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 . 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.
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 , 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 .
The role of polyamine metabolism in the maturation of the intestine was discovered by Luk et al., in 1980 . 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. 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].
Intestinal maturation induced by dietary polyamines
Oral intake of polyamines by immature animals induces modifications of different parameters characterizing the intestine.
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 , 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 . Additionally, other intestinal enzymes, such as aminopeptidase , Na+,K+-ATPase , N-acetylglucosaminidase  and alkaline phosphatase , 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 . 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.
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  and length  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 .
Otherwise, many authors have shown that, in suckling rats, ingestion of spermine [6,9,11,13,14,16] or spermidine  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 . A reduction in the neonatal intestinal Fc receptor concentration is also observed in spermidine fed pups .
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 . 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 . A ‘maturational’ effect was also observed in the same experimental conditions in the spleen (Peulen et al., personal communication).
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) . 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 . 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.
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 . Spermine induced maturation is reversible when the treatment is stopped . Surprisingly, partial reversibility is also observed when spermine administration is prolonged for more than 3 days .
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 . In the same way, intraperitoneal injection of spermine has a slight effect on maturation of the liver . Complementary to these results, it was shown that spermine given orally induces the secretion of adrenocorticotrophic hormone (ACTH)  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 .
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 . 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.
Polyamines in milk
As allergy problems seem to be less frequent in breast fed children when compared with bottle fed infants , 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 . 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 .
Additionally, the role of human milk polyamines in intestinal cell growth was examined in vitro. 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.
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 . 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 . 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 . 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.
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 . 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 . 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 . To our knowledge, no such study has been undertaken with spermidine or spermine enriched diets.
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.
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.
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 . In vitro, it was also shown that this polyamine stimulates DNA, RNA and protein synthesis in cultured intestinal epithelial cells (IEC-6) . 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 . 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 .
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 . 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  (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 .
Possible therapeutic effects of luminal polyamines
Therapeutic potential of dietary or luminal polyamines has been investigated in different pathological models in animals.
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 . 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 . 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 . With the same model, it was shown that intragastric spermine (50 mg/kg) treatment also promotes DNA synthesis  and increases gastric microcirculation .
Intestinal recovering and regeneration
Polyamine metabolism is known to intervene in intestinal healing and adaptation  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 . 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 . 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 .
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 . This is also observed in gut mucosal repair occurring after burn injury . 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.
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 . Otherwise, spermine ingestion can inhibit lipopolysaccharide-induced nitric oxide release as well as modulate the production of pro-inflammatory mediators .
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.
• Of special interest
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