This is Bob. He’s a grub. He became famous as a child star after appearing in a nature documentary time-lapse of beetle eggs hatching. A combination of poor financial advice, tabloid scandal and a lack of any noticeable talent have left his career in a ditch. Bob dreams of returning to the front pages for the right reasons so when his agent found him a slot on a hit reality TV show, he jumped – or at least wriggled vigorously – at the chance.
‘I’m in a celebrity, get me out of here!’ brings together the finest in modern TV production – state of the art nature photography and crowd pleasing stunts as celebrities debase themselves in a pitiful bid for publicity. Unfortunately for Bob, when his agent told him he would be appearing on the show he neglected to ask exactly how, until after he had signed the contract. By the time Bob realised he would be on the menu of a celebrity eating challenge, it was too late to back out without incurring hefty legal fees he could ill afford…
Bob and his agent are not on speaking terms at the moment.
We join Bob as he is dropped into the mouth of a Z-list celebrity, even more desperate than him to secure one more book or record deal or even just an appearance on ‘Celebrity Extreme Knitting on Ice’. It’s of little comfort to Bob, or the celebrity, that he is a rich source of the major nutrient groups: carbohydrate, protein and lipid. Although the stomach is typically associated as the digestive centre, digestion begins in the mouth through the action of salivary amylase.
First of all, let us consider what we are ingesting in terms of the nutrient content, what is in the food we shovel into our mouths? Most of what we eat falls into three broad classes: carbohydrates, proteins and lipids. However, apart from simple sugars and some oils, we generally consume these in forms that cannot be absorbed by the gut. Digestion is the process of converting food into a form that can be utilised by the body. This may sound trivial but is often overlooked when considering the claims for dietary supplements – collagen, chondroitin and the like must be broken down or else pass right through, they do not remain intact to specifically repair aching joints or remove wrinkles.
These different groups are digested and absorbed at different points along the gastrointestinal tract and the whole process involves the co-ordinated action of enzymes and pH changes.
Digestion begins in the mouth, where salivary amylase digests starch into oligosaccharides. The prefix ‘oligo-’ means ‘few’ so is an umbrella term to describe breaking down polysaccharides, mainly plant starch, into shorter lengths of sugar chains. Eventually these oligosaccharides will be reduced to disaccharides and then monosaccharides.
Proteins and lipids are not digested in the mouth, although the action of chewing helps to emulsify them for more effective digestion further along the gastrointestinal tract.
Fortunately for Bob, his celebrity diner was both too squeamish too chew and suppressed their gag reflex long enough for him to pass down the oesphagus unscathed. Just before tumbling into the fizzing pit of acid he managed to grab onto one of the wrinkles (known as rugae) in the stomach wall. Beneath him lay a pool of gastric acid, which has a pH close to 2, similar to lemon juice. He didn’t fancy getting any of that in his eye. Floating in the acid bath were lumps of congealed fat, he could see his terrified face reflected in their oily sheen.
Protein digestion begins in earnest in the stomach. The low pH of the stomach is due to hydrochloric acid secreted by parietal cells and disrupts the hydrogen bonding that holds proteins in shape, causing them to unravel. This makes more of the polypeptide chains accessible for protease enzymes to digest them into amino acids. The salivary amylase is not spared from this effect and becomes inactivated in the stomach.
The first of these proteases to act is pepsin which is secreted from chief cells in the stomach lining. Pepsin is made in the form of a zymogen called pepsinogen. Zymogens are inactive precursors of enzymes and demonstrate an important concept. Imagine what would happen if cells secreted active proteases – they would digest the very same cells that produce them! A similar concept happens with prohormones; in both cases, this key regulatory feature allows the body to activate proteins when and where they are needed. Whereas the gastric acid denatures most proteins, the conformational change in pepsinogen converts it to pepsin, an endopeptidase. Pepsin breaks peptide bonds and like all digestive enzymes does so by a process of hydrolysis, in which enzymes use reactions with water molecules to break bonds.
There are many types of protease, they all digest proteins but are divided into classes based on how they chew them up. Endopeptidases do this within the polypeptide chain while aminopeptidases and carboxypeptidases nibble amino acids from the respective ends of the protein. Endopeptidases are then divided into the type of residue they cut at, some recognise basic amino acids, others go for hydrophobic residues, you can see the various amino acids here. The net effect of all these different recognition sites, called motifs, is that diverse proteins can be efficiently broken down into amino acids.
Lipid digestion also begins in the stomach, lingual lipases are actually produced in the mouth but become active at the reduced pH of the stomach where they are supplemented by gastric lipases. A lot of lipid is still in particles that are too large for efficient enzymatic digestion so about three quarters of the lipid intake passes through the stomach undigested. That’s enough talk of biochemistry, people will be worrying about how long Bob can cling on for…
By a stroke of luck that defies anatomical probability, Bob manages to make it out of the stomach unscathed. He wriggles through the pyloric sphincter and plops into the duodenum, the start of the small intestine. At his feet is an oozing stream of chyme, the partly digested food pushed out of the stomach with him. No sooner has Bob peered down the small intestine wondering what lies ahead than he is submerged in shower of gunk. Pancreatic juices empty down on him from the sphincter of Oddi, more correctly called the hepatopancreatic sphincter. Nowadays there is a move away from naming structures after their discoverer. This loses something of the resonance of the names but makes sense. Firstly, it is much more informative. An eponym like Oddi tells you nothing about the function; hepatopancreatic does not roll off the tonigue nearly as well but gives you a strong hint about where it might be found. Secondly, attributing these ‘discoveries’ to someone is often arbitrary and in some cases likely to be plain wrong. Having said that, there are some structures (and diseases) that are so fundamentally linked to a name, for example Schwann cells or Golgi apparatus, that these are unlikely to ever be renamed.
On leaving the stomach, the food passes into the small intestine, beginning with the duodenum. By this point the churning action of the stomach, combined with the initial enzymatic actions has converted the food into chyme, an emulsion of smaller particles which creates a higher surface area for enzyme action. This is aided by the addition of bile acids which enter through the sphincter of Oddi with the pancreatic juice.
An important component of the pancreatic juice is bicarbonate which begins to neutralise the gastric acid, raising the pH to allow a wider range of enzymes to function. The pancreas supplies more amylase which continues the digestion of carbohydrates into disaccharides that had been begun by the salivary amylase.
The second important point is an explosion of protein digestion triggered by trypsin. Trypsin cleaves peptide chains at basic residues, mainly lysine and arginine, and activates the many protease zymogens delivered in the pancreatic juice such as chymotrypsin and elastase. Trypsin itself is derived from the zymogen trypsinogen so what lights the trypsin fuse? This is done by an enzyme called enteropeptidase that is attached to the duodenal brush border. This begs the question of what activates the enteropeptidase and the answer is unclear. Enteropeptidase is made of two protein chains which must be transported to the cell surface and assembled for it to be active. It is itself made as an inactive proenteropeptidase that can be activated by trypsin but obviously this assumes something has previously activated the trypsin! It is likely that exposure to the luminal environmental, possibly to bile acids, is sufficient to activate enough of the enteropeptidase to turn on some trypsin which sets up a self-sustaining cycle. This explanation is supported by the malabsorption seen in infants lacking enteropeptidase activity which can be treated by pancreatic extracts, containing trypsin. These can then be discontinued as the reactions appear to be self-maintained once initiated.
Wishing he had hands to wipe the gunk from his eyes, Bob crawls along the small intestine following the trail of chyme. As he enters the jejunum the walls begin to change, they are covered in thousands of fingerlike projections called villi. Buried amongst them are goblet cells secreting a thick mucus which he struggles through, still cursing his agent.
By the time the food reaches the jejunum, most of the carbohydrates have been broken down by amylase into disaccharides. These, together with dietary disaccharides, are then dissociated into monosaccharides for absorption. As with proteases, this is a hydrolytic reaction, with a specific hydrolase responsible for different disaccharides. Sucrose, lactose and maltose are found in sugar, milk and beer respectively. The fourth, trehalose, is found mainly in fungi and insects, it’s the fuel that powers the flight of the bumblebee.
These enzymes are expressed along the jejunum and into the proximal ileum. This means they are downstream of the amylase and receive the maximal amount of disaccharides but are also sufficiently upstream that the resulting monosaccharides can all be absorbed in the rest of the small intestine.
The uptake of glucose and galactose is tightly coupled to sodium and is an example of secondary active transport. The whole process is powered by the action of the Na,K-ATPase pump on the basolateral membrane which uses ATP to keep the intracellular sodium concentration low. This is why it is called active transport. The resulting sodium concentration gradient pulls glucose along with it, hence it is secondary transport. Linking these two aspects is the sodium-glucose co-transporter (SGLUT) a family of transporter proteins that plays a similar role in other organs such as the kidney.
SGLUT has a particular mode of action. First, two sodium atoms bind to the extracellular side of the transporter. Only once this has happened can a glucose molecule also bind. This triggers a conformational change which essentially flips the protein inside out and exposes the sodium and glucose to the inside of the cell. In this sense, my representation of it as a turnstile is a bit misleading, it’s more like a bucket with a flap in the bottom. Thanks to the action of the Na,K-ATPase the intracellular sodium concentration is low so the sodium ions dissociate from the SGLUT. This allows release of the glucose, completing the reversal of the binding sequence.
The incoming sodium is then pumped out of the basolateral side of the cell by the Na,K-ATPase and the glucose exits down its concentration gradient via the GLUT2 glucose transporter.
A key point is that the process requires sodium, energy and glucose and is why oral rehydration solution contains saline and glucose.
Glucose and galactose are sufficiently similar chemically that for most purposes they are transported identically. Fructose however can only bind to certain glucose transporters and not to the SGLUT or GLUT2 carriers that we have just looked at. The main route of fructose uptake is thought to be passively through the GLUT5 transporter in the brush border. Once inside the enterocyte, the fructose is converted to glucose and lactate; the former then passes across the basolateral membrane via GLUT2.
A better understanding of fructose metabolism is important because of its use as an additional sweetener in many processed foods and its implication in obesity. It is possible that unnaturally high levels of fructose do not trigger the same insulin signalling and compensatory feedback loops that glucose would set off and this may underlie chronic metabolic disturbances.
Amino acids vary widely in their size and chemical properties, consequently there is not a generic amino acid transporter, although neither is there a specific carrier for each amino acid. Instead there are a range of amino acid transporters which have specificity for groups of related amino acids. Some rely on facilitated diffusion of amino acids down concentration gradients, others are coupled to the active transport of other ions, often to sodium-proton exchangers. These keep the brush border environment slightly acidic and in turn are powered by the Na,K-ATPase workhouse which sets up the sodium gradient.
So far we have paid little attention to lipids. As mentioned, stomach churning and peristalsis in the gut create an emulsion of ever smaller lipid droplets. The addition of bile salts creates tiny lipid aggregates called micelles which attach to the brush border. Lipases act on the micelles to release fatty acids and monoglycerides which cross the membrane by a combination of facilitated transport and free diffusion. The exact mechanisms are poorly understood because it is difficult to reproduce these systems experimentally. Remember too that although the inner layers of the plasma membrane are hydrophobic, the outer ones are hydrophilic making an effective barrier to the simple diffusion of all but the smallest molecules. Cholesterol crosses the enterocyte membrane through Niemann-Pick C1-Like 1 (NPC1L1) channels, these are the target of drugs that can be used to treat hyperlipidaemia.
48 hours later, Bob tumbles into a bucket, his own cursing drowned out by the profanities being spluttered by his former host. The disgruntled celebrity’s day gets worse as they step backwards into the bucket, sending the contents splashing halfway up their leg and Bob spinning off into the jungle. Fortunately for our grub hero, he only crawls 100 metres before finding himself in a hotel compound. Who knew that all along they hadn’t really been in the middle of nowhere?! No-one suspects a beetle larva would steal their phone so he is able to swipe a nearby mobile and contact a very startled agent. Having explained in no uncertain terms – and from firsthand experience – exactly where any future job offers can be shoved, Bob leaves a review on a popular travel website.
