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Gastrointestinal hormone
Gastrointestinal hormone
Gastrointestinal hormone
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The gastrointestinal hormones (or gut hormones) constitute a group of hormones secreted by enteroendocrine cells in the stomach, pancreas, and small intestine that control various functions of the digestive organs. Later studies showed that most of the gut peptides, such as secretin, cholecystokinin or substance P, were found to play a role of neurotransmitters and neuromodulators in the central and peripheral nervous systems.[1]

Enteroendocrine cells do not form glands but are spread throughout the digestive tract. They exert their autocrine and paracrine actions that integrate gastrointestinal function.[2]

Types

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The gastrointestinal hormones[3] can be divided into three main groups based upon their chemical structure.

Ghrelin is a peptide hormone released from the stomach and liver and is often referred to as the "hunger hormone" since high levels of it are found in individuals that are fasting. Ghrelin agonistic treatments can be used to treat illnesses such as anorexia and loss of appetites in cancer patients. Ghrelin treatments for obesity are still under intense scrutiny and no conclusive evidence has been reached. This hormone stimulates growth hormone release. Amylin controls glucose homeostasis and gastric motility

Glucose-dependent insulinotropic polypeptide possesses an acute influence on food intake through its effects on adipocytes

Oxyntomodulin plays a role in controlling acid secretion and satiation

Characteristics of prominent forms of principal gut regulatory peptides[4]: 1719 
Hormone or peptide Molecular weight (Da) Number of amino acids Main gut localization Principal physiologic actions
Gastrin family
Cholecystokinin 3918 33 (also 385, 59) Duodenum and jejunum, Enteric nerves Stimulates gallbladder contraction and intestinal motility; stimulates secretion of pancreatic enzymes, insulin, glucagon, and pancreatic polypeptides; has a role in indicating satiety; the C-terminal 8 amino acid peptide cholecystokinin (CCK)-8 retains full activity
Little gastrin 2098 17 Both forms of gastrin are found in the gastric antrum and duodenum Gastrins stimulate the secretion of gastric acid, pepsinogen, intrinsic factor, and secretin; stimulate intestinal mucosal growth; increase gastric and intestinal motility
Big gastrin 3839 34
Secretin-glucagon family
Secretin 3056 27 Duodenum and jejunum Stimulates pancreatic secretion of HCO3, enzymes and insulin; reduces gastric and duodenal motility, inhibits gastrin release and gastric acid secretion
Vasoactive intestinal polypeptide (VIP) 3326 28 Enteric nerves Relaxes smooth muscle of gut, blood vessels, and genitourinary system; increases water and electrolyte secretion from pancreas and gut; releases hormones from pancreas, gut, and hypothalamus
Glucose-dependent insulinotropic 4976 42 Duodenum and jejunum Stimulates insulin release; reduces gastric and intestinal motility; increases fluid and electrolyte secretion from small intestine
Brief Description of Some GI Regulatory Peptides[4]: 1720 
Hormone or peptide Major tissue locations in the gut Principal known actions
Bombesin Throughout the gut and pancreas Stimulates release of cholecystokinin (CCK) and gastrin
Calcitonin gene-related peptide Enteric nerves Unclear
Chromogranin A Neuroendocrine cells Secretory protein
Enkephalins Stomach, duodenum Opiate-like actions
Enteroglucagon Small intestine, pancreas Inhibits insulin secretion
Galanin Enteric nerves
Ghrelin Stomach Stimulates appetite, increases gastric emptying
Glucagon-like peptide 1 Pancreas, ileum Increases insulin secretion
Glucagon-like peptide 2 Ileum, colon Enterocyte-specific growth hormone
Growth factors Throughout the gut Cell proliferation and differentiation
Growth hormone-releasing factor Small intestine Unclear
Leptin Stomach Appetite control
Motilin Throughout the gut Increases gastric emptying and small bowel motility
Neuropeptide Y Enteric nerves Regulation of intestinal blood flow
Neurotensin Ileum Affects gut motility; increases jejunal and ileal fluid secretion
Pancreatic polypeptide Pancreas Inhibits pancreatic and biliary secretion
Peptide YY Colon Inhibits food intake
Somatostatin Stomach, pancreas Inhibits secretion and action of many hormones
Substance P Enteric nerves Unclear
Trefoil peptides Stomach, intestine Mucosal protection and repair

See also

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Notes and references

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Gastrointestinal hormone

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Gastrointestinal hormones are mediators secreted primarily by enteroendocrine cells lining the mucosa of the and , serving as key regulators of digestive processes such as secretion, pancreatic release, contraction, intestinal motility, and absorption. These hormones, produced in response to luminal stimuli like , acids, or fats, act through endocrine, paracrine, or neurocrine pathways to coordinate the complex interplay of digestion and maintain gastrointestinal . The functions as the body's largest endocrine organ, with over 30 distinct hormone genes identified, enabling precise control over both local and systemic physiological responses. Among the classical gastrointestinal hormones, , secreted by G cells in the antrum, primarily stimulates production from parietal cells to facilitate protein and promotes mucosal growth. , released by I cells in the and , triggers contraction for release and pancreatic secretion while inhibiting gastric emptying to optimize fat and protein breakdown. , produced by S cells in the duodenal mucosa, enhances pancreatic secretion to neutralize in the , thereby protecting the intestinal lining during . Other notable hormones include glucose-dependent insulinotropic polypeptide (GIP), which promotes insulin release and in response to glucose and fats, and motilin, which initiates migrating motor complexes to clear the gut of residual contents during . Beyond their core roles in digestion, gastrointestinal hormones exert extragastrointestinal effects, influencing regulation, glucose , bone , and even . For instance, from gastric fundus cells stimulates and secretion, acting as an orexigenic signal, while glucagon-like peptide-1 (GLP-1), derived from L cells in the distal intestine, slows gastric emptying, enhances insulin sensitivity, and contributes to , making it a target for therapies in and . Disruptions in these hormones can lead to disorders such as Zollinger-Ellison syndrome from gastrin excess or , where analogs like (a GLP-2 mimic) promote intestinal . Ongoing research highlights their therapeutic potential in conditions such as non-alcoholic , with GLP-1 receptor agonists like showing efficacy in reducing liver fat and as of 2025.

Definition and Overview

Definition

Gastrointestinal hormones are primarily peptides, along with some biogenic amines, that are secreted by enteroendocrine cells (EECs) located within the mucosa of the , encompassing the stomach and intestines (including the colon). These cells form a diffuse endocrine system, representing the largest endocrine organ in the body, where EECs constitute about 1% of the epithelial cells and are specialized for hormone production in response to environmental cues within the gut lumen. Key characteristics of these hormones include their release triggered by luminal nutrients such as carbohydrates, proteins, and fats, as well as neural stimuli from the and circulating hormones that modulate gut activity. Once secreted, they exert effects through multiple modes: locally via to nearby cells, systemically through endocrine action via the bloodstream to distant organs, or directly as neurotransmitters within the gut's neural networks. Unlike classical hormones that are typically produced by discrete glands with singular primary targets, many gastrointestinal hormones exhibit pleiotropic effects extending beyond the digestive system, including along the gut-brain axis to influence , mood, and metabolic regulation. This multifunctionality underscores their role as versatile signaling molecules in integrated physiological networks. From an evolutionary perspective, gastrointestinal hormones derive from ancient peptide families that have been conserved across vertebrates, tracing back to early ancestors and reflecting adaptations for nutrient sensing and in complex digestive systems. These conserved structures highlight their fundamental importance in vertebrate physiology, with homologs identified in diverse from to mammals.

General Functions

Gastrointestinal () hormones play a central role in coordinating the complex processes of the digestive system, ensuring efficient nutrient processing from ingestion to . These hormones regulate key stages including the stimulation of secretion to initiate protein breakdown, the release of pancreatic enzymes for carbohydrate, fat, and protein , the promotion of bile flow from the to emulsify fats, and the facilitation of nutrient absorption in the intestines. Additionally, they influence overall GI motility to synchronize these events, such as promoting for propulsion and modulating tone to control transit. For instance, hormones like contribute to acid secretion during the cephalic phase of . Beyond direct GI coordination, these hormones integrate with neural and immune systems to maintain and protect the gut barrier. Through interactions with the , GI hormones modulate vagal signaling and local reflexes, while acts as a broad inhibitor to prevent excessive from endocrine and exocrine cells, thereby fine-tuning responses to luminal contents. Certain hormones also exert trophic effects, promoting the growth and repair of mucosal tissues in the , , and colon, which supports immune defense by enhancing epithelial integrity and against pathogens. Feedback mechanisms are integral to the regulatory actions of GI hormones, primarily through negative loops that adapt to nutritional status. Postprandial release of hormones such as (GLP-1) triggers the "ileal brake," slowing gastric emptying and intestinal to optimize and absorption of nutrients detected distally. further reinforces this by inhibiting upstream secretions like and acid production once pH thresholds are met. These mechanisms ensure balanced responses, preventing overload or inefficiency in the GI tract. GI hormone levels exhibit dynamic fluctuations, varying diurnally under influence and acutely in response to meals, which aligns their actions with feeding patterns and metabolic demands. Plasma concentrations typically range from picomolar (e.g., 10-75 pmol/L for glucose-dependent insulinotropic polypeptide postprandially) to nanomolar levels, reflecting their potent signaling at low doses. Such variability underscores their role in maintaining digestive across daily cycles.

History

Early Discoveries

The discovery of the first gastrointestinal hormone, , occurred in 1902 when British physiologists William Bayliss and demonstrated that acidic from the stomach triggers pancreatic secretion through a chemical messenger rather than neural reflexes. Using anesthetized dogs as their primary model, they isolated a segment of the , denervated it by cutting its nerves while preserving blood supply, and introduced dilute into the mucosal lining, which elicited flow. To confirm the humoral nature, they scraped the duodenal or jejunal mucosa, treated it with acid, filtered the extract, and injected it intravenously into another dog, observing robust pancreatic secretion without any neural involvement. This extract, named , was derived from the duodenal mucosa and marked the inaugural identification of a regulating digestive processes. Inspired by this work, John Sydney Edkins proposed the existence of in 1905 as a gastric counterpart to , suggesting it stimulated and secretion from the . In his experiments on anesthetized cats and dogs, Edkins prepared crude extracts from the pyloric mucosa by scraping and homogenizing the tissue, then injecting these into the of recipient animals and measuring increased gastric juice output via pouches. His bioassays relied on quantifying acid secretion volume and activity as indicators of potency, establishing as a released from antral G cells in response to food stimuli. However, Edkins' extracts were not purified, leading to initial acceptance but subsequent scrutiny. Early investigations into gastrointestinal hormones predominantly employed bioassays in intact or surgically prepared animal models, such as dogs and cats, to detect activity. Researchers typically used Pavlov pouches or Heidenhain isolated gastric segments to isolate gastric responses, injecting mucosal extracts and monitoring physiological outputs like pancreatic bicarbonate flow or pH via . These methods, building on Bayliss and Starling's intravenous injection technique, allowed quantification of hormonal effects through dose-response curves , though they required careful controls for neural influences via or atropine blockade. Significant challenges arose from the impurity of early extracts, which often contained contaminants that mimicked or confounded true hormonal effects, particularly in the case of gastrin. The 1910 discovery of histamine, a potent acid secretagogue present in mucosal tissues, led to widespread attribution of Edkins' observed gastric stimulation to histamine contamination rather than a distinct hormone; by the 1920s, experiments showed that histamine-free preparations failed to replicate the effects, prompting debates and temporary dismissal of gastrin as an independent entity. This misattribution delayed progress until purification techniques in the late 1930s separated the components, underscoring the limitations of crude bioassays in distinguishing specific hormonal signals.

Key Milestones in Research

In the 1960s, the development of by Rosalyn Yalow and Solomon Berson marked a pivotal advancement in quantifying low-abundance peptide hormones, initially demonstrated with insulin in 1960 and soon extended to gastrointestinal hormones. This sensitive technique, which uses radiolabeled antigens and specific antibodies to measure hormone concentrations in plasma, overcame limitations of earlier bioassays and enabled precise detection of circulating levels as low as picomolar ranges. By 1970, was applied to , allowing researchers to quantify its release in response to meals and elucidate its role in acid secretion regulation.80086-5/pdf) The 1970s and saw the identification and structural characterization of several key gastrointestinal hormones, alongside breakthroughs in . Gastric inhibitory polypeptide (GIP) was isolated and named in 1971 by and colleagues from porcine duodenal extracts, recognized for its insulinotropic effects. Motilin, a 22-amino-acid stimulating gastric , was discovered in 1972, also by Brown et al., through purification from intestinal mucosa. Cholecystokinin (CCK), previously known from bioassays, underwent detailed structural identification during this era, confirming its octapeptide form as the active component. Concurrently, cloning in the 1980s, including the proglucagon (encoding GLP-1 and related peptides) sequenced around 1983 and the CCK gene in 1985, provided insights into their precursor processing and tissue-specific expression.36196-6/fulltext) From the 1990s to the 2000s, discoveries highlighted the orexigenic and roles of GI hormones, influencing metabolic research. In 1999, Masayasu Kojima and colleagues identified , a 28-amino-acid acylated from gastric fundus, as an endogenous for the , potently stimulating and release. Simultaneously, (GLP-1), derived from proglucagon, was established as a major hormone; studies in the early 1990s, building on its 1987 isolation, confirmed its glucose-dependent insulin secretion enhancement, paving the way for therapies.00580-X/fulltext) Advancements in the and leveraged genomic technologies to uncover (EEC) diversity and connectivity. Single-cell RNA sequencing, applied to intestinal EECs starting around 2015–2019, revealed substantial heterogeneity, identifying multiple subtypes with co-expression of hormones like serotonin, GLP-1, and CCK, challenging the classical one-cell-one-hormone model. In the , imaging and functional studies demonstrated direct synaptic contacts between EEC neuropods and enteric neurons, enabling rapid of nutrient signals to the and gut-brain axis.

Classification

By Chemical Structure

Gastrointestinal (GI) hormones are primarily peptide-based signaling molecules, classified by chemical structure into distinct families based on shared sequences, post-translational modifications, and conformational features. This molecular taxonomy highlights evolutionary relationships and structural homologies that underpin their from common precursors. Key families include those with amidated C-termini, alpha-helical motifs, and unique acylations or cyclizations, alongside a non-peptide example. The /cholecystokinin (CCK) family consists of characterized by a conserved amidated C-terminal pentapeptide sequence (Gly-Trp-Met-Asp-Phe-NH₂), which confers . These hormones range in length from 17 to 39 , with primarily existing as 17- or 34-residue forms and CCK as 8-, 33-, or 58-residue variants, all derived from larger precursors through tissue-specific . This structural similarity reflects their common evolutionary origin within the neuroendocrine lineage. The secretin/glucagon family comprises polypeptides with alpha-helical secondary structures, enabling interaction with class B G-protein-coupled receptors. Members such as (27 amino acids), (29 amino acids), glucose-dependent insulinotropic polypeptide (GIP, 42 amino acids), (VIP, 28 amino acids), and (GLP-1, 30-31 amino acids) share , particularly in their N-terminal regions, and are processed from proglucagon or related precursors. These structural features underscore their divergence from a shared ancestral in vertebrate . Other notable peptide families include , an octanoylated 28- peptide with a critical n-octanoyl modification on serine-3 that enables receptor binding; motilin, a 22- linear peptide structurally related to ghrelin and interacting with erythromycin-binding receptors; and , which exists as cyclic 14- or 28- forms stabilized by a bridge. These structures highlight diverse post-translational modifications, with ghrelin and motilin sharing about 36% identity, suggesting a common evolutionary precursor. Non-peptide GI mediators include , a derived from with the chemical formula C₅H₉N₃ and an ring structure, primarily acting via paracrine mechanisms from enterochromaffin-like cells, though its classification as a true remains debated due to its short-range diffusion. Many GI hormones exhibit evolutionary homology with neuropeptides, sharing biosynthetic precursors and structural motifs; for instance, tachykinins like represent an ancient family of amidated peptides conserved across metazoans, with parallels in GI regulatory roles derived from early bilaterian ancestors.

By Location and Secretion Site

Gastrointestinal hormones are classified by their secretion sites within the , primarily from specialized enteroendocrine cells (EECs) distributed along the . These cells sense luminal contents through apical processes and release hormones basolaterally into the bloodstream or onto adjacent tissues, with at least a dozen distinct EEC subtypes identified based on molecular profiles and hormone expression. This spatial organization reflects adaptations to local nutrient environments, from the acidic to the nutrient-rich and distal colon. In the stomach, several EEC types predominate. G-cells, located mainly in the antrum, secrete . Enterochromaffin-like (ECL) cells, found throughout the oxyntic mucosa, release . D-cells (or P/D1 cells), distributed in the antrum and corpus, produce . Additionally, X/A-like cells in the fundus secrete . The and host EECs responsive to proximal . I-cells in the duodenal and jejunal mucosa secrete cholecystokinin (CCK). S-cells, primarily in the duodenal mucosa, release . K-cells, abundant in the duodenum and upper jejunum, produce glucose-dependent insulinotropic polypeptide (GIP). In the and colon, L-cells are key producers, with a proximal-distal gradient in expression. These cells secrete (GLP-1) and (PYY), among others. Plurihormonal secretion is prominent here, as many individual L-cells co-express and store GLP-1 and PYY in the same secretory vesicles. Pancreatic secretion of GI-related hormones occurs from the islets of Langerhans, endocrine clusters amid acinar tissue. Alpha cells in the islets release , while delta cells secrete . GI hormones from other sites influence acinar cell enzyme release, but the islets themselves contribute directly to circulating hormone pools. EEC diversity extends beyond classical types, with single-cell analyses revealing greater heterogeneity and multiple clusters of subtypes varying by region and co-expression patterns. Release typically occurs basolaterally via , enabling endocrine and , though apical sensing dominates stimulus detection.

Physiological Roles

Regulation of Digestion and Motility

Gastrointestinal hormones play a pivotal role in coordinating the gastric phase of , where , released from G cells in the antrum in response to stimuli, stimulates parietal cells to secrete (HCl) and chief cells to release pepsinogen, facilitating protein breakdown and sterilization of gastric contents. This process is tightly , with from D cells inhibiting release and directly suppressing acid secretion to prevent excessive acidity, maintaining an optimal gastric environment. In the intestinal phase, cholecystokinin (CCK), secreted by I cells in the and upon detection of fats and proteins, induces contraction to release and stimulates pancreatic acinar cells to produce such as , , and proteases, aiding in lipid emulsification and nutrient . Complementing this, from S cells responds to acidic entering the , promoting secretion from pancreatic ductal cells to neutralize and protect the intestinal mucosa while optimizing activity. GI hormones also govern motility to ensure efficient propulsion of contents. During fasting, motilin from enteroendocrine cells in the and initiates the (MMC), a cyclic pattern of contractions that clears residual contents from the upper gut, preventing bacterial overgrowth. Postprandially, (PYY), released from L cells in the and colon in response to nutrient arrival, slows intestinal transit by inhibiting , allowing prolonged nutrient absorption. These hormonal effects integrate with neural pathways for precise control; for instance, CCK activates vagal afferent neurons to signal and modulate , reducing gastric emptying and contributing to the mechanism. Quantitative aspects reveal dose-dependent responses, with physiological CCK levels rising to 1-10 pM postprandially, eliciting graded effects on contraction and intestinal , as shown in dose-response studies.

Metabolic and Systemic Effects

Gastrointestinal (GI) hormones exert significant metabolic and systemic effects beyond their local roles in the digestive tract, influencing , energy balance, and inter-organ communication. A prominent example is the incretin effect, mediated primarily by glucose-dependent insulinotropic polypeptide (GIP) and (GLP-1), which amplify insulin secretion from pancreatic β-cells in response to oral nutrient intake, contributing to approximately 50-70% of postprandial insulin release in healthy individuals. In , this effect is markedly impaired due to reduced GIP responsiveness, though GLP-1 retains partial efficacy in enhancing glucose-dependent insulin secretion while suppressing release from α-cells, thereby lowering hepatic glucose output and improving glycemic control. These actions underscore the therapeutic potential of GLP-1 receptor agonists, which mimic these effects to mitigate without excessive risk. Appetite regulation represents another key systemic influence of GI hormones, with acting as an orexigenic signal that promotes by binding to growth hormone secretagogue receptors in the , particularly activating /agouti-related peptide neurons in the arcuate nucleus to increase food intake. In contrast, postprandial hormones such as (PYY) and GLP-1 promote ; PYY, released from ileal L-cells, inhibits these same orexigenic neurons via Y2 receptors while stimulating pro-opiomelanocortin neurons, reducing ad libitum energy intake by up to 36% in physiological infusions. GLP-1 similarly induces through hypothalamic and receptors, delaying gastric emptying and suppressing , with intravenous doses as low as 0.3-0.9 pmol·kg⁻¹·min⁻¹ decreasing meal size by about 13% in lean subjects. These opposing mechanisms help maintain , though dysregulation contributes to . The gut-brain axis facilitates broader systemic effects of GI hormones, enabling communication with the (CNS) to modulate inflammation and behavior. Vasoactive intestinal peptide (VIP), secreted by enteric neurons, crosses the blood-brain barrier or signals via vagal afferents to inhibit microglial activation in the CNS, thereby attenuating neuroinflammatory responses and regulating cerebral blood flow during inflammatory states. Other GI hormones, such as and GLP-1, similarly traverse the blood-brain barrier or act through pathways to influence hypothalamic centers, integrating peripheral nutrient signals with central metabolic control. This bidirectional axis ensures coordinated responses to feeding and stress, with disruptions linked to neurological disorders. GI hormones also impact cardiovascular and immune functions, extending their influence to vascular health and immune modulation. inhibits immune , particularly T-lymphocyte responses, by reducing interleukin-2 production and mitochondrial respiration through subtype 3 signaling, thereby dampening excessive immune activation in inflammatory conditions. Meanwhile, GLP-1 provides endothelial protection by improving , reducing markers like nitrotyrosine, and decreasing adhesion in preclinical models of , effects mediated via GLP-1 receptor activation and independent of glycemic changes. Clinical trials, such as the LEADER study, demonstrate that GLP-1 receptor agonists like reduce major cardiovascular events by 13% in patients, highlighting these protective mechanisms. Circadian rhythms further illustrate the systemic orchestration by GI hormones, with ghrelin exhibiting daily oscillations that align metabolic cycles with feeding behavior. Ghrelin secretion from gastric oxyntic cells peaks pre-meal, typically in the biological evening or before anticipated food intake, driving food anticipatory activity and synchronizing peripheral clocks to meal timing rather than light-dark cycles. In rodents, these peaks occur at zeitgeber time 6 (ZT6), with plasma levels rising to stimulate hypothalamic orexigenic pathways, while clock gene mutants abolish this rhythm, underscoring ghrelin's role in entraining metabolic homeostasis to daily patterns.

Major Classes of GI Hormones

Gastrin and Cholecystokinin Family

The gastrin and cholecystokinin (CCK) family comprises hormones critical for regulating secretion and digestive processes in the . These hormones share structural similarities, including a conserved C-terminal pentapeptide sequence that enables interaction with common receptor subtypes, and are primarily synthesized in distinct enteroendocrine cells of the and . , predominantly produced in the antrum, stimulates production to facilitate protein digestion, while CCK, secreted in the , coordinates contraction and pancreatic release to aid in and protein breakdown. Their actions are tightly regulated by luminal nutrients and feedback mechanisms to maintain digestive . Gastrin exists mainly as amidated peptides of 17 or 34 , known as G-17 and G-34, respectively, derived from a common preprogastrin precursor. These forms retain bioactivity through a C-terminal amidated pentapeptide sequence essential for receptor binding. CCK, in contrast, occurs in multiple sulfated forms ranging from 8 to 58 (CCK-8, CCK-33, CCK-39, and CCK-58), all featuring a sulfated residue seven positions from the carboxyl terminus, which is crucial for high-affinity receptor interactions. The structural homology between and CCK, particularly in their bioactive C-termini, underscores their evolutionary relatedness and overlapping physiological roles. Synthesis of occurs in G-cells of the gastric antrum and , beginning with a 101-amino-acid preprogastrin precursor that undergoes post-translational processing, including cleavage and C-terminal amidation, to yield the mature G-17 and G-34 forms. of is upregulated in response to meal ingestion, driven by luminal protein breakdown products and neural stimuli. Similarly, CCK is synthesized in I-cells of the proximal from a prepro-CCK precursor, processed by prohormone convertases (primarily PC1/3) into its various bioactive forms, with secretion enhanced by the presence of nutrients during meals. This meal-responsive synthesis ensures coordinated hormonal release to match digestive demands. Gastrin exerts its primary effects by binding to CCK2 receptors on gastric parietal cells, directly stimulating secretion, and on enterochromaffin-like (ECL) cells, indirectly enhancing acid production via release. CCK, acting through CCK1 receptors, promotes gallbladder contraction to release for fat emulsification and stimulates pancreatic acinar cells to secrete , thereby optimizing nutrient absorption. These receptor-mediated actions highlight the family's role in integrating upper gastrointestinal responses to ingested food. Regulation of secretion involves from , which inhibits G-cell activity via release from D-cells, preventing excessive acid production. Luminal distension, vagal stimulation, and from protein digestion promote release, while hyperacidity suppresses it to maintain balance. CCK secretion is primarily triggered by fats and proteins in the duodenal lumen, activating G-protein-coupled receptors like GPR40 on I-cells to initiate calcium-dependent , with feedback modulated by clearance to fine-tune postprandial responses. In , excessive production from gastrinomas—neuroendocrine tumors often located in the or —leads to Zollinger-Ellison syndrome, characterized by uncontrolled hypersecretion, severe peptic ulcers, and gastroesophageal reflux due to loss of normal feedback inhibition. This condition affects approximately 0.1% of peptic ulcer cases and requires diagnostic confirmation via elevated fasting serum levels and stimulation testing.

Secretin and Glucagon Family

The secretin-glucagon family comprises a group of peptide hormones that play crucial roles in gastrointestinal physiology, particularly in regulating pancreatic secretion, nutrient absorption, and glucose homeostasis. These hormones share structural similarities and belong to the class B G-protein-coupled receptor (GPCR) ligand family, with key members including secretin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). Secretin primarily neutralizes gastric acid in the duodenum, while the incretins GIP and GLP-1 enhance postprandial insulin release and modulate digestive processes. Glucagon, though mainly known for its hyperglycemic effects from pancreatic islets, contributes to intestinal motility and energy balance within this superfamily. Structurally, these peptides exhibit high sequence homology, featuring a conserved C-terminal amide and an N-terminal helical domain essential for receptor binding. Secretin consists of 27 amino acids, derived from a 120-amino-acid preprosecretin precursor through post-translational proteolytic cleavage. Glucagon is a 29-amino-acid peptide processed from preproglucagon in pancreatic alpha cells. GIP comprises 42 amino acids, synthesized as a prohormone in K cells, while GLP-1 exists in two active forms—GLP-1(7-36)amide (30 amino acids) and GLP-1(7-37) (31 amino acids)—both derived from the same proglucagon precursor as glucagon but via tissue-specific cleavage in intestinal L cells. This shared proglucagon origin allows for differential processing, yielding glucagon in the pancreas and GLP-1 in the gut. Synthesis of these hormones occurs in specific enteroendocrine cells of the and . is produced predominantly by S cells in the duodenal mucosa, with expression also in the and other tissues. originates from alpha cells in the , whereas GIP is secreted by K cells located in the and . GLP-1 and the longer GLP-2 are generated in L cells of the distal and colon, as well as in alpha cells under certain conditions, involving enzymatic cleavage by convertases. Post-translational modifications, such as amidation and sulfation, are critical for their bioactivity and stability. The physiological actions of this family are diverse but interconnected, focusing on digestive and metabolic regulation. stimulates from pancreatic ductal cells and cholangiocytes, neutralizing acidic to protect the intestinal mucosa and optimize activity. GLP-1 slows gastric emptying and intestinal , promotes glucose-dependent insulin from beta cells, and suppresses release, thereby lowering postprandial glucose levels. GIP enhances insulin in a glucose-dependent manner and stimulates in adipocytes, while also exhibiting weaker effects on inhibition compared to its original naming. supports intestinal growth and inhibits gastric , complementing the family's inhibitory roles on upper GI functions. Notably, GLP-1 contributes to appetite suppression, though its broader metabolic effects extend beyond . Regulation of these hormones is primarily nutrient-driven, with neural and hormonal inputs providing fine-tuning. Incretins like GIP and GLP-1 are released in response to luminal glucose and fats, sensed via G-protein-coupled receptors such as GPR40 and GPR120 on enteroendocrine cells, leading to rapid postprandial elevation. secretion is triggered by low duodenal pH (below 4.5) from or fatty acids, while release is modulated by and sympathetic innervation. (VIP), a related member of the superfamily, influences and release through neural pathways, enhancing cAMP-mediated signaling in target tissues. Feedback inhibition by and other GI hormones further controls their levels to prevent overstimulation. Receptor signaling for the secretin-glucagon family uniformly involves class B GPCRs, which activate the adenylate cyclase pathway to increase intracellular cAMP levels, leading to (PKA) activation and downstream effects like and . The receptor (SCTR), (GCGR), GLP-1 receptor (GLP-1R), and GIP receptor (GIPR) each exhibit high affinity for their ligands, with shared structural features including an extracellular N-terminal domain for recognition and seven transmembrane helices for G-protein coupling. This cAMP-dependent mechanism underlies their roles in release (), insulin potentiation (GLP-1 and GIP), and (), ensuring coordinated responses to digestive challenges.

Other Notable Hormones

, a 28-amino acid , is acylated at the serine-3 position, which is essential for its binding to the (GHSR) and its orexigenic effects that stimulate . It is primarily produced by X/A-like cells in the oxyntic glands of the fundus and is released in response to , playing a key role in meal initiation and energy homeostasis. Unlike many GI hormones, ghrelin's acylation distinguishes it structurally from peptide families like or , enabling its unique signaling as a peripheral signal. Motilin, consisting of 22 , is secreted by enteroendocrine M cells in the and during phases, binding to motilin receptors (a subtype of G protein-coupled receptors) to initiate phase III of the , thereby accelerating gastric emptying and intestinal transit. This hormone's cyclic release every 90-120 minutes in the interdigestive state underscores its role in preventing stasis and preparing the gut for , with erythromycin acting as a motilin to mimic these effects in clinical settings. Structurally, motilin shares no close resemblance to the major GI hormone families, positioning it as a distinct regulator of . Somatostatin, available in 14- and 28-amino acid cyclic forms, functions as a broad-spectrum inhibitor secreted by D cells throughout the tract, potently suppressing the release of multiple hormones including , insulin, and via somatostatin receptors (SSTRs). Its universal inhibitory action helps fine-tune postprandial responses by dampening excessive secretion, with the 14-amino acid form being predominant in the and . As a member of the /urotensin family, it operates independently in GI inhibition. Peptide YY (PYY), a 36-amino acid from L cells in the distal and colon, exerts effects through Y2 receptor activation in the and gut, reducing food intake and absorption postprandially. Released in response to luminal s, particularly fats and carbohydrates, PYY slows gastric emptying and intestinal transit, contributing to energy balance regulation. It belongs to the family, sharing sequence similarity with , but its GI-specific secretion highlights its role in meal termination. The bombesin family includes the bombesin, a 14-amino acid originally isolated from frog skin, and its mammalian counterpart, (GRP), a 27-amino acid produced by fibers and enteroendocrine cells in the gut. GRP stimulates release from G cells and enhances gastric and colonic motility via bombesin receptors (BB2 subtype). This amphibian-derived analog influences pancreatic and gut contractility, with GRP mediating neural signaling in the . Structurally unrelated to the gastrin-cholecystokinin or secretin-glucagon families, the bombesin/GRP exemplify neuromodulators with trophic effects on GI mucosa.

Clinical Significance

Associated Disorders

Hypergastrinemia, characterized by excessive secretion, is a key feature of Zollinger-Ellison syndrome (ZES), a rare disorder caused by gastrin-secreting tumors known as gastrinomas, which lead to severe due to hyperchlorhydria. Gastrinomas, often located in the or , result in refractory ulcers, typically multiple and occurring distal to the , affecting over 90% of patients. Additionally, , or absence of secretion, induces secondary hypergastrinemia by removing the normal acid-mediated feedback inhibition on release, promoting (SIBO) and associated complications such as and diarrhea. This bacterial overgrowth in achlorhydric states, commonly seen in , exacerbates gastrointestinal symptoms through unconjugated accumulation and mucosal injury. Incretin hormones, including (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), exhibit defects in , where their impaired secretion and action contribute significantly to postprandial by reducing insulin response and allowing excessive secretion. The effect, responsible for approximately 50-70% of postprandial insulin secretion in healthy individuals, is markedly diminished in patients, leading to elevated glucose excursions after meals. Ghrelin dysregulation manifests as chronically elevated circulating levels in Prader-Willi syndrome (PWS), a associated with insatiable hyperphagia and , where high ghrelin concentrations from infancy may drive increased even before overt hyperphagia develops. In PWS, fasting ghrelin levels are often 3-4 times higher than in controls, correlating with the syndrome's characteristic feeding behavior. Conversely, ghrelin levels are also elevated in , reflecting a compensatory response to chronic energy deficit, though this fails to stimulate adequate food intake due to central resistance. Neuroendocrine tumors, such as carcinoid tumors arising from enterochromaffin cells, frequently overproduce serotonin, resulting in characterized by episodic flushing, secretory , and . Serotonin excess from carcinoids promotes intestinal hypermotility and fluid secretion, leading to watery in up to 70% of symptomatic cases. These tumors account for a subset of neuroendocrine neoplasms, with diagnosis often relying on elevated urinary (5-HIAA) as a marker. Dysregulation of (PYY)-like hormones has been implicated in chronic , with elevated circulating PYY levels observed in conditions such as celiac disease, where it contributes to adaptive responses to and , potentially explaining a portion of idiopathic cases through altered gut signaling. Recent investigations into PYY family members, including insulin-like 5, suggest their elevation in response to acids may underlie symptoms in up to 40% of acid-related or functional idiopathic chronic presentations.

Therapeutic Applications and Recent Advances

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as and , represent a cornerstone in the therapeutic management of and by mimicking the effects of endogenous GI hormones to enhance insulin secretion, suppress release, reduce , and improve glycemic control. These agents have demonstrated significant weight loss and cardiovascular benefits in clinical trials, with semaglutide achieving up to 15-20% body weight reduction in obese patients over 68 weeks. , administered at 3 mg daily, has been shown to reduce the risk of progression by 80% in individuals with and . Ghrelin receptor agonists, such as anamorelin, are under investigation for treating cancer-associated , where they stimulate appetite and promote lean body mass preservation without exacerbating tumor growth. In phase III trials, anamorelin increased body weight by approximately 2-3 kg and improved scores in patients with non-small cell experiencing . Motilin agonists, including erythromycin, are employed off-label for , accelerating gastric emptying through direct activation of motilin receptors on . Low-dose erythromycin (e.g., 50-100 mg three times daily) has been effective in improving symptoms and scintigraphic emptying rates in diabetic patients, though tachyphylaxis may limit long-term use. Somatostatin analogs like are widely used to inhibit excessive hormone secretion in , control variceal bleeding in , and manage neuroendocrine tumors by binding to receptors and suppressing , insulin, and gastrointestinal peptides. In , normalizes insulin-like growth factor-1 levels in about 50-60% of patients resistant to . For variceal bleeding, intravenous reduces rebleeding rates by 40-50% when combined with endoscopic . In neuroendocrine tumors, long-acting formulations like LAR stabilize disease progression in 60-70% of receptor-positive cases. Recent advances highlight the influence of food structure on GI hormone release, with a 2025 study demonstrating that intact (solid) food structures elicit greater GLP-1 secretion compared to broken (liquid) forms due to prolonged exposure in the upper gut, potentially informing dietary interventions for metabolic disorders. Discoveries from 2020-2023 have elucidated (EEC)-neural synapses, where neuropod EECs form direct synaptic contacts with vagal afferents to transmit rapid gut-brain signals for and regulation, bypassing hormonal diffusion delays. In 2024-2025 preclinical trials, engineered expressing GLP-1 analogs have shown promise in restoring gut barrier integrity and reducing inflammation in models by locally elevating GLP-1 levels in the colon. Looking ahead, plasma profiling of GI hormones offers potential for non-invasive diagnostics in (IBS), with multi-omics approaches identifying altered levels of cholecystokinin and as biomarkers that distinguish IBS subtypes from healthy controls with high accuracy (AUC >0.90). Such profiling could enable personalized therapeutic targeting based on hormonal dysregulations.

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