A Hypothesis: The Negative Health Effects of Fructose are Mediated Largely by the Production of Endotoxin

In my previous post I looked at studies showing sucrose to have similar health effects as glucose and starch (not entirely the same effects granted, but close). Yet hundreds of studies exist demonstrating the negative effects of fructose compared to glucose. If sucrose contains fructose, one might think sucrose should look worse compared to glucose.

So why then is sucrose not as unhealthy as the sum of its parts? I’ll be presenting a hypothesis on why I think this occurs.

So the question is: why is fructose unhealthy alone, but not nearly as bad when consumed with glucose?

When fructose in consumed in large quantities, it’s difficult to absorb it from the gastrointestinal tract, but consumption of fructose with glucose significantly improves the absorption of fructose. Why is this important? When fructose can’t be absorbed, as occurs in the absence of glucose, it passes through the intestines feeding bacteria, including the gram negative variety.

The cell wall of a gram negative bacteria is also known as endotoxin because it has a number of toxic effects in the human body. When fructose feeds these bacteria in the gut, endotoxin is produced and can pass into the blood stream where it exerts many of these negative effects. I have come to suspect that this phenomenon, through a variety of mechanisms, is responsible for much of the observed negative health effects of fructose and additionally explains why sucrose does not seem to have many of these negative effects.

The evidence? Well, other than the fact that fructose seems to increase endotoxin content in the gut, let’s compare studies of either fructose feeding or endotoxin injection:

  • Fructose and endotoxin both increase triglycerides.
  • Fructose and endotoxin both increase leptin (indicative of leptin resistance).
  • Fructose and endotoxin both promote liver fat accumulation.
  • Fructose and endotoxin both increase insulin resistance.
  • Fructose and endotoxin both increase inflammatory cytokines like tumor necrosis factor-alpha.
  • Fructose and endotoxin both promote obesity, especially visceral fat accumulation.

These negative effects of fructose and endotoxin are entirely blocked in mice with mutation of their TLR4 protein. TLR4 is famously known for being a receptor for endotoxin. It is not known to be a receptor for fructose.

Finally, are there any experiments further backing up the idea that these similarities aren’t just a series of crazy coincidences? Why yes, yes there are. So called “germ free mice” without bacteria in their gut to produce endotoxin are protected from obesity during high fructose diets, while their germ filled cousins are not protected on the same diet. Similarly, studies giving animals fructose and antibiotics eliminates the negative effects of fructose seen without concurrent antibiotic treatment. There are also studies using (gram positive) probiotics which produced similar results.

What does this all mean? A lot, in my opinion. This will be a topic I’ll touch on in the future, but for now I’ll say that I think a significant reason fructose is “bad” is because it can feed bacteria and lead to endotoxin production. Presumably, methods of improving fructose absorption and possibly increasing intestinal permeability could greatly reduce the negative effects of fructose consumption.

There’s a lot more to write about this subject, so I’ll leave this post with a visual graph of my current hypothesis, which I acknowledge will likely be oversimplified and imperfect at this point:

Endotoxin fructose hypothesis



I usually post a wall of citations, but I have gathered a enormous number of studies together in an unorganized manner, so this post will (for now) have no references. I’ll try to amend this in the future.


2 thoughts on “A Hypothesis: The Negative Health Effects of Fructose are Mediated Largely by the Production of Endotoxin

  1. dodny November 25, 2012 / 4:56 am

    It is good to see someone putting things back again into more correct perspective in this stage of still somewhat continuing witch hunt on all things fructose. Someone should definitely try to dis/prove your hypothesis, it seems to make sense in the current light of evidence. All thumbs up and thank you. And now, back to eating my dried figs :D.

    • Morgan November 25, 2012 / 9:47 am

      Thanks for your comment, dodney. Yes, I think this provides evidence that fructose is not inherently toxic, as many have claimed. I hope to look into this a lot more in the future..

      And dried figs are delicious =)

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