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Intestinal gland
Intestinal gland
Intestinal gland
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Intestinal gland
Micrograph of the small intestine mucosa showing the intestinal glands - bottom 1/3 of image. H&E stain.
Details
Identifiers
Latinglandula intestinalis
TA98A05.6.01.012
A05.7.01.008
TA22942, 2969
FMA15052
Anatomical terminology

In histology, an intestinal gland (also crypt of Lieberkühn and intestinal crypt) is a gland found in between villi in the intestinal epithelial lining of the small intestine and large intestine (or colon). The glands and intestinal villi are covered by epithelium, which contains multiple types of cells: enterocytes (absorbing water and electrolytes), goblet cells (secreting mucus), enteroendocrine cells (secreting hormones), cup cells, myofibroblast, tuft cells, and at the base of the gland, Paneth cells (secreting anti-microbial peptides) and stem cells.

Structure

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Intestinal glands are found in the epithelia of the small intestine, namely the duodenum, jejunum, and ileum, and in the large intestine (colon), where they are sometimes called colonic crypts. Intestinal glands of the small intestine contain a base of replicating stem cells, Paneth cells of the innate immune system, and goblet cells, which produce mucus.[1] In the colon, crypts do not have Paneth cells.[2]

Function

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The enterocytes in the small intestinal mucosa contain digestive enzymes that digest specific foods while they are being absorbed through the epithelium. These enzymes include peptidase, sucrase, maltase, lactase and intestinal lipase. This is in contrast to the gastric glands of the stomach where chief cells secrete pepsinogen.

Also, new epithelium is formed here, which is important because the cells at this site are continuously worn away by the passing food. The basal (further from the intestinal lumen) portion of the crypt contains multipotent stem cells. During each mitosis, one of the two daughter cells remains in the crypt as a stem cell, while the other differentiates and migrates up the side of the crypt and eventually into the villus. These stem cells can differentiate into either an absorptive (enterocytes) or secretory (Goblet cells, Paneth cells, enteroendocrine cells) lineages.[3] Both Wnt and Notch signaling pathways play a large role in regulating cell proliferation and in intestinal morphogenesis and homeostasis.[4]

Loss of proliferation control in the crypts is thought to lead to colorectal cancer.

Intestinal juice

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Intestinal juice (also called succus entericus[5]) refers to the clear to pale yellow watery secretions from the glands lining the small intestine walls. The Brunner's glands secrete large amounts of alkaline mucus in response to (1) tactile or irritating stimuli on the duodenal mucosa; (2) vagal stimulation, which increases Brunner's glands secretion concurrently with increase in stomach secretion; and (3) gastrointestinal hormones, especially secretin.[6]

Its function is to complete the process begun by pancreatic juice; the enzyme trypsin exists in pancreatic juice in the inactive form trypsinogen, it is activated by the intestinal enterokinase in intestinal juice. Trypsin can then activate other protease enzymes and catalyze the reaction pro-colipase → colipase. Colipase is necessary, along with bile salts, to enable lipase function. [citation needed]

Intestinal juice also contains hormones, digestive enzymes, mucus, substances to neutralize hydrochloric acid coming from the stomach. Various exopeptidase which further digests polypeptides into amino acids complete the digestion of proteins.[citation needed]

Colonic crypts

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Colonic crypts (intestinal glands) within four tissue sections. In panel A, the bar shows 100 μm and allows an estimate of the frequency of crypts in the colonic epithelium. Panel B includes three crypts in cross-section, each with one segment deficient for CCOI expression and at least one crypt, on the right side, undergoing fission into two crypts. Panel C shows, on the left side, a crypt fissioning into two crypts. Panel D shows typical small clusters of two and three CCOI deficient crypts (the bar shows 50 μm). The images were made from original photomicrographs, but panels A, B and D were also included in an article[7]

The intestinal glands in the colon are often referred to as colonic crypts. The epithelial inner surface of the colon is punctuated by invaginations, the colonic crypts. The colon crypts are shaped like microscopic thick-walled test tubes with a central hole down the length of the tube (the crypt lumen). Four tissue sections are shown here, two (A and B) cut across the long axes of the crypts and two (C and D) cut parallel to the long axes.

In these images the cells have been stained to show a brown-orange color if the cells produce a mitochondrial protein called cytochrome c oxidase subunit I (CCOI or COX-1). The nuclei of the cells (located at the outer edges of the cells lining the walls of the crypts) are stained blue-gray with haematoxylin. As seen in panels C and D, crypts are about 75 to about 110 cells long. The average crypt circumference is 23 cells.[8] From the images, an average is shown to be about 1,725 to 2530 cells per colonic crypt. Another measure was attained giving a range of 1500 to 4900 cells per colonic crypt.[9] Cells are produced at the crypt base and migrate upward along the crypt axis before being shed into the colonic lumen days later.[8] There are 5 to 6 stem cells at the bases of the crypts.[8]

As estimated from the image in panel A, there are about 100 colonic crypts per square millimeter of the colonic epithelium.[10] The length of the human colon is, on average 160.5 cm (measured from the bottom of the cecum to the colorectal junction) with a range of 80 cm to 313 cm.[11] The average inner circumference of the colon is 6.2 cm.[10] Thus, the inner surface epithelial area of the human colon has an area, on average, of about 995 cm2, which includes 9,950,000 (close to 10 million) crypts.

In the four tissue sections shown here, many of the intestinal glands have cells with a mitochondrial DNA mutation in the CCOI gene and appear mostly white, with their main color being the blue-gray staining of the nuclei. As seen in panel B, a portion of the stem cells of three crypts appear to have a mutation in CCOI, so that 40% to 50% of the cells arising from those stem cells form a white segment in the cross cut area.

Overall, the percentage of crypts deficient for CCOI is less than 1% before age 40, but then increases linearly with age.[7] Colonic crypts deficient for CCOI reaches, on average, 18% in women and 23% in men, by 80–84 years of age.[7]

Crypts of the colon can reproduce by fission, as seen in panel C, where a crypt is dividing to form two crypts, and in panel B where at least one crypt appears to be fissioning. Most crypts deficient in CCOI are in clusters of crypts (clones of crypts) with two or more CCOI-deficient crypts adjacent to each other (see panel D).[7]

Clinical significance

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Main article: Cryptitis

Crypt inflammation is known as cryptitis and characterized by the presence of neutrophils between the enterocytes. A severe cryptitis may lead to a crypt abscess.

Pathologic processes that lead to Crohn's disease, i.e. progressive intestinal crypt destruction, are associated with branching of the crypts.

Causes of crypt branching include:

Research

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Intestinal glands contain adult stem cells referred to as intestinal stem cells.[12] These cells have been used in the field of stem biology to further understand stem cell niches,[13] and to generate intestinal organoids.[12]

History

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The crypts of Lieberkühn are named after the eighteenth-century German anatomist Johann Nathanael Lieberkühn.

References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Intestinal gland

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from Grokipedia
Intestinal glands, also known as crypts of Lieberkühn, are simple tubular invaginations of the epithelial lining found in the mucosa of the small and large intestines, serving as key sites for cellular renewal and secretion in the gastrointestinal tract. These glands extend from the surface epithelium down to the muscularis mucosae, forming straight, unbranched structures that are essential for maintaining the intestinal barrier and facilitating digestion. In the small intestine, they are located between villi, while in the large intestine, they are more prominent without associated villi, adapting to region-specific roles in absorption and mucus production. The of intestinal glands reveals a diverse population of cells originating from stem cells at their base, which proliferate to renew the entire epithelial lining every 3 to 5 days. Key cell types include Paneth cells at the base, which secrete and lysosomal enzymes to protect against pathogens; goblet cells that produce for lubrication and ; enteroendocrine cells that release hormones such as cholecystokinin to regulate ; and absorptive enterocytes with microvilli for nutrient uptake. In the , Paneth cells are prominent, whereas the features a higher density of goblet cells and lacks Paneth cells, reflecting differences in immune and secretory demands. This cellular composition ensures continuous epithelial turnover, preventing damage from constant exposure to luminal contents. Functionally, intestinal glands play a critical role in nutrient absorption, immune defense, and mucosal protection within the gastrointestinal system. They secrete and to neutralize acidic , while from goblet cells shields the from mechanical and chemical stress. In the , the glands support the absorptive functions of villi by replenishing enterocytes, whereas in the , they contribute to water reabsorption and fecal lubrication. Disruptions in gland function, such as impaired proliferation, can lead to conditions like , underscoring their importance in gut .

Anatomy and Structure

Location and Morphology

Intestinal glands, also known as crypts of Lieberkühn, are simple tubular invaginations of the that extend into the underlying of the mucosa. These structures are present throughout the , including the , , and , as well as the , specifically the colon. They open directly into the intestinal lumen through narrow orifices located at the base of villi in the small intestine or along the flat mucosal surface in the colon. In terms of morphology, the crypts form straight or slightly coiled tubes, typically measuring 100-200 μm in depth in the and approximately 300 μm in the . Their diameter ranges from 50-150 μm, creating pocket-like compartments within the mucosa. Each villus in the is surrounded by 6-14 crypts, contributing to the overall organization of the epithelial layer. The density of crypts varies by region, with an estimated 10-40 villi per mm² in the leading to roughly 60-100 crypts per mm² when accounting for the crypts per villus. In the colon, the density is about 100 crypts per mm², resulting in approximately 10 million crypts in total. These glands are embedded within the mucosal layer, positioned between villi in the or across the flat in the colon, and are supported by surrounding of the along with an associated vascular and lymphatic supply.

Cellular Composition

The intestinal glands, also known as crypts of Lieberkühn, are lined by a composed primarily of absorptive enterocytes, which feature microvilli on their apical surface and oval nuclei positioned basally. Interspersed among these are specialized cell types that contribute to the gland's structural diversity. Goblet cells, identifiable by their mucin-filled apical , are scattered throughout the epithelium, becoming more numerous toward the . Enteroendocrine cells, located near the , exhibit a basal extension for release and are distributed diffusely within the . Tuft cells, characterized by prominent tufts of microvilli and irregular mitochondria, occur along the crypt-villus axis. At the base of the crypt, multipotent s predominate, marked by expression and positioned as crypt base columnar (CBC) cells, with approximately 15 such cells per crypt in mice. These s are interspersed with Paneth cells, which are unique to the and contain eosinophilic granules rich in such as and ; around 10 Paneth cells reside at the crypt base per gland. Additional populations, such as Bmi1+ cells at the +4 position above the base, also contribute to the stem cell compartment. In the , Paneth cells are absent, and the stem cell niche relies on other supporting cells, with a higher proportion of goblet cells overall. The cellular organization within the intestinal gland follows a hierarchical , with stem cells at the bottom generating transit-amplifying cells that proliferate and migrate upward toward the mouth and onto the villus surface. This migration results in differentiation into mature cell types, culminating in and of senescent cells at the villus tip. The base narrows to accommodate 16-20 cells circumferentially, expanding upward to a total of approximately 250 cells per full-length in the .

Function and Physiology

Secretory Mechanisms

The intestinal glands, or crypts of Lieberkühn, primarily function to secrete intestinal juice, known as succus entericus, which totals approximately 1-2 liters per day in humans and maintains a slightly alkaline of 7.4-7.8 to facilitate and neutralize acidic from the . This secretion originates from the epithelial cells lining the crypts, including enterocytes, goblet cells, and enteroendocrine cells, and contributes essential components for mucosal protection and hormonal signaling. Crypt enterocytes contribute to fluid and secretion, while the proliferative cells they produce migrate to the villi, differentiating into mature s that express and anchor key digestive enzymes on their brush border, including enterokinase (also called ), which activates to initiate protein in the lumen, as well as disaccharidases such as sucrase and for hydrolysis and peptidases for cleavage. These enzymes are not freely released but function as membrane-bound ectoenzymes, ensuring efficient contact with luminal substrates while minimizing loss into the intestinal contents. Goblet cells in the crypts secrete , composed primarily of glycoproteins, which forms a protective gel-like layer over the to shield against mechanical abrasion, pathogens, and digestive acids while lubricating the passage of . This secretion occurs via of mucin granules, with constitutive release maintaining baseline mucus renewal and stimulated discharge enhancing barrier function during irritation. Enteroendocrine cells scattered throughout the crypts and villi release hormones such as and cholecystokinin (CCK) in response to luminal stimuli like acids, fats, and proteins, with promoting bicarbonate secretion from the and CCK stimulating contraction and enzyme release. Although is predominantly gastric, minor contributions from intestinal G cells support overall digestive coordination. Secretory activity is tightly regulated by neural and hormonal mechanisms, including parasympathetic stimulation via the , which enhances fluid and output, and (VIP), a that activates and secretion to maintain luminal pH balance. ions, secreted by enterocytes and augmented by in the , further neutralize , preventing epithelial damage.

Epithelial Renewal

The undergoes complete renewal every 3–5 days in humans, representing one of the highest turnover rates in the body and ensuring continuous replacement of the single-cell layer lining the gut. This process is primarily driven by the proliferation of stem cells located at the base of the intestinal crypts, which generate daughter cells that replenish the epithelial sheet. Approximately 10^11 epithelial cells are shed daily in humans, balancing the rapid production to maintain epithelial integrity. Newly generated cells from the crypt base migrate upward along the crypt-villus axis, advancing at rates estimated from labeling studies as 1–2 cell positions per hour in the upper crypt regions, with progressive differentiation into specialized lineages such as enterocytes and goblet cells occurring during transit. This migratory flow propels cells toward the villus tips over the course of several days, forming a dynamic "" that coordinates tissue . Upon reaching the crypt-villus junction or villus apex, epithelial cells undergo via , followed by extrusion into the intestinal lumen to prevent accumulation and preserve . This shedding mechanism eliminates senescent or damaged cells while minimizing disruptions to the epithelial , thus sustaining against luminal pathogens and toxins. The renewal process maintains homeostatic balance by tightly coupling proliferation, migration, differentiation, and , which collectively uphold the mucosal barrier's impermeability and functional capacity. Factors such as nutrient availability can modulate the renewal rate; for instance, increased dietary nutrients enhance proliferation and epithelial expansion through metabolic signaling. In response to injury, such as , renewal accelerates to facilitate repair, with support promoting faster crypt regeneration and structural recovery.

Regional Variations

Small Intestine Crypts

In the , crypts of Lieberkühn are positioned at the bases of villi, forming crypt-villus units that enable continuous epithelial renewal and maximize surface area for nutrient absorption. This structural arrangement ensures that stem cells in the crypts generate new enterocytes that migrate upward along the villus axis, replacing shed cells and maintaining absorptive efficiency. Small intestine crypts demonstrate adaptations suited to nutrient processing, including a higher density with 6–14 crypts surrounding each villus to meet elevated absorptive demands. Their depth typically measures 100–200 μm, allowing compact organization while supporting rapid . Paneth cells, which are particularly prominent at the crypt base in the , secrete antimicrobial factors such as and to safeguard the nutrient-rich lumen from bacterial colonization. These crypts integrate functionally with overlying villus enterocytes by providing progenitor cells that differentiate into mature absorptive cells expressing diverse brush-border enzymes, including disaccharidases like and sucrase for carbohydrate and peptidases for protein degradation. This coordination ensures final stages of occur on the villus surface, optimizing breakdown of complex nutrients in the proximal gut.

Colonic Crypts

Colonic crypts, also known as crypts of Lieberkühn in the , exhibit distinct morphological features adapted to the colon's environment of high bacterial load and low nutrient availability. These crypts are typically deeper, measuring approximately 300-500 μm in length, compared to those in the , and possess a straighter, more cylindrical shape that facilitates efficient cellular migration and flow. The epithelial cells within colonic crypts undergo slower turnover, with a renewal cycle of 4-5 days driven by stem cells at the crypt base, allowing for sustained barrier maintenance in a fermentation-dominated milieu. Unlike small intestinal crypts, colonic crypts lack Paneth cells, which are absent in the healthy colon and instead rely on alternative antimicrobial defenses produced by goblet cells and enterocytes. Goblet cells, present in higher density in the colon than in the , secrete mucins such as MUC2 that form a protective layer enriched with like trefoil factors and resistin-like molecules, shielding the from the dense . This elevated goblet cell population supports increased production, providing lubrication and a physical barrier in the low-nutrient, bacteria-rich colonic lumen to prevent invasion while accommodating commensal . Functionally, colonic crypts play a key role in supporting through the absorption of (SCFAs), such as butyrate, produced by bacterial of undigested fibers. Colonocytes in the crypt epithelium express transporters like (MCT1) to uptake SCFAs, which serve as an energy source and regulate epithelial proliferation and barrier integrity. With age, colonic crypts show progressive mitochondrial dysfunction, including subunit I (MT-CO1) deficiencies that rise to an average of 16% in women and 23% in men by ages 80-84, potentially contributing to impaired energy metabolism and increased vulnerability to clonal expansion.

Clinical Significance

Pathological Changes

Intestinal glands, or , undergo various pathological alterations in response to inflammatory, infectious, and neoplastic processes, reflecting disruptions in their normal architecture and function. In (IBD), these changes are particularly prominent and serve as key diagnostic features. , involving neutrophilic infiltration of the , and , with pus accumulation in the crypt lumen, are characteristic of (UC), often accompanying mucosal ulceration in active disease. In (CD), architectural distortions such as crypt branching predominate, arising from repeated cycles of injury and repair that lead to irregular, forked crypt structures. These alterations, including branching and distortion, are observed in IBD biopsies, highlighting their prevalence in chronic mucosal inflammation. Infectious enteritides induce reactive changes in intestinal crypts, primarily through hyperplasia and distortion as part of the host's defensive response. Bacterial infections, such as those caused by Clostridium difficile, feature cryptitis and acute inflammatory infiltrates within the glands, contributing to pseudomembranous . Similarly, in models of attaching-effacing bacterial like Citrobacter rodentium infection, crypt hyperplasia compensates for surface epithelial loss, with elongated and increased crypt numbers. Viral , exemplified by , also triggers crypt hyperplasia alongside villus blunting, as immature crypt-type enterocytes migrate upward to repair the damaged mucosa. These distortions underscore the crypts' role in rapid epithelial regeneration during acute infections. Neoplastic transformations target the niche within intestinal , leading to dysregulated growth and architectural abnormalities. frequently originates from mutations in base , which, when transformed, drive formation and progression to while remaining anchored at the bottom. In adenomatous polyps, dysplastic architecture manifests as irregular serrations, branching, or ectopic foci, marking the shift from hyperplastic to neoplastic . Additional pathological features include adaptive responses in non-infectious inflammatory conditions and regenerative processes. In celiac disease, crypt hyperplasia predominates, with increased proliferative activity in the glands counteracting gluten-induced villous atrophy and lymphocytic infiltration. fission, where a single gland divides symmetrically or asymmetrically into daughter crypts, facilitates tissue expansion during regeneration following injury, such as or . These vulnerabilities often arise from the sensitivity of crypt stem cells to inflammatory signals, amplifying pathological remodeling.

Diagnostic and Therapeutic Implications

of intestinal glands plays a central role in diagnosing (IBD), where histological scoring systems evaluate to differentiate active inflammation from chronic changes. The Geboes index, a widely used validated score, grades architectural —characterized by branching, irregularity, , and variations in size and shape—as a key feature of chronicity in and , aiding in confirming and assessing disease extent. For instance, scores indicating marked correlate with longstanding IBD, guiding therapeutic escalation beyond mild cases. Imaging techniques enhance the diagnostic precision of intestinal gland alterations by providing visualization of morphology. Conventional and image-enhanced reveals openings as oval or tubular structures surrounded by vascular patterns, with distortions such as irregular openings signaling mucosal in IBD. endomicroscopy further refines this by offering cellular-level resolution, depicting glandular changes like epithelial irregularities and increased cellular density in real-time during procedures, which improves detection of subtle or . Therapeutic strategies targeting intestinal glands focus on reducing crypt inflammation and supporting epithelial integrity. Anti-inflammatory agents like 5-aminosalicylic acid (5-ASA) effectively ameliorate crypt distortion in IBD by promoting mucosal healing and normalizing architecture, as evidenced by higher rates of normal crypt biopsies in treated patients compared to . Emerging biologics, such as anti-TNF agents and IL-23 inhibitors, modulate intestinal function within crypts to enhance regeneration and reduce proliferative zones associated with chronic . Regenerative approaches leverage microbial influences on glandular health, with fecal microbiota transplantation (FMT) restoring crypt-associated microbial communities to mitigate dysbiosis-driven inflammation. FMT refurbishes the microbiota niche in colonic , promoting epithelial barrier recovery and reducing inflammatory markers in patients achieving remission. The prognostic value of intestinal gland features, particularly crypt fission, informs strategies in IBD. Increased crypt fission rates, observed in active disease, predict progression to by facilitating the clonal expansion of mutated cells, necessitating intensified endoscopic monitoring in high-risk patients. Asymmetric crypt fission, detectable in biopsies, further signals potential dysplastic evolution, guiding proactive interventions like in protocols.

Research and Development

Stem Cell Biology

Intestinal glands, also known as crypts of Lieberkühn, harbor a population of primarily located at the base, which drive the continuous renewal of the . These base columnar (CBC) are characterized by expression of the marker , a receptor for R-spondin that enhances Wnt signaling, and Olfm4, a secreted that marks active . In addition, a of reserve expressing Bmi1 contributes to tissue under normal conditions but plays a critical role in injury response by repopulating the pool following damage to + cells. Typically, 4-6 active reside at the base of each , maintaining a balance between self-renewal and differentiation to support epithelial turnover every 3-5 days. The niche in intestinal is tightly regulated by key signaling pathways that dictate proliferation and lineage commitment. The Wnt pathway is essential for maintenance, with β-catenin stabilization promoting proliferation specifically at the base. Notch signaling inhibits secretory differentiation while favoring absorptive lineages, ensuring proper cell fate decisions as progenitors migrate upward. BMP signaling is actively inhibited at the base by antagonists like Noggin secreted from Paneth cells, preventing premature differentiation and preserving the compartment; higher BMP levels toward the crypt-villus junction promote maturation. Paneth cells, interspersed among stem cells at the crypt base, form a critical component of the niche by secreting ligands such as EGF and Wnt proteins that support proliferation and survival. Mesenchymal cells in the underlying further enhance this environment by producing R-spondin, which amplifies Wnt signaling through to sustain self-renewal.00546-2) These interactions create a localized of signals that confines activity to the base. Stem cells in intestinal glands exhibit notable plasticity, allowing adaptation to physiological stresses. During injury or ablation of active + stem cells, committed progenitors can dedifferentiate into stem-like cells to restore the pool, highlighting a flexible hierarchy. Additionally, circadian rhythms regulate stem cell division, with higher proliferative activity during the active phase modulated by clock genes like Per, ensuring temporally coordinated renewal.00123-X)

Organoid Models

Intestinal organoids, three-dimensional (3D) cultures derived from + intestinal stem cells isolated from crypts, were first established in 2009 by Toshiro Sato and colleagues in ' laboratory. These organoids self-organize into crypt-villus-like structures that recapitulate the architecture and function of intestinal glands, including epithelial differentiation into enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, without requiring a non-epithelial niche. This breakthrough enabled long-term expansion of stem cell-derived mini-guts in vitro, providing a scalable model for studying intestinal epithelial dynamics. Subsequent refinements have allowed derivation from both mouse and human tissues, with human organoids grown from samples in supplemented with growth factors like EGF, Noggin, and R-spondin-1. Organoids have become pivotal for disease modeling, particularly for genetic and inflammatory disorders of the intestine. In , patient-derived organoids exhibit defective (CFTR) function, manifesting as impaired swelling in response to , which has been used to predict individual responses to modulators like . For (IBD), organoids from patients show altered barrier integrity and cytokine responses, enabling mechanistic studies of epithelial dysfunction in and . In drug screening, these models assess toxicity and efficacy, with 2024 reviews emphasizing their role in by testing therapies on patient-specific organoids to tailor treatments for and IBD, reducing reliance on animal models. Recent advances from 2020 to 2025 have enhanced complexity through co-cultures. Integrating commensal or pathogens into organoid systems has facilitated studies, such as modeling or interactions with the epithelial barrier, revealing host-microbe dynamics in a controlled 3D environment. Vascularized organoids, achieved by co-differentiating endothelial cells with epithelial progenitors, improve delivery and mimic physiological , supporting preclinical transplantation trials for intestinal repair.00628-2) These developments, including multi-lineage co-cultures, address prior simplifications and expand applicability to systemic studies. Despite progress, organoids face limitations, notably the absence of full immune and stromal components, which restricts modeling of immune-epithelial in chronic inflammation or tumorigenesis. Scalability remains challenging for high-volume applications, as manual dissection and variable requirements hinder and cost-effectiveness in large-scale screening. Looking ahead, intestinal organoids hold promise for regenerative therapies, particularly in , where transplantation of stem cell-derived organoids could restore absorptive capacity, with preclinical murine models demonstrating engraftment and functional integration. High-throughput platforms, incorporating automated bioreactors and microfluidic arrays, are emerging to accelerate and enable genome-wide screens for intestinal disorders.

Historical and Embryological Context

Embryological Origin

The intestinal glands, also known as crypts of Lieberkühn, originate from the endodermal lining of the primitive gut tube, which forms during weeks 3-4 of human gestation through incorporation of the into the trilaminar . This endodermal layer differentiates into the epithelial component of the , with the initial gut tube patterned along anteroposterior and radial axes by molecular cues such as and signaling gradients. By weeks 5-6, the and regions elongate and rotate, establishing the foundational architecture for future glandular structures, though crypt invaginations themselves emerge later. Morphogenesis of the crypts begins around weeks 10-12 of , coinciding with the formation of intestinal villi, which protrude from the epithelial surface and induce downward invaginations into the underlying to form tubular . This process is driven by epithelial-mesenchymal interactions, where Sonic hedgehog (Shh) signaling from the endodermal epithelium patterns the , promoting villus clustering and base specification. Shh induces mesenchymal expression of 4 (Bmp4), creating a BMP gradient that restricts proliferative to the base while suppressing them at villus tips; this gradient works in opposition to Wnt/β-catenin signaling, which sustains stem cell proliferation and elongation. By weeks 10-12, mitotic activity shifts predominantly to the intervillus epithelium and nascent , solidifying their role as proliferative niches. Intestinal stem cells within the crypts arise from multipotent endodermal progenitors marked by transcription factors such as and , which emerge during epithelial remodeling; these progenitors give rise to all epithelial lineages, including enterocytes, goblet cells, and enteroendocrine cells. Paneth cells, which secrete factors and support the niche, first appear around 13-14 weeks of in s, with maturation continuing postnatally. In terms of species variations, crypts achieve structural maturity and localization by birth, with a transition from polyclonal to monoclonal crypt domains occurring , whereas in like mice, crypt formation initiates shortly after birth and completes by postnatal day 14, often post-weaning. Developmental anomalies of intestinal glands, such as or duplications, frequently result from disruptions in Wnt/BMP signaling gradients or Shh-mediated patterning, leading to failed , lumen obliteration, or ectopic glandular formations. For instance, reduced Shh activity impairs mesenchymal remodeling and epithelial organization, contributing to in congenital intestinal malformations. These disruptions highlight the precision of gradient-based mechanisms in establishing functional glandular architecture during embryogenesis.

Historical Milestones

The discovery of intestinal glands, also known as crypts of Lieberkühn, is attributed to the German anatomist Johann Nathanael Lieberkühn, who provided the first detailed microscopic descriptions of these tubular structures at the base of intestinal villi in his 1745 publication De fabrica et actione villorum intestinorum tenuium. Lieberkühn's observations, made using early techniques including his invention of the solar microscope, revealed the glands' role in secreting digestive juices and producing epithelial cells that line the intestinal surface. These findings marked a foundational milestone in understanding the microscopic architecture of the digestive tract. In the 19th century, French anatomist Marie-François-Xavier Bichat advanced the recognition of the glandular nature of intestinal tissues through his 1802 work Traité des membranes, where he classified membranes and glands, including those in the intestine, as distinct tissue types with secretory functions, emphasizing their role in absorption and vitality without microscopic aid. Later, Rudolf Virchow's seminal 1858 lectures on Cellular Pathology linked pathological changes in glandular structures, such as those in the intestine, to alterations at the cellular level, establishing the principle that diseases arise from cellular dysfunction rather than humoral imbalances and applying this framework to epithelial renewals in glandular organs. These contributions shifted focus toward tissue-specific pathology in intestinal glands. The 20th century brought experimental insights into the dynamic renewal of intestinal glands, with Charles Philippe Leblond's radiolabeling studies in the 1960s demonstrating the continuous proliferation and migration of epithelial cells from crypt bases to villus tips in , highlighting the glands as sites of rapid cellular turnover. Building on this, Hazel Cheng and Leblond's 1974 series of papers identified a of undifferentiated stem cells at the crypt base—termed crypt base columnar cells—that give rise to all major epithelial lineages, including enterocytes, goblet cells, enteroendocrine cells, and Paneth cells, via a unitarian model of differentiation. These radiolabeling and autoradiographic techniques provided the first evidence of stem cell-driven in the . In the late 20th and early 21st centuries, molecular discoveries elucidated key regulatory pathways, with the identified in the 1990s as essential for maintaining intestinal proliferation and preventing differentiation in crypts, as shown in studies linking gene mutations to disrupted Wnt activity in colorectal cancers. The leucine-rich repeat-containing G-protein coupled receptor 5 () emerged as a specific marker for cycling s in 2007, when Nick Barker and colleagues demonstrated through lineage tracing that Lgr5-positive crypt base columnar cells self-renew and generate all intestinal epithelial cell types over extended periods. These findings integrated signaling mechanisms with identity. Subsequent milestones included the 2009 development of intestinal organoids by Toshiro Sato and , who cultured single Lgr5-positive stem cells to form crypt-villus structures mimicking native and function, enabling long-term expansion without stromal support through defined growth factors like Wnt agonists. More recently, single-cell sequencing analyses since 2018 have revealed transcriptional heterogeneity within cell populations, identifying distinct stem and states along the crypt-villus axis and uncovering spatial gradients in that refine models of epithelial diversification. More recently, as of 2024, single-cell integration studies have revealed epithelial originating from stem cells in inflammatory gut diseases, enhancing models of dynamics. These advances have transformed experimental approaches to intestinal gland biology.

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