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Paneth cell
Paneth cell
Paneth cell
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Paneth cell
Paneth cells, located at the base of the crypts of the small intestinal mucosa, and displaying bright red cytoplasmic granules. H&E stain.
Details
LocationSmall intestine epithelium
Identifiers
Latincellula panethensis
MeSHD019879
THH3.04.03.0.00017
FMA62897
Anatomical terms of microanatomy

Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells.[1] Some can also be found in the cecum and appendix. They are located below the intestinal stem cells in the intestinal glands (also called crypts of Lieberkühn) and the large eosinophilic refractile granules that occupy most of their cytoplasm.

When exposed to bacteria or bacterial antigens, Paneth cells secrete several anti-microbial compounds (notably defensins and lysozyme) that are known to be important in immunity and host-defense into the lumen of the intestinal gland, thereby contributing to maintenance of the gastrointestinal barrier by controlling the enteric bacteria. Therefore, Paneth cells play a role in the innate immune system.

Paneth cells are named after 19th-century pathologist Joseph Paneth.

Structure

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The gastrointestinal tract is composed of numerous cell types that are important for immune activation and barrier surface defenses. The gastrointestinal epithelium is composed of enterocytes, goblet cells, Paneth cells, enteroendocrine cells, tuft cells, and stem cells. In contrast, the lamina propria is composed of immune cells such as dendric cells, T cells, and macrophages.

Paneth cells are found throughout the small intestine and the appendix at the base of the intestinal glands.[2] There is an increase in Paneth cell numbers towards the end of the small intestine.[3] Like the other epithelial cell lineages in the small intestine, Paneth cells originate at the stem cell region near the bottom of the gland.[4] There are on average 5–12 Paneth cells in each small intestinal crypt.[5]

Unlike the other epithelial cell types, Paneth cells migrate downward from the stem cell region and settle just adjacent to it.[4] This close relationship to the stem cell region suggests that Paneth cells are important in defending the gland stem cells from microbial damage,[4] although their function is not entirely known.[2] Furthermore, among the four aforementioned intestinal cell lineages, Paneth cells live the longest (approximately 57 days).[6]

Function

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Paneth cells secrete antimicrobial peptides and proteins, which are "key mediators of host-microbe interactions, including homeostatic balance with colonizing microbiota and innate immune protection from enteric pathogens."[7]

Small intestinal crypts house stem cells that serve to constantly replenish epithelial cells that die and are lost from the villi.[7] Paneth cells support the physical barrier of the epithelium by providing essential niche signals to their neighboring intestinal stem cells. Protection and stimulation of these stem cells is essential for long-term maintenance of the intestinal epithelium, in which Paneth cells play a critical role.[8]

Paneth cells display merocrine secretion, that is, secretion via exocytosis.[9]

Sensing microbiota

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Paneth cells are stimulated to secrete defensins when exposed to bacteria (both Gram positive and Gram-negative types), or such bacterial products as lipopolysaccharide, lipoteichoic acid, muramyl dipeptide and lipid A.[10] They are also stimulated by cholinergic signaling normally preceding the arrival of food which potentially may contain a new bacterial load.[10]

Paneth cells sense bacteria via MyD88-dependent toll-like receptor (TLR) activation which then triggers antimicrobial action.[11] For example, research showed that in the secretory granules, murine and human Paneth cells express high levels of TLR9. TLR9 react to CpG-ODN and unmethylated oligonucleotides, pathogen-associated molecular patterns (PAMPs) typical for bacterial DNA. Internalizing these PAMPs and activating TLR9 leads to degranulation and release of antimicrobial peptides and other secretions.[12] Surprisingly, murine Paneth cells do not express mRNA transcripts for TLR4.[5]

Antimicrobial secretions

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The principal defense molecules secreted by Paneth cells are alpha-defensins, which are known as cryptdins in mice.[13] These peptides have hydrophobic and positively charged domains that can interact with phospholipids in cell membranes. This structure allows defensins to insert into membranes, where they interact with one another to form pores that disrupt membrane function, leading to cell lysis. Due to the higher concentration of negatively charged phospholipids in bacterial than vertebrate cell membranes, defensins preferentially bind to and disrupt bacterial cells, sparing the cells they are functioning to protect.[14]

Human Paneth cells produce two α-defensins known as human α-defensin HD-5 (DEFA5) and HD-6 (DEFA6).[15] HD-5 has a wide spectrum of killing activity against both Gram positive and Gram negative bacteria as well as fungi (Listeria monocytogenes, Escherichia coli, Salmonella typhimurium, and Candida albicans).[5] The antimicrobial activity of HD-6 consists of self-assembling into extracellular nets that entrap bacteria in the intestine and thereby preventing their translocation across the epithelial barrier.[16]

Human Paneth cells also produce other AMPs including lysozyme, secretory phospholipase A2, and regenerating islet-derived protein IIIA.[17] Lysozyme is an antimicrobial enzyme that dissolves the cell walls of many bacteria, and phospholipase A2 is an enzyme specialized in the lysis of bacterial phospholipids .[10] This battery of secretory molecules gives Paneth cells a potent arsenal against a broad spectrum of agents, including bacteria, fungi and even some enveloped viruses.[18]

Secretory autophagy

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During conventional protein secretion, proteins are transported through the ER-Golgi complex packaged in secretory granules and released to the extracellular space. Should invasive pathogens disrupt the Golgi apparatus, causing an impairment in the Paneth cell secretion of antimicrobial proteins, an alternative secretion pathway exists: it has been shown that lysozyme can be rerouted through secretory autophagy. In secretory autophagy, cargo is transported in an LC3+ vesicle and discharged at the plasma membrane, thus bypassing the ER-Golgi complex. Not all bacteria prompts secretory autophagy: commensal bacteria, for example, does not cause Golgi breakdown and therefore does not trigger the secretory autophagy of lysozyme. A dysfunction in secretory autophagy is thought to be a possible contributing factor to Crohn's disease.[19]

Phagocytic function

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Paneth cells maintain the health of the intestine by acting as macrophages; it has been shown that Paneth cells clear dying cells via apoptotic cell uptake. The phagocytic function of Paneth cells was discovered using a series of experiments, one of which made use of mice that were radiated with a low dose Cesium-137 (137Cs), mimicking chemotherapy undergone by cancer patients.[20] These findings may be significant for addressing the side effects suffered by cancer patient whose intestinal health is damaged by chemotherapy: approximately 40% of all cancer therapy patients experience gastrointestinal (GI) mucositis during their treatment, with the number jumping to 80% in patients receiving abdominal or pelvic irradiation.[21]

Epithelium maintenance

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Paneth cells participate in the Wnt signaling pathway and Notch signalling pathway, which regulate proliferation of intestinal stem cells and enterocytes necessary for epithelium cell renewal. They express the canonical Wnt ligands: Wnt3a, Wnt9b, and Wnt11, which bind to Frizzled receptors on intestinal stem cells to drive β-catenin/Tcf signaling. Paneth cells are also a major source of Notch ligands DLL1 and DLL4, binding to Notch receptors Notch1 and Notch2 on intestinal stem cells and enterocyte progenitors.[8]

Recently, however, it has been discovered that the regenerative potential of intestinal epithelial cells declines over time as a result of aged Paneth cells secreting the protein Notum, which is an extracellular inhibitor of Wnt signaling. If Notum secretion is inhibited, the regenerative potential of the intestinal epithelium could increase.[22]

Zinc

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It has been established that zinc is essential for the function of Paneth cells. A defect in the Zn transporter (ZnT)2 impairs Paneth cell function by causing uncoordinated granule secretion. Mice lacking the (ZnT)2 transporter not only exhibit impaired granule secretion, they also suffer from increased inflammatory response to lipopolysaccharide and are less capable of bactericidal activity.[23] Normally, zinc is stored in the secretory granules and, upon degranulation, is released in the lumen. It has been speculated that the storage of heavy metals contributes to direct antimicrobial toxicity, as Zn is released upon cholinergic PC stimulation.[24]

Zinc deficiency is also implicated in alcohol‐induced Paneth cell α‐defensin dysfunction, which contributes to alcohol-related steatohepatitis. Zinc can stabilize human α‐defensin 5 (HD5), which is responsible for microbiome homeostasis. In line with this, the administration of HD5 can effectively alter the microbiome (especially by increasing Akkermansia muciniphila), and reverse the damage inflicted on the microbiome by excessive alcohol consumption. Dietary zinc deficiency on the other hand exacerbates the deleterious effect of alcohol on the bactericidal activity of Paneth cells.[25]

Clinical significance

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Abnormal Paneth cells with reduced expression or secretion of defensins HD-5 and HD-6 (in human) and antimicrobial peptides are associated with inflammatory bowel disease.[26][17] In addition to that, several of the Crohn's disease-risk alleles are associated with Paneth cell dysfunction are involved in processes such as autophagy, the unfolded protein response, and the regulation of mitochondrial function.[17]

It is believed that the dysfunction of Paneth cells compromises antimicrobial peptides leading to a microbiota composition shift, and even dysbiosis.[27] Crohn's disease patients with a higher percentage of abnormal Paneth cells showed significantly reduced bacterial diversity compared with patients with a lower percentage of abnormal Paneth cells, reflecting a reduced abundance of anti-inflammatory microbes.[28] Collectively, these findings support the theory that Paneth cell dysfunction may lead to a dysbiotic microbiota that, in turn, could predispose an individual to the development of Crohn's disease.[17] However, it is yet to be established whether Paneth cell dysfunction is the cause of dysbiosis, or its concomitant effect.[27]

Necrotizing enterocolitis

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Paneth cells develop gradually during gestation and therefore preterm babies might not have them in sufficient numbers. This leaves preterm babies vulnerable to necrotizing enterocolitis. About mid-way though the development of the small intestine, cathelicidin secretion is replaced by α-defensin secretion.[29] The small intestine of the premature baby is at this transition stage when the baby is born, making preterm babies susceptible to intestinal injury and, subsequently, to necrotizing enterocolitis.[18] It should furthermore be noted that early Paneth cells do not possess fully functional, mature granules.[30]

The mechanism that links Paneth cells to necrotizing enterocolitis remains unclear, but it has been theorized that a bloom of Proteobacteria and, more specifically, Enterobacteriaceae species precedes the development of the condition.[31] When an inflammation then subsequently occurs, nitrates can be fermented by Enterobacteriaceae sp. but not by obligate anaerobes, which cannot use nitrates as a growth substrate. Thus, Proteobacteria are able to use this selective pressure to out-compete the obligate anaerobic Firmicutes and Bacteroidetes, resulting in their overgrowth and consequent dysbiosis.[18]

The process is thought to begin when the premature infant is exposed to foreign antigens via formula feeding. Inflammatory cytokines are subsequently released, creating a more aerobic state leading to a competitive advantage for Proteobacteria. As the microbiome becomes more dysbiotic, anti-inflammatory mechanisms weaken, which contributes to a cycle of increasing intestinal inflammation. The inflammation leads to a further loss in Paneth cells density and function, resulting in the impairment of AMP secretion and the destruction of the stem cell niche.[18]

Non-alcoholic fatty liver disease

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Whereas the role of Paneth cells in irritable bowel syndrome and Crohn's disease has received ample attention,[32][17] relatively little is known about the effect Panth cell impairment has on the pathogenesis of non-alcoholic steato-hepatitis or non-alcoholic fatty liver disease.

Murine models indicate that obesity may decrease the secretion of α-defensin from Paneth cells, leading to dysbiosis.[33] and at least one murine model suggests that when α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration, liver fibrosis is ameliorated as a result of the dysbiosis resolving. It is hypothesized that selective microbicidal activities, as well as increasing Muribaculaceae and decreasing Harryflintia, contribute to amelioration in fibrogenesis.[34]

One study described the injection of dithizone, which can disrupt cell granulates, into mice that were fed a high-fat diet in order to identify Paneth-cell-oriented microbial alterations. The application of dithizone improved high-fat diet glucose intolerance and insulin resistance and was associated with an alleviation in the severity of liver steatosis in HFD mice, possibly through gut microbiome modulation involving the increase in Bacteroides. It has therefore been suggested that microbiome-targeted therapies may have a role in the treatment of non-alcoholic fatty liver disease.[35]

Further research is needed to elucidate the connection between Paneth cells and the gut-liver-axis.

See also

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References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Paneth cell

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from Grokipedia
Paneth cells are specialized, post-mitotic epithelial cells located at the base of the crypts of Lieberkühn in the of mammals, including humans and mice. These pyramidal-shaped cells are distinguished by their abundant rough , well-developed Golgi apparatus, and prominent apical secretory granules filled with , enzymes such as , and growth factors. First identified in the late by Gustav Schwalbe based on their eosinophilic granules and later detailed by Josef Paneth in 1888—for whom they are named—Paneth cells have a lifespan of approximately two months and are integral to intestinal epithelial architecture. The primary functions of Paneth cells revolve around supporting intestinal and defense. They secrete (AMPs), including α-defensins and cathelicidins, to shape and regulate the by limiting bacterial overgrowth and invasion. Additionally, these cells provide essential niche signals, such as Wnt3a and (EGF), to neighboring intestinal stem cells, promoting their proliferation and differentiation within the crypt niche. Paneth cells also exhibit phagocytic and efferocytotic capabilities to clear debris and apoptotic cells, uptake heavy metals like for storage and release, and contribute to barrier integrity by modulating inflammation and epithelial repair. Dysfunction of Paneth cells has profound implications for health, linking them to various gastrointestinal disorders. Genetic mutations, environmental factors, or stressors like stress can impair their secretory functions, leading to and increased susceptibility to inflammatory bowel diseases such as . In preterm infants, immature Paneth cell development—emerging around 13.5 weeks gestation but reaching full competence near term—heightens vulnerability to due to reduced activity. Ongoing research utilizes models and cell sorting techniques (e.g., + markers) to study Paneth cell biology, underscoring their role as cornerstones of intestinal and organismal health.

Anatomy and Morphology

Location and Distribution

Paneth cells are specialized epithelial cells primarily located at the base of the crypts of Lieberkühn in the small intestine, where they occupy the lowest positions within these glandular invaginations. They are interspersed with Lgr5+ crypt base columnar intestinal stem cells (ISCs), forming a critical component of the stem cell niche at the crypt base, while also supporting quiescent stem cells in the +4 position approximately four to six cells above the base. This positioning allows Paneth cells to directly interact with ISCs, contributing to epithelial renewal. The density of Paneth cells varies along the , with numbers generally increasing from the proximal to the distal regions; for instance, human ileal crypts contain a higher average density (approximately 5–15 Paneth cells per ) compared to jejunal or duodenal segments. In mice, this ranges from 5 to 16 cells per , influenced by genetic strain and showing a similar proximal-to-distal gradient that correlates with escalating microbial load toward the . Paneth cells are typically absent or exceedingly rare in the , though they are normally present in the human and , becoming scarce in the and . Under pathological conditions, such as or chronic , ectopic Paneth cells can appear in atypical sites like the or distal colon through a process known as , potentially reflecting adaptive responses to . This aberrant distribution is not observed in healthy tissue and may indicate underlying mucosal injury. Paneth cells exhibit evolutionary conservation across mammals, including humans, , and other species like horses and sheep, underscoring their fundamental role in intestinal defense. However, species-specific differences exist, such as variations in α-defensin expression and crypt cell counts, with displaying particularly prominent populations that make them valuable models for study.

Cellular Structure

Paneth cells exhibit a distinctive pyramidal morphology, with a broader base compared to neighboring columnar enterocytes, contributing to their identification in histological sections of the small intestinal crypts. This granulated appearance arises primarily from numerous large secretory granules that dominate the apical , measuring 0.5-1 μm in diameter and containing essential for innate defense. These granules stain eosinophilically in hematoxylin and eosin preparations, appearing as prominent supranuclear structures that are positive for via immunohistochemical detection, distinguishing Paneth cells from other epithelial cell types. Ultrastructural analysis by electron microscopy reveals the granules as electron-dense organelles with homogeneous cores, reflecting their packed proteinaceous content. The basal nucleus is oval and euchromatic, supporting active transcription, while the perinuclear and mid-cytoplasmic regions feature extensive rough and a prominent supranuclear Golgi apparatus, which together enable robust protein synthesis and granule maturation. In contrast to absorptive enterocytes, the apical surface of Paneth cells bears shorter, stubby microvilli, optimized for rather than nutrient uptake. Key molecular markers further define Paneth cell identity, including for lysosomal activity, human α-defensins such as HD5 and HD6 stored within the granules, and the zinc transporter ZIP4 involved in metal ion for granule function. These features collectively underscore the specialized secretory architecture of Paneth cells, setting them apart from adjacent cells.

Development and Maintenance

Differentiation from Stem Cells

Paneth cells primarily originate from + intestinal stem cells (ISCs) positioned at the base through , which produces one renewing ISC and one transit-amplifying committed to the secretory lineage. Reserve stem cells at the +4 position, marked by markers such as Bmi1, also contribute to Paneth cell generation, particularly under homeostatic conditions or following injury when + ISCs are depleted. This process ensures a steady supply of Paneth cells intermingled with ISCs to maintain the niche. Differentiation along the secretory lineage into Paneth cells is governed by key transcription factors, including Gfi1, , and Foxo1. Gfi1 functions downstream of Atoh1 to specify Paneth cells, as evidenced by the complete absence of Paneth cells in Gfi1-deficient mice. is essential for Paneth cell maturation, with its conditional deletion in the blocking differentiation and reducing progenitor proliferation. Foxo1 regulates the transition from stem to secretory fates, where its loss increases Paneth cell numbers by promoting secretory differentiation at the expense of ISC maintenance. Wnt and Notch signaling gradients further direct fate decisions, with elevated Wnt activity at the crypt base promoting Paneth specification over differentiation through interactions with these factors. The timeline for Paneth cell differentiation spans 3-5 days post-ISC , involving 4-5 rounds of transit-amplifying divisions before terminal commitment at the base. In neonatal development, accelerates this process by inducing immune signaling that enhances Paneth maturation, as germ-free models show delayed differentiation until microbial exposure. Stochastic mathematical models of lineage commitment incorporate BMP/Wnt signaling ratios to predict Paneth fate probabilities. Environmental factors, such as diet, modulate differentiation efficiency; for example, high-fat diets impair Paneth cell formation via PPARδ activation and alterations, while caloric restriction boosts ISC-driven Paneth production and niche function.

Lifespan and Turnover

Paneth cells exhibit a notably long lifespan within the , typically ranging from 20 to 60 days, in stark contrast to the rapid turnover of neighboring enterocytes, which survive only 3 to 5 days. This extended duration allows Paneth cells to maintain stable defenses at the base, where they number approximately 5 to 15 per . Their slow turnover rate, estimated at about 0.2 to 0.5 cells replaced per per day based on average crypt occupancy and lifespan, underscores their role in long-term epithelial rather than rapid renewal. This rate can be modeled using kinetics, where the decay constant λ\lambda is given by λ=ln⁡(2)t1/2\lambda = \frac{\ln(2)}{t_{1/2}}, with a half-life t1/2t_{1/2} of approximately 30 days for Paneth cells. Replacement of Paneth cells occurs through continuous differentiation from intestinal stem cells (ISCs) located at the base, ensuring steady-state maintenance without significant proliferation of mature Paneth cells themselves. Disruption of this differentiation process, such as through genetic of key regulators like Math1, can lead to loss and impaired epithelial regeneration, highlighting the interdependence between Paneth cell renewal and overall integrity. Under homeostatic conditions, this replacement mechanism supports a balanced niche environment, with Paneth cells contributing factors that reciprocally sustain ISC function. Apoptosis in Paneth cells is primarily regulated to preserve their longevity, with survival promoted by the PI3K/Akt signaling pathway, which inhibits pro-apoptotic signals and enhances cellular resilience. Under stress conditions, such as or , becomes Bax/Bak-dependent, involving mitochondrial outer membrane permeabilization to execute and prevent accumulation of damaged cells. This controlled elimination ensures that only viable Paneth cells persist to support the niche. With aging, Paneth cell numbers and functionality decline in the elderly, often linked to ISC exhaustion and diminished Wnt signaling within the niche, resulting in reduced production and compromised epithelial barrier integrity. Studies in and models show lower levels of like human defensin 5 in older individuals, correlating with age-related dysfunction and increased susceptibility to intestinal perturbations. Recent studies (as of 2025) indicate that while Paneth cells enhance niche function, they are dispensable for basic maintenance, and compounds like can prevent age-related declines in organoids and models. This progressive loss contributes to broader declines in regenerative capacity, though compensatory mechanisms like altered architecture may partially mitigate effects in some contexts.

Physiological Functions

Antimicrobial Secretions

Paneth cells secrete a variety of agents stored within their characteristic granules, primarily as inactive proforms that are processed into mature, active molecules prior to or during release. The major include α-, such as human defensins 5 (HD5) and 6 (HD6) or their murine counterparts known as cryptdins, which exhibit broad-spectrum activity against bacteria, fungi, and viruses by disrupting microbial membranes. Additional key secretions encompass , which hydrolyzes bacterial peptidoglycans; secretory (sPLA2), which targets components of microbial membranes; and factor 3 (TFF3), a peptide that supports mucosal integrity while contributing to host defense through stabilization of the antimicrobial environment. These components are packaged in large, electron-dense granules located at the apical pole of the cell, ensuring targeted delivery into the intestinal lumen. The release of these antimicrobial agents occurs through a regulated process of stimulus-secretion coupling, involving calcium ion (Ca²⁺) influx that triggers at the apical surface. Stimuli such as bacterial (LPS) or extracellular ATP bind to receptors on the Paneth cell, leading to an increase in intracellular Ca²⁺ levels, which promotes granule fusion with the plasma membrane and discharge of contents into the crypt lumen. This mechanism allows rapid response to microbial challenges, maintaining a sterile environment immediately adjacent to the stem cell niche. Paneth cell granules create a specialized microenvironment enriched with high concentrations of zinc ions (Zn²⁺), which significantly enhances the efficacy of α-. The zinc transporter ZIP4 (also known as SLC39A4) facilitates Zn²⁺ uptake into the cell and subsequent sequestration into granules, where it stabilizes defensin structure and potentiates their membrane-disrupting activity. Additionally, the granules support the proteolytic maturation of pro-defensins into their active forms by enzymes like matrix metalloproteinase 7 (MMP7). The interaction between defensins and can be represented as: Def+Zn2+⇌Def-Zn(Kd≈10−10 M)\text{Def} + \text{Zn}^{2+} \rightleftharpoons \text{Def-Zn} \quad (K_d \approx 10^{-10} \, \text{M}) This high-affinity binding (with dissociation constants in the picomolar range) underscores zinc's role in optimizing defensin function under physiological conditions. Upon stimulation, a single Paneth cell can release a large number of antimicrobial peptides, contributing to microbicidal concentrations in the crypt lumen and profoundly shaping the composition of the intestinal microbiota by selectively enriching beneficial bacteria while limiting pathogens. This secretory output not only provides direct innate immunity but also indirectly supports epithelial homeostasis by preventing microbial overgrowth.

Sensing and Response to Microbiota

Paneth cells detect microbial signals primarily through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs). Specifically, TLR4 recognizes (LPS) from , while , an NLR, senses peptidoglycan motifs from bacterial cell walls. These receptors initiate signaling cascades that are largely dependent on the adaptor protein MyD88, which is essential for Paneth cell responses to commensal bacteria. Upon microbial detection, these PRRs activate downstream response pathways in Paneth cells, culminating in transcription factor activation, which upregulates the expression of defensins such as α-defensins. signaling further enhances this process by cooperating with TLR pathways to amplify activity and defensin production. Additionally, the IL-17/ axis contributes to chronic adaptations, where IL-17 signaling promotes functions and -dependent maturation in response to microbial cues, helping maintain long-term . The presence of profoundly influences Paneth cell development and function; in germ-free mice, Paneth cells exhibit immature morphology, reduced granule numbers, and diminished expression compared to conventionally raised counterparts. Specific commensal bacteria, such as thetaiotaomicron, promote Paneth cell granule maturation and of bactericidal proteins like angiogenin-4, thereby enhancing host defense. Paneth cell secretions establish feedback loops that shape the composition and prevent by selectively enriching beneficial bacteria while inhibiting pathogens. This reciprocal interaction ensures microbial balance, as disruptions in Paneth cell function lead to shifts favoring pro-inflammatory species. Recent studies from 2023 highlight how microbiota-derived (SCFAs), such as butyrate, modulate Paneth cell sensing via G-protein-coupled receptor 43 (GPR43), ameliorating defects and restoring antimicrobial responses in dysbiotic conditions. Dysregulation of these sensing mechanisms, particularly NOD2 mutations, impairs bacterial recognition and reduces α-defensin production in Paneth cells, leading to microbiota dysbiosis and increased susceptibility to ileal . Patients with NOD2 variants show abnormal Paneth cell granules and defective responses to microbial stimuli, underscoring the link between genetic alterations in sensing pathways and inflammatory pathology.

Support for Stem Cell Niche

Paneth cells play a crucial role in providing the niche for intestinal stem cells (ISCs) by secreting key signaling molecules that promote ISC proliferation and maintenance. These cells produce Wnt ligands, such as Wnt3a, which activate canonical Wnt/β-catenin signaling essential for ISC self-renewal. Additionally, Paneth cells express and secrete Notch pathway activators, including the ligands Dll1 and Dll4, which sustain Notch signaling to prevent ISC differentiation and support their undifferentiated state. They also release members of the epidermal growth factor (EGF) family, further enhancing ISC proliferation through receptor tyrosine kinase pathways. The physical proximity of Paneth cells to ISCs at the crypt base facilitates juxtacrine and , forming a supportive niche microenvironment. This close is dispensable for ISC maintenance under steady-state conditions, where other cells like mesenchymal stromal cells can partially compensate, but it becomes essential during intestinal regeneration following or stress. In the small intestinal , Paneth cells and ISCs are present in roughly equal numbers, reflecting their balanced distribution to optimize niche support without overcrowding the proliferative compartment. Dynamic regulation of the niche involves bidirectional interactions between Paneth cells and ISCs. Experimental depletion of Paneth cells, such as through administration in Defa6-Cre;iDTR models, results in slowed ISC proliferation and reduced crypt regenerative capacity. Reciprocally, ISCs contribute to niche by signaling back to modulate BMP signaling, helping to inhibit differentiation cues that could disrupt the balance. This interplay ensures robust function, particularly evident in neonatal development where early Paneth cell maturation around postnatal day 7-14 is critical for de novo crypt establishment and the transition from fetal to adult ISC niches. Recent research as of 2024 has further elucidated that enteric regulate Paneth cell secretion, influencing microbial homeostasis and indirectly supporting the niche through modulated antimicrobial activity.

Phagocytic and Autophagic Roles

Paneth cells exhibit phagocytic activity, enabling them to engulf and clear apoptotic epithelial cells and luminal debris through apical . This process involves the uptake of dying intestinal cells, as demonstrated in enteroid models where Paneth cells internalize membrane-labeled apoptotic material via their apical surface. Phagocytosis in Paneth cells is actin-dependent, relying on cytoskeletal rearrangements to facilitate and particle internalization, similar to mechanisms in other professional . Under inflammatory conditions, such as those induced by or microbial challenge, phagocytic efficiency increases, aiding in the rapid clearance of cellular debris to maintain epithelial . Additionally, Paneth cells can phagocytose luminal and trophozoites, contributing to direct elimination beyond secretory defenses. Autophagy plays a critical role in Paneth cell function, particularly through secretory autophagy that supports the biogenesis of granules. This process is dependent on core autophagy genes such as Atg5 and Atg7, which facilitate the formation and maturation of secretory granules containing and . In Atg7-deficient Paneth cells, granule size is reduced and numbers increased, leading to impaired packaging and secretion of like , highlighting 's necessity for unconventional protein secretion pathways. Secretory autophagy ensures the proper delivery of granule contents to the apical lumen, linking intracellular degradation machinery to extracellular activity. Phagocytosis and autophagy in Paneth cells intersect via phagolysosomal fusion, where engulfed pathogens or debris are degraded within lysosome-fused compartments. This crosstalk enhances intracellular clearance, with delivering ubiquitinated cargo to lysosomes for . The pathway negatively regulates this autophagic flux; inhibition by rapamycin promotes autophagosome formation and lysosomal fusion in Paneth cells, boosting degradation capacity during stress. Recent studies have shown that α-lipoic acid (ALA) suppresses signaling specifically in Paneth cells, enhancing autophagic processes to restore granule secretion and reduce atypical Paneth cell accumulation in aging models, thereby exerting anti-inflammatory effects through improved . Autophagy in Paneth cells maintains basal turnover of cytoplasmic components to support overall cellular homeostasis.

Clinical and Pathological Relevance

Role in Inflammatory Bowel Diseases

Paneth cells play a central role in the pathogenesis of inflammatory bowel diseases (IBD), particularly Crohn's disease (CD), where their dysfunction contributes to intestinal barrier impairment and chronic inflammation. In CD, which frequently affects the ileum, Paneth cell abnormalities lead to reduced secretion of antimicrobial peptides such as human α-defensins HD5 and HD6, promoting bacterial translocation and dysbiosis. This dysfunction is less pronounced in ulcerative colitis (UC), which primarily involves the colon and lacks Paneth cells in the healthy state, though metaplastic Paneth cells may emerge in inflamed colonic mucosa. Pathophysiologically, Paneth cell defects in are characterized by erosions and dropout in the ileal crypts, exacerbating mucosal inflammation. Reduced expression is strongly linked to mutations, a key genetic risk factor for ileal , as normally regulates Paneth cell antimicrobial responses; variants impair granule formation and peptide release, leading to increased susceptibility to luminal pathogens. Similarly, histological findings reveal dysmorphic Paneth cells with abnormal granules and metaplastic changes in active lesions, contrasting with normal architecture in controls. Mechanistically, genetic variants like ATG16L1 mutations disrupt autophagy in Paneth cells, causing accumulation of dysfunctional granules and impaired bacterial clearance, which further drives IBD progression. Microbiota dysbiosis amplifies this loss, as defective Paneth cells fail to maintain microbial diversity, allowing overgrowth of adherent-invasive Escherichia coli and other pathobionts that perpetuate inflammation. Endoplasmic reticulum stress in Paneth cells, triggered by these genetic and microbial factors, promotes barrier breakdown, as highlighted in recent studies linking unfolded protein response activation to ileal erosions. Clinically, Paneth cell depletion correlates with disease severity; dysmorphic or reduced Paneth cells in ileal biopsies predict postoperative in up to 50% of pediatric patients and are observed in approximately 20-50% of adult cases, with higher rates in ileal-predominant disease affecting 70% of patients overall. Therapeutic interventions like anti-TNF agents, such as , can restore Paneth cell function by alleviating inflammation-induced stress, improving expression and reducing in responsive patients. A 2023 review underscores that targeting Paneth cell stress pathways may enhance barrier integrity and prevent in IBD.

Involvement in Metabolic Disorders

Paneth cells contribute to the of non-alcoholic (NAFLD), now termed metabolic dysfunction-associated (MASLD), by maintaining intestinal barrier integrity; their dysfunction promotes a leaky gut, allowing bacterial translocation and portal endotoxemia that exacerbates hepatic and . In a 2023 review, Paneth cells are described as the "missing link" in the progression from obesity-related NAFLD to metabolic dysfunction-associated steatohepatitis (MASH), as impaired antimicrobial secretions lead to and systemic endotoxemia via lipopolysaccharide (LPS) leakage into the . In , high- diets reduce Paneth cell numbers and function, altering the composition—such as increasing Firmicutes and decreasing Bacteroidetes—which disrupts insulin signaling and promotes metabolic dysregulation. Animal models demonstrate that consumption of a Western diet (40% ) for 8 weeks induces Paneth cell defects in mice, correlating with shifts involving elevated species and secondary bile acids like , which activate farnesoid X receptor (FXR) and type I pathways to impair Paneth cell integrity. , often linked to high- diets, further exacerbates these defects by limiting peptide production, though Paneth cells' secretion supports barrier maintenance under normal conditions. Key pathways involve gut-derived LPS activating Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) in the liver, driving inflammation and fibrosis in NAFLD/MASH; this gut-liver axis is amplified by Paneth cell-mediated dysbiosis. Therapeutic strategies targeting Paneth cell restoration, such as probiotics to modulate microbiota and reduce endotoxemia, show promise in preclinical models for mitigating hepatic steatosis and portal hypertension. Epidemiological observations indicate Paneth cell alterations in a significant proportion of NAFLD cases, with and obese individuals (BMI ≥ 25) exhibiting reduced normal Paneth cells and increased defects compared to lean controls. corroborate this, showing Paneth cell depletion accelerates in high-fat diet models, with defects observed in up to 70% of affected mice after prolonged exposure. A 2022 study showed that Paneth cell depletion reduces and lymphangiogenesis in experimental models by downregulating C/D and related proteins, attenuating in obesity-associated .

Associations with Other Conditions

Paneth cells play a critical role in the pathogenesis of (), a severe inflammatory condition primarily affecting preterm infants, where immaturity of these cells leads to impaired defense and increased susceptibility to bacterial overgrowth in the immature gut. In preterm neonates, Paneth cells are underdeveloped, resulting in reduced secretion of such as , which compromises the intestinal barrier and contributes to and inflammation characteristic of . Studies in murine models demonstrate that disruption or of Paneth cells, particularly in the presence of pathogens like , induces -like injury, highlighting their essential function in maintaining epithelial integrity during early postnatal development. Infants with exhibit significantly fewer Paneth cells compared to age-matched controls, underscoring the link between Paneth cell deficiency and disease onset. Prematurity remains the primary risk factor for , with incidence rates of 5-12% in infants born before 33 weeks gestation, where Paneth cell immaturity exacerbates vulnerability to enteral feeding and hypoxia. In , Paneth cells promote tumorigenesis by supporting the niche through secretion of growth factors like Wnt ligands, fostering an environment conducive to initiation and progression. Accumulation of Paneth cells in early colorectal correlates with reduced disease-free in patients, as these cells provide essential niche signals that sustain cancer . IDO1-expressing Paneth cells within tumor crypts enhance immune evasion by cells, leading to increased tumor burden in models; their depletion in Stat1-deficient intestinal tumors reduces tumor load and improves anti-tumor immune infiltration. In some contexts, transient Paneth cell depletion facilitates intestinal regeneration by allowing repopulation without excessive niche support for residual malignant cells, potentially enhancing post-treatment recovery in preclinical models. With aging, Paneth cell function declines, contributing to intestinal barrier dysfunction and overall frailty in the elderly through altered and reduced support for maintenance. Aged intestines show increased Paneth cell numbers per but with impaired secretory capacity, leading to dysregulated and heightened that exacerbates age-related frailty. In celiac disease, gluten exposure induces stress in Paneth cells, resulting in reduced numbers and diminished lysozyme secretion, which impairs innate immunity and perpetuates mucosal damage in untreated patients. Paneth cell deficiency is observed in a subset of celiac cases, correlating with poor response to -free diets and persistent . Recent studies highlight emerging protective roles for Paneth cells in various pathologies. A 2025 investigation demonstrated that α-lipoic acid (ALA) supplementation targets Paneth cells to prevent intestinal aging, reducing atypical Paneth cell accumulation in human organoids and aged intestines, thereby mitigating inflammation-associated decline. In injury models, Paneth cell dysfunction disrupts α-defensin expression and microbiota balance, worsening ; however, IL-17 receptor signaling to Paneth cells preserves epithelial integrity post-gamma irradiation, suggesting therapeutic potential for enhancing their resilience.

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