of symptoms…

bollixed?

 

 

Study #2. Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial (Di Sabatino et al., 2015)

It was another high quality study design: “Randomized, Double-Blind, Placebo-Controlled, Cross-Over.”  And it was addressing a basic question: do people who strongly suspect they have non-celiac gluten sensitivity (NCGS) really have NCGS?  Alternatively, is NCGS real?

Intervention was strong:

1) 4.375 grams of gluten or placebo (rice starch) daily for a week.  This is roughly equivalent to two slices of bread (note: this is way more than enough gluten to destroy the intestines of a patient with bona fide celiac disease).

2) important: they defined the what they would classify as NCGS prior to starting the trial.  A priori.

61 patients strongly suspected of NCGS started the trial, and one withdrew due to gluten-related symptoms in both the gluten and placebo groups.

 

Results:  regardless of whether they were assigned to gluten or placebo FIRST (prior to the crossover), most patients reported gluten-related symptoms.  More importantly, 3 of the 59 patients exhibited significantly worse symptoms on gluten relative to placebo according to the endpoint they defined prior starting the trial.  In one sense, this could be interpreted to mean 5% of people who strongly believe they have NCGS actually have NCGS.

 

gluten sensitive patients

 

Two patients reacted just as selectively strongly to the placebo as the three “real” NCGS patients did to gluten.  Rice-starch sensitivity?

 

See here for a more detailed description of the statistics involved in this study.  I’m willing to accept the “5%” rate, despite the strength of the placebo-responders, whereas the author of that blog post is not.  That’s fair, imo.

And here is another article which questions the legitimacy of NCGS based on this study.  I don’t think that’s totally fair.

And Raphael’s post, where he humorously concludes: “[Gluten-free] does not include advice to sport a gas mask when walking past bakeries.”

 

 

Study #3. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity (Hollon et al., 2015)

 

 

gluten increases intestinal permeability

 

 

“Delta TEER” is basically the amount of intestinal permeability in intestinal explants exposed to media + gluten (experimental condition) minus those exposed to plain media (control condition).  A better control condition, imo, would’ve been something like they did above: substitute gluten with another protein like whey protein.

 

NC: healthy people
RCD: celiac patients in remission
ACD: celiac patients with active disease
GS: non-celiac gluten sensitivity

 

Active celiac samples responded significantly worse than those in remission, which is good as it functions as a positive control for the experimental protocol.

 

However, gluten sensitive samples responded significantly worse than celiac remission samples; actually, they responded just as badly as celiac samples with active disease.  Celiac disease is supposed to be a million times worse than non-celiac gluten sensitivity… and statistically speaking, even permeability the normal samples declined as much as NCGS samples.

 

This led some to conclude that gluten is bad for EVERYONE.  I’d say it means the assay is bollixed.  Occam’s razor?

 

 

My advice: don’t be anti-science, but don’t use bad science to justify diet choices.  We simply need better studies on non-celiac gluten sensitivity and FODMAPs.

If bread doesn’t work for you, don’t eat bread.  You’re not missing much.

 

If you like what I do and want to support it, check out my Patreon campaign!

 Affiliate links: still looking for a pair of hot blue blockers? Carbonshade and TrueDark are offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HEREIf you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE.

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else.

Join Earn.com with this link. Get paid to answer questions!

calories proper

 

 

calories proper

 

Become a Patron!

 

 

Save

Carbs: Low vs. Lower

 

 

This was met with much backlash from the low carb cavalry, because, well, if low is good then lower must be better

I’m not anti-keto; but I’m not anti-science.  FACT.

 

“…some people are not genetically equipped to thrive in prolonged nutritional ketosis.” –Peter Attia

Continue reading

LIGHT, Leptin, and Environmental Mismatch

For a long time, the melanocortin system was basically thought to control the color of skin and hair.  It still does, and many redheads are redheaded due to polymorphisms in one of the melanocortin receptors.

Fast forward to 2015: to make a long story short, melanocortins are HUGE players in circadian biology.

 

POMC ACTH a-MSH

 

Brief background (also see figure above):

Fed state -> high leptin -> a-MSH -> MC4R (the receptor for a-MSH) = satiety, energy production, fertility, etc.

Fasted state -> low leptin -> AgRP blocks MC4R = hunger, energy conservation, etc.

MC4R polymorphisms in humans are associated with obesity.  Melanotan II causes skin darkening (marketed as “photoprotection” [no bueno, imo]), enhanced libido, and appetite suppression.

 

Continue reading

Circadian Disruption Impairs Survival in the Wild

…just read that huge disasters, ranging from Exxon Valdez to Chernobyl, may have been due, in part, to ignorance of basic principles of circadian rhythms.  Gravitas.

 

circadian rhythms

Continue reading

Meal timing and peripheral circadian clocks

More on why breakfast in the morning, with light onset is important to avoid circadian desynchrony.

FOOD is excellent at entraining peripheral circadian clocks: if you restrict animals to one meal per day, their peripheral circadian clocks rapidly become entrained to this, regardless of when the meal is administered (Hirao et al., 2010):

 

zeitgeber entraining

ZT0 = “zeitgeber time 0,” or “lights on.” pZT indicates a phase shift coinciding almost exactly with meal timing. Mice normally eat at night, but this doesn’t stop their peripheral clocks from entraining to the day time if that’s when their fed.

This study took it to the next level: they fed 2 meals per day, varying in size, time of day, and duration between meals in almost every conceivable combination.  Actually, it was a quite epic study… some poor grad students working, literally, around the clock, for months…

Continue reading

Entraining Central and Peripheral Circadian Rhythms

“Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake, can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and type 2 diabetes.”

If you haven’t been following along, a few papers came out recently which dissect this aspect of circadian rhythms — setting the central vs. peripheral clocks.

In brief (1):  Central rhythms are set, in part, by a “light-entrainable oscillator (LEO),” located in the brain.  In this case, the zeitgeber is LIGHT.

Peripheral rhythms are controlled both by the brain, and the “food-entrainable oscillator (FEO),” which is reflected in just about every tissue in the body – and is differentially regulated in most tissues. In this case, the zeitgeber is FOOD.

In brief (2):  Bright light in the morning starts the LEO, and one readout is “dim-light melatonin onset (DLMO),” or melatonin secretion in the evening. Note the importance of timing (bright light *in the morning*) – if bright light occurs later in the day, DLMO is blunted: no bueno.

Morning bright light and breakfast (FEO) kickstart peripheral circadian rhythms, and one readout is diurnal regulation of known circadian genes in the periphery.  This happens differently (almost predictably) in different tissues: liver, a tissue which is highly involved in the processing of food, is rapidly entrained by food intake, whereas lung is slower.

Starting the central pacemarker with bright light in the morning but skimping on the peripheral pacemaker by skipping breakfast represents a circadian mismatch: Afternoon Diabetes? Central and peripheral circadian rhythms work together.  Bright light and breakfast in the morning.

Continue reading

Mushrooms are awesome (P<0.05)

“Without leaves, without buds, without flowers;
Yet they form fruit.
As a Food, as a tonic, as a medicine;
The entire creation is precious.”

-weird mushroom poem of sketchy origin

Mushrooms: They have B12! When exposed to UV light, they make vitamin D2.  Protein, fibre, and selenium.  Shall I go on?

Continue reading

Vitamin D, Fiat Lux, and Circadian Rhythms

Vitamin D synthesis is TEAMWORK!

Skin: 7-dehydrocholesterol + UVB = previtamin D3.
Liver: Previtamin D3 –> 25(OH)-Vitamin D3.
Kidney: 25(OH)-Vitamin D3 –> 1,25(OH)2-Vitamin D3 if you need it or 24,25(OH)2-Vitamin D3 if you don’t.

N.B. one of the major regulatory pathways occurs in skin: if you’re getting a lot of sunlight, then skin darkens to block this step.  Supplemental and dietary Vitamin D3 bypass this… but the dietary Vitamin D supply rarely produces toxicity because it’s not very abundant.  In other words, sunlight Vitamin D never reaches toxic levels.  Supps could (rare, but possible).

Disclaimer: I’m not against Vit D supps, but prefer sunlight whenever possible.

The other major regulatory step is in the kidney.  Production of 1,25(OH)2-Vitamin D3 is tightly regulated — so blood levels don’t decline until your very deficient… so 25(OH)-Vitamin D3 is a better indicator of skin production and dietary intake.

Disclaimer #2: this post is not about any of the pleiotropic effects of Vitamin D or D supps, which range in value from worthless to helpful to possibly harmful.

 

 

Continue reading

CICO and rant

“Wait… what?  nutrient partitioning?”

Calories In, Calories Out should not be interpreted as “eat less, move more,” but rather kept in its more meaningless form of: “if you eat less than you expend, you’ll lose weight.”  At least then, it’s correct… meaningless, but correct.  Eating less and moving more is no guarantee of fat loss, in part, because total energy expenditure isn’t constant and there’s that whole thing with nutrient partitioning.

For obese insulin resistant folks, this is Low Carb’s strong suit: it causes “eat less, move more”spontaneously.

For some obese insulin sensitive patients, for whatever reason, their adherence and success is greater with Low Fat.  You might say, “yeah, but those suckers had to count calories.”  To that, I’d counter with: “it doesn’t matter, THEY WERE MORE SUCCESSFUL COUNTING CALORIES ON LOW FAT THAN NOT COUNTING ON LOW CARB.”  The spontaneous reduction in appetite obviously didn’t cut it.  Do not be in denial of these cases.

Continue reading

Ketone bodies as signaling metabolites

*non sequiter*

One of the ways dietary carbohydrate contributes to liver fat is via ChREBP: “carbohydrate-response element binding protein.”  It responds to a glucose metabolite and activates transcription of lipogenic genes.  Insulin helps.  Ketones do the opposite (Nakagawa et al., 2013), by inhibiting the translocation of ChREBP into the nucleus where it does it’s dirty work:

 

ChREBP

 

More interestingly, ketones are histone deacetylase inhibitors (HDACi)… this leads to more histone acetylation.  Benefits of fasting sans fasting?  Modulating of acetylation is a MAJOR regulator of circadian rhythmicity.

Butyrate is another HDACi, so have some fibrous plant foods with your red wine and dark chocolate.  Anti-aging (mostly worm studies, but still).

 

Continue reading