Version May 2024
INTRODUCTION — Gastrointestinal (GI) hormones are predominantly polypeptides produced in and secreted from specialized gut endocrine cells [1,2]. These cells produce a variety of chemical transmitters that are involved in GI motility, secretion, absorption, growth, development, and regulation of food intake. Many of the peptides in the GI tract are also found in the enteric and central nervous systems.
An overview of the synthesis, secretion, and regulation of GI peptides; their role in causing disease; and their clinical application will be discussed here. The regulation and functions of the individual GI peptides are discussed separately. (See "Physiology of gastrin" and "Ghrelin" and "Pancreatic polypeptide, peptide YY, and neuropeptide Y" and "Insulin action" and "Physiology of somatostatin and its analogues" and "Physiology of cholecystokinin" and "Secretin".)
CLASSIFICATION — Gastrointestinal (GI) peptides are classified into families based on their primary structure (table 1). Conservation of amino acid sequence among different GI peptides suggests a common biosynthetic origin.
SYNTHESIS AND SECRETION
Synthesis — Enteroendocrine cells producing gastrointestinal (GI) peptides are dispersed throughout the GI tract. However, specific types of cells demonstrate regional specificity (table 2) [3]. This specificity may be related to the physiologic action of the peptide and receptor location. With the exception of the L cell, which produced both proglucagon and peptide YY (PYY), it had long been believed that an enteroendocrine cell produced only one hormone. However, using single-cell RNA analysis it was discovered that there is greater diversity than previously appreciated [4]. For example, secretin, reported to be produced exclusively by S cells, is expressed in virtually all enteroendocrine cells. Cholecystokinin, proglucagon, and PYY are commonly expressed in the same cell type. In light of these new findings, it is likely that a new classification system for enteroendocrine cells will be forthcoming.
All GI peptides are synthesized via gene transcription of DNA into messenger RNA (mRNA) and subsequently undergo translation into precursor proteins known as preprohormones. Translation occurs on ribosomes, which are complex organelles composed of many proteins (greater than 50) and multiple large RNA molecules [5,6].
Posttranslational processing — Preprohormones undergo intracellular processing in the rough endoplasmic reticulum and packaging in the Golgi apparatus prior to being stored in secretory granules as hormones (figure 1) [7]. Some peptides undergo further modification while in the secretory granule. The amino terminal sequence of a GI preprohormone contains a signal peptide that targets it for secretion. Enzymatic cleavage of the signal peptide produces a prohormone. Signal peptide cleavage and the vast majority of peptide modifications occur in the endoplasmic reticulum. Posttranslational modification of peptide hormones is important in receptor binding, signal transduction, and consequent cell responses, all of which may affect biological activity [8].
Other posttranslational modifications are specific to the particular hormone. Some undergo peptide cleavage to smaller forms (eg, somatostatin), amidation of the carboxyl terminus (eg, gastrin), and sulfation of tyrosine residues (eg, cholecystokinin [CCK]). These processing steps are usually critical for biological activity of the hormone [7]. As an example, sulfated CCK is 100-fold more potent than its unsulfated form.
In addition, many hormone genes are capable of manufacturing alternatively spliced mRNAs or proteins that undergo different posttranslational processing steps (figure 1 and figure 2), ultimately producing hormones of different sizes from the same gene. Gastrin and CCK exist in multiple molecular forms in blood and tissues.
The biochemical complexity of gastroenteropancreatic hormone processing is evident in the different tissues that produce these peptides. Many GI hormones are secreted from endocrine cells as well as nerves. The distinct tissue involved often determines the processing steps for production of the hormone.
Secretion — Many gut endocrine cells have their apical surfaces open to the intestinal lumen and contain abundant secretory granules that are concentrated along the basolateral surfaces. Because of this orientation, endocrine cells can be directly influenced by luminal contents. When endocrine cells are stimulated, peptides are secreted into the paracellular space, where they act (figure 3):
●On the same cells from which they are released (autocrine).
●On neighboring cells (paracrine).
●On distant cells via the blood (endocrine).
●On adjacent nerves through a synaptic connection [9].
Although GI peptides are typically thought of as hormones, not all peptides act via the traditional endocrine pathway by which they are secreted into the blood stream and act at a distant site. Thus far, only gastrin, secretin, and CCK have been proven to act as true hormones, although multiple other peptides may function in this manner (table 3). Neural transmission has been demonstrated by somatostatin-producing D cells. D cells in the stomach have cellular processes that extend to neighboring gastrin-producing G cells in the antrum and inhibit gastrin release. CCK-producing I cells and peptide YY (PYY)-producing L cells also possess basal processes called neuropods that extend to epithelial cells and penetrate the lamina propria to reach subepithelial cells [10,11]. Neuropods are comprised of neurofilaments and contain large numbers of secretory vesicles and abundant mitochondria [12]. They are escorted by glia, suggesting they directly communicate with other nearby cells including neurons.
REGULATION — Regulation of gastrointestinal (GI) peptide secretion is necessary for normal bowel function, including nutrient assimilation and homeostasis. All cellular proteins are regulated at the genetic level. The biochemical information that encodes for the production of proteins resides in the genome, in defined regions of specific chromosomes. Specific gene regulatory elements determine if and when a protein is produced, and the particular cell in which it will be expressed. Gut hormone gene expression is regulated according to the physiologic needs of the organism. The production of GI hormones increases when gut endocrine cells are stimulated by food, intraluminal pH, releasing factors, other hormones, or transmitters. Once a biologic response is elicited, signals may then be sent to the endocrine cell to turn off secretion. This negative feedback mechanism is common to many physiologic systems and avoids excess production and secretion of hormone. (See "Physiology of gastrin" and "Ghrelin" and "Pancreatic polypeptide, peptide YY, and neuropeptide Y" and "Insulin action" and "Physiology of somatostatin and its analogues".)
ASSOCIATED DISEASES — Alterations in either gastrointestinal (GI) peptide secretion or action can have deleterious effects [13]. Clinically significant disease can occur due to overproduction of by GI tumors (eg, gastrinoma, VIPoma), loss of regulation (eg, medication-induced hypersecretion), and receptor signaling errors (eg, toxin-induced diarrhea).
Any enteroendocrine cell within the GI tract can serve as a nidus for hyperplasia or neoplasia [14]. Although these tumors are rare, their secreted hormones often produce clinical manifestations (table 4). Most gut endocrine tumors elaborate several secretory products, but one hormone usually predominates. The clinical findings are determined by the amount and type of peptide secreted. As an example, gastrinomas, the most common functional pancreatic neuroendocrine tumors, are caused by hypersecretion of gastrin and result in severe acid-related peptic disease and diarrhea. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
Most peptide hormones transduce their information through G protein-coupled receptors. In certain circumstances, defects in receptor signaling or coupling can produce disease in the absence of excess hormone production. As an example, Vibrio cholerae toxin covalently modifies the alpha-subunit of the stimulatory G protein in enterocytes. This activates the signaling pathway and stimulates intestinal secretion, resulting in voluminous watery diarrhea [15]. (See "Peptide hormone signal transduction and regulation" and "Cholera: Epidemiology, clinical features, and diagnosis".)
CLINICAL APPLICATION — Understanding the physiology of gastrointestinal (GI) peptides has led to novel diagnostic and therapeutic uses (table 5) [16].
Diagnostic evaluation — Several gut peptides have been used in diagnostic evaluation. As examples, a radiolabeled form of the somatostatin analog octreotide (111-indium pentetreotide) using somatostatin-receptor scintigraphy (OctreoScan) is used to localize neuroendocrine tumors; secretin is used as an adjunct with magnetic resonance imaging (MRI) to evaluate pancreatic secretion and ductal obstruction; cholecystokinin (CCK)-stimulated cholescintigraphy is used to estimate the gallbladder ejection fraction (table 5).
Therapeutic uses — A number of GI peptides or their analogues or drugs targeted at specific GI hormone receptors are used clinically. Some examples of therapeutic application of GI peptides include the following (table 5):
●Diarrhea – Somatostatin analogue, octreotide is used for the treatment of chronic diarrhea, GI hormone-secreting tumors (particularly VIPoma), and GI tract fistulas. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)
A glucagon-like peptide-2 analog (teduglutide) has been used to treat short bowel syndrome [17-20]. (See "Management of short bowel syndrome in adults", section on 'Pharmacologic therapy to reduce fluid loss'.)
●Diabetes mellitus – Synthetic glucagon-like peptide (GLP)-1-based therapies (eg, GLP-1 receptor agonists [eg, exenatide, liraglutide, semaglutide] and dipeptidyl peptidase 4 [DPP-4] inhibitors) are used to treat diabetes mellitus. GI hormones that possess incretin activity (eg, glucose-dependent insulinotropic peptide [GIP] and GLP-1) are potentially useful for treatment of diabetes mellitus [21]. However, GLP-1 exhibits a short half-life of one to two minutes due to N-terminal degradation by the enzyme DPP-4. GLP-1-agonists (eg, exenatide, liraglutide) are more resistant to degradation by DPP-4. DPP-4 inhibitors (eg, sitagliptin) inhibit the degradation of both GIP and GLP-1. GLP-1-based therapies affect glucose control through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and of food intake [22]. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus" and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)
●Gastrointestinal tract bleeding – Octreotide is used in the treatment of gastroesophageal variceal bleeding and may also reduce the risk of GI bleeding due to nonvariceal causes [23]. Octreotide is not recommended for routine use in patients with acute nonvariceal upper GI bleeding. Its role is generally limited to settings in which endoscopy is unavailable or as a means to help stabilize patients before definitive therapy can be performed. (See "Methods to achieve hemostasis in patients with acute variceal hemorrhage", section on 'Somatostatin and its analogs' and "Approach to acute upper gastrointestinal bleeding in adults", section on 'Vasoactive medications'.)
●Obesity – The US Food and Drug Administration (FDA) has approved two GI peptide-based therapies for long-term management of obesity. GLP-1 agonists, liraglutide and semaglutide, which were first approved for treatment of type 2 diabetes, are now used for treating nondiabetic individuals with body mass index (BMI) >30.
Other investigational uses
●Obesity – Investigational GI peptide-based drugs for weight loss include small molecule CCK receptor agonists peptide YY (PYY) analogues (eg, PYY [3-36]), oxyntomodulin, amylin, and ghrelin [24] (see "Physiology of cholecystokinin" and "Pancreatic polypeptide, peptide YY, and neuropeptide Y" and "Ghrelin"). It remains to be determined whether combinations of peptide agonists, such as GLP-1 and glucose-dependent-insulinotropic peptide (GIP), or synthetic agonists with dual activities, are more effective than individual peptide agonists alone [25].
SUMMARY
●Gastrointestinal (GI) peptides are involved in GI motility, secretion, absorption, growth, and development. GI peptides are classified according to their primary structure (table 1). (See 'Introduction' above and 'Classification' above.)
●GI peptides are produced by enteroendocrine cells that are dispersed throughout the GI tract. However, specific types of cells demonstrate regional specificity (table 2). This specificity may be related to the physiologic action of the peptide and receptor location. (See 'Secretion' above.)
●All GI peptides are synthesized via gene transcription of DNA into messenger RNA (mRNA) and subsequently undergo translation into precursor proteins known as preprohormones. Subsequently, preprohormones are modified by posttranslational processing into various peptide cleavage products that are eventually secreted. Posttranslational modification of peptide hormones is important in receptor binding, signal transduction, and consequent cell responses, all of which may affect biological activity. (See 'Posttranslational processing' above.)
●When enteroendocrine cells are stimulated, peptides are secreted into the paracellular space. From the paracellular space, GI peptides can act on the same cells from which they are released (autocrine), neighboring cells (paracrine), on distant cells via the blood (endocrine), on cells following their release from nerves (neurocrine), or on adjacent nerves through a synaptic connection (figure 3). Negative feedback mechanisms avoid excess production and secretion of GI peptides. (See 'Secretion' above and 'Regulation' above.)
●Alterations in either GI peptide secretion or action can have deleterious effects. Clinically significant disease can occur due to overproduction by GI tumors (eg, gastrinoma, VIPoma), loss of regulation (eg, medication-induced hypersecretion), and receptor signaling errors (eg, toxin-induced diarrhea). (See 'Associated diseases' above.)
●Several GI peptides or their analogues or drugs targeted at specific GI hormone receptors have diagnostic and therapeutic uses (table 5). As an example, the somatostatin analogue, octreotide has been used for the treatment of endocrine tumors, chronic diarrhea, variceal hemorrhage, GI hormone-secreting tumors, and GI tumor diagnostic testing (somatostatin receptor scintigraphy). (See 'Clinical application' above.)
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