This chapter is addressed to Section O1(iii) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "outline the digestion and absorption of fat, protein, carbohydrates and the absorption of water, electrolytes and vitamins". The term "outline" suggests that a summary of the important points is all that is expected here, which is perhaps for the best, as this topic has no visible horizon, and to behold its true form may drive an unprepared exam candidate to madness and despair. Fortunately, at this stage no written exam question has asked about this topic, making it completely ignorable, potentially for the rest of your fruitful career in Intensive Care. Your patients will continue to safely absorb carbohydrates lipids and proteins, whether you know about it or not.
- Digestion and absorption of carbohydrate:
- Enzymes: salivary and pancreatic amylase; brush border enzymes
- Starches and oligosaccharides are transformed into monosaccharides
- Monosaccharides are absorbed by sodium-coupled co-transport (SGLT1 for glucose) or facilitated diffusion (fructose by the GLUT5 transporter).
- Digestion and absorption of fat:
- Enzymes: lingual lipase, pancreatic lipase, bile salts (emulsification)
- Bile contributes by increasing the micelle surface area for lipase
- Triglycerides are converted into glycerol and fatty acids
- Free fatty acids are absorbed by diffusion and protein-mediated uptake
- Digestion and absorption of protein:
- Enzymes: pepsin in the stomach, pancreatic proteases, gastric acid
- Gastric acid contributes by denaturing protein to increase access for proteases
- Proteins are degraded into amino acids and oligopeptides;
- Amino acids and oligopeptides are absorbed by low-selectivity transport proteins (eg PEPT1) which faciltate co-transport with sodium or H+.
- Digestion and absorption of micronutrients:
- Most vitamins are absorbed in the jejunum
- Exceptions are niacin (stomach, duodenum), cholecalciferol (duodenum and ileum) and cobalamin (ileum)
- Ileum also contributes to the absorption of Vit C, riboflavin (B2), tocopherol (E) and pyridoxine (B6)
- Intestinal absorption of water and electrolytes:
- Water: transcellular diffusion in the proximal small bowel
- Sodium: co-transport with other substances, mainly jejunum
- Chloride: balance of channel-mediated absorption and active secretion (CFTR)
- Potassium: absorption by passive diffusion and colonic ENac
- Magnesium: absorption by passive paracellular mechanisms
- Calcium: both active transcellular and passive paracellular mechanisms
There is an abundance of peer-reviewed material to support the exam candidate's reading on this topic, and a literature search for "digestion and absorption" yields multiple suitable results, often actually titled "Digestion and absorption". Of these, specific recommendations go to Goodman (2010), as it is specifically aimed at the professional physiology educator, and MacFarlane (2018), as it is simplified to facilitate quick revision. If either of them have any fault, it is their tendency to reference textbook chapters to support their statements, instead of the original experiments. For nutrient-specific work, more detail for carbohydrates can be found in Levin (1994), for lipids in Carey et al (1983), for protein in Erikson & Kim (1990), and for micronutrients in Basu & Donaldson (2003). Unless otherwise referenced, most of the material in this chapter has come from these sources.
There are two main ways to structure this discussion (and the answer to any exam questions). One could discuss each nutrient group in turn, discussing the fate of that specific metabolic substrate on its way though the gastrointestinal tract. Alternatively, one could take the gastrointestinal tract, and discuss each segment, explaining how it contributes to the digestive process. The following sections try to do a little of both.
Let's start with the carbs, as they tend to be the more important from a caloric standpoint. Roughly 70% of the NG-fed ICU patient's caloric intake will be supplied by carbohydrates, as this is the usual ratio used to create their enteric nutrition formula. For the purposes of delivering maximum calories with efficiency, these NG dietary supplements are usually formulated using corn maltodextrin which is basically just an oligosaccharide made of a random number of glucose molecules (say, 10 or so), the advantage of it being that it is easy to digest even if your pancreas is healing from gunshot wounds. A hospital patient fed the more conventional hospital-grade glorp will probably be consuming some combination of simple sugars like dextrose and some complex starch (a branching polymer of amylose), which might require a little bit more work. But not that much more. Broadly speaking, carbohydrates are the easiest to digest and absorb out of all the nutrient groups.
Sometimes a picture can be worth a thousand words, but whether this diagram clarifies anything remains unclear:
So, here are a thousand words on carbohydrate absorption
Saliva contains α-amylase which begins to digest the complex carbohydrates while they are still being chewed in the mouth. Amylases in general target the α-1,4 glycosidic bonds between sugar molecules in an oligosaccharide, snipping the long molecules into smaller chunks. These enzymes tend to function only within a narrow range of pH, which means that stomach acid will usually halt their activity, unless the amylase and its substrate are trapped together in the middle of some kind of large food bolus, protected from gastric juices.
Gastric juice contributes nothing directly to the digestion of carbohydrates, but the presence of carbohydrates in the stomach does appear to stimulate the production of more gastric acid, which in turn stimulates the release of pancreatic enzymes.
Pancreatic secretions in the small intestine finish the job started by salivary amylase. The neutralising effect of these alkaline secretions return the luminal content to something a bit more civilised and conducive to the function of enzymes, and the most important of these for carbohydrate metabolism is pancreatic α-amylase. Large oligosaccharides and starches are hydrolysed to make maltose, isomaltose, and various di- and tri-saccharides.
Brush border enzymes finish the job of converting disaccharides and trisaccharides further into monosaccharides. These are membrane-spanning enzymes at the villous brush border, and they are so numerous and specific that it would be pointless to list them all. A clinically relevant one is lactase, which separates lactose into glucose and galactose in milk sugar, and which is deficient in a number of adults. These lucky people can drink as much milk as they like without gaining any unsightly milk-weight, as their ability to extra calories from milk is impaired. Another interesting one is trehalase, which is responsible for the breakdown of trehalose (a disaccharide mainly found in insects fungi and algae) which may give us some insight into the nutritional preferences of primitive man at the dawn of time.
All these brush border enzymes are scattered variably and regionally along the small intestine, such that specific lengths are responsible for the digestion and absorption of specific carbs. Asp et al (1975) biopsied some obese patients and found the following distribution:
Absorption of monosaccharides is by specific transport proteins. Glucose is absorbed by the SGLT1 sodium-glucose co-transporter, and fructose by the GLUT5 transporter. Of these, the distribution is greatest in the proximal small bowel, predominantly the proximal jejunum and distal duodenum.
Fats in the diet of a normal person (or a booked-out ICU patient enjoying hospital food) are mainly in the form of triglycerides, with only a small minority arriving in the form of fatty acids.
Saliva contains lipase, sometimes referred to as lingual lipase because its origin is generally the tongue (to be precise, it comes from Von Ebner serous glands). This contributes somewhat to the processing of fats, and patients with pancreatic insufficiency might be somewhat dependent on this enzyme. Under normal circumstances, its role as a digestive enzyme is probably secondary.
Gastric acid probably plays only some sort of bystander role in the overall digestive process for fats, though some enzyme-mediated gastric lipolysis does occur. After collecting the gastric juice of several healthy volunteers, Bank et al (1964) incubated it with some triglycerides and found that about 16% of the triglycerides in the emulsion were hydrolysed after an hour. The main actors here were probably swallowed lingual lipase and the gastric lipase secreted by chief cells. Overall, the only reason these have any influence whatsoever is probably that fatty meals tend to delay gastric emptying, which means the fat and lipase get to spend some quality time together.
Bile salts empty from the gall bladder in response to cholecystokinin, the release of which is triggered by fat being detected in the duodenum. They have several roles:
Bile needs to be mentioned here because their contribution to digestion is very important, as the performance of other lipolytic enzymes is dependent on their effect. This importance is demonstrated by the effects of chronic cholestasis in humans, where weight loss due to poor energy intake and other fairly hideous effects resulting from the deficiency of fat-soluble vitamins. However, it is not completely essential. When in a series of nightmarish experiments Minish et al (1999) diverted the bile ducts of rats to empty externally, they found the rats still capable of absorbing fatty acids, and when they examined their small intestine microscopically they were greeted with an unexpectedly tall forest of villi. Clearly there are adaptations which can compensate somewhat for a lack of bile. Unfortunately, with high-fat meals, up to 50% of the ingested fat remained unabsorbed, pointing to the limited capacity of such compensation.
Pancreatic lipase and colipase are the main digestive forces behind the hydrolysis of dietary fat. Most of the work is done in the proximal jejunum. Triglycerides are degraded into 2-monoacylglycerol and fatty acids, which are available for absorption.
Absorption of fat occurs via various poorly defined mechanisms. Iqbal & Hussain (2009) report that "a protein-independent diffusion model and protein-dependent mechanisms have been proposed", which sounds like we really don't know enough about this fundamental mechanism. There's certainly plenty of fatty acid-binding proteins on the enterocyte apical membrane, which has resulted in the impression that protein-mediated uptake is more important. Protein-mediated uptake is also how cholesterol is absorbed (a process that is thought to be inhibited by ezetimibe).
The dietary protein substrate consists not only of the normal daily enteral intake (something like 1g/kg of protein), but also of the copious amount of protein-rich intestinal debris. Munro (1966), in an estimate which has been described as conservative, suggested that about 20-30g of gastric and intestinal mucus protein and 30g or so of dead sloughed enterocytes ends up being reabsorbed every day. Most of the work of digesting protein is done by the pancreatic enzymes, and most of the products of digestion are absorbed in the proximal small bowel:
Of the exogenous protein, some (perhaps 20g/meal) is used for protein synthesis, and the rest is thought to be deaminated or oxidized for energy. What effect critical illness has on this, remains to be fully determined. Van Gassel et al (2020) reviewed this topic and concluded that the availability of amino acids can actually increase during critical illness, as they are released from catabolised muscle (up to 20% of muscle mass can be lost over the first ten days of ICU admission). What happens to them, nobody seems to know. Nor do we have a clear idea of whether or not exogenous protein supplementation has much of an effect on the rate of muscle catabolism during critical illness. Certainly, in health it seems to strongly stimulate muscle protein synthesis: Groen et al (2015) found that 55% of ingested radiolabeled amino acids were made available to the circulation, and about 20% are incorporated rather quickly into muscle protein (the investigators took muscle biopsies only five hours following a meal). Similarly, Schoenfeld & Aragon (2018) recommended a minimum total daily protein intake of 1.6g/kg, and ideally up to 2.2g/kg/day, to maximise anabolism in the context of muscle-building. From this, we may surmise that it might be possible to rebuild a critically weakened ICU patient by hyperalimenting them with protein (and all evidence seems to suggest that critically ill patients benefit from more protein in their diet). Anyway, this is a digression into CICM Part Two material, but is perhaps helpful to anchor the discussion to something clinically relevant and useful. Now, back to abstract theory:
Saliva and mastication play no role in the breakdown of protein. Just forget about the oral cavity, all the real business is below.
Gastric acid and gastric pepsin are responsible for the initial stages of protein digestion, and specifically gastric acid is a necessary element. Gastric acid denatures the proteins, making them unravel and expose more of their amino acids to the endopeptidases. It also activates pepsinogen, which is an inactive form of pepsin. Pepsin then goes on to hydrolyse the proteins into peptide fragments of various lengths.
Logically, one might extend to thinking that PPIs and other drugs which neutralise gastric pH may somehow prevent the proper digestion of protein. Certainly, in laboratory tests this seems to be the case. Evenepoel et al (1998) fed some kind of egg-based proteinaceous glurp to healthy volunteers and determined that pre-treatment with omeprazole decreased their absorption of the glurp proteins, by perhaps as much as 30%. However, there does not seem to be any clinical relevance to this, to the point that authors such as Keller (2012) have called the very need for gastric acid into question ("Brauchen wir Magensäure?"). The reason we don't need pepsin or Magensäure is that pepsin only cleaves very specific peptide bonds, and can only digest about 10-15% of the overall dietary protein, whereas "broad-spectrum" peptidases from pancreatic secretions can take care of the same proteins and all the others. For this reason, people who have had a total gastrectomy do not suffer from any serious protein malnutrition.
Pancreatic peptidases take over the work started by pepsin. These are all secreted as inactive pro-enzymes which are activated by the change in duodenal pH (otherwise they would autodigest the pancreas). It is probably not essential for the CICM trainee to know every detail about these enzymes, other than perhaps some of their names (trypsin, chymotrypsin, elastase, carboxypeptidase, etc). The bottom line is that the end product of their activity are small protein fragments and solitary amino acids.
Protein absorption then takes place, with the majority of the breakdown products taking the shape of tripeptides, dipeptides or amino acids. In infancy, neonates are able to absorb whole proteins by pinocytosis (in this fashion passive immunity can be conveyed via mother's milk), but adult enterocytes can only absorb small protein fragments. This absorption occurs by transmembrane transport proteins. Each can transport multiple different amino acids, and they tend to be stereoselective, with a higher affinity for L-amino acids. The transport is usually coupled to the co-transport of an ion, usually sodium or H+.
Of the oligopeptide transporters at the gut border, the ICU trainee probably needs to know about PEPT1 the most. This is a relatively promiscuous transport protein that use the steep H+ gradient at the brush border to facilitate the absorption of various peptides, it cares not which. It is so nonselective that it accepts incredibly random things as substrates, and is probably responsible for the absorption of all the more important drugs. Brandsch (2013) lists β-lactams, cephalosporins, antiparkinson drugs, and various antiviral drugs as just some of the possible beneficiaries of this transport mechanism.
For something that seems really important, there is remarkably little literature out there to describe what happens to ingested vitamins and micronutrients. The most authoritative and comprehensive entry seems to be the chapter by Said & Treble from Sleisenger and Fordtran's Gastrointestinal and Liver Disease (2020). To protect the reader from the experience of handling this monstrous 2700-page publication, the most meaningful content was drained from this chapter and presented below:
A (Retinol) is fat-soluble and ends up incorporated into micelles, as well as being generated as the product of carotenoids and retinyl esters which are biotransformed in the enterocytes. Diffusion and protein-mediated transport probably both contribute to its absorption. The most rapid uptake is seen when fat is co-ingested.
B1 (Thiamine) is readily absorbed in the proximal jejunum, even though its two transport proteins (THTR-1 and THTR-2) are found in the rest of the gut. The most interesting or examinable aspect of its handling in the gut is the fact that its absorption can be affected by chronic alcohol intake.
B2 (Riboflavin) is absorbed in the small and large bowel. The active transport mechanism is not dependent on sodium or pH.
B3 (Niacin) is one of those rare substances that can be absorbed through the stomach wall (as well as more conventionally in the small intestine). Nobody seems to have a clear idea as to how exactly it is absorbed, other than that the mechanism seems to be dependent on pH and temperature.
B5 (Pantothenic acid) is absorbed in the jejunum by a Na+- dependent carrier-mediated process, but in high enough concentrations it can sneak through by direct diffusion as well.
B6 (Pyridoxine) is absorbed by a Na+- dependent carrier-mediated process, which is only interesting because it is apparently blocked by amiloride. Another interesting feature is that the colon also has some capacity to absorb B6.
B7 (Biotin) is present in the diet as a part of protein, which means it does not become available until it has been liberated by pancreatic peptidases and biotinidase. It is transported mainly in the proximal jejunum, by an active sodium-dependent process (the transporter is referred to as SMVT).
B9 (Folate) is present in the diet in the form of a polymer, which needs to be hydrolysed in the proximal half of the small bowel. It is then absorbed in the proximal half of the small bowel by a proton-coupled pH-dependent mechanism, through several different transport proteins.
B12 (Cobalamin) comes in a complex with dietary protein, and is usually liberated by the action of pepsin in the stomach. It is then protected by being bound to Intrinsic Factor, a glycoprotein that protects it from the lytic activity of upper GI enzymes. That is how it makes its way to the terminal ileum, where it is absorbed (the whole IF-cobalamin complex is entrained by the absorption mechanism).
C (Ascorbic acid) is actively co-transported with sodium by a brush border transport protein SVCT1. The transport is saturable, or at least regulated in a way that ensures that excess ingestion does not translate into dangerously high blood levels. The site of absorption is distal ileum and jejunum
D (Cholecalciferol) is absorbed by passive diffusion in the duodenum and ileum.
E (Tocopherol) is absorbed by passive diffusion in the distal jejunum and ileum.
K (Phytomenadione) is absorbed by passive diffusion in the jejunum
In general, all the fat soluble vitamins are thought to be absorbed by passive diffusion, though nobody is completely clear on the exact mechanism of their absorption. They probably depend on the same mechanisms for absorption as triglycerides do, because that conditions that decrease lipid absorption (pancreatitis, biliary stasis) are also seen to decrease absorption of vitamins A, D, E and K.
You could possibly present these data much more neatly as a table:
|Site of absorption|
|A (Retinol)||Fat||Diffusion? Active?||Proximal jejunum|
|B1 (Thiamine)||Water||pH-dependent process||Proximal jejunum|
|B2 (Riboflavin)||Water||Independent transporter||Jejunum, ileum, colon|
|B3 (Niacin)||Water||pH-dependent process||Stomach, duodenum|
|B5 (Pantothenic acid)||Water||Active Na+coupled||Jejunum|
|B6 (Pyridoxine)||Water||pH-dependent process||Jejunum, ileum, colon|
|B7 (Biotin)||Water||Active Na+coupled||Proximal jejunum|
|B9 (Folate)||Water||pH-dependent process||Jejunum|
|B12 (Hydroxocobalamin)||Water||Co-transport with IF||Terminal ileum|
|C (Ascorbic acid)||Water||Active Na+coupled||Jejunum and ileum|
|D (Cholecalciferol)||Fat||Passive diffusion||Duodenum and ileum|
|E (Tocopherol)||Fat||Passive diffusion||Distal jejunum, ileum|
|K (Phytomenadione)||Fat||Passive diffusion||Jejunum|
Or, the same basic information could be organised into a diagram, for whatever reason:
All of these are dealt with in more detail in other chapters, to which the links will take you. For the purposes of revising gastrointestinal physiology, these brief entries will probably be enough.
Water absorption is near-complete, rapid, and mainly occurs in the proximal small bowel. Most of the diffusion is transcellular. It is driven by osmotic mechanisms: an osmotic gradient is generated by the active absorption of other electrolytes, especially sodium.
Sodium absorption is coupled to the transport of other substances, as one might have noticed from the above. Virtually everything is co-transported with sodium in the jejunum. In the ileum and colon, there are other mechanisms, including transport by sodium/proton transporters (NHE2, NHE3, and NHE8) as well as the aldosterone-responsive ENac channels.
Chloride absorption and sodium absorption are linked in order to maintain electroneutrality. Chloride is usually absorbed as the net result of the balance between channel-mediated absorption and cAMP/ATP-gated channel-mediated secretion. The latter is the work of the CFTR protein, the same chloride channel affected by cystic fibrosis and the toxin of Vibrio cholerae.
Potassium absorption in the small intestine occurs by passive paracellular diffusion, which is completely unregulated. Absorption is purely driven by the concentration gradient.
Magnesium absorption is 90% by passive paracellular mechanisms, and the rest is subject to some sort of saturable transcellular facilitated transport. This mainly happens in the distal small bowel (jejunum and ileum).
Calcium absorption occurs in the duodenum by some active transcellular process, and passively along the rest of the gut. When calcium uptake is high or normal, it is the paracellular passive uptake that accounts for the majority of the gastrointestinal absorption.
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