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Gut Check: Polyamines in Human Milk Are Essential for Intestinal Maturation

    3D model of polyamines

    Written by: Lauren Milligan Newmark, Ph.D. | Issue # 62 | 2017

    • Polyamines are amino acid-derived molecules found in all living cells and the milk of all mammals, including humans.
    • Human milk polyamine concentration is highest during the first weeks of lactation and varies across mothers.
    • Milk polyamines are essential for optimal maturation of the neonatal gut.

    Putrescine, spermine, and spermidine may not have the most appetizing names, but these amino acid-derived molecules (called polyamines) are ingredients of all mammal milks. The presence of polyamines in milk is not surprising—putrescine, spermine, and spermidine are manufactured by all mammalian body cells, including mammary tissue. But polyamines are not accidental milk ingredients, passed on simply because they are ubiquitous in mammalian cells. Research from human and non-human animal models demonstrates that optimal nutrient absorption, the composition of the intestinal microbiome, and even food allergy may all depend on a sufficient supply of polyamines during the neonatal period [1–11]. Milk polyamines, although odd in name, are essential for the proper maturation of the gastrointestinal tract in humans and other mammals.

    Making Polyamines

    Amino acids, the building blocks of proteins, are comprised of a carboxyl group and an amine group. Polyamines, as the name suggests, are composed of two or more amine groups. All living cells synthesize polyamines, and mammalian cells make three—putrescine, spermidine, and spermine—by removing the carboxyl groups from the amino acids methionine and ornithine [1].

    In mammals, polyamines are involved in numerous functions within cells: they influence cellular growth, cellular differentiation, and the function of cell membranes, and also play a role in protein synthesis by regulating DNA and messenger RNA [1, 2]. Although all cells in a mammal’s body can synthesize polyamines, the importance of a sufficient dietary supply to maintain essential physiological functions indicates that cellular polyamine requirements exceed the body’s manufacturing capabilities [5, 7]. In this sense, polyamines are considered essential nutrients, just like certain amino acids, vitamins, and fatty acids [8].

    The body’s polyamine requirements vary over time and are at their highest during growth periods, like infancy, which is characterized by rapid and widespread cellular proliferation [2]. Thus, the infancy period is a time when a sufficient dietary supply of polyamines may be especially critical.

    Polyamines are present in all mammalian milks, and although the concentration varies across species (e.g., human milk has higher values than cow milk), all milks peak in polyamine concentration during early lactation [1, 2]. For example, in human milk, polyamines increase in concentration during the first two weeks of lactation, reach their maximum value during the first month, and then decrease [1]. These changes in concentration are believed to be due to the action of the lactation hormone prolactin, which augments mammary gland synthesis of polyamines [2,8].

    That milk from cows, rats, pigs, and humans all peak in polyamine concentration at the same stage of lactation indicates an important functional role for these molecules during this period. But if it were simply about growth (making new cells), polyamines would be important throughout lactation. Why are polyamines so important for newborn mammals?

    A Gut Feeling

    Mammals vary in developmental maturity at birth; some are born altricial requiring significant parental investment, whereas others are more developmentally mature, or precocial. One thing they all have in common, however, is the consumption of milk as a first food. During the neonatal period, the mammalian gastrointestinal tract undergoes rapid maturation in preparation for the introduction of non-milk foods. Polyamine ingestion from milk is believed to have an essential role in this accelerated development of the small and large intestines.

    To understand and identify specific functions of polyamines in mammalian infants, scientists performed experiments on non-human animals that included study groups that did not receive any polyamines—what better way to figure out what something does than to observe what happens when you take it away.

    The earliest studies (during the 1990s) focused on rat models and found that rat pups receiving formula supplemented with polyamines (specifically spermine and spermidine) had several physiological differences relating to gut maturation compared with controls that consumed fewer or no polyamines. Key differences included heightened enzymatic activity of the gut (including enzymes responsible for protein digestion) and decreased gut permeability to macromolecules [reviewed in 5].

    Taken together, these observations led Dandrifosse and colleagues [5] to propose that polyamines play a role in the development of food allergy. Because food proteins are the source of food allergies, improved protein digestion (via increased protein-digesting enzyme activity) coupled with a less permeable gut, reduces the potential for food antigens to make their way into the bloodstream and to come in contact with the immune system. Infants with more permeable guts due to reduced polyamine intake (particularly spermine) would thus be at a higher risk for developing food allergies [5].

    Dandrifosse and colleagues tested their hypothesis in a small sample (n = 45) of human subjects. First, milk samples were collected from mothers and analyzed for polyamine concentration. Five years later, all mothers were contacted and sent a questionnaire requesting information about environmental and food allergies in their child. They found that breastfed children with an allergy at age 5 consumed milk with lower polyamine concentration than those without allergies. They even established what they believed was a “critical value” below which children have an increased risk of allergy (5.02 nmol/ml) [5].

    Researchers have long grappled with the question of whether breastfeeding is protective against allergy. Whereas several studies have found decreased risk associated with breastfeeding, many have found the risk factors are identical between the formula- and breastfed infants. This study [5] helps to make sense of those contradictory findings by highlighting the differences in risk associated with breastfeeding alone. Some mothers produce milk with relatively high concentrations of spermine and spermidine with little to no risk of producing allergy, whereas others produce milk with lower concentrations more similar to those found in formula, which has a probability of producing a food allergy that is believed to be closer to 80% [2,5].

    Infant formula is made from soy or cow milk, which can explain the lower concentration of polyamines compared with breast milk [9]. But what can explain the variation in breast milk polyamine concentration among human mothers? Several lines of evidence suggest that the polyamine composition of the maternal diet influences milk polyamine concentration. Citrus fruits, such as oranges and grapefruit are high in putrescine, whereas beans and meat are good sources of spermine and spermidine [8]. However, polyamines are found in so many different types of foods that it is difficult to determine a particular dietary pattern that may result in higher polyamine intake.

    Gómez-Gallago et al. [4] found significant differences in the concentration of milk putrescine and spermidine (but not spermine) across four different human populations (Finland, Spain, China, and South Africa), which they attributed to dietary differences across cultures. Atiya Ali et al. demonstrated this relationship with a more detailed study [7], wherein breastfeeding mothers of newborns kept a 3-day food diary. After calculating daily intake of all three polyamines, they found that the concentration of putrescine, spermidine, and spermine in milk were all significantly associated with their concentration in the diet.

    In another study, Atiya Ali et al. [8] found that obese mothers produced significantly lower levels (14%) of putrescine and spermidine (but again, not spermine) compared with mothers with a healthy body mass index. Although obesity itself could be a contributing factor to milk polyamine levels, they observed that obese mothers that received nutritional counseling and advice during the study period increased their milk polyamine levels to those matching healthy controls. This finding suggests it is not what the mother has eaten in the past, but what the mother is currently consuming that determines milk polyamine concentration. Except, perhaps, for spermine, the very polyamine implicated in gut permeability.

    All three studies [4,7,8] concluded that spermine appears less susceptible to environmental influences. However, interpretations of results are complicated by the fact that polyamines can be interconverted by the infant (putrescine is a precursor to spermine and spermidine, and can be broken down to make either polyamine; spermine and spermidine can also be converted back into putrescine). Thus, the total content of polyamines in milk should be the metric of interest.

    Growing the Gut

    Two recent animal studies have provided more detailed evidence of the potential health outcomes associated with low milk polyamine concentration [6,10]. Van Wettere et al. [10] were interested in the relationship between milk polyamines and the development of the absorptive, or mucosal, surface of the intestines (that is, the surface where the food meets the intestinal cells). The mucosal surface of the intestines looks a bit like a rollercoaster, with a series of peaks (called villi) and valleys (called crypts). It is along this surface that nutrients (including proteins, fats, carbohydrates, vitamins and minerals) are absorbed into the intestines for eventual transfer into the bloodstream. This roller coaster-like structure is a rather ingenious way of getting more surface area for nutrient absorption; the higher the peaks and the deeper the valleys, the more cells for food to contact for absorption. Van Wettere et al. [10] found that piglets supplemented with spermine every other day over a 10-day period had an increase in the surface area of their gastrointestinal tract. And the increase was significant; spermine supplementation was associated with a 41% increase in villus height (the peaks) and a 21% decrease in crypt depth (the valleys) along the small intestine [10]. Importantly, the investigators were able to link the changes in the intestinal surface area with improved growth both during supplementation and after weaning [10]. Higher hills and lower valleys meant improved nutrient absorption, which they argue was critical in helping the piglets maintain optimal growth rates as they transitioned from milk to non-milk foods.

    The surface area of the intestines is not the only thing in the gut that milk polyamines help to grow—these molecules are also growth factors for the healthy bacteria that populate the gastrointestinal tract. In a new study, Gómez-Gallago and colleagues [6] found that newborn mice consuming polyamine-supplemented formula had bacterial communities similar to those of mice consuming their mother’s milk, validating their results from a previous study [11]. Because of the strong connection between the development of a healthy gut microbiome and immune function, their new study went one step further and investigated the types of lymphocytes (cells of the immune system) that populated the gut as well as genes related to immune activity within the gut. Again, mice fed the supplemented formula were grouped statistically closer to the suckling mice than those consuming formula without polyamines [6].

    It is intriguing to think that human infants would have identical responses to polyamine supplementation as the piglets and mouse pups in the experimental models. Optimal intake levels of polyamines for human infants have not been established. However, both studies [6,10] found significant results using concentrations of polyamines that were lower than those in mouse or pig milk, indicating that human breast milk concentrations could be a helpful signpost for determining an appropriate concentration. Could something as simple as polyamine supplementation in formula (or increased polyamine consumption in the diet of breastfeeding mothers) help resolve health issues associated with food allergy, nutrient absorption, or the intestinal microbiome? Gómez-Gallago et al. [6] suggest this question is important enough to go “one step forward” by reproducing their experiments using human subjects.

    1. Löser, C., 2000. Polyamines in human and animal milk. British Journal of Nutrition, 84(S1): 55-58.
    2. Larqué, E., Sabater-Molina, M., Zamora, S., 2007. Biological significance of dietary polyamines. Nutrition, 23(1): 87-95.
    3. Plaza-Zamora, J., Sabater-Molina, M., Rodriguez-Palmero, M., Rivero, M., Bosch, V., Nadal, J.M., Zamora, S., Larque, E., 2013. Polyamines in human breast milk for preterm and term infants. British Journal of Nutrition, 110(03): 524-528.
    4. Gómez-Gallego C, Kumar H, García-Mantrana I, du Toit E, Suomela JP, Linderborg KM, Zhang Y, Isolauri E, Yang B, Salminen S, Collado MC., 2017. Breast milk polyamines and microbiota interactions: Impact of mode of delivery and geographical location. Annals of Nutrition and Metabolism, March 17.
    5. Dandrifosse, G., Peulen, O., El Khefif, N., Deloyer, P., Dandrifosse, A.C.  Grandfils, C., 2000. Are milk polyamines preventive agents against food allergy?. Proceedings of the Nutrition Society, 59(01): 81-86.
    6. Gómez-Gallego C., Garcia Romo M., Frias R., Periago, M.J., Ros, G., Salminen S., Collado M.C., 2017. Mice exposed to infant formula enriched with polyamines: impact on host transcriptome and microbiome. Food & Function.
    7. Atiya Ali, M., Strandvik, B., Sabel, K.G., Palme Kilander, C., Strömberg, R. Yngve, A., 2014. Polyamine levels in breast milk are associated with mothers’ dietary intake and are higher in preterm than full‐term human milk and formulas. Journal of Human Nutrition and Dietetics, 27(5): 459-467.
    8. Atiya Ali, M., B. Strandvik, C. Palme‐Kilander, A. Yngve., 2013. Lower polyamine levels in breast milk of obese mothers compared to mothers with normal body weight. Journal of Human Nutrition and Dietetics 26 (s1): 164-170.
    9. Buts, J. P., De Keyser, N., De Raedemaeker, L., Collette, E., & Sokal, E. M., 1995. Polyamine profiles in human milk, infant artificial formulas, and semi-elemental diets. Journal of pediatric gastroenterology and nutrition, 21(1): 44-49.
    10. van Wettere, W.H.E.J., Willson, N.L., Pain, S.J., Forder, R.E.A., 2016. Effect of oral polyamine supplementation pre-weaning on piglet growth and intestinal characteristics. animal (Oct 1): .1-5.
    11. Gómez -Gallego C., Collado, M.C., Perez, G., Ilo, T., Jaakkola, U.M., Bernal, M.J., Periago, M.J., Frias, R., Ros, G., Salminen, S., 2014. Resembling breast milk: influence of polyamine-supplemented formula on neonatal BALB/cOlaHsd mouse microbiota. Br J Nutr 111: 1050-1058.

    Photo credit: A Polyamine (image by SubDural12 is licensed under CC by 2.0)