Medical Physiology, 3rd Edition

Regulation of Gastrointestinal Function

The ENS is a “minibrain” with sensory neurons, interneurons, and motor neurons

The ENS (see pp. 339–340) is the primary neural mechanism that controls GI function and is one of the three divisions of the autonomic nervous system (ANS), along with the sympathetic and parasympathetic divisions. One indication of the importance of the ENS is the number of neurons consigned to it. The ENS consists of ~100 million neurons, roughly the number in the spinal cord or in the rest of the entire ANS. The ENS is located solely within GI tissue, but it can be modified by input from the brain. Neurons of the ENS are primarily, but not exclusively, clustered in one of two collections of neurons (Fig. 41-3A ): the submucosal plexus and the myenteric plexus. The submucosal (or Meissner'splexus is found in the submucosa only in the small and large intestine. The myenteric (or Auerbach'splexus is located between the circular and longitudinal muscle layers throughout the GI tract from the proximal end of the esophagus to the rectum.

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FIGURE 41-3 Schematic representation of the ENS. A, The submucosal (or Meissner's) plexus is located between the muscularis mucosae and the circular muscle of the muscularis externa. The myenteric (or Auerbach's) plexus is located between the circular and longitudinal layers of the muscularis externa. In addition to these two plexuses that have ganglia, three others—the mucosal, deep muscular, and tertiary plexuses—are present. B, The ENS consists of sensory neurons, interneurons, and motor neurons. Some sensory signals travel centrally from the ENS. Both the parasympathetic and the sympathetic divisions of the ANS modulate the ENS. This figure illustrates some of the typical circuitry of ENS neurons.

The ENS is a complete reflex circuit and can operate totally within the GI tract, without the participation of either the spinal cord or the cephalic brain. As with other neurons, the activity of the ENS is the result of the generation of action potentials by single neurons and the release of chemical neurotransmitters that affect either other neurons or effector cells (i.e., epithelial or muscle cells). The ENS consists of sensory circuits, interneuronal connections, and secretomotor neurons (see Fig. 41-3B ). Sensory (or afferent) neurons monitor changes in luminal activity, including distention (i.e., smooth-muscle tension), chemistry (e.g., pH, osmolality, levels of specific nutrients), and mechanical stimulation. These sensory neurons activate interneurons, which relay signals that activate efferent secretomotor neurons that in turn stimulate or inhibit a wide range of effector cells: smooth-muscle cells, epithelial cells that secrete or absorb fluid and electrolytes, submucosal blood vessels, and enteric endocrine cells.

The largely independent function of the ENS has given rise to the concept of a GI “minibrain.” Because the efferent responses to several different stimuli are often quite similar, a generalized concept has developed that the ENS possesses multiple preprogrammed responses. For example, both mechanical distention of the jejunum and the presence of a bacterial enterotoxin in the jejunum can elicit identical responses: stimulation of profuse fluid and electrolyte secretion, together with propagated, propulsive, coordinated smooth-muscle contractions. Such preprogrammed efferent responses are probably initiated by sensory input to the enteric interneuronal connections. However, efferent responses controlled by the ENS may also be modified by input from autonomic ganglia, which are in turn under the influence of the spinal cord and brain (see p. 336). image N41-1  In addition, the ENS receives input directly from the brain via parasympathetic nerves (i.e., the vagus nerve).

N41-1

Hierarchical Reflex Loops in the ANS

Contributed by George Richerson

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EFIGURE 41-1 At the lowest level, the ENS is an independent system consisting of afferent neurons, interneurons, and motor neurons. One level up, the autonomic ganglia control the autonomic end organs, including the ENS. One further level up, the spinal cord controls certain autonomic ganglia and integrates response among different levels of the spinal cord. The brainstem receives inputs from visceral afferents and coordinates the control of all viscera. Finally, forebrain CNS centers receive input from the brainstem and coordinate the activity of the ANS via input to the brainstem.

ACh, peptides, and bioactive amines are the ENS neurotransmitters that regulate epithelial and motor function

ACh is the primary preganglionic and postganglionic neurotransmitter regulating both secretory function and smooth-muscle activity in the GI tract. In addition, many other neurotransmitters are present in enteric neurons. Among the peptides, vasoactive intestinal peptide (VIP) has an important role in both inhibition of intestinal smooth muscle and stimulation of intestinal fluid and electrolyte secretion. Although VIP was first identified in the GI tract, it is now appreciated that VIP is also an important neurotransmitter in the brain (see Table 13-1). Also playing an important role in GI regulation are other peptides (e.g., enkephalins, somatostatin, and substance P), amines (e.g., serotonin), and nitric oxide (NO).

Our understanding of ENS neurotransmitters is evolving, and the list of identified agonists grows ever longer. In addition, substantial species differences exist. Frequently, chemical neurotransmitters are identified in neurons without a clear-cut demonstration of their physiological role in the regulation of organ function. More than one neurotransmitter has been identified within single neurons, a finding suggesting that regulation of some cell functions may require more than one neurotransmitter.

The brain-gut axis is a bidirectional system that controls GI function via the ANS, GI hormones, and the immune system

Well recognized, but poorly understood, is the modification of several different aspects of GI function by the brain. In other words, neural control of the GI tract is a function of not only intrinsic nerves (i.e., the ENS) but also nerves that are extrinsic to the GI tract. These extrinsic pathways are composed of elements of both the parasympathetic and, to a lesser extent, the sympathetic nervous system and are under the control of autonomic centers in the brainstem (see p. 338).

Parasympathetic innervation of the GI tract from the pharynx to the distal colon is through the vagus nerve; the distal third of the colon receives its parasympathetic innervation from the pelvic nerves (see Fig. 14-4). The preganglionic fibers of the parasympathetic nerves use ACh as their neurotransmitter and synapse on some neurons of the ENS (see Fig. 41-3B ). These ENS neurons are thus postganglionic parasympathetic fibers, and their cell bodies are, in a sense, the parasympathetic ganglion. These postganglionic parasympathetic fibers use mainly ACh as their neurotransmitter; however, as noted in the previous section, many other neurotransmitters are also present. Parasympathetic stimulation—after one or more synapses in a very complex ENS network—increases secretion and motility. The parasympathetic nerves also contain afferent fibers (see p. 339) that carry information to autonomic centers in the medulla from chemoreceptors, osmoreceptors, and mechanoreceptors in the mucosa. The loop that is initiated by these afferents, integrated by central autonomic centers, and completed by the aforementioned parasympathetic efferents, is known as a vagovagal reflex.

The preganglionic sympathetic fibers to the GI tract synapse on postganglionic neurons in the prevertebral ganglia (see Fig. 14-3); the neurotransmitter at this synapse is ACh (see p. 341). The postganglionic sympathetic fibers either synapse in the ENS or directly innervate effector cells (see Fig. 41-3B ).

In addition to the control that is entirely within the ENS, as well as control via autonomic centers in the medulla, the GI tract is also under the control of higher CNS centers. Examples of cerebral function that affects GI behavior include the fight-or-flight response, which reduces blood flow to the GI tract, and the sight and smell of food, which increase gastric acid secretion.

Communication between the GI tract and higher CNS centers is bidirectional. For example, cholecystokinin from the GI tract mediates, in part, the development of food satiety in the brain. In addition, gastrin-releasing peptide, a neurotransmitter made in ENS cells (see p. 868), inhibits gastric acid secretion when experimentally injected into the ventricles of the brain. Table 41-1 summarizes peptide hormones made by the GI tract as well as their major actions.

TABLE 41-1

GI Peptide Hormones image N41-2

HORMONE

SOURCE

TARGET

ACTION

Cholecystokinin

I cells in duodenum and jejunum and neurons in ileum and colon

Pancreas

↑ Enzyme secretion

Gall bladder

↑ Contraction

Gastric inhibitory peptide

K cells in duodenum and jejunum

Pancreas

Exocrine: ↓ fluid absorption
Endocrine: ↑ insulin release

Gastrin

G cells, antrum of stomach

Parietal cells in body of stomach

↑ H+ secretion

Gastrin-releasing peptide

Vagal nerve endings

G cells in antrum of stomach

↑ Gastrin release

Guanylin

Ileum and colon

Small and large intestine

↑ Fluid absorption

Motilin

Endocrine cells in upper GI tract

Esophageal sphincter
Stomach
Duodenum

↑ Smooth-muscle contraction

Neurotensin

Endocrine cells, widespread in GI tract

Intestinal smooth muscle

Vasoactive stimulation of histamine release

Peptide YY

Endocrine cells in ileum and colon

Stomach

↓ Vagally mediated acid secretion

Pancreas

↓ Enzyme and fluid secretion

Secretin

S cells in small intestine

Pancreas

↑ image and fluid secretion by pancreatic ducts

Stomach

↓ Gastric acid secretion

Somatostatin

D cells of stomach and duodenum, δ cells of pancreatic islets

Stomach

↓ Gastrin release

Intestine

↑ Fluid absorption/↓ secretion
↑ Smooth-muscle contraction

Pancreas

↓ Endocrine/exocrine secretions

Liver

↓ Bile flow

Substance P

Enteric neurons

Enteric neurons

Neurotransmitter

VIP

ENS neurons

Small intestine

↑ Smooth-muscle relaxation
↑ Secretion by small intestine

Pancreas

↑ Secretion by pancreas

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GI Peptide Hormones

Contributed by Emile Boulpaep, and Walter Boron

The amino-acid sequences of several of the peptide hormones listed in Table 41-1 are presented elsewhere in the text or below:

• Cholecystokinin (CCK): The amino-acid sequence is presented in Figure 42-7C .

• Cholecystokinin-like peptide (CCK-8): The amino-acid sequence is presented in Figure 13-9. This is one of several cleavage products of CCK.

• Gastric inhibitory peptide: See Table 41-1. A peptide consisting of 42 amino acids. The single-letter code for these amino acids is YAEGTFISD YSIAMDKIHQ QDFVNWLLAQ KGKKNDWKHN ITQ.

• Gastrin (“little” and “big”): The amino-acid sequences are presented in Figure 42-7.

• Gastrin-releasing peptide (GRP): The amino-acid sequence is presented in Figure 13-9.

• Guanylin (guanylyl cyclase activator 2A): A peptide consisting of 15 amino acids. The single-letter code for these amino acids is PGTCEICAYA ACTGC.

• Neurotensin: The amino-acid sequence is presented in Figure 13-9.

• Peptide YY: Peptide YY (also known as PYY-I) consists of 36 amino acids. The single-letter code for these amino acids is YP IKPEAPGEDA SPEELNRYYA SLRHYLNLVT RQRY. Notice that the sequence starts and ends with a Y (i.e., tyrosine). PYY-II lacks the first two residues of PYY-I (i.e., YP) and thus is only 34 residues in length (see p. 1005).

• Secretin: This peptide (see p. 876) consists of 27 amino acids: HSD GTFTSELSRL REGARLQRLL QGLV.

• Somatostatin: The amino-acid sequence is presented in Figure 13-9.

• Substance P: The amino-acid sequence is presented in Figure 13-9.

• Vasoactive intestinal peptide (VIP): The amino-acid sequence is presented in Figure 13-9.

In addition to the “hard-wired” communications involved in sensory input and motor output, communication via the gut-brain axis also requires significant participation of the immune system. Neuroimmune regulation of both epithelial and motor function in the small and large intestine primarily involves mast cells in the lamina propria of the intestine. Because the mast cells are sensitive to neurotransmitters, they can process information from the brain to the ENS and can also respond to signals from interneurons of the ENS. Mast cells also monitor sensory input from the intestinal lumen by participating in the immune response to foreign antigens. In turn, chemical mediators released by mast cells (e.g., histamine) directly affect both intestinal smooth-muscle cells and epithelial cells. Our understanding of how the immune system modulates the neural control of GI function is rapidly evolving.

In conclusion, three parallel components of the gut-brain axis—the ENS, GI hormones, and the immune system—control GI function, an arrangement that provides substantial redundancy. Such redundancy permits fine-tuning of the regulation of digestive processes and provides “backup” or “fail-safe” mechanisms that ensure the integrity of GI function, especially at times of impaired function (i.e., during disease).