Hormonal response to a meal

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. 

In summary:

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.

Phases of the integrated response to a meal

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:

• Cephalic phase (historically also referred to as the "nervous" phase), where the orosensory and psychological anticipatory responses to the sight smell and the very idea of food tend to cause physiological changes in the activity of the gut
• Gastric phase, or the "chemical" phase, characterised by increased gastric acid secretion
• Intestinal phase, characterised by the digestive activities of the pancreas and by the increased  peristalsis of the small bowel
• Absorption phase, added by some authors to describe the biochemistry and endocrinology of nutrient handling which follows a meal

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).

Integrated response during the cephalic phase

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:

Table 1 (Power & Schulkin, 2008):
Selected Known Cephalic Phase Responses

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
Insulin	Pancreas
Pancreatic polypeptide	Pancreas
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
Thermogenesis

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. 

Cephalic phase:

• Stimuli are numerous:
  • Gustatory and olfactory sensation of food
  • Mastication and the orotactile sensation of food
  • Perceived palatability of the meal (even when viewed in a plastic container) is enough to act as a stimulus for the cephalic phase, but it is clearly not essential, as even decerebrate animals are able to produce a competent cephalic phase response when their oral cavivites are irrigated with glucose. 
• Afferents likely include the trigeminal, glossopharyngeal, hypoglossal and olfactory nerves, as well as descending central pathways from the higher CNS
• Central processing probably occurs at the level of the brainstem, for example in the raphe nuclei of the medulla (Browning & Travagli, 2016).
• Efferent and effector organs are easiest to discuss when they are described together:
  • Facial and glossopharyngeal nerves (to salivary glands), where they supply parasympathetic cholinergic innervation which stimulates the secretion of saliva
  • Vagus nerve:
    • Histamine-mediated stimulation of gastric acid release in the stomach
    • Relaxation of the proximal gastric smooth muscle to accommodate the contents
    • Stimulation of gastrin release from G-cells
    • Cholinergic stimulus for the release of pancreatic secretions and insulin
    • Increased small intestine motility

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:

• Gastrin, which:
  • stimulates gastric parietal cells, increasing acid production
  • increases the volume of bile produced b the liver
  • increases the volume of pancreatic exocrine secretions
• Histamine, which also stimulates gastric parietal cells, increasing acid production
• Insulin, which enhances the uptake of absorbed carbohydrates into cells

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. 

Integrated response during the gastric phase

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:

• Accommodation, - a vagally mediated "receptive relaxation"  which occurs as the food is being swallowed, intended to prevent premature satiety
• Trituration, during which the food is mixed and ground together with gastric acid to form chyme
• Gastric emptying, during which small particles (1-2mm) are sieved out of the pylorus

The reflex-like elements of the gastric phase response to a meal can be summarised as follows:

• Stimuli include
  • Pharyngeal sensation of the food bolus being swallowed, which stimulates the vagal receptive relaxation reflex
  • Stretch, sensed by gastric mechanoreceptors 
  • Change in gastric pH, sensed by parietal cells and gastric mucosal chemoreceptors
• Afferents, efferents and integration:
  • Myenteric reflex (mediated by the enteric nervous system) in response to stretch increases intestinal peristalsis and trituration by the antral pump. 
  • An increase in gastric pH results in the release of hormones that stimulate gastric acid secretion (gastrin, ghrelin and histamine)
• Specific hormones and their influences:
  • Histamine, a paracrine hormone that increases gastric acid secretion
  • Gastrin, which contributed slightly to the overall gastric motility, and which is a major stimulus for gastric acid secretion
  • Ghrelin, secreted by the ghrelin cells of the oxyntic glands, increases gastric motility substantially, and slightly increases acid secretion

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. 

Integrated response during the intestinal phase

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.   

• Stimuli are specific characteristics of the chyme, and the receptors for all of these are specific duodenal chemoreceptors
  • Caloric content, approximated by the osmolality of the chyme, which is mainly the function of its carbohydrate content
  • Fat content
• Hormonal responses result in:
  • Delayed gastric emptying (essentially all of the hormones listed here have this effect as well as their other effects)
  • Increased peristalsis of the small intestine (this is also in part due to the myenteric reflex, i.e. peristalsis is stimulated by the mechanical effect of emptying chyme into it)
  • Increased rate of pancreatic and biliary secretion
  • Emptying of pancreatic secretions from the pancreas
  • Emptying of bile from the gall bladder
• Specific hormones and their influences:
  • 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

Or, to list them in a slightly different way,

• Hormones that slow gastric emptying:
  • Cholecystokinin
  • Secretin
  • Leptin
  • Gastric inhibitory polypeptide
  • Glucagon
  • Glucagon-like peptides 1 and 2
• Hormones that stimulate pancreatic and biliary activity:
  • Cholecystokinin
  • Secretin
• Hormones that enhance peristalsis
  • Motilin
  • Gastrin

Integrated response during the "absorbed nutrient phase"

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.

Differences in the nasogastrically fed patient

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:

• Sedation, which dampens reflexes and central processing
• Continuous feeding, which reduces distending stimulus
• All nutrients available in liquid form, which requires 
• Uncomplicated nutrients, engineered for easier absorption

The effect of these is:

• Abolished cephalic phase. To sedate the patient means to rob them of the normal sensory and anticipatory stimuli. Not that there's much to anticipate from the look and taste of the usual nasogastric nutrient glurp, which is not designed to be looked at, smelled or tasted. The result is a decreased secretion of gastric acid, which
• Decreased saliva, as well as decreased voluntary swallowing of saliva, reduces the total amount of digestive enzymes available to the gastrointestinal tract, which could be a major issue if you were relying on those (eg. if one's pancreas is missing or on strike).
• Diminished autonomic reflexes. Sedatives and opioids decrease the normal operation of the vagal reflexes involved in the cephalic and gastric phases; digestive secretory activity is reduced as the result
• Decreased gastric acid secretion is to be expected, as there is no anticipatory release of acid during the cephalic phase, but then the volume of the delivered nutrients in the stomach is also usually lower, which means the reduced acid secretion is not such a big deal. Overall, because of the close feedback control of gastric acidity, continuous nutrition seems to eventually produce stable gastric pH levels which resemble those of the fasting state (Armstrong et al, 1992), with a pH of around 1.5.
• Reduced peristasis: sedatives and opioids decrease intestinal motility, and small continuous volumes have a less vigorous prokinetic effect,  as compared to intermittent large volumes.
• "Dumping syndrome", due to the liquid nature of gastric contents and poor autonomic regulatory control,  can sometimes be observed especially in patients following gastrectomy, or those with poor vagal function. This phenomenon results in a rapid emptying of nutrient-rich chyme into the duodenum, from where it is rapidly absorbed.
• Increased availability of nutrients: pureed nutrient mixtures usually feature a particle size  much smaller than what your pylorus could naturally grind. The increased surface area markedly increases their absorption rate (especially in the case of fats). Additionally, some formulations intentionally have a high concentration of readily absorbed nutrient molecules, eg. so-called "elemental feeds". 
• Decreased endocrine response to absorbed nutrients: the lack of the cephalic phase means a loss of the anticipatory secretion of insulin, which upsets the blood glucose homeostasis (Teff & Engleman, 1996)

So, this is the effect of nasogastric feeding. How would this be different in the parenterally fed patient?

Differences 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:

• Endocrine effects:
  • As TPN is initiated, blood glucose tends to peak (unless one starts the TPN very slowly), and then slowly declines as insulin secretion ramps up
  • Insulin secretion increases (in that specific study by Burne et al it had quadrupled)
  • Cortisol and growth hormone remain basically stable during TPN
  • Motilin, gastrin and secretin levels are decreased, but not by much
  • Pancreatic and intestinal hypoplasia (eg. villus atropy and pancreatic volume loss) results from decreased intestinal hormones (specifically secretin and cholecystokinin), which appears to act as a trophic stimulus. When Mok et al (1993)  administered these hormones to their chronically TPN-dependent rats, no pancreatic or villous atrophy was observed.
  • For lack of cholecystokinin stimulus, biliary stasis develops, which can lead to acalculous cholecystitis