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Dietary polyamines and non-neoplastic growth and disease

Deloyer, Patricia; Peulen, Olivier; Dandrifosse, Guy

European Journal of Gastroenterology & Hepatology: September 2001 - Volume 13 - Issue 9 - p 1027-1032
Review in Depth
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This review presents the data that are now available concerning the effects of dietary polyamines at either postnatal or adult stages in non-neoplastic growth and disease. Polyamines provided by food have a potential role in growth and development of the digestive system in neonatal mammals (and fishes). In humans, this property could be of importance in preventing the appearance of food allergies. Dietary polyamines also seem necessary for the maintenance of normal growth and general properties of adult digestive tract. Their possible therapeutic effects have been investigated in gastric, intestinal, and, more recently, whole-body healing.

Biochemistry and General Physiology Department, Chemistry Institute, Sart Tilman, Liege, Belgium

Correspondence to Dr Guy Dandrifosse, Biochemistry and General Physiology Department, Chemistry Institute, B6c, Sart Tilman, B-4000, Liege, Belgium Tel: +32 4 366 35 78; fax: +32 4 366 28 87; e-mail: g.dandrifosse@ulg.ac.be

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Introduction

The polyamines (putrescine, spermidine and spermine) are present in variable amounts in almost all kinds of food or foodstuffs [1,2]. The daily polyamine intake for adults is estimated to vary between 350 and 550 μmol [1]. The aim of this review is to present what is known at present about the effects of these dietary polyamines on the growth and disease in animals and humans, either at postnatal or adult stages.

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Postnatal period

In many vertebrates, maturation of the intestine (and of the digestive tract in general) is known to occur in the first postnatal weeks. This maturation is essential for the organism to adapt to a new environment, especially to new food constituents and antigens. For example, in the rat [3], intestinal mucosa undergoes many structural and functional modifications at weaning, allowing the animal to pass from a milk diet to a solid diet. In humans, the intestine of babies born at term is more permeable to food proteins during the first 3 postnatal months than later in life [4].

The role of polyamine metabolism in the maturation of the intestine was discovered by Luk et al., in 1980 [5]. These authors have established that ornithine decarboxylase (ODC) specific activity (SA) and polyamine concentration increase in the intestinal mucosa during weaning in rats. They have also proven that α-difluoromethylornithine (DFMO), an inhibitor of ODC, delays the intestinal maturation process. Therefore, further research was undertaken to determine whether exogenous polyamine treatment could induce precocious maturation of the intestine. Dufour et al.[6] showed that spermidine or spermine administered orally to suckling rats causes structural and biochemical changes in the intestinal mucosa comparable to those observed at weaning. This observation and others obtained afterwards (see below) indicate that dietary polyamines may be of importance in the normal development of the digestive tract and moreover that, particularly in humans, these substances could play a role in the prevention of food allergies [7,8].

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Intestinal maturation induced by dietary polyamines

Oral intake of polyamines by immature animals induces modifications of different parameters characterizing the intestine.

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Intestinal enzyme activity

The effect of dietary polyamines on the SA of several intestinal enzymes was studied in various neonatal animal models, i.e. in the rat, the mouse and the sea bass (Dicentrachus labrax).

In the rat, as already mentioned [6], oral administration of spermidine or spermine to pups which are from 7 to 11 days old, at doses from 3 to 8 μmol (not toxic), once or twice a day, for 3 days, induces changes in disaccharidase SA similar to those occurring at weaning (i.e. when the animals are about 3 weeks old): lactase SA, which is essential for the digestion of lactose, decreases whereas maltase and sucrase SAs, which are important in the digestion of solid food carbohydrates, display an increase. These results were confirmed by several other studies and authors, in the rat [9–16] and in the mouse [17]. Additionally, other intestinal enzymes, such as aminopeptidase [10], Na+,K+-ATPase [12], N-acetylglucosaminidase [12] and alkaline phosphatase [18], exhibit an adult pattern after spermidine or spermine oral treatment. These ingested polyamines also induce an increased fucolysation of intestinal brush-border membrane glycoproteins, an event naturally observed at weaning time [19,20].

In a fish species, the sea bass, a diet enriched in spermine can accelerate the appearance of the intestinal adult enzymatic profile [21]. Larvae fed for 18 days with 0.33% of supplemental spermine exhibit higher activities of brush-border membrane enzymes (leucine aminopeptidase and alkaline phosphatase) compared to a basal diet fed group.

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Intestinal morphological aspects

Dietary polyamines modify morphological and histological aspects of the intestine when administered to unweaned rats or mice. Oral intake of spermine induces an increase in wet weight [10,22], dry weight [17] and length [17] of the small intestine in neonatal rodents. The ratio of mitosis in the crypts also increases in the small intestine and caecum of treated animals [14].

Otherwise, many authors have shown that, in suckling rats, ingestion of spermine [6,9,11,13,14,16] or spermidine [12] causes a precocious loss of the supranuclear vacuole and endosomal complex that characterize immature enterocytes in the ileum. At weaning, the disappearance of these vacuolated cells results in the cessation of intestinal macromolecular transport (gut closure). This is also observed precociously in unweaned rats when they have ingested spermine. For example, bovine IgG transport decreases drastically following spermine treatment [14]. A reduction in the neonatal intestinal Fc receptor concentration is also observed in spermidine fed pups [13].

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Intestinal immune system

At weaning, immunological adaptation of the gut to nutritional and microbial antigens occurs in parallel with biochemical and morphological maturation. As oral administration of spermine can induce precocious biochemical and morphological maturation, it was hypothesized that this polyamine also affects development of the intestinal immune system. Indeed, spermine ingestion enhances precociously the concentration of the secretory component of polymeric immunoglobulins both in the villus and crypt cells in the suckling rat [10]. Recently, another experiment performed on neonatal mice has shown that the percentage of intra-epithelial lymphocytes expressing the T-cell receptor αβ (TCRαβ), clusters of differentiation (CD) 4, CD5, and CD54, as well as the levels of expression of these antigens, increase after oral spermine treatment similarly to natural maturation [17]. A ‘maturational’ effect was also observed in the same experimental conditions in the spleen (Peulen et al., personal communication).

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Liver and pancreas maturation induced by dietary spermine

In rodents, other organs of the digestive system are concerned with the maturation process that occurs at weaning. Many modifications appear in the liver and in the pancreas of these animals, allowing a progressive transition from a milk to a solid regimen.

In the liver, oral spermine treatment produces a decrease of the percentage of hepatocytes in the S phase, keeps the majority of cells in the G0–G1 phases, and induces the appearance of binuclear cells (cells at the basis of tetraploid cell formation) [23]. These observations indicate that the parenchymal cells enter their adult differentiation pattern. This is confirmed by the fact that ornithine aminotransferase activity, a current marker of postnatal liver maturation, increases following spermine ingestion and reaches the value observed in the weaned rat. Orally administered spermine also influences the development of immunological properties in the liver. Indeed, spermine treated rats exhibit a higher content of the receptor for polymeric immunoglobulins in comparison with control animals, although the value obtained does not reach the adult one.

The effect of oral administration of spermine on pancreatic maturation was investigated in the suckling rats [7,24]. The proliferating cell nuclear antigen (PCNA) index decreases significantly in spermine treated rats, indicating that spermine slows the proliferation rate of the organ [24]. In these animals, the morphology of the pancreatic cells as well as the cytoplasmic activity (evidenced by haematoxylin/eosin staining) are close to those observed in adult rats and are indicative of higher differentiation. This agrees with the fact that spermine treatment induces an increase in trypsin, chymotrypsin and α-amylase SA in the pancreas as well as in the duodenal content [7,24]. This observation indicates an early differentiation of the acinar cells of the pancreas and a precocious maturation of the whole exocrine function of this organ.

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Mechanisms of spermine action

The effects of dietary polyamines on intestinal maturation are dose dependent regarding disaccharidase SA [6,10,14] and are more marked for spermine than for spermidine [6,25]. Putrescine has almost no effect, either in the rat [5,25] or in the mouse [26]. Spermine induced maturation is reversible when the treatment is stopped [9]. Surprisingly, partial reversibility is also observed when spermine administration is prolonged for more than 3 days [27].

To induce precocious maturation of the intestine, spermine must be present at the luminal side of the mucosa. Indeed, intraperitoneal, intravenous or subcutaneous administration of this polyamine does not show any effect on this organ in the suckling rat [28]. In the same way, intraperitoneal injection of spermine has a slight effect on maturation of the liver [23]. Complementary to these results, it was shown that spermine given orally induces the secretion of adrenocorticotrophic hormone (ACTH) [29] and corticosterone [10,29], a hormone well-known to be involved in the maturational process occurring at weaning. This activation of the hypophyseal–adrenal axis probably arises via the stimulation of the intestinal immune and nervous systems [30–32] but the target of spermine on or in the intestinal cells remains to be determined. A general hypothesis allowing an explanation of the molecular events at the basis of the spermine effects was given recently [18].

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Dietary polyamines and the prevention of food allergy

The main factors favouring the appearance of food allergy, in addition to genetic predispositions, are abnormal intestinal permeability to macromolecules and lack of maturity of the submucosal immunological system [4]. As already mentioned, passage of antigens across the intestinal epithelium would be especially easy in premature babies and in babies younger than 3 months old. As factors inducing maturation of the digestive system, dietary polyamines could play a role in the prevention of food allergy. Indeed, the results mentioned above show, among other things, that, in the suckling rodents, spermine ingestion (1) increases the SA of pancreatic and duodenal proteases, indicating that a better digestion of proteins and, thus, of allergens could be achieved; (2) modifies the intestinal permeability to macromolecules; and (3) induces ‘maturation’ of several intestinal immunological properties. So, the manner in which dietary polyamines could be of interest in human intestinal development was investigated.

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Polyamines in milk

As allergy problems seem to be less frequent in breast fed children when compared with bottle fed infants [4], it was interesting to compare the polyamine concentration in breast milk and in infant formulas. Different studies showed that, effectively, spermine and spermidine concentrations are always higher in human milk [33–35]. Moreover, polyamine concentration varies little throughout the lactating period: spermine and spermidine concentrations in the human milk rise markedly during the first week post-partum [33,35] and show a tendency to decrease after 1–2 months of lactation [33,34]. However, a large individual variation in the polyamine concentration of breast milk has been reported, indicating that several mothers seem to produce milk having consistently quite high or quite low concentrations of putrescine, spermidine and spermine [33]. How this is due to the diet, the way of life or the genetic background of each mother is still to be established, even if, in rats, it was shown that the polyamine content of the milk can be increased by adding polyamines or precursors of these substances to drinking water [36].

Additionally, the role of human milk polyamines in intestinal cell growth was examined in vitro[37]. It was shown that human milk, but neither bovine milk nor infant formula, contains sufficient bioactive polyamines to sustain IEC-6 cell growth during inhibition of polyamine synthesis by DFMO.

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Epidemiological analysis

With the aim of evaluating the possible implications of breast milk polyamines for the health of babies, especially as preventive agents against allergy, an epidemiological study was performed to determine the correlation between the polyamine mean concentration of the maternal milk drunk during the first postnatal month and the appearance of allergy in children who drank this milk and were examined 5 years later [38]. Based on a logit model, analysis showed that the spermine concentration is the best variable for predicting the allergy appearance. The probability of developing an allergy reaches 80% if the spermine mean concentration in the milk is lower than 2 nmol/ml and is near 0% if the spermine mean concentration is higher than 13 nmol/ml. The critical value above which children have a reduced risk of allergy is 5.02 nmol spermine/ml of milk.

Recently, a similar study was undertaken to establish the relation between polyamine levels in human colostrum and mature milk and, on the other side, maternal atopy and atopic development in children [39]. In this study it appears that putrescine and spermine concentrations are lower in mature milk from atopic mothers than non-atopic mothers but no relationship is found between milk putrescine and spermine levels and the development of atopy in children, in contradiction with the results presented above [38]. Nevertheless, it has to be noticed that considerable differences exist between the two studies, which can explain these contradictory conclusions. Indeed, for example, in the second analysis mature milk was collected after more than 3 months of lactation and, secondly, the observation of atopy development in children was carried out during their first year of life.

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Polyamine food supplementation in growing animals

The nutritional efficacy and body growth potential of dietary polyamines were examined in different growing animal models. In chicks 1 week old, a putrescine enriched diet (0.2%), provided for 2 weeks, increases growth rate beyond that of controls [40]. This promoting effect is not observed at higher doses, the 0.8 and 1% supplements even being critical. Results observed after ingestion of a spermidine or spermine enriched diet, under the same conditions, are more questionable [41,42]. As little as 0.4% of supplemental spermidine or 0.2% of supplemental spermine inhibits growth. Lower concentrations have no significant effect on body weight gain. However, it is noticeable that spermidine administered at 0.6% promotes growth of the pancreas and of the duodenum during the first days of the treatment, indicating a modification of the functionality of these organs [41]. These results and those obtained in the neonatal rats (see above) show that we have to be careful when using diets supplemented with polyamines during the neonatal period, mainly because the precocious maturation induced by this kind of treatment, especially the acquisition of the adult enzymatic machinery, might make the digestive system unable to digest the food ingested during this period.

Otherwise, other experiments undertaken in calves and piglets have shown that putrescine, when added to a soybean protein diet, restores enterocyte proliferation and partially prevents reduction in nutrient absorption associated with soybean protein feeding [43,44]. This therapeutic effect of putrescine has also been demonstrated in chicks [45]. To our knowledge, no such study has been undertaken with spermidine or spermine enriched diets.

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Adult stage

Polyamines are well-known to be essential molecules for cell growth. Dietary and probably gut bacterial derived polyamines may contribute significantly to the polyamine body pool (see the article by V. Milovic in this Review). The function of these luminal polyamines was examined in normal, physiological growth in adult animals.

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Role of luminal polyamines in physiological growth

The role of luminal polyamines in physiological growth has been analysed either by introducing these substances in the lumen of the digestive tract or by suppressing their supply.

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Mucosal growth promotion

Several experiments suggest that, under normal conditions, polyamines may be important luminal stimulants of gastrointestinal mucosal growth. Indeed, infusion of putrescine in the ileal lumen of fasted rats, at the rate of 1 μmol/h for 66 h, produces a 150% increase in total mucosal DNA, RNA, and protein content of the organ at the site of infusion as well as at some distance from this point [46]. In vitro, it was also shown that this polyamine stimulates DNA, RNA and protein synthesis in cultured intestinal epithelial cells (IEC-6) [47]. Ingested spermine (20 μmol once a day for 2 days) also increases the mitotic index and the DNA content of the jejunal mucosa during fasting in adult rats (Deloyer et al., unpublished results). Otherwise, intragastric administration of spermidine or spermine at a dose of 4.5 mg each/100 g body weight for 6 days increases the normal rate of mucosal growth in the rat duodenum and jejunum as well [48]. However, another experiment showed that food intake and body weight gain are diminished in rats fed with 0.1% spermidine supplemented diet for 14 days [49].

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Polyamine deficient diets

The influence of polyamine deficient diets on growth and properties of different gastrointestinal organs has been evaluated in normally growing rats, with or without suppressing their gut bacterial flora, another source of luminal polyamines. A low polyamine diet given for 1 week to germ-free rats has little effect on intestinal functional parameters such as sucrase, maltase and lactase SAs [50]. The same diet administered for 2 months, again in germ-free conditions, induces mainly significant modifications in RNA content of the jejunal mucosa and of the liver as well as of the kidneys and of the lungs [51] (Deloyer et al., unpublished results). Finally, it was proven that long-term (6 months) feeding of polyamine deficient diet results in a significant hypoplasia of small intestinal and colonic mucosa [52].

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Possible therapeutic effects of luminal polyamines

Therapeutic potential of dietary or luminal polyamines has been investigated in different pathological models in animals.

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Gastric protection and healing

Administration of a single dose (4 or 8 μmol) of spermine by the oral route inhibits the histamine stimulated gastric acid secretion in rats, in a dose dependent manner [53]. In the same way, ingestion of polyamines prevents the gastric mucosal lesions produced by acidified ethanol in rats, the protective potency being spermine > spermidine > putrescine [54]. In rats stressed by water immersion and restraint, intragastric administration of polyamines (100 mg/kg), particularly of spermine, increases the normal rate of healing of the gastric mucosal ulcers induced by stress [55]. With the same model, it was shown that intragastric spermine (50 mg/kg) treatment also promotes DNA synthesis [56] and increases gastric microcirculation [57].

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Intestinal recovering and regeneration

Polyamine metabolism is known to intervene in intestinal healing and adaptation [58] but luminal polyamines have also been demonstrated to play a role in these processes. For example, as observed in the stomach, intragastrically administered spermine stimulates the rate of repair of stress induced damage in the duodenum [59]. Other experiments are indicative of the fact that dietary or luminal polyamines may be involved in intestinal healing. Polyamines provided via the ingestion of lyophilized Saccharomyces boulardii are believed to be responsible for the improved functional adaptation observed in enterectomized rats [60]. In an ischaemia–reperfusion rat model, mucosal regeneration does not depend on de novo synthesis of polyamines as DFMO treatment does not prevent intestinal repair, indicating that other sources of polyamines, among which luminal polyamines, may be mobilized [61].

In contrast, the promoting effect of luminal spermine on the healing of stress induced damage in the duodenum is even more clear if DFMO is administered to the stressed animals [59]. This is also observed in gut mucosal repair occurring after burn injury [62]. The process is inhibited by DFMO while concomitant spermidine gavage reverses the inhibitory action of DFMO. These results indicate that in the case of ODC deficiency (for example, in an ageing organism) dietary polyamines may be of importance in maintaining the healing capacity.

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Whole-body effect

The potential for dietary polyamines to significantly contribute to whole-body healing has also been explored. Recently, it was suggested that a 0.05% spermidine supplemented diet improves protein utilization efficiency and ameliorates trauma effects on amino acid levels in rats traumatized by fractures [63]. Otherwise, spermine ingestion can inhibit lipopolysaccharide-induced nitric oxide release as well as modulate the production of pro-inflammatory mediators [64].

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Conclusions

Dietary polyamines were considered for a long time as without interest, or even toxic. At present, it appears that these substances could play an important role in the prevention of allergy or of other diseases, in the maintaining of digestive tract functional properties and general healing capacity of the organism. Polyamine containing diet can be considered as functional food. Nevertheless, more studies are still needed to state very precisely the molecular mechanisms at the basis of dietary polyamine effects.

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Annotated references

 Of special interest

•• Of outstanding interest

1. •Bardócz S, Grant G, Brown DS, Ralph A, Pusztai A. Polyamines in food – implications for growth and health. J Nutr Biochem 1993; 4: 66–71. This paper presents numerous data about polyamine content in different foods and foodstuffs (British diet).
2. Okamoto A, Sugi E, Koizumi Y, Yanagida F, Udaka S. Polyamine content of ordinary foodstuffs and various fermented products. Biosci Biotech Biochem 1997; 61: 1582–1584.
3. Henning SJ. Postnatal development: coordination of feeding, digestion, and metabolism. Am J Physiol 1981; 241: G199–G214.
4. Iyngkaran N, Yadav M. Food allergy. In:Food Allergy. Immunopathology of the Small Intestine. Marsch MN (editor). New York: John Wiley and Sons Ltd; 1987. pp. 415–449.
5. Luk GD, Marton LJ, Baylin SB. Ornithine decarboxylase is important in intestinal mucosal maturation and recovery from injury in rats. Science 1980; 210: 195–198. These authors have shown that polyamine metabolism is implicated in the mucosal maturation of the intestine occurring at weaning.
6. ••Dufour C, Dandrifosse G, Forget PP, Vermesse F, Romain N, Lepoint P. Spermine and spermidine induce intestinal maturation in the rat. Gastroenterology 1988; 95: 112–116. First demonstration that polyamine ingestion induces precocious intestinal maturation in the suckling rat.
7. Dandrifosse G, Forget PP, Romain N, Deloyer P, Wéry I. Early maturation of rat intestine by spermine: results and prospects. In:Les Polyamines:Chimie, Biologie, Médecine. Moulinoux JP, Quémener V (editors). Paris: Flammarion; 1991. pp. 237–247 (in French).
8. ••Dandrifosse G, Peulen O, El Khefif N, Deloyer P, Dandrifosse AC, Grandfils C. Are milk polyamines preventive agents against food allergy? Proc Nutr Soc 2000; 59: 81–86. A complete review about dietary polyamines and postnatal development, based on investigations made in suckling rodents and in children.
9. Georges P, Dandrifosse G, Vermesse F, Forget PP, Deloyer P, Romain N. Reversibility of spermine-induced intestinal maturation in the rat. Dig Dis Sci 1990; 35: 1528–1536.
10. Buts JP, De Keyser N, Kolanowski J, Sokal E, Van Hoof F. Maturation of villus and crypt cell functions in rat small intestine. Role of dietary polyamines. Dig Dis Sci 1993; 38: 1091–1098.
11. Shimizu K, Mushiake S, Yoshimura N, Harada T, Okada S. The effect of spermine on the disaccharidase activities in suckling rats of different age. Cell Biol Int 1993; 17: 543–546.
12. Wild GE, Daly AS, Sauriol N, Bennett G. Effect of exogenously administered polyamine on the structural maturation and enzyme ontogeny of the postnatal rat intestine. Biol Neonate 1993; 63: 246–257.
13. Capano G, Bloch KJ, Schriffin EJ, Dascoli JA, Israel EJ, Harmatz PR. Influence of the polyamine, spermidine, on intestinal maturation and dietary antigen uptake in the neonatal rat. J Pediatr Gastroenterol Nutr 1994; 19: 34–42.
14. Harada E, Hashimoto Y, Syuto B. Orally administered spermine induces precocious maturation of macromolecular transport and disaccharidase development in suckling rats. Comp Biochem Physiol A 1994; 109: 667–673.
15. Dorhout B, van Faassen A, van Beusekom CM, Kingma AW, de Hoog E, Nagel GT. et al. Oral administration of deuterium-labelled polyamines to sucking rat pups: luminal uptake, metabolic fate and effects on gastrointestinal maturation. Br J Nutr 1997; 78: 639–654.
16. Peulen O, Pirlet C, Klimek M, Dandrifosse G. Comparison between the natural postnatal maturation and the spermine-induced maturation of the rat intestine. Arch Physiol Biochem 1998; 106: 46–55.
17. •ter Steege JC, Buurman WA, Forget PP. Spermine induces maturation of the immature intestinal immune system in neonatal mice. J Pediatr Gastroenterol Nutr 1997; 25: 332–340. First clear demonstration that oral intake of spermine promotes neonatal development of the intestinal immune system.
18. Peulen O, Deloyer P, Grandfils C, Loret S, Dandrifosse G. Intestinal maturation induced by spermine in young animals. Livestock Production Science 2000; 66: 109–120.
19. Gréco S, George P, Hugueny I, Louisot P, Biol MC. Spermidine-induced glycoprotein fucosylation in immature rat intestine. C R Acad Sci III 1999; 322: 543–549.
20. Gréco S, Hugueny I, George P, Perrin P, Louisot P, Biol MC. Influence of spermine on intestinal maturation of the glycoprotein glycosylation process in neonatal rats. Biochem J 2000; 345: 69–75.
21. •Péres A, Cahu CL, Zambonino Infante JL. Dietary spermine supplementation induces maturation in sea bass (Dicentrachus labrax) larvae. Fish Physiol Biochem 1997; 16: 479–485. Spermine-induced intestinal maturation is not only observed in mammals but also in a fish species.
22. Wéry I, Deloyer P, Dandrifosse G. Effects of a single dose of orally-administered spermine on the intestinal development of unweaned rats. Arch Physiol Biochem 1996; 104: 163–172.
23. •Wéry I, Kaouass M, Deloyer P, Buts JP, Barbason H, Dandrifosse G. Exogenous spermine induces maturation of the liver in suckling rats. Hepatology 1996; 24: 1206–1210. Oral intake of spermine promotes precocious maturation of digestive organs other than the intestine, e.g. the liver.
24. •Romain N, Gesell MS, Leroy O, Forget PP, Dandrifosse G, Luk GD. Effect of spermine administration on pancreatic maturation in unweaned rats. Comp Biochem Physiol A 1998; 120: 379–384. Oral intake of spermine promotes precocious maturation of digestive organs other than the intestine, e.g. the pancreas.
25. Peulen O, Grandfils C, Dandrifosse G. Maturation of the small intestine is induced by spermine but not by other similar amines. Pflügers Arch – Eur J Physiol 2000; 440: R253.R253.
26. Etienne-Poncin A, Dandrifosse G, Forget PP, Lepoint A. Evolution of biochemical characteristics of the intestinal mucosa during the first postnatal weeks in C57 mice. Effects of thyroxine and putrescine. J Pediatr Gastroenterol Nutr 1989; 9: 375–382.
27. Deloyer P, Nollet N, Dandrifosse G. Spermine-induced intestinal maturation in the suckling rat: effect of prolonged oral treatment. Pflügers Arch – Eur J Physiol 2000; 440: R247.R247.
28. Kaouass M, Deloyer P, Dandrifosse G. Intestinal development in suckling rats: direct or indirect spermine action? Digestion 1994; 55: 160–167.
29. Kaouass M, Sulon J, Deloyer P, Dandrifosse G. Spermine-induced precocious intestinal maturation in suckling rats: possible involvement of glucocorticoids. J Endocrinol 1994; 141: 279–283.
30. Kaouass M, Deloyer P, Gouders I, Peulen O, Dandrifosse G. Role of interleukin-1 beta, interleukin-6 and TNF alpha in precocious intestinal maturation induced by dietary spermine in suckling rats. Endocrine 1997; 6: 187–194.
31. Peulen O, Dandrifosse G. Cyclosporin A inhibits partially spermine induced differentiation but not cell loss of suckling rat small intestine. Dig Dis Sci 2000; 45: 750–754.
32. Kaouass M, Deloyer P, Dandrifosse G. Involvement of bombesin in spermine-induced corticosterone secretion and intestinal maturation in suckling rats. J Endocrinol 1997; 153: 429–436.
33. Romain N, Dandrifosse G, Jeusette F, Forget PP. Polyamine concentration in rat milk and food, human milk and infant formulae. Pediatr Res 1992; 32: 58–63.
34. Pollack PF, Koldovsky O, Nishioka K. Polyamines in human and rat milk and in infant formulas. Am J Clin Nutr 1992; 56: 371–375.
35. Buts JP, De Keyser N, De Raedemaeker L, Collette E, Sokal EM. Polyamine profiles in human milk, infant formulas and semi-elemental diets. J Pediatr Gastroenterol Nutr 1995; 21: 44–49.
36. Peulen O, Dandrifosse G. Effect of dietary polyamines and amino-acids on polyamines content of the rat milk. In:Biogenically Active Amines in Food: Metabolism and Physiology, Vol VI. Morgan D, Dandrifosse G (editors). Luxembourg: EC Publication (in press).
37. Capano G, Bloch KJ, Carter EA, Dascoli JA, Schoenfeld D, Harmatz PR. Polyamines in human and rat milk influence intestinal cell growth in vitro. J Pediatr Gastroenterol Nutr 1998; 27: 281–286.
38. •Peulen O, Dewé W, Dandrifosse G, Henrotay I, Romain N. The relationship between spermine content of human milk during the first postnatal month and allergy in children. Public Health Nutr 1998; 1: 184–188. A very important, even if preliminary, statistical study indicating a negative correlation between spermine content of human milk and the appearance of allergies in children of 5 years old having drunk this milk.
39. Duchén K, Thorell L. Nucleotide and polyamine levels in colostrum and mature milk in relation to maternal atopy and atopic development in the children. Acta Paediatr 1999; 88: 1338–1343.
40. Smith TK. Effect of dietary putrescine on whole body growth and polyamine metabolism. Proc Soc Exp Biol Med 1990; 194: 332–336.
41. Smith TK, Mogridge JL, Sousadias MG. Growth-promoting potential and toxicity of spermidine, a polyamine and biogenic amine found in foods and feed stuffs. J Agric Food Chem 1996; 44: 518–521.
42. Sousadias MG, Smith TK. Toxicity and growth-promoting potential of spermine when fed to chicks. J Anim Sci 1995; 73: 2375–2381.
43. Grant AL, Holland RE, Thomas JW, King KJ, Liesman JS. Effects of dietary amines on the small intestine in calves fed soybean protein. J Nutr 1989; 119: 1034–1041.
44. Grant AL, Thomas JW, King KJ, Liesman JS. Effect of dietary amines on small intestinal variables in neonatal pigs fed soy protein isolate. J Anim Sci 1990; 68: 363–371.
45. Mogridge JL, Smith TK, Sousadias MG. Effect of feeding raw soybeans on polyamine metabolism in chicks and the therapeutic effect of exogenous putrescine. J Anim Sci 1996; 74: 1897–1904.
46. Seidel ER, Haddox MK, Johnson LR. Ileal mucosal growth during intraluminal infusion of ethylamine or putrescine. Am J Physiol 1985; 249: G434–G438.
47. Ginty DD, Osborne DL, Seidel ER. Putrescine stimulates DNA synthesis in intestinal epithelial cells. Am J Physiol 1989; 257: G145–G150.
48. Wang JY, McCormack SA, Viar MJ, Johnson LR. Stimulation of proximal small intestinal mucosal growth by luminal polyamines. Am J Physiol 1991; 261: G504–G511.
49. Jeevanandam M, Holaday NJ, Begay CK, Petersen SR. Nutritional efficacy of a spermidine supplemented diet. Nutrition 1997; 13: 788–794.
50. Deloyer P, Dandrifosse G, Bartholomeus C, Romain N, Klimek M, Salmon J. et al. Polyamines and intestinal properties in adult rats. Br J Nutr 1996; 76: 627–637.
51. Deloyer P, Peulen O, Klimek M, Remacle R, Focant C, Dandrifosse G. Effects of a long-term low-polyamine diet on biochemical parameters and polyamine content in different organs of the germ-free rat. In:Biogenically Active Amines in Food. Metabolic Effects of Biologically Active Amines in Food, Vol II. Bardócz S, White A, Hajós G (editors). Luxembourg: EC Publication; 1998. pp. 130–135.
52. •Löser C, Eisel A, Harms D, Fölsch UR. Dietary polyamines are essential luminal growth factors for small intestinal and colonic mucosal growth and development. Gut 1999; 44: 12–16. This study shows clearly that dietary polyamine deprivation, if applied for 6 months, induces atrophy of intestinal mucosa.
53. •Nandi J, Wright MV, Fromm D, Ray TK. Oral administration of spermine inhibits gastric acid secretion in rats. Dig Dis Sci 1983; 28: 513–517. One of the first papers suggesting a therapeutic potential for dietary polyamines, spermine being completely ineffective when injected by the intravenous route.
54. Mizui T, Shimono N, Doteuchi M. A possible mechanism of protection by polyamines against gastric damage induced by acidified ethanol in rats: polyamine protection may depend on its antiperoxidative properties. Jpn J Pharmacol 1987; 44: 43–50.
55. Wang JY, Johnson LR. Luminal polyamines stimulate repair of gastric mucosal stress ulcers. Am J Physiol 1990; 259: G584–G592.
56. Brzozowski T, Konturek SJ, Majka J, Dembinski A, Drozdowicz D. Epidermal growth factor, polyamines, and prostaglandins in healing of stress-induced gastric lesions in rats. Dig Dis Sci 1993; 44: 276–283.
57. Konturek PC, Brzozowski T, Konturek SJ, Szlachcic A, Hahn EG. Polyamines and epidermal growth factor in the recovery of gastric mucosa from stress-induced gastric lesions. J Clin Gastroenterol 1998; 27: S97–S104.
58. Luk GD, Yang P. Polyamines in intestinal and pancreatic adaptation. Gut 1987; 28 (suppl) : 95–101.
59. Wang JY, Johnson LR. Luminal polyamines substitute for tissue polyamines in duodenal mucosal repair after stress in rats. Gastroenterology 1992; 102: 1109–1117.
60. Buts JP, De Keyser N, Marandi S, Hermans D, Sokal EM, Chae YH. et al. Saccharomyces boulardii upgrades cellular adaptation after proximal enterectomy in rats. Gut 1999; 45: 89–96.
61. Kummerlen C, Seiler N, Galluser M, Gossé F, Knodgen B, Hasselmann M. et al. Polyamines and the recovery of intestinal morphology and function after ischemic damage in rats. Digestion 1994; 55: 168–174.
62. Chung DH, Evers BM, Townsend CM Jr, Huang KF, Herndon DN, Thompson JC. Role of polyamine biosynthesis during gut mucosal adaptation after burn injury. Am J Surg 1993; 165: 144–149.
63. •Jeevanandam M, Holaday NJ, Begay CK, Petersen SR. Amelioration of the protein metabolic response in spermidine-supplemented trauma rats. Metabolism 1998; 47: 223–229. This interesting paper presents possible therapeutic effects of dietary polyamines considering the whole-body functioning.
64. ter Steege JC, Forget PP, Buurman WA. Oral spermine administration inhibits nitric oxide-mediated intestinal damage and levels of systemic inflammatory mediators in a mouse endotoxin model. Shock 1999; 11: 115–119.
Keywords:

adult; food allergy prevention; healing; maturation; postnatal, regeneration

© 2001 Lippincott Williams & Wilkins, Inc.