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The importance of nucleotides in physiological processes

 

Ribonucleic Acid: the precursor

Ribonucleic acid is the molecule that transmits genetic information during cellular duplication phase. The function of this molecule is to “copy” DNA Nucleotides sequences, in order to transmit the information to the new cells. Nucleic acids cover a primary role in the transmission of genetic information and in the cellular synthesis. Multiplication rate naturally changes because of different physiological phases, tissue type and nutrients availability.

 

Rna and nucleotides - Nucleotides basis of DNA.

Fig. 1. Thymine, Adenine Thymine, Adenine, Guanine and Cytosine are the Nucleotides basis of DNA. Uridine, Adenine, Guanine and Cytosine are the Nucleotides basis of RNA

 

What are Nucleotides?

Nucleotides are the constitutive units of DNA and RNA Nucleic Acids. Nucleotides are true nutraceuticals or functional ingredients frequently used to improve the disease resistance, to decrease mortality and to promote the growth rate. They are widely utilized in clinical nutrition, in mother milk substitutes and in some integrators. Nucleotides participate to different important physiological processes in the body.  As carriers, they allow the transport of ATP the main energetic molecule for the living cells. Moreover, they play a focal role in several enzymatic reactions, affecting proteins, fats and carbohydrates metabolism which together essential amino represent a key factor in the protein synthesis.

 

How benefit from nucleotides use

De-novo synthesis does not satisfy the Nucleotides requirements of many tissues and particular life physiological phases, making necessary a reinforcement by dietary source. Particularly, some cells at high turn-over rate, such as gut and immune system ones (lymphocytes, erythrocytes and bone marrow cells) are not able to produce enough Nucleotides to cover their needs. Numerous studies demonstrated that the inclusion of a suitable quantity of RNA or Nucleotides in the diet is of primary importance to face critical steps, such as the growing period and during the recovering after diseases problems. Studies carried out on humans have shown that dietary inclusion of RNA and nucleotides bring about different positive effects on different body tissues. The main are the following:

Nucleotides: dietary inclusion of RNA and nucleotides bring about different positive effects on different body tissues.

Fig. 2 Need exogenous nucleotides

 

Immune system

Nucleotides show a positive effect on the immune system acting on two sides: the humoral immune response and the cell-mediated response. For what concerns the first side, Nucleotides promote the lymphocytes B antibodies production (especially IgM), directly related to the dosage supplied. Nucleotides dietary intake positive influences the local immune response, as indicated by IgA higher production.

Nucleotides promote the lymphocytes B antibodies production (especially IgM)

Coming to the cell-mediated immune response, Nucleotides stimulate the proliferation, differentiation and maturation of neutrophils, increasing the pathogens resistance.

Nucleotides stimulate the proliferation, differentiation and maturation of neutrophils

Furthermore, Nucleotides promote the proliferation of bone marrow cells, stimulate the production and secretion of interleukin-2 and interferon gamma and increase the cyto-toxicity of the natural killer cells.

Nucleotides increase the cyto-toxicity of the natural killer cells.

 

The usage of Nucleotides, alone or in combination with pharmaceuticals, is very effective in case of chemotherapy, immuno-suppressive pathologies and organs transplantation. Treatment of Candida, Staphylococcus aureus and Cryptosporidiosis infections shown major effect.

 

 

Recent studies about RNA and Nucleotides immune properties

In 2007 on British Journal of Nutrition has been published a meta-study which demonstrated that feeding infants with Nucleotides is associated to a better anti-bodies response to the vaccines Haemopillus influenza (P=0.001), diphtheria toxoid (P=0,001), oral antipolio vaccine (P=0,001). The data confirm the positive effects of Nucleotides inclusion without risk correlated. 9 studies conducted between 1991 and 2006 with low dosage (12-35 mg/L) and 6 studies between 1998 and 2004 with high dosage of nucleotides in the diet (72 mg/L) have registered an improvement of immune parameters and less diarrhoea events, with lower performances with mother milk feeding only. In 2001, 2003, 2007 some studies collected and elaborated the results on different clinical experimentations conducted on several hospitalized subjects and feed with enteral foods.

Many single studies and at least five meta-studies about the combination of different immune-modulating components, among which Nucleotides, gave positive homogeneous results.

In particular a study conducted on 22 experimentations that involved approx. 2000 patients, demonstrated a positive connection between enteral nutrition with integration of immune-modulating substances (nucleotides, arginine, omega-3, glutamine) and the decrease of complications due to infections. In 2003, a study reported that in patients with gastro-intestinal tumour, the pre and post operation nutrition with immune factors (RNA and Nucleotides) has reduced the gastro-intestinal side effects in post operation phase.

 

Gastro-intestinal beneficial effects

Dietary Nucleotides act as “growth factors” on the gut cells, promoting their differentiation and maturation: a higher thickness of intestinal mucosa and of villi and an increased activity of the digestive enzymes are subsequent to the benefit on the intestinal cells. Beside higher villi surface and crypts depth increase upon inclusion of Nucleotides in the diet.

Different studies have shown a higher nutrients intestinal absorption, specifically Calcium, Phosphorous and carotenoids.  Besides, Nucleotides act improving intestinal immune defences and promoting bacteria growth, mostly Lactobacilli and Bifidobacteria to the detriment of the Gram-negative bacteria, responsible of enteritis like Escherichia Coli. Immediate results are a higher disease and infections resistance, besides a more rapid recovery of enteritis and nutritional or protein privation.

Recent meta-studies on different clinical researches pointed out less diarrhoea events and an improvement of the composition of intestinal flora in comparison with subjects fed with milk not added with Nucleotides. Various in vitro studies demonstrated the beneficial Nucleotides effect on Bifidobacteria. The reason of this effect could be due to the increase of ion Iron absorption, ion that promotes the development of Enterobacteria in the intestine and the fact that Nucleotides are a growth factor for Bifidobacteria, although overall, Nucleotides are absorbed as Nucleosides in the first gut tract. It seems that a percentage of approx. 10% of the dietary Nucleotides is present in the colon and there exercises its growing effect on Bifidobacteria. A Nucleotides rich diet is very useful in the clinical and functional recovery of hepatic infections; actually, after hepatic intoxications, fibrosis and cirrhosis, the entity of the damage is lower and the recovery is faster. The facts are that Nucleotides promote the hepatic activity, speeding up the protein synthesis, the glucose deposit, stopping cholesterol and other lipids storage.

 

Learning and memory improvement

The cerebral cells are not able to synthesize Nucleotides; therefore, the dietary supply is focal for the central nervous system. Nucleotides stimulate the glial cells proliferation, promote the cerebral vascular circulation and improve the lipid metabolism of the cerebral cortex. As consequence memory and learning improvements are naturally occurring, overall in elderly subjects.

 

Where to use Rna and Nucleotides

Infant formula a mother milk replacement

Maternal milk composition is one of the primary reference point for the formulation of infant foods. Data of maternal milk Nucleotides content are often not in accordance as they change because of the used analytical method, the lactation phase and whether RNA or nucleosides content is included or not in the calculation. Maternal mature milk contains around 10 mg/L total Nucleotides present in different ratio depending of lactation phase, while bovine milk contains less Nucleotides and in different ratio, furthermore its heat treatment degrades the most of Nucleotides. Nucleotides addition to infant milk is nowadays common for most of the market leaders and represents a standard supplementation in nutrition of new born up to 6 months age and even further.

 

Enteral clinical nutrition

The feeding of hospitalized patients it is very important, above all in critical situations as intensive therapy and post-surgery recovery. The enrichment of enteral feeding with ingredients as Nucleotides, amino acids, fatty acids, omega-3 represents an effective support for the restore of the functionality of gastro-intestinal tract and to the stimulation of immunity response. From the 1960 the characterization of the primary role developed by intestinal tract for the immunity response, determined a strong research in the pharmaceutical sector of the “most adapt formulation” for every specific clinical case and shelter phase.

Nestlè-Novartis, Mead Johnson, Abbott are names of the main pharmaceutical factories engaged in the research, formulation and production of enteral nutrition preparations. A large numbers of recent clinical study, demonstrate the advantages of enriched and complete formulations use in comparison with standard-protein ones, utilized sometimes in pre-shelter phase. The main are:

  • Infections decrease
  • A better post-operation recover and in case of diseases
  • Shelter duration decrease

 

Dietary supplements

The new frontier of Nucleotides application is dietary supplements as immune-nutrients. The use of industrially produced foods changed the nutrition pattern. Allergies, intolerances and metabolic disease rapidly grew in last decades, drawing more and more life quality, public and family sanitary cost. Foods composition and education strongly connect with these changes. We hope that all the operators can use the clinical studies to verify RNA and Nucleotides functional properties in different operating conditions  and then offer to the consumers an effective support for a more complete and balanced nutrition.  On the market, we can find RNA and Nucleotides capsules apt to increase immunity response, digestive function and intestine health treating diarrhoea.

The dosages are obtained by studies conducted on the estimate of consumes in the first pregnancy and for adults subjects are approx. 50 – 200 mg/d of single Nucleotides based on age and physiological statement.

 

Aquaculture

There is a clear demonstration that Nucleotides addition to aquaculture diet improves the health of fishes, the resistance to different bacterial infections, limiting the diffusion of diseases, that, in these types of breeding, cause huge economic damages. Nucleotides have also an intensive anti-stress action, which has a particular positive effect in any intensive breeding.

 

LEGISLATION REFERENCES

 

Infant formula

European Directive 2006/141/CE allows the use Nucleotides in infant milk at the maximum dosage of 5 mg/100 kcal

In the United States, Life Sciences Research Office (LSRO) allows to use until 16 mg/100 kcal (www.lsro.org). Italian Department of Health allows the use of Nucleotides in the production of supplements and regulates the composition of infant formula under the Decree nr 62 of April 9, 2009 (www.salute.gov.it). Claim requests for different functional properties related to the use of Nucleotides are under EFSA scrutiny.

Dietary supplements

Italian Department of Health allows using Nucleotides in the production of supplements (on the website www.salute.gov.it there is the list of the substances with nutritive and physiological effects admitted for in dietary supplements).EFSA is examining some claims requests for different functional properties related to the use of Nucleotides.

 

Bibliografy

  • Singhal A., Macfarlane G., Macfarlane S., Lanigan J., Kennedy K., Elias-John A., Stephenson T., Dudek P., Lucas A.,  Dietary nucleotides and fecal microbiota in formula-fed infants: a randomized controlled trial, Am. J. Clin. Nutr. 2008:87:1785-92. Printed in USA 2008 American Society for Nutrition.

  • Martindale R.G., Zhou M., Immune-modulating enteral formulations: optimum conponents, appropriate patients, and controversial use of arginine in sepsis, Curr Gastroeneterol. Rep. 2007 Aug; 9(4):329-37.

  • Schaller J.P., Buck R.H., Rueda R., Ribonucleotides: conditionally essential nutrients shown to enhance iimmune function and reduce diarrheal disease in infants, Semin Fetal Neonatal Med. 2007 Feb;12(1):35-44. Epub 2006 Nov 30. Erratum in Semin Fetal Neonatal Med. 2007 Aug;12(4):326-8.

  • Gutiérrez-Castrellòn P., Mora-Magaña I., Diaz-Garcia L., Jiménez-Gutiérrez C., Ramirez-Mayans J., Solomon-Santibáñez G.A.,  Immune response to nucleotide-supplemented infant formulae: systematic review and meta-analysis, Br. J. Nutr. 2007 Oct; 98 Suppl 1:S64-7.

  • Belo A. Marchbank T., Fitzgerald A. Ghosh S., Playford R.J., Gastroprotective effects of oral nucleotide administration, Gut 2006; 55:165-171.

  • Dancey C.P., Attree E. A., Brown K.F., Nucleotide supplementation: a randomised double-blind placebo controlled trial of intestaidib in people with irritable bowel syndrome, Nutrition Journal 2006, 5:16.

  • Domeneghini C., Di GIancamillo A., Arrighi S., Bosi G., Gut-trophic feed additives and their effects upon the gut structure and intestinal metabolism. state of the art in the pig, and perspectives towards humans, Histol. Histopathol., 2006 Mar; 21(3):273-83.

  • Eshach Aadiv O., Berant M., Shamir R., New supplements to infant formulas, Pediatr. Endocrinol. Rev., 2004 Dec; 2(2):216-24
  • Holen E., Jonsson R., Dietary nucleotides and intestinal cell lines: i. modulation of growth, Nutrition Research 24 (2004) 197-207.
  • Agostoni C., Haschke F., Infant formulas. recent developments and new issues, Minerva Pediatr. 2003 Jun;55(3):181-94.
  • Carver Jane D., Allan Walker W., The role of nucleotides in human nutrition, Nutritional Biochemistry 6:58-72, 1995.
  • Sugawara M., Sato N., Nakano T., Idota T., Nakajima I., Profile of nucleotides and nucleosides of human milk, J. Nutr. Sci. Vitaminol., 41, 409-418, 1995.
  • Uauy R., Dietary nucleotides and requirements in early life,  Textbook of Gastroenterology and Nutrition in Infancy, Second Edition, edited by E. Lebenthal Raven Press, Ltd., New York 1989.

 

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