Thiamin, Carbs, Ketogenic Diets, and Microbes | MWM 2.14

If you want to make your thiamin feel
needed, the last thing you want to do is
go on a ketogenic diet. But thankfully
for you keto dieters out there, thiamin
doesn’t have any feelings.
A ketogenic diet has neurological benefits.
Why do we have to eat such an enormous
amount of food?
Complex Science
Clear Explanations
Class is starting now
Hi. I’m Dr. Chris Masterjohn of
And you’re watching
Masterclass with Masterjohn.
Today we’re in our fourteenth in a
series of lessons on the system of
energy metabolism. And our topic today is
the intersection between thiamin,
carbohydrate metabolism, and the
environment. Because, believe it or not,
although diet can be a source of
thiamin deficiency, there’s a lot of
reasons to believe that thiamin
deficiency could be a problem in the
environment, such as exposures to toxic
molds or other things of that nature.
This is something that’s really poorly
explored. But it’s something that’s
really serious and that we need to pay
attention to. So let’s dig right into it.
As shown on the screen,
burning carbohydrate for energy requires
twice as much thiamin as fat. That’s
because the two key roles of thiamin in
energy metabolism are in the
alpha-ketoglutarate dehydrogenase complex
and the entirely analogous pyruvate
dehydrogenase complex. Now the alpha-ketoglutarate
dehydrogenase complex needs
to convert alpha-ketoglutarate to
succinyl CoA during the citric acid
cycle, whether you’re getting your energy
from protein, carbohydrate, or fat doesn’t
matter. And the pyruvate dehydrogenase
complex, by contrast,
needs to convert pyruvate to
acetyl CoA only during carbohydrate
metabolism because pyruvate is derived
from glucose. Now we’re leaving out
protein metabolism and thiamin is not
irrelevant to protein metabolism.
And in fact even pyruvate can be
derived from the amino acid alanine. And
so even the pyruvate dehydrogenase
complex can be used in protein
metabolism. However, we’re going to ignore
those for two reasons: number 1 is we
haven’t gotten to protein metabolism yet.
And we’re not in a position to talk
about it at that level of detail for
protein. Number 2, quantitatively
those things don’t matter. If we just
ignore protein metabolism, it doesn’t
really alter to a meaningful degree the
main crux of the issue in terms of how
you would manipulate your macronutrients
in order to spare thiamin. So what we
can say is the big take-home message is
that you need twice as much thiamin when
you burn carbohydrate as when you burn
fat. And overall the biggest bang for
your buck in terms of sparing thiamin
is going to be to go on a low-carbohydrate
diet, regardless of whether
you’re eating a low-carbohydrate,
moderate-fat, moderate-protein diet, or a
low-carbohydrate, low-protein, high-fat
diet. You will get some benefit from
further restricting protein. And so the
diet that would maximally spare thiamin
would be a ketogenic diet: one that is
very low in carbohydrate, very low in
protein, and also high in fat. But the
difference you
get from restricting protein is
relatively small and operating on the
margins. Because thiamin is so much more
important to carbohydrate metabolism
than to the metabolism of the other
macros, it makes sense to posit that
thiamin could have a specific role in
diabetes and prediabetes, characterized
by elevated fasting glucose and by
postprandial glucose intolerance. Shown
on the screen is a small study from a
few years ago investigating that. What
they did was they took 17 subjects who
had impaired glucose tolerance, three of
whom were recently diagnosed with type 2
diabetes, the others of whom were
pre-diabetic. They gave them 100 milligrams
of thiamin hydrochloride
3 times per day for 6 weeks for a
total dose of 300 milligrams per day
over the course of that time period.
Then they gave them an oral glucose load
of 75 grams and they took their two-hour
glucose, which is shown on the screen.
And you can see that from baseline in
the black bars to the diagonally striped
bars, which represent the six-week mark,
nothing happened in the placebo group.
But two-hour glucose was reduced in the
thiamin group. Now this was a very small
study. And the effect looks meaningful.
But it’s not the be-all end-all of
treating diabetes. When we go from a
little under 10 to a little under nine
we’re talking about decreasing
postprandial glucose from 180 to 162
milligrams per deciliter, units that are
way more familiar to me and to many of
you who are in my United States audience.
We really want to get those under
140 or in these units at least
under 7.8 to say that we’ve resolved the
glucose tolerance. Nevertheless, this is a
small study in what is a
very limited pool of data overall. But
it’s hopeful, and it really does drill
home the point that there may be a
specific role for thiamin in dealing with
carbohydrate metabolism.
Now if we
really wanted to investigate this, what
we would want to do is select from among
the people who have impaired glucose
tolerance, the people in whom thiamin
deficiency is most likely to be the
reason. If we can find those people and
treat them, I think that’s where we’ll
get the best results. What’s really
interesting is that so far we’re not
looking at thiamin-deficient people. We’re
now going to turn to thiamin deficiency.
And what we’ll see is that when you’re
talking about a profound deficiency the
signs and symptoms are overwhelmingly
neurological. Now we’re not in a position
yet to talk about all of the signs and
symptoms and relate them back to thiamin
and metabolism. Because thiamin has
important effects on the antioxidant
system, which we haven’t talked about yet.
And on neurotransmitter synthesis, which
we haven’t talked about yet. And in fact
many of the symptoms that we’re going to
gloss over include cardiac symptoms like
an enlarged heart. What we’re going to
focus on today is the neurological
symptoms. Which are the overwhelming
symptoms with or without the cardiac
involvement anyway. But the reason
they’re so fascinating in the
context of talking about carbohydrate
versus fat metabolism, is that if you
look at ketogenic diets,
which derive their metabolism
overwhelmingly from fat, and thereby
would be the most thiamin-sparing
diets that there are when considering
macronutrient metabolism. The cases in
which ketogenic diets have proven to be
most useful so far are largely
neurological applications. The ketogenic
diet was born in the treatment of
refractory epilepsy, seizures that didn’t
respond to normal treatments. Even now,
people are considering it for
Alzheimer’s. Anecdotally people are using
it for things like infection-induced
brain fog and things like that. So let’s
turn our attention now to looking at the
neurological consequences of severe
thiamin deficiency. The early models of
experimental thiamin deficiency in
animals described it as polyneuritis,
inflammation of many nerves. And what you
see on the screen is a slide from the
pictures of Robert McCarrison, in his
book “Studies in Deficiency Disease” in
1921. Every animal that’s thiamin deficient
has its own characteristic species-
specific neurological condition that
results. And in birds, you have a
characteristic retraction of the head
that’s called star gazing, and rigid legs.
In monkeys, the characteristic sign is
called wrist drop, where the wrist
becomes limp and the monkey loses the
ability to hold up the hand. Although I
have no way of showing it on
the screen, the characteristic sign in rats is
that they keep walking around in circles.
The well-established signs of thiamin
deficiency in humans are shown on the
screen. Biochemically you’re going to see
elevations of pyruvate and alpha-
ketoglutarate for the reasons that we’ve
discussed. But you’re a lot more likely,
for reasons we’ll talk about in the next
lesson, to see lactate. Because lactate is
what you’d expect to find outside of
cells. You’d have to get
enormous accumulations of
pyruvate for it to be spilling over in
the urine. Lactate again for reasons
we’ll talk about in the next lesson, could
elevate for many other reasons.
Alpha-ketoglutarate out of these would be
most specific to thiamin deficiency.
There are other aspects of amino acid
metabolism that we’re not ready to
discuss yet where you could see other
biochemical signs, but we’ll save that
for later.
Classically, thiamin deficiency has been
known as beriberi.
It includes peripheral neuropathy, which
is weakness, numbness, pain, or tingling in
the extremities. Impairment of reflexes,
with or without cardiovascular symptoms
that can include an enlarged heart,
elevated heart rate, elevated cardiac
output, and congestive heart failure.
Another well-established syndrome of
thiamin deficiency is Wernicke’s
This can involve weakness or paralysis
of the muscles around the eye, ataxia,
which is problems with your coordination,
and confusion. Also peripheral neuropathy
is very frequent. Korsakoff’s psychosis
can be a progression of Wernicke’s
encephalopathy, but it can also be found
on its own. It involves amnesia and
confabulation. Confabulation is to have
fake or distorted or misinterpreted
memories that become real to you.
Decreased spontaneity and initiative.
If someone with Wernicke’s
encephalopathy is treated in the
emergency room by people who understand
the disease, high-dose intravenous
thiamin can prevent the progression to
Korsakoff’s psychosis. So it’s incredibly
important to recognize Wernicke’s
encephalopathy. Nevertheless, as we’ll see
in the next slide it often goes
unrecognized and diagnosed at death. The
quote on the screen is from the thiamin
chapter the latest edition of the
well-respected textbook, “Modern Nutrition
in Health and Disease.” “The diagnosis of
Wernicke’s encephalopathy is based
generally on the
acute appearance of ocular palsies,” which
is paralysis possibly with tremors of
the muscles around the eye. “Nystagmas,”
which is rapid uncontrollable eye
movements. “And gait ataxia,” which is the
inability to coordinate your movements
during walking. “As well as disorders of
mentation,” which is disorders of how you
think. “In addition, more than 80% of
patients with Wernicke’s encephalopathy
shows signs of peripheral neuropathy.
However, these diagnostic criteria are
nonspecific, and the diagnosis of
Wernicke’s encephalopathy is missed in
many patients with alcoholism, as well as
those with HIV or AIDS. The reason for
the high degree of underdiagnosis rests
with the overzealous use of the classic
triad of symptoms (ophthalmoplegia)” which
is the disorders of the
muscles around the eye, “(ataxia)” the
disorders of walking “(and confusion)
espoused by many textbooks. In practice,
many cases of Wernicke’s
encephalopathy are confirmed at autopsy
and do not manifest this triad of
symptoms. And patients may show only
psychomotor slowing or apathy.” They go
on: “A rewriting of this textbook definition
of Wernicke’s encephalopathy is long overdue.
In the meantime, thiamin deficiency
should be suspected in all patients with
grossly impaired nutritional status
associated with chronic diseases, with
particular attention paid to patients
with chronic alcoholism, gastrointestinal
diseases, HIV and AIDS, and persistent
vomiting. Thiamin should be administered
parenterally, in a timely manner. It is
essential to administer thiamin to all
patients before infusions of glucose or
parenteral nutrition are given.” Wait a
They said confirmed at autopsy? [Wah wah wah.]
Clearly even severe cases of thiamin
deficiency are massively
under-recognized and under-diagnosed.
Bu I’d also like to suggest that there are
many causes of moderate thiamin
deficiency that go unnoticed even beyond
this. Because what if suboptimal thiamin
status plays a role in glucose
intolerance for example? Furthermore, as
we’ve seen, thiamin deficiency is so
overwhelmingly neurological that we have
to wonder in cases where people report
improvements in their neurological
outcomes or their cognitive outcomes,
with low-carbohydrate diets, including
ketogenic diets, could this be related to
the key role of thiamin and
carbohydrate metabolism and the sparing
effect of a fat-based diet on thiamin
status? Now let’s move on to talk about
some of the reasons why people may have
suboptimal thiamin status, because
understanding this might help us
understand how to improve the metabolic
flexibility of people who have
difficulty tolerating carbohydrates. The
most well-established causes of thiamin
deficiency are shown on the screen. They
include a diet poor in thiamin-rich
foods, such as whole grains, legumes and
meat. Gastrointestinal and liver diseases.
Persistent vomiting and chronic
alcoholism. Because ethanol decreases the
absorption of thiamin, impairs the
storage of thiamin in the liver, and
inhibits brain thiamin phosphorylation.
Remember thiamin pyrophosphate or
diphosphate is the active form. Now if you
look at thiamin-rich foods, you’ll notice
that whole grains, legumes and meat are
listed. In fact, if you exclude foods that
are enriched with supplemental
thiamin, you’ll see that most thiamin-rich
foods have about a milligram
of thiamin per 100 grams, which is enough to
meet your daily requirement of thiamin
if you eat just over one serving of
those foods. And you’ll also notice that
if it’s found in whole grains and
legumes, then you could easily meet your
thiamin requirement on a vegan diet. On
the other hand, if it’s found in meat you
could easily meet your thiamin
requirement on a carnivorous diet.
However, there are two types of diets
where you can’t easily meet your
thiamin requirement. Number one is a
diet overwhelmingly composed of foods
that have been stripped of their natural
nutrients. Historically beriberi was
associated with the consumption of white
rice for that reason. Nowadays, junk food
is fortified with thiamin. So you’re
unlikely to get a thiamin deficiency
from eating refined enriched flours, like
white bread products, today. However, you
could still get a thiamin deficiency if
you mostly eat fat. Because thiamin is
found in whole grains,
it’s found in legumes, and it’s found in
meat. But it’s not found in large
quantities in fat. And who eats diets
that are mostly fat? Ketogenic dieters.
This is really critical because I’ve
been saying through this entire lesson
that a ketogenic diet is thiamin
sparing. But the diet that maximally
spares thiamin is also the diet that if
it doesn’t contain supplemental thiamin,
doesn’t have any thiamin. Shown on the
screen is an example from 1979 where
people developed optic neuropathy when
they were being treated with ketogenic
diets for refractory epilepsy. And that
happened because they were given the
ketogenic diet with no B vitamin
supplements. As soon as they were given
thiamin supplements, everything started
turning around.
So we have to remember that even
though fat requires half as much
thiamine as carbohydrate does, it doesn’t
require zero thiamin. So if you cut your
thiamin requirement in half, but you
don’t eat any thiamin, you can still get
a thiamin deficiency. There are other
potential causes of thiamin deficiency.
For example, raw fish can contain
thiaminases that destroy thiamin.
This was initially discovered when
people tried feeding wolves on
exclusively raw fish diets. Now no one
really knows where the thiaminases in
fish come from, but it appears not to be
an intrinsic property of fish but
something that happens because of the
fish’s environment, and we’ll come back
to that in a few minutes. Heat and
processing causes significant losses of
thiamin. During baking you destroyed 20
to 30 %, during pasteurization you
destroy 20% and pet food processing
destroys 90%. In fact, what they do with
pet food is they add ten times more
thiamin to the pet food than they want,
and then they blow it to smithereens,
knowing that 10% will be left, which is
just enough to satisfy your pet’s thiamin
requirement. Now keep in mind, of course,
that as we said before if you’re eating
a natural diet of natural whole foods
that includes either meat, legumes or
whole grains, you’re probably going to
exceed your thiamin requirement enough
that destroying 20 to 30 percent in
baking or pasteurization is okay.
Nevertheless, if you’re borderline or you
have other reasons for thiamin
deficiency, then the toll that heat and
processing takes could become
significant. Gut bacteria have been found
to cause thiamin deficiency.
Unfortunately all the data that we have
on this is from a long, long time ago. So
we don’t really have any basis to find
thiamin-destroying gut microbes in
humans with current fecal stool tests,
because no one’s studying it right now.
In addition, in cattle in veterinary
science it’s been known that thiamin
destroying microbes in the rumen of
cattle are the major source of thiamin
deficiency in that context. In humans who
consume the larvae of an African moth,
anaphe venata,
which they eat in the rainy season in
Nigeria in the southwest, July through
October, they get thiaminases from those
moth larvae. And they eat the larvae
traditionally with carbohydrate-rich
foods. So on the background of a thiamin-
deficient diet, they consume
thiamin-destroying thiaminases in the
moths together with carbohydrates that
increase their need for thiamin, and
clinical thiamin deficiency results. Out
of these, the most fascinating is
environmental thiamin deficiency. There
are regional outbreaks of thiamin
deficiency in wildlife that are
attributed to antagonists in the
environment, and we don’t really know
what they are. This really brings to the
front burner for me the question of: are
we humans subject to environmental
thiamin deficiency? On the left panel of
the screen is a bird that was found in
an area surrounding the Baltic Sea. You can
see that it has the
characteristic star gazing neurological
defect that Robert McCarrison had
identified in experimental thiamin
deficiency in birds almost a hundred
years before this publication. They find
this with paralysis and seizures a lot
in some of the areas around the Baltic
Sea. On the right is data showing that
when they treat these birds with thiamin,
9 out of 10 recovered.
But in the birds that weren’t treated
with thiamin, none of them recovered,
providing pretty strong evidence that
what’s happening is a regional outbreak
of thiamin deficiency. They also find
tremors, seizures, and death among these
birds. When studied in more detail, they
found low-tissue concentrations of
thiamin, and high latency of alpha-
ketoglutarate dehydrogenase and another
enzyme, transketolase. High latency means
that they took the enzymes and they
tested them to see their activity. Then
they added thiamin and tested their
activity again. If there’s a large
increase in the activity of the enzyme
after adding thiamin to it, that means
there’s high latency. High ability of the
enzyme to be activated with extra
thiamin. When that’s the case, it’s a
strong sign of thiamin deficiency
because it means that that bird has been
making thiamin-dependent enzymes that
don’t have any thiamin in them. And why
would the bird do that unless the bird
didn’t have enough thiamin to activate the
enzymes it was trying to make?
Now this enzyme, transketolase, is a
thiamin-dependent enzyme that protects
against oxidative stress. We haven’t
talked about that in this series of
lessons yet, but let’s note it now
because it’ll come up later. But also
because in humans you can test
transketolase in red blood cells. It’s
the best marker of thiamin deficiency
in humans that we have and no laboratory
in the United States offers it as a
clinical test. If you’re out there and
you run a clinical laboratory, I plead
with you, begin offering erythrocyte
transketolase activity as a test for
human thiamin status. So far no one
knows exactly what’s causing thiamin
deficiency in the Baltic Sea. The
researchers have speculated that it
might be traceable to thiamin
antagonists produced by algae in the
dead zones and is thus traceable to the
environmental problems that are
causing those dead zones to arise.
Meanwhile, lake trout in the Great Lakes
have also been subject to these
outbreaks of regional thiamin
deficiency. In that case, investigators
have partly traced it to alewifes, which
are non-native fish that have been
introduced in that environment. And
alewifes produce thiaminases that can
accumulate up the food chain and cause
thiamin deficiency in the animals that
are above them in the food chain.
Now the alewifes do have thiaminase in
their tissue, but it’s only been partly
traced to specific microbes in their
tissue. And no one knows where 90% of the
thiaminases from the alewifes is
coming from. So these outbreaks are
really mysterious. Here’s what we know
about potential thiamin antagonists.
Very early on it was shown that sodium
sulfite in vitro, meaning in a test-tube,
irreversibly cleaves thiamin. Now I
don’t know if this has any clinical relevance.
However, sulfite is something that you
normally turn into sulfate with enzymes
that require molybdenum, an essential
mineral, to be activated. So I think it’s
theoretically possible that someone
could have a molybdenum deficiency, then
produce sulfite in their metabolism that
doesn’t get metabolized to sulfate, and
that could destroy thiamin. Again, that’s
speculative, but it seems like it could
happen. We know that fish and shellfish
contain thiaminases. And we have the
evidence that seems to correlate them
with things in the environment and trace
them to bacteria. But these are very
poorly understood.
We know that ferns produce thiaminases.
And we know that in ferns they vary
seasonally. As I mentioned before, the
larvae of the African silkworm
produces thiaminases. And in human feces,
clinical thiamin deficiency,
particularly in Japan studied many
decades ago, has been traced to bacteria
such as Bacillus thiaminolyticus, Bacillis
aneurinolyticus, and Clostridium thiaminolyticum,
which is now, or at least later
became called Paenibacillus
thiaminolyticus. Now it’s
important to note that the people who
were naming these were naming them after
thiamin destruction or nervous system
destruction. And this research has
largely been abandoned to my knowledge
decades ago. So I think it’s very
possible that there are thiamin-
destroying microbes in the human gut,
with no good way to test them right now,
until we start doing more research on it.
There are fungi such as Trichosporum
aneurinolyticum, Candida aneurinolytica,
Lentinus edodes.
And finally most recently an
amoebaflagellate, Naegleria gruberi.
I have no idea if I’m pronouncing
these right, so don’t hold me to it.
But most recently the first amoeba was
found that can be a contaminant of water
to produce thiaminases.
So there’s a lot of things that we don’t
know about thiamin deficiency. And yet
there’s a lot of things that we know. For
example, you can suspect it on the basis
of glucose intolerance and toleration of
fat better that carbohydrate. You can suspect
it on the basis of neurological
conditions. And you shouldn’t wait to
diagnose it at autopsy, but you should
look for it with even any plausible
scenario of nutritional deficiency
combined with neurological symptoms.
And we know that it isn’t just caused by a
diet that lacks either meat, whole grains
or legumes.
But it can also be caused by microbes
and poorly understood things in the
environment. What that means is we may be
dealing with gut issues, with toxic mold
exposure, maybe even chemical exposures
and things that vary in our environment
that are poorly studied. On that basis, we
need to start thinking outside of the
box and realize that there could be
things that are interfering with
thiamin even when dietary thiamin
deficiency seems implausible. And even
when someone doesn’t have things like
persistent vomiting, alcoholism, and those
other classical things associated with
the history of Wernicke’s encephalopathy.
Therefore, I plead especially with the
healthcare practitioners out there, start
thinking more about thiamin deficiency
when you see something as simple as
glucose intolerance, especially if it’s
accompanied by neurological problems.
And start thinking beyond just diet as a
plausible explanation of thiamin
deficiency. And think through things like
mold exposure and other environmental
causes. Finally we don’t have, at least in
the United States, the ideal marker of
thiamin status, erythrocyte transketolase.
But we do have the ability to look for
urinary organic acids. And if we see
things like elevated lactate and alpha-
ketoglutarate in the urine, that can be
really helpful in trying to understand
the possibility or look for the
possibility of a thiamin deficiency.
Fnally there’s no known detriment to
taking thiamin supplements. And so if
everything seems plausible, then whether
someone gets better with thiamin
supplementation could be a useful way of
going about trying to figure out and
solve the problem. The audio of this
lesson was generously enhanced and
post-processed by Bob Davodian of Taurean Mixing,
giving you strong sound and
dependable quality. You can find more
of his work at
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All right, I hope you found this useful.
Signing off, this is Chris Masterjohn of You’ve been
watching Masterclass with Masterjohn.
And I will see you in the next lesson.

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