This chapter does not deal with any specific section of the 2017 CICM Primary Syllabus, because there is no corresponding section to this topic, but nonetheless, hormonal responses to a normal meal were the subject of Question 5 from the first paper of 2013. The examiners cast a wide net ("candidates were expected to have an integrated knowledge of gastrointestinal physiology", and even "some mention
of insulin was required"). The neuro-hormono-endocrinological responses to the ingestion of a meal are obviously much too complex to describe comprehensively within the timeframe of a ten-minute written exam answer, nor could it possibly be essential to have detailed knowledge of them to practice safe intensive care medicine. What follows is a glib oversimplification, the objectives of which are to help people answer exam questions and to impress upon them some of the complexity of the topic, rather than to lead them to some kind of enlightenment.
Stimuli Neurohormonal response Cephalic phase: anticipatory neuroendocrine responses Anticipation of food;
thoughts about food;
sensory characteristics of food (taste, smell, mouthfeel, mastication, appearance of food)
- Mainly vagal responses:
- Accommodative relaxation of proximal gastric smooth muscle
- Stimulation of gastrin and histamine release
- Cholinergic stimulus for the release of pancreatic secretions and insulin
- Increased small intestine motility)
- Saliva is also secreted (parasympathetic effect)
- Specific hormones involved in this phase:
- Histamine (stimulates gastric acid secretion)
- Gastrin (stimulates gastric acid and pepsin secretion)
Gastric phase: reactive gastric hormonal and local reflex responses
Pharyngeal sensation of swallowing;
gastric mechanoreceptor stretch;
the increase in gastric pH results in the release of hormones that stimulate gastric acid secretion (gastrin, ghrelin and histamine)
- Mechanical stretch stimulates antral pump activity
- Specific hormones acting in this phase:
- Histamine, increases gastric acid secretion
- Gastrin, slight increase to the overall gastric motility, major stimulus for gastric acid and pepsin secretion
- Ghrelin, secreted by the ghrelin cells of the oxyntic glands, which increases gastric motility substantially, and which slightly increases acid secretion
Intestinal phase: endocrine modulation of gastric and biliary activity by the duodenum Stimulated by the volume, osmolality and chemical composition of the chyme entering the duodenum
- Cholecystokinin, which causes gall bladder contraction and increased pancreatic secretions
- Secretin, which increases the
- Motilin, which stimulates small bowel peristalsis
- Leptin, gastric inhibitory polypeptide, glucagon and glucagon-like peptides 1 and 2, all of which mainly act to decrease the gastric emptying rate
Absorptive phase: endocrine response to absorbed nutrients Stimulated by increased blood glucose
- Insulin secreted in response to increased blood glucose
The process of compiling this information was made more frustrating by a lack of primary sources, and by the obstinate refusal of major textbooks to give references for any of the material they compile. Fortunately, there were some oases in that desert. What follows was cobbled together from Pandol (2008), Camilleri (2006) and Livovsky et al (2020), none of which are comprehensive in any sense of the word, but which can at least act as bibliographies of original research.
Presumably because the word "neuro-hormono-endocrinological" is an abomination, most authors use the term "integrated response" to describe how the nervous and endocrine systems come together to coordinate the act of eating. It is described as "a complex set of regulated GI secretory and motor behaviors designed to perform digestion and absorption of a meal and elimination of its wastes". The literature tends to separate this response into stages or phases which represent different events in the course of normal digestion:
Of course, these phases all overlap, and the main purpose of separating this series of near-simultaneous events into discrete groups is mainly to act as a narrative aide.
It seems impossible to track down the origins of the term "integrated responses" and the names of the phases, but it may be that they actually date back to Ivan Pavlov in the 1890s, whose sham feeding experiments in dogs with oesophageal diversion were instrumental in describing the way the nervous system influences gastric secretory function. The first mention of them in the English literature which uses the modern meaning and terminology was probably the series of articles by Lim et al (1925), who had articulated the distinct properties of each phase in their conclusion. Those early studies mainly used the phases to describe the different events which influenced gastric secretion, but clearly at some stage physiologists must have decided that they are a convenient system for describing the integrated response to eating, and so they have become the default method of teaching this subject. Most textbooks will usually include a chapter on this, and for gastroenterology textbooks often it will be the first chapter (eg. Raybould et al, Textbook of Gastroenterology, 2003; p. 2-12).
The cephalic phase is essential for nutrition for many reasons, of which the most important is probably efficiency. For a standard 400g meal, most normal people will require approximately 600-900ml of gastric secretions, containing about 50-80 mEq of hydrochloric acid. Considering that even maximally stimulated gastric mucosa can produce no more than about 10-15mEq of the acid in 15 minutes (Lawrie & Forrest, 1965), it would be inefficient to wait for the arrival of food to stimulate acid secretion. Ergo, in order for the organism to be ready to digest the meal immediately, some anticipatory responses need to occur, well before the meal itself is being eaten.
These are described in great detail by Power & Schulkin (2008). One could probably do no better than to simply reproduce their Table 1, as it serves the purpose of this chapter perfectly, listing the responses without digressing overmuch into pointless detail:
|Cephalic phase response||Organ(s)||Function(s)|
|Salivation||Mouth||Lubricate food, begin digestion of starch, dissolves food particles (essential for taste)|
|Gastric acid secretion||Stomach||Hydrolysis of food|
|Gastrin||Stomach||Stimulates gastric acid secretion|
|Lipase||Stomach; pancreas||Fat digestion|
|Gastric emptying||Stomach||Regulate food passage|
|Intestinal motility||Intestine||Regulate food passage|
|Bicarbonate||Intestine||Neutralizes stomach acid|
|Cholecystokinin (CCK)||Small intestine||Terminate feeding|
|Digestive enzymes||Pancreas||Digestion of protein, carbohydrates and fat|
|Bile||Gall bladder||Fat emulsification|
|Leptin||Adipose tissue; stomach||Reduce appetite|
|Ghrelin||stomach||Stimulate appetite; stimulate GH secretion, fat absorption|
The table is comprehensive, but fails to convey the integration of responses, and this is often what the CICM examiners are looking for in the First Part exam answers. One way of demonstrating this understanding would be to treat the phases as reflexes, with stimuli, afferents, processors, efferents and effector organs.
So: the cephalic phase of the response to a meal is a neurohormonal response where the neuro does most of the heavy lifting. Specifically it is the vagus nerve, responsible for basically everything here, including the release of hormones which act as paracrine secondary messengers. Still, if for some reason you needed to behold the hormonal milieu on its own (for example, if you were asked about the hormonal response to a meal), you could list all the vagally mediated hormone release phenomena in this phase of digestion:
The cephalic phase is generally viewed as very brief, as under conventional conditions only a short time passes between experiencing the sensory qualities of food and filling your stomach with it.
Also historically referred to as the "chemical phase", the gastric phase is characterised by stereotypical responses of the stomach to the volume and acidity of its content. Again, neurological and paracrine hormonal events take place, but this time they are both equally important. These responses are even more clearly reflex-like than the cephalic phase, as in there is a predictable effect from each stimulus. There are also three distinct sub-phases:
The reflex-like elements of the gastric phase response to a meal can be summarised as follows:
The gastric phase and the intestinal phase overlap considerably, with the gastric emptying rate being as slow as it is (200 kcal/hr). It may take the stomach three hours to empty out a particularly fatty nutrient-dense meal. During this time, the "intestinal phase" is clearly in progress, because it is the main source of the aforementioned delay.
So-named presumably because at last the small bowel takes centre stage, the intestinal phase is characterised by the duodenal secretion of hormonal signals which modulate the activity of the stomach, typically by slowing its emptying rate. The main objective of their action is to slow the delivery of half-digested chyme enough that the biliary and pancreatic systems have enough time to supply the right amount of enzymatic reagents to finish the digestive process to completion.
Or, to list them in a slightly different way,
For most textbooks, this isn't even a phase of the digestive process. Or, more accurately, it does not seem to be mentioned in most articles that describe the integrated response to a meal, unless they specifically deal with the affairs of the pancreas. For example, Liddle's chapter on the Regulation of Pancreatic Secretion for the 2018 edition of Physiology of the Gastrointestinal Tract has a short section dealing with this phase at the very end.
The concept of an "absorbed nutrient phase" only exists because of the occasionally noted observation that absorbed nutrients can have various effects on the hormonal activities of the gastrointestinal system after they have left the lumen and entered the bloodstream, particularly on the exocrine pancreas. At face value, this is obviously correct. For example, blood glucose clearly influences insulin and glucagon secretion. Unfortunately, that is the only nutrient-related hormonal effect on the gastrointestinal system that we can currently support with evidence. Investigators seem to disagree about the influence of absorbed amino acids and fats on the activity of the pancreas. The main reason to even mention this disputed phase is that CICM examiners clearly expected something to be said about insulin here, judging by their comments to Question 5 from the first paper of 2013.
All of the statements made above are relevant mainly to the context of the processing of a substantial lunch by the healthy normal human adult. We don't usually see those in the (public) ICU; many of the patients encountered by the CICM trainee in their practice will be fed by means of an enteric feeding tube. How does this influence the phases of digestion?
Well. There turns out to be very little published literature on the subject, among which Palma et al (2019) is perhaps the best. To summarise, the following factors are probably of greatest importance:
The effect of these is:
So, this is the effect of nasogastric feeding. How would this be different in the parenterally fed patient?
Predictably, it would be very different. Not only is the cephalic phase completely lost, but all of the other enteroendocrine effects of chyme are also gone, as there is no chyme and nothing to distend the intestine. Only the "absorbed nutrient phase" remains, which most people don't even recognise as a phase. In short, parenteral nutrition takes away this interplay of neural and hormonal influences on gut function, and replaces it with a brutally stupid binary insulin response. Glucose goes in, insulin goes up. Obviously, that's a massive oversimplification, but the bottom line is that the adaptations to the sudden massive influx of raw nutrients into the central venous bloodstream are mainly endocrine and metabolic, rather than digestive (more detail is available in Byrne et al, 1981, and Greenberg et al, also 1981). In the briefest summary:
Pandol, Stephen J. "Integrated response to a meal." Journal of Parenteral and Enteral Nutrition 32.5 (2008): 564-566.
Camilleri, Michael. "Integrated upper gastrointestinal response to food intake." Gastroenterology 131.2 (2006): 640-658.
Livovsky, Dan M., Teorora Pribic, and Fernando Azpiroz. "Food, eating, and the gastrointestinal tract." Nutrients 12.4 (2020): 986.
Raybould, H. E., S. J. Pandol, and H. Yee. "The integrated responses of the gastrointestinal tract and liver to a meal." Textbook of Gastroenterology, (2003): 2-12.
Lim, Robert KS, A. C. Ivy, and J. E. McCarthy. "Contributions to the physiology of gastric secretion. I: gastric secretion by local (mechanical and chemical) stimulation." Quarterly Journal of Experimental Physiology: Translation and Integration 15.1 (1925): 13-53.
Dragstedt, Lester R., et al. "Antrum motility as a stimulus for gastric secretion." Gastroenterology 24.1 (1953): 71-78.
Pavlov, I. P. "The centrifugal (efferent) nerves to the gastric glands and of the pancreas." The work of the digestive glands 2 (1910): 48-59.
Power, Michael L., and Jay Schulkin. "Anticipatory physiological regulation in feeding biology: cephalic phase responses." Appetite 50.2-3 (2008): 194-206.
Gardner, Jerry D., Arthur A. Ciociola, and Malcolm Robinson. "Measurement of meal-stimulated gastric acid secretion by in vivo gastric autotitration." Journal of Applied Physiology 92.2 (2002): 427-434.
Malagelada, Juan-R., et al. "Measurement of gastric functions during digestion of ordinary solid meals in man." Gastroenterology 70.2 (1976): 203-210.
Lawrie, J. H., and A. P. M. Forrest. "The measurement of gastric acid." Postgraduate medical journal 41.477 (1965): 408.
Feldman, Mark, and Charles T. Richardson. "Role of thought, sight, smell, and taste of food in the cephalic phase of gastric acid secretion in humans." Gastroenterology 90.2 (1986): 428-433.
Browning, Kirsteen N., and R. Alberto Travagli. "Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions." Comprehensive physiology 4.4 (2014): 1339.
Liddle, Rodger A. "Regulation of pancreatic secretion." Physiology of the Gastrointestinal Tract. Academic Press, 2018. 895-929.
Palma, María Angeles Zafra, et al. "Enteral Feeding: Brain-Visceral Interactions in the Processing of Nutrients." Feed Your Mind-How Does Nutrition Modulate Brain Function throughout Life?. IntechOpen, 2019.
Teff, KAREN L., and K. Engelman. "Oral sensory stimulation improves glucose tolerance in humans: effects on insulin, C-peptide, and glucagon." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 270.6 (1996): R1371-R1379.
Gonzalez, Javier T., et al. "Intermittent versus continuous enteral nutrition attenuates increases in insulin and leptin during short-term bed rest." European Journal of Applied Physiology 120.9 (2020): 2083-2094.
Armstrong, David, et al. "The effect of continuous enteral nutrition on gastric acidity in humans." Gastroenterology 102.5 (1992): 1506-1515.
Bowling, T. E., and D. B. A. Silk. "Hormonal response to enteral feeding and the possiblerole of peptide YY in pathogenesis of enteral feeding-related diarrhoea." Clinical Nutrition 15.6 (1996): 307-310.
Byrne, William J., et al. "Adaptation to increasing loads of total parenteral nutrition: metabolic, endocrine, and insulin receptor responses." Gastroenterology 80.5 (1981): 947-956.
Greenberg, Gordon R., et al. "Effect of total parenteral nutrition on gut hormone release in humans." Gastroenterology 80.5 (1981): 988-993.
Mok, King‐Tong, and H. C. Meng. "Intestinal, pancreatic, and hepatic effects of gastrointestinal hormones in a total parenteral nutrition rat model." Journal of Parenteral and Enteral Nutrition 17.4 (1993): 364-369.