Content uploaded by Olivier Peulen
Author content
All content in this area was uploaded by Olivier Peulen
Content may be subject to copyright.
A preview of the PDF is not available
Polyamines in Gut Inflammation and Allergy
Abstract and Figures
The natural polyamines, named 1,4-diaminobutane, N-aminopropyl-1,4-diaminobutane and N,N′-bisaminopropyl-1,4-diaminobutane, are also designated respectively as putrescine, spermidine and spermine. They are polycationic compounds found in all eukaryotic cells. As they are deeply involved in cell functions, e.g. cellular growth, their concentration and their equilibrium in the intracellular pool are maintained in very narrow limits by regulatory mechanisms acting in a very fast, sensitive and precise way. These compounds are involved in gut inflammatory processes and in allergy. Indeed, they control the production of inflammatory mediators in several cell lines or tissues. Polyamine metabolism could be considered as a putative target for inflammation, allergy prevention or therapy.
Figures - uploaded by Olivier Peulen
Author content
All figure content in this area was uploaded by Olivier Peulen
Content may be subject to copyright.
... It has been already known that spermine concentrations are significantly elevated in tissues during infection, malignant and inflammatory diseases, proposing a direct role of spermine in control of these processes (Wallace, 2003;Bachrach, 2004;Peulen et al., 2004;Moinard et al., 2005). Up to now there is no data about interrelationship between polyamines and the gut immune system (Peulen, 2004). ...
... It has been already known that spermine concentrations are significantly elevated in tissues during infection, malignant and inflammatory diseases, proposing a direct role of spermine in control of these processes (Wallace, 2003;Bachrach, 2004;Peulen et al., 2004;Moinard et al., 2005). Up to now there is no data about interrelationship between polyamines and the gut immune system (Peulen, 2004). Also, there is no insight about the effects of spermine on immune system of spleen, an organ playing an important role in immune response (Jolois et al., 2002), as well as about changes in polyamine oxidase activity (PAO), which is a key enzyme in polyamine catabolism (Holtta, 1977;Vujic, 2002;Seiler, 2004). ...
Glucocorticoids are potent anti-inflammatory and immunosuppressive agents. As endogenous inhibitors of cytokine synthesis, glucocorticoids suppress immune activation and uncontrolled overproduction of cytokines, preventing tissue injury. Also, polyamine spermine is endogenous inhibitor of cytokine production (inhibiting IL-1, IL-6 and TNF synthesis). The idea of our work was to examine dexamethasone effects on the metabolism of polyamines, spermine, spermidine and putrescine and polyamine oxidase activity in liver and spleen during sensitization of guinea pigs. Sensitization was done by application of bovine serum albumin with addition of complete Freund's adjuvant. Our results indicate that polyamine amounts and polyamine oxidase activity increase during immunogenesis in liver and spleen. Dexamethasone application to sensitized and unsensitized guinea pigs causes depletion of polyamines in liver and spleen. Dexamethasone decreases polyamine oxidase activity in liver and spleen of sensitized guinea pigs, increasing at the same time PAO activity in tissues of unsensitized animals.
... It has been showed that the activity of OCD increased during inflammation in colonic mucosa from patients with IBD 29 . The increase in OCD and PAs content during chronic intestinal inflammation might result from an increased cell proliferation through the repair phase of mucosal injury 30 . The impairment in the PAs synthesis pathway leads to many diseases for example inflammtion 31 . ...
This study was aimed estimate the levels of spermidine (SPD), spermine (SPM) and total peroxidase activity in serum of Iraqi patients with inflammatory bowel disease (IBD). A total 60 IBD patients were enrolled in the present research the age range is 16-40 years. They were classified into two main groups: 30 patients (15male & 15female) with Crohn’s disease (CD), and 30 patients (15male & 15female) with ulcerative colitis (UC). The healthy control group (HC) consist of 30 healthy subjects (15 male & 15 females). SPD and SPM were measured by using HPLC technique. The levels of serum of SPD were (90.22±20.05 and 141.88±24.16 µg/ml) in the CD and UC patients, respectively. These values refer to a highly significant increase (p<0.001) comparison in sera of healthy controls (17.41±8.47 µg/ml). The SPM levels were (248.75±49.19 and 386.88±72.64 µg/ml) in CD and UC, respectively, which similarly revealed highly significant increase (p<0.001) in comparison SPM levels in the HC group (145.19±14.63 µg/ml). Meanwhile, the SPD/SPM ratio was (0.370±0.088 and 0.369±0.061) in CD and UC, respectively, This indicates a highly significant increase (p<0.001) in comparison to their ratio in (HC). The results of total peroxidase activity show a highly significant increase (p<0.001) in both patient groups compared to a healthy control group. The current study suggests that increased levels of SPD and SPM play an essential role in increasing oxidative stress in patients with IBD.
... All these polyamines 1-4 were also demonstrated to possess antioxidant and anti-apoptotic activities, involved in gut inflammatory processes, allergies as well in tumor growth [3,8,9]. In this latter case, the specific biosynthesis pathway involved has been targeted for the development of antineoplastic therapy as well as cancer treatments [3,4]. ...
Recently, extensive researches have emphasized the fact that polyamines conjugates are becoming important in all the biological and medicinal fields. In this review we will focus our attention on natural polyamines and highlight recent progress in both fundamental mechanism studies and interest for the development and application for a therapeutic human use of polyamine derivatives.
... Polyamine biosynthesis, one of the modules which represents both CDT split graphs (Fig. 6), is considered to be essential for proliferation and differentiation of the renewing intestinal mucosa [37]. In several studies, the authors suggested that polyamine deficiency can be the cause of inflammation [38,39]. ...
Background:
Microbiomes play vital roles in shaping environments and stabilize them based on their compositions and inter-species relationships among its species. Variations in microbial properties have been reported to have significant impact on their host environment. For example, variants in gut microbiomes have been reported to be associated with several chronic conditions, such as inflammatory disease and irritable bowel syndrome. However, how microbial bacteria contribute to pathogenesis still remains unclear and major research questions in this domain remain unanswered.
Methods:
We propose a split graph model to represent the composition and interactions of a given microbiome. We used metagenomes from Korean populations in this study. The dataset consists of three different types of samples, viz. mucosal tissue and stool from Crohn's disease patients and stool from healthy individuals. We use the split graph model to analyze the impact of microbial compositions on various host phenotypes. Utilizing the graph model, we have developed a pipeline that integrates genomic information and pathway analysis to characterize both critical informative components of inter-bacterial correlations and associations between bacterial taxa and various metabolic pathways.
Results:
The obtained results highlight the importance of the microbial communities and their inter-relationships and show how these microbial structures are correlated with Crohn's disease. We show that there are significant positive associations between detected taxonomic biomarkers as well as multiple functional modules in the split graph of mucosal tissue samples from CD patients. Bacteria Moraxellaceae and Pseudomonadaceae were detected as taxonomic biomarkers in CD groups. Higher abundance of these bacteria have been reported in previous study and several metabolic pathways associated with these bacteria were characterized in CD samples.
Conclusions:
The proposed pipeline provides a new way to approach the analysis of complex microbiomes. The results obtained from this study show great potential in unraveling mechansims in complex biological systems to understand how various components in such complex environments are associated with critical biological functions.
... (°) p < 0.05 compared to PTG + L.GG treated cells. ered as markers of hyperproliferation following the gliadin toxic effect, as it occurs during inflammatory processes of the intestine leading to a derangement of mucosa ( Peulen, Deloyer, Deville, & Dandrifosse, 2004). Functional, structural, and molecular analyses have established that the regulation of the epithelial paracellular permeability is also under the control of the apical intercellular junctional complex whose major constituents are TJs and AJs ( Utech, Bruwer, & Nusrat, 2006). ...
Celiac disease (CD) is an immune-mediated enteropathy characterized by an increase in paracellular permeability. The improvements in barrier integrity have been related to changes in tight junction (TJ) structure as a consequence of modifications in TJ protein expression. Recently, also polyamines have been suggested to play a part in the control of intestinal permeability by modulating TJ and adherens junction (AJ) expressions.
The present work investigated the protective role of Lactobacillus rhamnosus GG (L.GG) towards alterations of the paracellular permeability induced by Pepsin-Trypsin digested Gliadin (PTG) in Caco-2 cells.
The results from this study clearly indicate that L.GG protects Caco-2 cells from PTG induced damage and, interestingly, the presence of cellular polyamines seems to be essential in the modulation of TJ and AJ protein expression exerted by this probiotic. On these bases, a role for L.GG as a dietary supplement to promote health also for CD patients could be hypothesized.
... Anne sütü alan bebeklerde, allerji ve diğer hastalıklara karşı olumlu etkiler görülmektedir (23). Bu etkilerin, anne sütündeki yüksek poliamin seviyesi ile olan ilgisi çeşitli araştırmalara konu olmuştur (6,24). İlk beş yılda anne sütü ile yüksek poliamin alınması, besin allerjisini, azaltmaktadır. ...
Human milk is the ideal food for all newborns and infants. It involves macro nutrients and functional compounds for growth and development. The composition of breast milk differs between preterm and term milk. Polyamines are essential for cell proliferation and differentiation. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as food, and intestinal microbiota. Breast milk is the first source of exogenous polyamines. The level of putrescine is lower than the levels of spermine and spermidine. During lactation, polyamines in breast milk increase in first 1-2 weeks reaching the maximum value and then tend to decrease. The levels of polyamines in breast milk associate with lactation period, sampling time, and mother’s diet. Polyamine intake is important for postnatal maturation of the immune system and small intestine. Cow milk or formulas can be used in case of insufficient breast milk and a requirement for supplemental feeding. Cow milk includes less amount of polyamines than breast milk has. Ideal formula composition involves macro and micro nutrients which take a role in growth and development. The formulas enriched with polyamines might have beneficial effects on the immune system of infants. This review aims to evaluate the functions of polyamines in breast milk, the effects on infant development, and to compare the levels of polyamines in between breast milk, cow milk and formulas. © Güncel Pediatri Dergisi, Galenos Yayınevi tarafından basılmıştır.
... In this context, polyamine levels could be regarded as markers of a hyperproliferative state in response to toxic effects of gliadin. This behavior by polyamines has already been reported during inflammation of intestine leading to derangement of the mucosa [34]. ...
Celiac disease is characterized by enhanced intestinal paracellular permeability due to alterations of function and expression of tight junction (TJ) proteins including ZO-1, Claudin-1 and Occludin. Polyamines are pivotal in the control of intestinal barrier function and are also involved in the regulation of intercellular junction proteins. Different probiotic strains may inhibit gliadin-induced toxic effects and the Lactobacillus rhamnosus GG (L.GG) is effective in the prevention and treatment of gastrointestinal diseases. Aims of the study were to establish in epithelial Caco-2 cells whether i) gliadin affects paracellular permeability and polyamine profile; ii) co-administration of viable L.GG, heat-killed L.GG (L.GG-HK) or its conditioned medium (L.GG-CM) preserves the intestinal epithelial barrier integrity. Additionally, the effects of L.GG on TJ protein expression were tested in presence or absence of polyamines.
Administration of gliadin (1 mg/ml) to Caco-2 cells for 6 h caused a significant alteration of paracellular permeability as demonstrated by the rapid decrease in transepithelial resistance with a concomitant zonulin release. These events were followed by a significant increase in lactulose paracellular transport and a slight lowering in ZO-1 and Occludin expression without affecting Claudin-1. Besides, the single and total polyamine content increased significantly. The co-administration of viable L.GG (108 CFU/ml), L.GG-HK and L.GG-CM with gliadin significantly restored barrier function as demonstrated by transepithelial resistance, lactulose flux and zonulin release. Viable L.GG and L.GG-HK, but not L.GG-CM, led to a significant reduction in the single and total polyamine levels. Additionally, only the co-administration of viable L.GG with gliadin significantly increased ZO-1, Claudin-1 and Occludin gene expression compared to control cells. When Caco-2 cells treated with viable L.GG and gliadin were deprived in the polyamine content by alpha-Difluoromethylornithine, the expression of TJ protein mRNAs was not significantly different from that in controls or cells treated with gliadin alone.
Gliadin modifies the intestinal paracellular permeability and significantly increases the polyamine content in Caco-2 cells. Concomitant administration of L.GG is able to counteract these effects. Interestingly, the presence of cellular polyamines is necessary for this probiotic to exert its capability in restoring paracellular permeability by affecting the expression of different TJ proteins.
... Polyamines are important mediators of inflammation [3], and studies have indicated that polyamine biosynthesis is increased during sepsis [4,5]. Although the functions of the upregulated polyamines during sepsis and inflammation are not clear, we hypothesize that polyamine levels may increase during inflammation to help fuel hypusine biosynthesis, which is a polyamine-dependent reaction. ...
Many novel therapeutics have failed to reduce all-cause mortality associated with severe sepsis. Eukaryotic translation initiation factor 5A (eIF5A) is a regulator of apoptosis as well as inflammatory cell activation, making it a potential target for sepsis therapy.
In a murine model of severe sepsis, mice were intraperitoneally challenged with lipopolysaccharide (LPS). Mice were treated both before and after LPS challenge with liposome complexes containing either an eIF5A-specific or control small interference RNA (siRNA), and both survival and serum concentrations of inflammatory cytokines were monitored. The ability of eIF5A siRNA to reduce inflammatory cytokines was also tested in a model of acute lung injury established by intranasal administration of LPS to mice.
There was a statistically significant increase in the rate of survival for mice intraperitoneally challenged with LPS that received eIF5A siRNA, compared with that noted for mice that received control siRNA (71% vs. 5%; P< .001), as well as a reduction in cytokine expression in serum. Concentrations of proinflammatory cytokines were also reduced in the lung homogenates and serum of mice that were intranasally challenged with LPS and received eIF5A siRNA (P< or = .05).
eIF5A siRNA-liposome complexes reduced inflammation and contributed to increased survival in a model of severe sepsis, decreased inflammation in a model of acute lung injury, and should be considered for clinical use.
Atopic diseases like asthma and allergies to various food born proteins are among the wide spread chronic diseases in newborns because of their allergy prone Th2 skewed immune response. Increasing scientific reports point out that the mother’s immune system plays a crucial role in mediating the development of fetal-infant immune responses. Lactating mammary glands are part of an integrated mucosal immune system with confined production of antibodies which is particularly targeted against pathogenic agents in the mother’s environment and later encounter by the newborns. Passive immunity through mother’s milk is critical for newborn’s immune maturation. Thus, understanding the maternal influence on the childhood atopic risk during the newborn immune maturation could suggest novel treatment and prevention strategies. Probiotics have been proposed to harmonize Th1/Th2 imbalance in allergic diseases however the mechanism largely unknown. Probiotic feeding to mothers and offspring during prenatal and postnatal periods to inhibit allergies in newborns may be a possible preventive approach in atopic disease. Hence, the present review focuses on the role of feeding probiotics to mothers during pregnancy and lactation as well to newborns during suckling and post weaning periods as possible modulators for activation of maternal infant immune response to down regulate allergy prone Th2 biased newborn system.
The activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase increase in the livers of rats during the acute-phase response to inflammation. The increase reaches its maximum at 2.5 hr from injection of turpentine, and is maintained at the same level for the following 2 days. Pretreatment in vivo with an inhibitor of cyclooxygenase prevents the inflammation-associated increases of both polyamine biosynthetic decarboxylases: an inhibitor of the lipoxygenase pathway seems to counteract only the increase of ornithine decarboxylase. The administration of diaminopropane, an inhibitor of ornithine decarboxylase, has only limited effects on the activation of RNA synthesis by liver nuclei, which occurs 10 hr after turpentine treatment. The results suggest that stimulation of the polyamine biosynthetic decarboxylases is surely part of the acute-phase response and depends on the previous activation of arachidonate metabolism: however its role in supporting later events of the acute-phase response will need further investigations.
Polyamines are known to play a major role in postprandial adaptation of the digestive tract. Experiments were designed to determine whether ingested polyamines induce change in intestinal motility associated with a cholecystokinin (CCK) release and whether endogenous polyamines are involved in the intestinal and colonic motor response to a meal. Intestinal and colonic motility was assessed in rats equipped with intestinal electrodes, and plasma CCK was determined using a bioassay. Orogastric administration of putrescine, spermidine, or spermine (20 mumol) disrupted intestinal migrating myoelectric complexes (MMCs) and increased the frequency of colonic spike bursts. After a 6-day treatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine, the duration of postprandial disruption of MMCs, but not the stimulation of colonic motility, induced by a 3-g meal was significantly reduced. The duration of MMC disruption and the increase in colonic spike burst frequency after spermidine administration (20 mumol) were significantly reduced by CCK-A and CCK-B antagonists. Eight minutes after saline administration plasma CCK concentration was 0.9 +/- 0.4 pM; it rose to 4.7 +/- 2.8 pM, 8 min after spermidine (20 mumol). These results indicate that exogenous polyamines disrupt intestinal MMCs and stimulate colonic motility through a release of CCK acting at CCK-A and CCK-B receptors and suggest that endogenous polyamines are involved in the postprandial control of intestinal motility.
A group of ninety-five infants was followed from birth to one year of age, and the total serum IgE concentration was studied. The infants were fed on breast milk, home-prepared cow's milk formula, or proprietary infant milk formula. Solid foods were introduced at 3.5 months of age. The breast milk group had lower IgE than the cow's milk group up to 4 months of age, i.e. until the end of exclusive milk feeding. The formula group had intermediate IgE values. The difference was not due to the presence of IgE antibodies to cow's milk in bottle-fed infants, since no such antibodies could be detected. After the introduction of solid foods the differences between the groups disappeared. Our data suggest that exclusive breast milk feeding can reduce total serum IgE concentration in early infancy. Reference values for unselected infants and for infants with no atopic manifestations are reported.
The effect of turpentine, a chemical inflammatory agent, on polyamine synthesis has been studied. Ornithine decarboxylase activity is markedly increased in liver 6 hrs after subcutaneous injection of turpentine, and then decreases. No significant modification is observed in S-adenosylmethionine decarboxylase. Putrescine injected prior to turpentine prevents this increase.
Putrescine, spermidine and spermine concentrations are all increased following turpentine, but with different patterns: spermidine alone keeps increasing for 50 hours.
Putrescine and spermidine injected prior to turpentine partially counteract the increase of serum α2-macroglobulin, which is believed to be a marker of inflammation.
Previous studies have shown that amine groups are ototoxic. The interaction between different polyamines and phospholipid vesicles was studied using vesicle aggregation and fluorescence techniques (DPH and ANS as the fluorescence probes). The results showed that the interaction between polyamines (spermine, spermidine and 1,3-diaminopropane) and acidic phospholipids (PS, PE, PI and PIP2) is an ionic one. The polyamine with the highest positive charges and the phospholipid with the highest content of negative groups showed the strongest ionic interaction. There was no indication of any hydrophobic interaction within the phospholipid bilayer. The strong interaction between amine groups and PIP2 support the proposal that the latter is crucially involved in aminoglycoside toxicity in the inner ear and kidney.
Urine polyamine content is increased in patients with colorectal malignancy and may be a useful tumor marker in the management of these patients. Urinary excretion of putrescine and spermidine was measured preoperatively and in the first week postoperatively in nine patients with inflammatory bowel disease, eight with other benign colorectal disease, and 13 with colorectal cancer. Preoperative urine putrescine levels were elevated similarly in patients with inflammatory bowel disease and malignancy. Polyamine levels were increased in all three groups in the early postoperative period. Urinary polyamine excretion did not correlate with serum CEA levels, tumor volume, or stage of disease in patients with cancer. Because elevated levels of urinary polyamines are not specific for malignancy and do not correlate with other prognostic indicators, such measurements are unlikely to be useful in tumor detection and determining prognosis. Polyamine levels, however, may prove useful in monitoring response to therapy and detecting recurrences in individual patients.
We report an interesting case of congenital inflammatory bowel disease and intestinal epithelial immaturity that presented as secretory diarrhea. No infectious, metabolic, or anatomical basis for these findings was identified. As differentiated from previous reports of neonatal enteropathies, this infant demonstrated involvement of both the small and large intestine with histopathologic findings of acute and chronic inflammation, extensive submucosal fibrosis, and "flat" small intestine mucosa. In addition, this patient had a polyamine deficiency (a primary or secondary phenomenon), which may have contributed to delayed epithelial maturation. These findings suggest that the inflammatory bowel disease and altered epithelial maturation contributed to a fatal intractable diarrhea.
Polyamines and RNA accumulate in the rat mammary gland during pregnancy, but the major increases occur after parturition. Therefore the major increases occur after the gland has obtained its maximal complement of epithelial cells. During lactation, the spermidine concentration rises above 5mm and RNA content in the lactating mammary gland reaches a value 16 times that of the unstimulated mammary gland. The ratio of spermidine/spermine, an increase of which initially signals an elevation in biosynthetic activity, is near 1 in the normal mammary gland and is greater than 10 in the lactating mammary gland. Putrescine concentration is very low during the entire course of mammary-gland development, with the exception of early pregnancy. The low putrescine concentration probably reflects the very rapid conversion of putrescine into spermidine. Both ornithine decarboxylase, the enzyme that synthesizes putrescine, and putrescine-stimulated S-adenosyl-l-methionine decarboxylase, the enzyme that synthesizes spermidine, increase in activity during middle and late pregnancy; during lactation, both enzyme activities are elevated until the 21st day of lactation, and then decline. These declines are concomitant with involution. Also, it was found that the amount of ribonuclease activity in the mammary gland was very high during lactation, almost double that in the gland during pregnancy.
The present studies were designed to evaluate the parietal cell acid production in response to short-time stimulation by epidermal growth factor (EGF). Studies were performed in vitro using isolated cells from rat stomachs, and acid production was indirectly determined by [14C]aminopyrine accumulation. EGF inhibited histamine-stimulated aminopyrine accumulation from standard incubation medium (K+ = 5 mM) but not from that with increased K+ concentration (K+ = 70 mM). EGF significantly stimulated ornithine decarboxylase (ODC) activity, an effect that was blocked by the specific ODC inhibitor, difluoromethylornithine (DFMO). In the presence of DFMO, EGF failed to inhibit histamine-stimulated aminopyrine uptake. Like EGF, the polyamine spermine, which is a direct product of enhanced ODC activity, also inhibited histamine-stimulated aminopyrine uptake. Unlike EGF, the spermine-induced inhibition of aminopyrine accumulation was not altered by DFMO. Thus the DFMO effect was specific to EGF. Taken together, these results are consistent with the postulate that EGF inhibits parietal cell secretory response through the induction of ODC activity and increased synthesis of polyamines.