Why the Colon Must Stay Anoxic

What is the function of the colon? The current understanding is surprisingly narrow in scope. Once food passes through the small intestine and reaches the colon, most digestible macronutrients have already been absorbed. The structural features also change from the ileum to the colon in a way that suggests functional divergence. The ileal lumen has features that increase surface area (circular folds, villi, and brush border) for efficient nutrient absorption. This area-maximizing architecture is lost in the colon. Instead, the tube enlarges in diameter, with a characteristic segmental pouching called haustration. The mucosal surface is largely flat and rich in mucus-secreting cells, suggesting that the stool is more dehydrated and mechanically abrasive at this point. Transit time through the colon is also significantly slower than through the ileum. So at first glance, the colon appears to be simply a storage organ for stool until defecation.

Colon (original diagram from Gray's anatomy)

In fact, many animals, including carnivores and many fish, lack a colon altogether. Humans, along with animals such as horses, elephants, and rabbits, rely to varying degrees on microbial fermentation in the distal gut, with a substantial microbial load in the cecum and colon. In both non-fermenters and hindgut fermenters, the small intestine remains the predominant site of enzymatic digestion and absorption of macronutrients. Plant fibers, however, cannot be digested directly by animal enzymes, and therefore require a separate fermentation chamber to convert them into short-chain fatty acids (SCFAs) that can be absorbed and used as energy. The colon is that chamber.

Why rely on microbes for the digestion of plant fibers? Plant fibers are polymers of simple sugars, but the sugars are linked differently from those in digestible starch. The chemical bond itself may seem easy enough to break with similar hydrolase chemistry. But that is not the real problem. Plant fibers such as cellulose form densely packed structures that are poorly accessible to water and enzymes. And if enzymes cannot physically access the bond, hydrolysis becomes difficult.

Cellulose is made out of glucose, but cannot be easily digested since they are densely packed, held together by hydrogen bonds (cyan). This is why cotton (90% cellulose) cannot be digested by many organisms, unlike cotton candy.

While mammals never evolved an efficient way to do this themselves, certain microbes did. They deploy specialized extracellular and cell-surface carbohydrate-degrading machinery that can attach to plant material and slowly erode the cell wall. Rather than evolving this entire machinery themselves, fiber-eating animals entered into a symbiotic relationship with such microbes by housing them in the distal gut.

But this collaborative relationship contains a major conflict of interest. Releasing digestible sugars from plant fiber is the investment part; it does not yield energy unless those sugars are further metabolized. The real question is: who gets the energy stored in the sugar? If the host takes it all, there is no energetic benefit for the microbe. But these degradative systems are not free for bacteria to produce, so that would be a terrible trade. If microbes instead extract all the redox energy from those sugars by oxidizing them completely to carbon dioxide, that maximizes energy yield for the bacteria but leaves little for the host. The ideal arrangement is to stop somewhere in the middle — preferably early, so much of the energy remains in the product and can still benefit the host. But why would bacteria have any interest in stopping halfway?

The answer lies in the availability of terminal electron acceptors. Metabolism extracts energy by oxidizing reduced carbons. As electrons flow from carbon to oxygen, much like water flowing downhill through a hydroelectric dam, that flow can be converted into usable energy. But when suitable terminal electron acceptors are unavailable, full oxidation is no longer possible. Energy can still be partially harvested, however, by carrying out a kind of internal redox rearrangement within the same molecule, which is called fermentation. Specifically, the electrons extracted during glycolysis can be transferred back onto product metabolites in a way that leaves part of the carbon skeleton more oxidized while still yielding some energy. In animals, those electrons are returned to pyruvate to produce lactate. In many microbes, they are instead incorporated into metabolites such as the SCFAs, mainly acetate, propionate, and butyrate. These molecules still retain substantial usable energy, yet under the strongly oxygen-limited conditions of the healthy colon, microbes are constrained from oxidizing them much further. And this is a perfect product for the host: much of the original energy remains intact, but it has been converted into a form the host can absorb.

To preserve this arrangement, the lumen of the colon must be kept extremely low in oxygen. The inner lining of the colon actively helps maintain this state through its own metabolism, in part by consuming oxygen while oxidizing butyrate, one of the SCFAs. This process is vital for microbial ecology in the colon. When Salmonella or a toxic chemical damages the colonic epithelium that helps maintain this low-oxygen environment, oxygen, which is of course still present in the colonic wall to keep the tissue alive, begins to be more readily available in the lumen. Now facultative anaerobes, which can extract more energy by further oxidizing plant-fiber-derived carbons, gain a competitive advantage over obligate anaerobes.

At the same time, inflammatory cells infiltrate the damaged colon in an attempt to kill invading bacteria. These cells release nitric oxide and related reactive molecules as part of their antimicrobial strategy. Alas, this creates yet another opportunity for facultative anaerobes: they can use alternative terminal electron acceptors generated during inflammation to continue oxidizing carbon even when oxygen itself remains limited. Facultative anaerobes are not necessarily harmful in themselves. But their expansion undermines the main reason for maintaining a microbial fermentation chamber in the first place. A healthy colon is not merely one that contains microbes; it is one that preserves the right energetic arrangement between host and microbe.

This is why several findings point in the same direction. 5-ASA, a drug used in inflammatory bowel disease, appears to work in part by promoting colonic oxygen consumption and thereby helping keep the lumen hypoxic. Many facultative anaerobes use molybdenum-dependent enzymes for these oxidative reactions, whereas obligate anaerobes generally do not. In experimental systems, inhibition of these molybdenum-dependent enzymes with tungstate ameliorates colonic inflammation. All of this supports the same idea: maintaining a low-oxygen colonic environment, and thus favoring obligate anaerobic fermentation, is central to colonic health.

Bacteroides biacutis — one of many obligate anaerobes in our colons

I sometimes wonder whether the gut microbiome should simply be considered part of the host body. But one feature still sharply distinguishes microbes from host tissues: the conflict of interest over energy. Unlike somatic cells, which are largely constrained to serve the organism, microbes will seize any opportunity to maximize their own fitness, even at the host’s expense. This almost demands a host regulatory mechanism. The host must somehow monitor which microbes are keeping the bargain and which have begun to defect from it.

One major problem in immunology is how the body distinguishes beneficial microbes from harmful ones. For the former, inflammatory escalation is usually unnecessary; for the latter, the immune system must be engaged. Yet the immune system generally relies on microbial molecular patterns as activation signals, and obligate anaerobes and facultative anaerobes often share very similar ones. The body cannot do anything like a laboratory PCR and check whether the sequence belongs to a known “good” or “bad” species.

One plausible solution is to respond to microbial molecular patterns in general, but suppress inflammatory activation when SCFAs are abundant. In other words, the marker of a healthy microbial community is not the identity of every species, but the metabolic product of a successful energetic deal: dietary fiber has been only partially oxidized, and the host is receiving the benefit. Using that beneficial product itself as a regulatory signal would be an elegant way to manage the microbiota without micromanaging which species should be promoted and which eliminated. Indeed, SCFAs are now well established as anti-inflammatory molecules in the colon. In this sense, they can be understood as metabolic signals carrying the message that all is quiet on the colonic front: the bargain has held, the microbes are fermenting rather than over-oxidizing, and no immune gangs are needed to straighten out the energy thieves.

So why do we have a colon? Why is it anoxic? Why are SCFAs so beneficial? The answer is this: the colon is a fermentation chamber. It is kept strongly oxygen-limited to prevent microbes from oxidizing fibers all the way down to carbon dioxide, thereby preserving part of that energy for the host. And the host, in turn, uses the end products of that fermentation as signals that the colon is colonized by microbes operating under the proper energetic terms. While most of us are blissfully unaware of our colons, they labor every day to strike and maintain this valuable deal. If that is not an exciting little fact to know, I do not know what is.

This essay was inspired by and heavily based on the works of Andreas Bäumler lab at UC Davis. Check him out.

All images from Wikipedia.