scholarly journals Butyric Acid and Leucine Induce α-Defensin Secretion from Small Intestinal Paneth Cells

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2817 ◽  
Author(s):  
Akiko Takakuwa ◽  
Kiminori Nakamura ◽  
Mani Kikuchi ◽  
Rina Sugimoto ◽  
Shuya Ohira ◽  
...  
Keyword(s):  
Butyric Acid ◽  
Pathogenic Bacteria ◽  
Ex Vivo ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Short Chain ◽  
Immune Functions ◽  
Cell Secretion ◽  
Small Intestinal ◽  
Granule Secretion

The intestine not only plays a role in fundamental processes in digestion and nutrient absorption, but it also has a role in eliminating ingested pathogenic bacteria and viruses. Paneth cells, which reside at the base of small intestinal crypts, secrete α-defensins and contribute to enteric innate immunity through potent microbicidal activities. However, the relationship between food factors and the innate immune functions of Paneth cells remains unknown. Here, we examined whether short-chain fatty acids and amino acids induce α-defensin secretion from Paneth cells in the isolated crypts of small intestine. Butyric acid and leucine elicit α-defensin secretion by Paneth cells, which kills Salmonella typhimurium. We further measured Paneth cell secretion in response to butyric acid and leucine using enteroids, a three-dimensional ex vivo culture system of small intestinal epithelial cells. Paneth cells expressed short-chain fatty acid receptors, Gpr41, Gpr43, and Gpr109a mRNAs for butyric acid, and amino acid transporter Slc7a8 mRNA for leucine. Antagonists of Gpr41 and Slc7a8 inhibited granule secretion by Paneth cells, indicating that these receptor and transporter on Paneth cells induce granule secretion. Our findings suggest that Paneth cells may contribute to intestinal homeostasis by secreting α-defensins in response to certain nutrients or metabolites.

scholarly journals Mouse Paneth Cell Secretory Responses to Cell Surface Glycolipids of Virulent and Attenuated Pathogenic Bacteria

2005 ◽  
Vol 73 (4) ◽  
pp. 2312-2320 ◽  
Author(s):  
Hiroki Tanabe ◽  
Tokiyoshi Ayabe ◽  
Brian Bainbridge ◽  
Tina Guina ◽  
Robert K. Ernst ◽  
...  
Keyword(s):  
Cell Surface ◽  
Bacterial Cell ◽  
Pathogenic Bacteria ◽  
Lipid A ◽  
Ex Vivo ◽  
Secretory Granules ◽  
Acyl Chain ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Cell Secretion

ABSTRACT Mouse Paneth cells respond to bacteria and bacterial cell surface antigens by discharging secretory granules into the lumen of small intestinal crypts (T. Ayabe et al., Nat. Immunol. 1:113-118, 2000). To investigate mechanisms regulating these responses, purified surface glycolipid molecules with known acyl chain modifications and attenuated properties were tested for the ability to stimulate Paneth cell secretion. The antigens included lipopolysaccharide (LPS) from wild-type and msbB-null Escherichia coli and phoP-null and phoP-constitutive Salmonella enterica serovar Typhimurium strains, as well as LPS, lipid A, and lipoteichoic acid from Pseudomonas aeruginosa and Listeria monocytogenes grown in Mg2+-limited media. Measurements of total secreted protein, secreted lysozyme, and the bactericidal peptide activities of collected secretions showed that the purified antigens elicited similar secretory responses from Paneth cells in mouse crypts ex vivo, regardless of glycolipid acyl chain modification. Despite their impaired Tlr4 pathway, Paneth cells in ex vivo C3H/HeJ mouse crypts released equivalent amounts of bactericidal peptide activity in response to purified bacterial antigens, including lipid A. Thus, mouse Paneth cells respond equivalently to purified bacterial cell envelope glycolipids, regardless of functional Tlr4, the structural properties of glycolipid acyl chains, or their association with virulence in humans.

scholarly journals Enteric Salmonella Infection Inhibits Paneth Cell Antimicrobial Peptide Expression

2003 ◽  
Vol 71 (3) ◽  
pp. 1109-1115 ◽  
Author(s):  
Nita H. Salzman ◽  
Margaret M. Chou ◽  
Hendrik de Jong ◽  
Lide Liu ◽  
Edith M. Porter ◽  
...  
Keyword(s):  
Type Iii Secretion ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Enteric Pathogens ◽  
Intestinal Lumen ◽  
Oral Inoculation ◽  
Serovar Typhimurium ◽  
Peptide Expression ◽  
Small Intestinal ◽  
Antimicrobial Peptide Expression

ABSTRACT Paneth cells, highly secretory epithelial cells found at the bases of small intestinal crypts, release a variety of microbicidal molecules, including α-defensins and lysozyme. The secretion of antimicrobials by Paneth cells is thought to be important in mucosal host defense against invasion by enteric pathogens. We explored whether enteric pathogens can interfere with this arm of defense. We found that oral inoculation of mice with wild-type Salmonella enterica serovar Typhimurium decreases the expression of α-defensins (called cryptdins in mice) and lysozyme. Oral inoculation with Salmonella serovar Typhimurium strains that are heat killed, lack the PhoP regulon, and lack the SPI1 type III secretion system or with Listeria monocytogenes does not have this effect. Salmonella may gain a specific survival advantage in the intestinal lumen by decreasing the expression of microbicidal peptides in Paneth cells through direct interactions between Salmonella and the small intestinal epithelium.

scholarly journals Norepinephrine released by intestinal Paneth cells exacerbates ischemic AKI

2020 ◽  
Vol 318 (1) ◽  
pp. F260-F272 ◽  
Author(s):  
Sang Jun Han ◽  
Mihwa Kim ◽  
Vivette Denise D’Agati ◽  
H. Thomas Lee
Keyword(s):  
Tyrosine Hydroxylase ◽  
Systemic Inflammation ◽  
Critical Role ◽  
Paneth Cell ◽  
Protein A ◽  
Kidney Injury ◽  
Paneth Cells ◽  
Plasma Norepinephrine ◽  
Norepinephrine Release ◽  
Small Intestinal

Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition, intestine-derived norepinephrine is a major mediator of hepatic injury and systemic inflammation in sepsis. We tested the hypothesis that small intestinal Paneth cells synthesize and release norepinephrine to exacerbate ischemic AKI. After ischemic AKI, we demonstrated larger increases in portal venous norepinephrine levels compared with plasma norepinephrine in mice, consistent with an intestinal source of norepinephrine release after renal ischemia and reperfusion. We demonstrated that murine small intestinal Paneth cells express tyrosine hydroxylase mRNA and protein, a critical rate-limiting enzyme for the synthesis of norepinephrine. We also demonstrated mRNA expression for tyrosine hydroxylase in human small intestinal Paneth cells. Moreover, freshly isolated small intestinal crypts expressed significantly higher norepinephrine levels after ischemic AKI compared with sham-operated mice. Suggesting a critical role of IL-17A in Paneth cell-mediated release of norepinephrine, recombinant IL-17A induced norepinephrine release in the small intestine of mice. Furthermore, mice deficient in Paneth cells (SOX9 villin Cre mice) have reduced plasma norepinephrine levels after ischemic AKI. Finally, supporting a critical role for norepinephrine in generating ischemic AKI, treatment with the selective α-adrenergic antagonists yohimbine and phentolamine protected against murine ischemic AKI with significantly reduced renal tubular necrosis, inflammation, and apoptosis and less hepatic dysfunction. Taken together, we identify Paneth cells as a critical source of norepinephrine release that may lead to intestinal and liver injury and systemic inflammation after AKI.

scholarly journals Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

2011 ◽  
Vol 80 (1) ◽  
pp. 266-275 ◽  
Author(s):  
Nadine R. Martinez Rodriguez ◽  
Marjannie D. Eloi ◽  
Alexandria Huynh ◽  
Teresa Dominguez ◽  
Annie H. Cheung Lam ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Population ◽  
Salmonella Enterica ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Differentiation Markers ◽  
Gastrointestinal Infections ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Small Intestinal

ABSTRACTPaneth cells residing at the base of the small intestinal crypts contribute to the mucosal intestinal first line defense by secreting granules filled with antimicrobial polypeptides including lysozyme. These cells derive from the columnar intestinal stem cell located at position 0 and the transit amplifying cell located at position +4 in the crypts. We have previously shown thatSalmonella entericaserovar Typhimurium (ST), a leading cause of gastrointestinal infections in humans, effects an overall reduction of lysozyme in the small intestine. To extend this work, we examined small-intestinal tissue sections at various time points after ST infection to quantify and localize expression of lysozyme and assess Paneth cell abundance, apoptosis, and the expression of Paneth cell differentiation markers. In response to infection with ST, the intestinal Paneth cell-specific lysozyme content, the number of lysozyme-positive Paneth cells, and the number of granules per Paneth cell decreased. However, this was accompanied by increases in the total number of Paneth cells and the frequency of mitotic events in crypts, by increased staining for the proliferation marker PCNA, primarily at the crypt side walls where the transit amplifying cell resides and not at the crypt base, and by apoptotic events in villi. Furthermore, we found a time-dependent upregulation of first β-catenin, followed by EphB3, and lastly Sox9 in response to ST, which was not observed after infection with aSalmonellapathogenicity island 1 mutant deficient in type III secretion. Our data strongly suggest that, in response to ST infection, a Paneth cell differentiation program is initiated that leads to an expansion of the Paneth cell population and that the transit amplifying cell is likely the main progenitor responder. Infection-induced expansion of the Paneth cell population may represent an acute intestinal inflammatory response similar to neutrophilia in systemic infection.

scholarly journals IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity

2020 ◽  
Author(s):  
Stephen J. Gaudino ◽  
Michael Beaupre ◽  
Xun Lin ◽  
Preet Joshi ◽  
Sonika Rathi ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Defense ◽  
Knockout Mice ◽  
Paneth Cell ◽  
Cell Types ◽  
Paneth Cells ◽  
Lineage Tracing ◽  
Interleukin 22 ◽  
Serovar Typhimurium ◽  
Small Intestinal

Abstract Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1fl/fl;Lgr5-EGFP-creERT2-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5+ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.

scholarly journals Paneth Cell α-Defensins from Rhesus Macaque Small Intestine

2004 ◽  
Vol 72 (3) ◽  
pp. 1470-1478 ◽  
Author(s):  
Hiroki Tanabe ◽  
Jun Yuan ◽  
Melinda M. Zaragoza ◽  
Satya Dandekar ◽  
Agnes Henschen-Edman ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Rhesus Macaques ◽  
Paneth Cell ◽  
Peptide Sequencing ◽  
Paneth Cells ◽  
Molecular Masses ◽  
Bactericidal Activities ◽  
Small Intestinal

ABSTRACT Antimicrobial peptides are secreted by small intestinal Paneth cells as components of innate immunity. To investigate the role of α-defensins in enteric host defenses in nonhuman primates, α-defensin cDNAs were isolated, α-defensin peptides were purified from rhesus macaque small bowel, and the bactericidal activities of the peptides were measured. Six rhesus enteric α-defensin (RED) cDNAs, RED-1 to RED-6, were identified in a jejunum cDNA library; the deduced RED peptides exhibited extensive diversity relative to the primary structures of rhesus myeloid α-defensins. RED-4 was purified from monkey jejunum, and N-terminal peptide sequencing of putative RED-4 peptides identified two N termini, RTCYCRTGR… and TCYCRTGRC…; these corresponded to alternative N termini for the RED-4 molecules, as deduced from their molecular masses and RED cDNAs. In situ hybridization experiments localized RED mRNAs exclusively to small intestinal Paneth cells. Recombinant RED-1 to RED-4 were purified to homogeneity and shown to be microbicidal in the low micromolar range (≤10 μg/ml) against gram-positive and gram-negative bacteria, with individual peptides exhibiting variable target cell specificities. Thus, compared to myeloid α-defensins from rhesus macaques, enteric α-defensin peptides are highly variable in both primary structure and activity. These studies should facilitate further analyses of the role of α-defensins in primate enteric immunity.

scholarly journals Exploring Mucin as Adjunct to Phage Therapy

2021 ◽  
Vol 9 (3) ◽  
pp. 509
Author(s):  
Amanda Carroll-Portillo ◽  
Henry C. Lin
Keyword(s):  
Pathogenic Bacteria ◽  
Structural Changes ◽  
Phage Therapy ◽  
Bacterial Species ◽  
Gi Tract ◽  
Beneficial Bacteria ◽  
Phage Cocktail ◽  
Small Intestinal ◽  
Gastrointestinal Dysbiosis

Conventional phage therapy using bacteriophages (phages) for specific targeting of pathogenic bacteria is not always useful as a therapeutic for gastrointestinal (GI) dysfunction. Complex dysbiotic GI disorders such as small intestinal bowel overgrowth (SIBO), ulcerative colitis (UC), or Crohn’s disease (CD) are even more difficult to treat as these conditions have shifts in multiple populations of bacteria within the microbiome. Such community-level structural changes in the gut microbiota may require an alternative to conventional phage therapy such as fecal virome transfer or a phage cocktail capable of targeting multiple bacterial species. Additionally, manipulation of the GI microenvironment may enhance beneficial bacteria–phage interactions during treatment. Mucin, produced along the entire length of the GI tract to protect the underlying mucosa, is a prominent contributor to the GI microenvironment and may facilitate bacteria–phage interactions in multiple ways, potentially serving as an adjunct during phage therapy. In this review, we will describe what is known about the role of mucin within the GI tract and how its facilitation of bacteria–phage interactions should be considered in any effort directed at optimizing effectiveness of a phage therapy for gastrointestinal dysbiosis.

scholarly journals Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn’s Disease

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1349
Author(s):  
Kibrom M. Alula ◽  
Dakota N. Jackson ◽  
Andrew D. Smith ◽  
Daniel S. Kim ◽  
Kevin Turner ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Lipid Metabolism ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Mitochondrial Damage ◽  
Paneth Cells ◽  
Cell Phenotype ◽  
Type I ◽  
Targeted Therapeutics ◽  
Gene Signatures

Paneth cell defects in Crohn’s disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD inflammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.

scholarly journals Modulation of Intestinal Phosphate Transport in Young Goats Fed a Low Phosphorus Diet

2021 ◽  
Vol 22 (2) ◽  
pp. 866
Author(s):  
Joie L. Behrens ◽  
Nadine Schnepel ◽  
Kathrin Hansen ◽  
Karin Hustedt ◽  
Marion Burmester ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Phosphate Transport ◽  
Ussing Chambers ◽  
Intestinal Epithelia ◽  
Pi Transport ◽  
Low Phosphorus ◽  
Small Intestinal ◽  
Underlying Mechanisms ◽  
Growing Goats ◽  
1,25 Dihydroxy Vitamin D3

The intestinal absorption of phosphate (Pi) takes place transcellularly through the active NaPi-cotransporters type IIb (NaPiIIb) and III (PiT1 and PiT2) and paracellularly by diffusion through tight junction (TJ) proteins. The localisation along the intestines and the regulation of Pi absorption differ between species and are not fully understood. It is known that 1,25-dihydroxy-vitamin D3 (1,25-(OH)2D3) and phosphorus (P) depletion modulate intestinal Pi absorption in vertebrates in different ways. In addition to the apical uptake into the enterocytes, there are uncertainties regarding the basolateral excretion of Pi. Functional ex vivo experiments in Ussing chambers and molecular studies of small intestinal epithelia were carried out on P-deficient goats in order to elucidate the transepithelial Pi route in the intestine as well as the underlying mechanisms of its regulation and the proteins, which may be involved. The dietary P reduction had no effect on the duodenal and ileal Pi transport rate in growing goats. The ileal PiT1 and PiT2 mRNA expressions increased significantly, while the ileal PiT1 protein expression, the mid jejunal claudin-2 mRNA expression and the serum 1,25-(OH)2D3 levels were significantly reduced. These results advance the state of knowledge concerning the complex mechanisms of the Pi homeostasis in vertebrates.

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