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Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. 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 , Paneth cells secrete several anti-microbial compounds (notably 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.
Unlike the other epithelial cell types, Paneth cells migrate downward from the stem cell region and settle just adjacent to it. This close relationship to the stem cell region suggests that Paneth cells are important in defending the gland stem cells from microbial damage, although their function is not entirely known. Furthermore, among the four aforementioned intestinal cell lineages, Paneth cells live the longest (approximately 57 days).
Small intestinal crypts house stem cells that serve to constantly replenish epithelial cells that die and are lost from the villi. 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.
Paneth cells display merocrine secretion, that is, secretion via exocytosis.
Paneth cells sense bacteria via MyD88-dependent toll-like receptor (TLR) activation which then triggers antimicrobial action. 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. Surprisingly, murine Paneth cells do not express mRNA transcripts for TLR4.
Human Paneth cells produce two α-defensins known as human α-defensin HD-5 (DEFA5) and HD-6 (DEFA6). 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 C andida albicans). 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.
Human Paneth cells also produce other AMPs including lysozyme, secretory phospholipase A2, and regenerating islet-derived protein IIIA. 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 . This battery of secretory molecules gives Paneth cells a potent arsenal against a broad spectrum of agents, including bacteria, fungi and even some enveloped .
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.
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.
It is believed that the dysfunction of Paneth cells compromises antimicrobial peptides leading to a microbiota composition shift, and even dysbiosis. 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. 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. However, it is yet to be established whether Paneth cell dysfunction is the cause of dysbiosis, or its concomitant effect.
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. 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 Bacteroidota, resulting in their overgrowth and consequent dysbiosis.
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.
Murine models indicate that obesity may decrease the secretion of Alpha defensin from Paneth cells, leading to dysbiosis. 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.
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.
Further research is needed to elucidate the connection between Paneth cells and the gut-liver-axis.
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