Butyrate: fuel for the colon

The cells lining your colon do something unusual. They largely do not run on glucose. They run on a molecule made by the microbes living next to them — and what happens as they burn it turns out to hold the whole system together.

The cells and their fuel

The lining of your colon is a single layer of cells called colonocytes, renewed constantly. Their preferred fuel is butyrate, and it supplies a large majority of their energy — commonly cited as around 70% (Roediger, 1980; Donohoe et al., 2011).

That is a genuinely odd arrangement. Most cells in your body are fed by what you ate. These are substantially fed by what your microbes made from what you could not eat.

One consequence follows immediately. A diet low in fermentable fibre does not only slow transit — it under-fuels the cells that maintain the barrier between the contents of your gut and the rest of you.

Burning butyrate uses oxygen

Here is the part that is rarely explained, and it is the most interesting thing in this course.

Butyrate is a fatty acid, and burning it requires oxygen. Colonocytes consuming butyrate therefore draw oxygen down inside themselves, and the tissue becomes markedly low in oxygen.

Two things follow from that low-oxygen state.

The barrier tightens. Low oxygen stabilises a regulator called HIF-1α, which drives expression of genes involved in the junctions between cells and in barrier function (Kelly et al., 2015). The fuel and the seal are connected.

The lumen stays anaerobic. Oxygen consumed by the lining is oxygen that does not diffuse out into the gut contents — and the organisms that make butyrate are strict anaerobes that require exactly that.

The loop

Read those together and it closes on itself. Fibre feeds microbes, microbes make butyrate, colonocytes burn butyrate and consume oxygen, low oxygen keeps the lumen anaerobic, and anaerobic conditions are what those microbes need to keep making butyrate.

A self-reinforcing system — which also means it can unwind in the same direction. Less fermentable fibre means less butyrate, so less oxygen consumed by the lining, so more oxygen reaching the lumen, which favours a different set of organisms that tolerate it.

This is why "feed your gut" is not a slogan. There is a mechanism with a direction, and it runs both ways.

Butyrate also signals

Separately from fuelling anything, butyrate acts on gene expression. It inhibits a class of enzymes called histone deacetylases, which changes how accessible certain genes are — and through that route it is studied for effects on antioxidant defences and on inflammatory signalling.

Worth being precise about one thing here, because it is easy to get wrong: this signalling route is not the same as the energy route. Butyrate's effects on inflammation are transcriptional, not a consequence of making mitochondria run more cleanly. Two mechanisms, one molecule.

Go deeper: where butyrate enters the energy system

Butyrate is a four-carbon fatty acid, so it bypasses glycolysis entirely. Inside the mitochondrion it is activated and put through one round of beta-oxidation, which yields the electron carriers FADH₂ and NADH and two acetyl-CoA. Those acetyl-CoA units go into the TCA cycle, generating further carriers, and the carriers feed the electron transport chain to make ATP.

The oxygen consumption described above is precisely this: the electron transport chain's terminal step reduces oxygen. So the barrier effect and the energy yield are not two separate facts about butyrate — the first is a consequence of the second.

Note what is not claimed. Butyrate has also been shown in animal and cell studies to promote mitochondrial biogenesis via AMPK and PGC-1α. That is real work, but it has not been shown in people taking a daily fibre, and we keep it separate from the chain above.

Colonocytes burn butyrate. Burning it consumes oxygen. Low oxygen holds the barrier and keeps the lumen anaerobic — which is what the butyrate-makers need. The loop feeds itself, and starving it unwinds it.

What to hold on to

Butyrate is not a supplement ingredient in this story. It is something your colon makes, continuously, from material you cannot digest — and the making of it maintains the conditions for more of it.

Which leaves one question. If fermentation is this consequential, does it matter where along the colon it happens?