Epigenomic programing: a future way to health?

Abstract

It is now generally accepted that the 'central genome dogma' (i.e. a causal chain going from DNA to RNA to proteins and downstream to biological functions) should be replaced by the 'fluid genome dogma', that is, complex feed-forward and feed-back cycles that interconnect organism and environment by epigenomic programing - and reprograming - throughout life and at all levels, sometimes also down the generations. The epigenomic programing is the net sum of interactions derived from own metabolism and microbiota as well as external factors such as diet, pharmaceuticals, environmental compounds, and so on. It is a growing body of results indicating that many chronic metabolic and degenerative disorders and diseases - often called 'civilization diseases' - are initiated and/or influenced upon by non-optimal epigenomic programing, often taking place early in life. In this context, the first 1,000 days of life - from conception into early infancy - is often called the most important period of life. The following sections present some major mechanisms for epigenomic programing as well as some factors assumed to be of importance. The need for more information about own genome and metagenome, as well as a substantial lack of adequate information regarding dietary and environmental databases are also commented upon. However, the mere fact that we can influence epigenomic health programing opens up the way for prophylactic and therapeutic interventions. The authors underline the importance of creating a 'Human Gut Microbiota and Epigenomic Platform' in order to facilitate interdisciplinary collaborations among scientists and clinicians engaged in host microbial ecology, nutrition, metagenomics, epigenomics and metabolomics as well as in disease epidemiology, prevention and treatment.

REVIEW ARTICLE

Epigenomic programing: a future way to health?

Boris A. Shenderov1* and Tore Midtvedt2

1Laboratory of Biology of Bifidobacteria, Moscow Research Institute of Epidemiology and Microbiology after G.N. Gabrichevsky, Moscow, Russia; 2Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden

Abstract

It is now generally accepted that the 'central genome dogma' (i.e. a causal chain going from DNA to RNA to proteins and downstream to biological functions) should be replaced by the 'fluid genome dogma', that is, complex feed-forward and feed-back cycles that interconnect organism and environment by epigenomic programing - and reprograming - throughout life and at all levels, sometimes also down the generations. The epigenomic programing is the net sum of interactions derived from own metabolism and microbiota as well as external factors such as diet, pharmaceuticals, environmental compounds, and so on. It is a growing body of results indicating that many chronic metabolic and degenerative disorders and diseases - often called 'civilization diseases' - are initiated and/or influenced upon by non-optimal epigenomic programing, often taking place early in life. In this context, the first 1,000 days of life - from conception into early infancy - is often called the most important period of life. The following sections present some major mechanisms for epigenomic programing as well as some factors assumed to be of importance. The need for more information about own genome and metagenome, as well as a substantial lack of adequate information regarding dietary and environmental databases are also commented upon. However, the mere fact that we can influence epigenomic health programing opens up the way for prophylactic and therapeutic interventions. The authors underline the importance of creating a 'Human Gut Microbiota and Epigenomic Platform' in order to facilitate interdisciplinary collaborations among scientists and clinicians engaged in host microbial ecology, nutrition, metagenomics, epigenomics and metabolomics as well as in disease epidemiology, prevention and treatment.

Keywords: epigenomic programing; gut microbiota; mitochondria; energy metabolism; food and microbial bioactive molecules; feces conservation

Responsible Editor: Elisabeth Norin, Karolinska Institutet, Sweden.

*Correspondence to: Boris A. Shenderov, Moscow Research Institute of Epidemiology and Microbiology after G.N. Gabrichevsky, Moscow, Russia, Email: [email protected]

Received: 20 February 2014; Revised: 17 March 2014; Accepted: 1 April 2014; Published: 8 May 2014

Microbial Ecology in Health & Disease 2014. © 2014 Boris A. Shenderov and Tore Midtvedt. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Citation: Microbial Ecology in Health & Disease 2014, 25: 24145 - http://dx.doi.org/10.3402/mehd.v25.24145

In the decades after Watson and Crick in 1953 had published their article about the structure of DNA (1), it was a generally accepted axiom that biologically important information could only flow from DNA through RNA to proteins and virtually nothing could be added from the outside. However, in the last few years of the last century, a growing body of results indicated an 'intricate crosstalk between the organism and its environment at all levels, with feed-forward and feed-back cycles in the epigenetic and metabolic network of molecular interactions that mark and change genes as the organism goes about its business of living, with effects reverberating and amplified down the generations'(2). These events can be summarized in a statement that all organisms have a 'fluid genome', thus making truth to the statement 'panta rhei', that is, everything floats, by Heraklitos around 2,500 years ago.

In the 1990s, it became evident that prokaryotes play important roles in shaping the fluid genome in eukaryotes (3, 4). Today, a human being is often described as a 'superorganism', consisting of a consortium of vast number of representatives of Viruses, Eukarya, Bacteria, and Achaea. In terms of cell number, adult humans are more prokaryotic than eukaryotic with 90% of our cells estimated to be of microbial, and only 10% of human origin (5). Adding bacteriophages to the number, human cells may account for less than one per mille.

To receive the fullest information regarding this superorganism's behavior in various environment conditions, a set-up of 'omic' technologies have been introduced into medico-biological science and practice:

genomics and metagenomics which analyses the human genome and microbiome structure;

epigenomics and metaepigenomics, describing how certain genes in eukaryotic and prokaryotic cells are turned on or off without alterations in the DNA nucleotide sequence;

transcriptomics, which measures mRNA transcript levels;

proteomics, which evaluates protein abundance and spectrum;

metabolomics, which determines abundance of low molecular weight cellular metabolites that enable quantitative monitoring of the multiple of various biological molecules and their interactions in the human body;

phenomics that both qualitatively and quantitatively measures organism phenomic changes in response to genetic and epigenetic changes caused by various environmental factors and agents. (6-8)

The multi-'omics' approach is a powerful tool for understanding the functional symbiotic interplay of human eukaryotic and prokaryotic cells and dynamics of molecular modifications of this multi-cellular system in different environmental conditions. Accumulation of 'omic' databases, especially integrated, and their bioinformatic analysis permits a better understanding of the molecular bases of human health and diseases and designing of novel effective drugs and functional foods (8-13).

Analysis of current scientific and clinical data facilitates selection of some molecular and cellular hallmarks (genomic instability, epigenetic alterations, disorders of multiple signal pathways outside membrane and inside cells, water-salt imbalance, disorders of energy metabolism and mitochondrial dysfunction, oxidative stress and imbalance of antioxidative protective mechanisms, accelerated cellular senescence, disorders of proliferation and apoptotic processes, stem cell exhaustion, chronic inflammation, gut microbiota imbalance, altered intra- and inter-species communication in eukaryotic and prokaryotic cells, etc.) that are closely connected with accumulated cellular damages, uncontrolled cellular growth, progressive disorders of neuro-physiological homeostasis, impairments of functional and/or behavioral reactions arising during long-time alterations of a superorganism homeostasis.

When determined, most of these hallmarks are found to be altered in the majority of 'civilization diseases' (atherosclerosis, cancer, obesity, neurodegenerative diseases, type II diabetes, behavioral alterations as autism spectrum disorders). Taken together, these diseases can be looked upon as different manifestations of the same underlying pathophysiological processes. The relative 'balance' between these processes determines the phenotypic expression of corresponding disorder or disease (14-17).

Epigenomics and its link with energy metabolism

In the past decade, the results of many studies have placed epigenomics at the 'epicenter' of modern medicine because it helps explaining the relationship between individual genetic background, aging, lifestyle and environment, and because any perturbations in the epigenotype may result in health disturbances. Epigenomic processes regulate when and how certain genes are turned on or off without alterations in the DNA nucleotide sequence. Epigenetics is the sum of molecular-biochemical mechanisms that focuses on processes regulating the covalent attachment of different chemical groups to DNA, chromatin, histones, and other associated proteins during post-translation period. Epigenetic DNA and chromatin alterations may persist from one cell division to the next and can occur for several cell generations.

In addition to DNA methylation, it is known multiple different classes of post-translation modification of the core histones (e.g. methylation, acetylation, biotinylation, phosphorylation, ADP-ribosylation, ubiquitination, sumoylation), participating in the nucleosome and chromatin structure formation directed to the unfolding of the genetic program for organism development. It has also been shown that the same and other (e.g. glycosylation, glucuronidation, sulfatation) reactions can occur with proteins that do not connect with chromatin (8, 18-23).

Modifications of structural gene activity may be connected with non-coding microRNAs (miRNAs) as well. MiRNAs occur in two variants: small and long. Small miRNAs are 16-29 nucleotide-long eukaryotic and prokaryotic non-coding RNAs that can regulate gene expression on the different post-transcriptional levels by acting as inhibitors of transcription, modulators of DNA and histone methylation, chromatin reconstruction, and so on. Long non-coding RNAS (LncRNAs) are mostly eukaryotic RNA molecules greater than 200 nucleotides. They are regulators of epigenetic silences, transcriptional regulation, RNA processing and modification, and many other cellular functions (24). Currently, about 5,000 mammalian miRNAs have been identified and about 30% of protein-coding genes may be regulated by miRNA (25). Human miRNA, 6-27%, could be detected in the human mitochondria (26). More than half of known prokaryotic cell RNA can also be referred to as miRNAs (10) that can modulate host gene expression (11). On an individual level, epigenomic programing can be tissue- and stage-of-life-dependent, but it may vary markedly between individuals and species (27).

Epigenetics help to explain the relationship between individual genotype and the environment during all stages of life. Perturbations in epigenetic mechanisms may result in various health disturbances (metabolic syndrome, type II diabetes, autoimmune diseases, cancer, autism and so on) and also in phenotypic differences between monozygotic twins (22). Details of biochemical events associated with epigenomic regulations of gene expression in eukaryotic and prokaryotic organisms have been presented in some recent papers and reviews (8, 19, 21, 28-35).

Epigenomic DNA and chromatin remodeling are closely linked with processes of energy production and with the levels of total caloric intake in eukaryotic and prokaryotic cells in a superorganism. Mitochondria, besides the production of energy and increased oxygen species, have several biochemical mechanisms by which they participate in epigenetic modification of the nuclear genome, alteration of DNA methylation, chromatin remodeling, formation and microRNA expression (32, 36-38).

It is well known that prokaryote and eukaryote cells share common pathways for energy production, especially in the Krebs cycle (39, 40). It means that in mammalian organisms, mitochondria and human microbiota should consider to be both a collective metabolically active internal 'organ' affecting the host's energy metabolism (39-41) and a regulator of gene expression of the mitochondrial and nuclear genome (18, 36, 38). Cell energy metabolism needs many tens of different enzyme cofactors: vitamins (B1, B2, pantothenic acid - B5, B6, biotin - B7, B9, B12, C, phyloquinone-K1, menaquinone-K2), non-vitamins (NAD, NADH, NADP+, NADPH), adenosine triphosphate (ATF), cytidine triphosphate (CTP), S -adenosyl methionine (SAM), 3?phosphoadenosine-5?-phosphosulfate (PAPS), glutathione (GSH), Coenzyme B, Coenzyme M, Cofactor F-430, Coenzyme Q10, haem, alpha lipoic acid, methanofuran, molybdopterin/molybdenum cofactor, pyrroloquinoline quinone (PQQ), tetrahydrobiopterin (THB/BH4), tetrahydromethanopterin (THMPT/H4MPT), minerals (Ca, Cu, Fe+ +, Fe+ + +, Mg, Mn, Mo, Ni, Se, Zn), amino acids (arginine, lysine, methionine, cysteine, ?-alanine, serine, threonine, histidine, tryptophan, aspartic acid), Krebs cycle organic acids and some nucleotides (pyrimidine), miRNA (26, 36, 39, 42, 43).

Molecular investigations of epigenomic-associated processes have demonstrated (8, 18, 30, 42, 44-46) that most major participants in the epigenomic machinery (Table 1) are formed during energy metabolism in the eukaryotic cell mitochondria and in the prokaryotic cell membranes.

[Table omitted -see PDF.]

Epigenetic alterations associated with imbalance of diet and symbiotic gut microbiota might be inherited and affect the health of future generations. It is now apparent that food nutrients and bioactive compounds of host microbiota origin play the critical roles in a person's life during a narrow window of time, that is, the 1,000 days beginning at conception and continuing through the second year of life (18, 30, 70-74). During this period, an imbalance in food and/or microbiota may give rise to 'developmental shadows' later in life, as indicated in some of the following examples. Recent results indicate that underfeeding or overeating in pregnant women and infants (30), their long feeding with fat enriched foods (22, 23, 30, 75), feeding infant and children with protein deficit diet (23, 30, 76), as well as a diet with certain nutrient deficiencies (22, 30) or chronic alcohol consumption (22) have a negative impact on the epigenomic program of development resulting in general or local specific epigenomic disorders, thereby influencing gene expression and the risk of metabolic imbalance later in life.

On the contrary, food for mothers and infants containing enough compounds for an adequate epigenomic programing are assumed to be of importance for health later in life (18, 27, 77-81). However, as underlined by Park et al. (77), in this field, 'there is much to be done that has great potential to yield findings with significant public health implication'.

Where do we go from here?

Accepting the fluid genome axiom, the growing body of data indicating that many metabolic 'civilization diseases' are due to epigenomic programing disorders, especially in a certain period after fertilization, and also many data indicating that we can influence upon this programing, represent a huge challenge to human society. The tasks ahead of us can very briefly be summarized as follows.

Genome characterization - either in utero or at birth - is here to stay. In the context for prevention of civilization diseases, this knowledge is still of very limited value. However, when we have more information about epigenetically 'sensitive' regions as well as external and internal factors capable of 'playing' on these regions in an age-dependent matter, it is easy to forecast that an individual genome characterization will increase in importance.

Microbiome characterization. This approach is also here to stay. However, we do have to accept that even the largest investigations represent 'fecal snap-shots' (e.g. one or few fecal samples taken over a short period of time in a limited number of individuals). Most of the results published so far are from individuals living on food based on a few carbohydrates (wheat, rice, corn, and potatoes). The need for studies in larger groups of individuals followed over longer periods of time is obvious, as well as the need for data from cohorts living on other sources of carbohydrates (82, 83); more information is also needed about microbiota in various intestinal compartments. In addition, accepting the lifelong cross-talks that take place between a host and its microbiota and the adaptability of the microflora to local or regional food, we should start thinking about the sustainability of intestinal microbiota in cohorts of people not living on a 'Westernized diet', and attempts should be made to investigate or at least save feces from groups of people living on such food. As the first attempt, works should be started to collect and store feces from cohorts of people not living on a 'Westernized' diet. A proper place for storage could be the United Nation Global Seed Vault at Svalbard, Norway, or, if that proves to be difficult, a novel, specially organized free International Cryobank of natural human Microbiocenoses should be established. In the future, such samples may give us valuable guidelines if we want to go back to base-line again.

Dietary databases. Never before have that many people been on their move - from rural to urban areas - from country to country - and from one climate zone to another. As a consequence, never before have that many individuals changed dietary habits, never before has the need for more food been greater and never before have that large quantities of food been moved all around the world. Assumingly, these macro-scaled alterations create the main background for the observed increase in 'civilization diseases'. Obviously, there is a need for updated, reliable, and easily searchable information about food consumption in defined populations (84).

Environmental databases. All through life, man is virtually 'swimming' in an ocean of chemicals present in the biosphere. Recent reviews clearly underline that many groups of such environmental pollutants as phthalate esters (85), other endocrine disrupting chemicals, dioxins, hydrocarbons, and various groups of pesticides may influence upon epigenomic programing in many species, including Homo sapiens (85-89). A key problem is that reports often focus on genomic and/or epigenomic effects of one chemical or one class of chemical whereas the human population, including pregnant women and infants, are exposed to a multiplicity of chemicals and additive effect(s) are far less investigated. Acetaminophen (paracetamol-the most commonly used 'pain-killer' in the industrial world), by acting on mitochondrial DNA may influence the development of some civilization diseases (81). Fortunately, epidemiological tools for evaluating probable health effects of exposure to multiple environmental factor problems are now under establishment (90).

More information in these four areas listed above will allow us to investigate epigenomic programing - and hopefully also epigenomic reprograming - on an individual base far more precisely than at present (49). Out of many future tasks, initial focus could be on:

1. Identifying epigenetically 'sensitive' region in the human genome.

2. Identifying more microbial, dietary, and environmental factors of importance and how they may interact on an individual as well as on a cohort level.

3. Identifying critical age-related 'windows' in which compound-related epigenetic programing may take place.

Future goals and problems

At present, health for all throughout life is nothing but a dream. However, accepting the fluid genome axiom and the postulate that many civilization disasters and diseases are 'man-influenced', we have been given the opportunity to interact. Working in parallel on the tasks outlined above, development of function foods represents reachable goals. Surely, 'no food fits all'. Therefore, specialized nutria-epigenetic and microbiota-epigenetic-based functional foods have to be developed (18, 63, 78, 79, 91). The intention is to have age- and cohort-related specialized functional foods that positively affect specific groups of hosts resulting in a decrease or elimination of negative consequences caused by the factors described above. Focus should be on foods to pregnant women and infants, and in these fields, much attention have been paid to the probiotic concept. In laboratory animals, it is well established that probiotics can perform epigenomic programing and some results indicate that this is the case also in humans (92). However, rules for such studies are not described in recent guidelines (93). The mere fact that most civilization disasters and diseases increase in incidence underline the importance of coordinating our effects in establishing an international platform 'Human Gut Microbiota and Epigenomics' that facilitates interdisciplinary collaborations among scientists and clinicians engaged in host microbial ecology, nutrition, metagenomics, epigenomics, and metabolomic investigations, as well as in disease epidemiology, prevention and treatment. It is not reasonable to think that our descendants will be impressed by our relatively little interest in this important field. If we are not increasing our efforts, we will be looked upon as if we are following an approach from pre-revolutionary France:

Apres nous, le deluge!

Acknowledgements

The main positions of this review were presented during the XXXVI Congress of the SOMED (September, 2013, Kosice, Slovakia).

Conflict of interest and funding

The authors have declared that they have no interests that might be perceived as posing a conflict or bias.

References

1. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acids. Nature 1953; 171: 737-8. PubMed Abstract | Publisher Full Text

2. Mae-Wan Ho. The new genetics and natural versus artificial genetic modification. Entropy 2013; 15: 4748-81. doi: 10.3390/e15114748. Publisher Full Text

3. Bry L, Falk PG, Midtvedt T, Gordon JI. A model of host-microbial interactions in an open mammalian ecosystem. Science 1996; 273: 1380-3. PubMed Abstract | Publisher Full Text

4. Falk PG, Hooper LV, Midtvedt T, Gordon JI. Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology. Microbiol Mol Biol Rev 1998; 62: 1157-70. PubMed Abstract | PubMed Central Full Text

5. Lederberg J. Infectious history. Science 2000; 288: 287-93. PubMed Abstract | Publisher Full Text

6. Tuohy KM, Gougoulias C, Shen D, Walton G, Fava F, Ramnani P. Studying the human gut microbiota in the trans-omics era-focus on metagenomics and metabonomics. Curr Pharm Des 2009; 15: 1415-27. PubMed Abstract | Publisher Full Text

7. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, et al. Host-gut microbiota metabolic interactions. Science 2012; 336: 1262-7. PubMed Abstract | Publisher Full Text

8. Shenderov BA. "OMIC"-technologies and their importance in current prophylactic and regenerative medicine. Regenerative Med J 2012; 3: 70-8. (in Russian).

9. Collins CD, Purohit S, Podolsky RH, Zhao HS, Schatz D, Eckenrode SE, et al. The application of genomic and proteomic technologies in predictive, preventive and personalized medicine. Vascul Pharmacol 2006; 45: 258-67. PubMed Abstract | Publisher Full Text

10. O'Flaherty S, Klaenhammer TR. The impact of omic technologies on the study of food microbes. Annu Rev Food Sci Technol 2011; 2: 353-71. PubMed Abstract | Publisher Full Text

11. Dalmasso G, Nguyen HTT, Yan Y, Laroui H, Charania MA, Ayyadurai S, et al. Microbiota modulate host gene expression via microRNAs. PLoS One 2011; 6: e19293. doi: 10.1371/journal.pone.0019293. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

12. Yeoman CJ, Thomas SM, Berg Miller ME, Ulanov AV, Torralba M, Lucas S, et al. A multi-omic systems-based approach reveals metabolic markers of bacterial vaginosis and insight into the disease. PLoS One 2013; 8: e56111. doi: 10.1371/journal.pone.oo56111. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

13. Zempleni J, Wijeratne SS, Hassan YI. Biotin. Biofactors 2009; 35: 36-46. PubMed Abstract | Publisher Full Text

14. Shenderov BA. Functional foods in metabolic syndrome prophylaxis. Moscow: DeLi Print; 2008, 319 p. (in Russian).

15. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-74. PubMed Abstract | Publisher Full Text

16. Bomba A, Brandeburova A, Ricanyova J, Strojny L, Chmelarova A, Szabadosova V, et al. The role of probiotics and natural bioactive compounds in modulation of the common molecular pathways in pathogenesis of atherosclerosis and cancer. Biologia 2012; 67: 1-13. Publisher Full Text

17. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013; 153: 1194-217. doi: 10.1016/j.cell.2013.05.039. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

18. Shenderov BA. Gut indigenous microbiota and epigenetics. Microb Ecol Health Dis 2012; 23: 17461. doi: 10.3402/mehd.v23i0.17461. Publisher Full Text

19. Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA 2008; 299: 1345-50. PubMed Abstract | Publisher Full Text

20. Furrow RE, Christiansen FB, Feldman MW. Environment sensitive epigenetics and the heritability of complex diseases. Genetics 2011; 189: 1377-87. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

21. Tollefsbol TO. Handbook of epigenetics: the new molecular and medical genetics. London: Academic Press; 2010, 618 p.

22. Relton CL, Smith GD. Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment. PLoS Med 2010; 7: e1000356. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

23. Engeham S, Mdaki K, Jewell K, Austin R, Lehner AN, Langley-Evans SC. Mitochondrial respiration is decreased in rat kidney following fetal exposure to a maternal low-protein diet. J Nutr Metab 2012; 2012: 989037. doi: 10.1155/2012/989037. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

24. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet 2009; 10: 155-9. PubMed Abstract | Publisher Full Text

25. Wolfson M, Tacutu R, Budovsky A, Aizenberg N, Fraifeld VE. Common epigenetic mechanisms of age and age-related diseases: the role for microRNA. Probl Aging Longevity 2008; 17: 184-201.

26. Barrey E, Saint-Auret G, Bonnamy B, Damas D, Boyer O, Gidrol X. Pre-micro RNA and mature micro RNA in human mitochondria. PLoS One 2011; 6: e20220. doi:10.1371/journal.pone.0020220. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

27. Kussmann M, Van Bladeren PJ. The extended nutrigenomics--understanding the interplay between the genomes of food, gut microbes, and human host. Front Genet 2011; 2: 21. doi: 10.3389/fgene.2011.00021. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

28. McKay JA, Mathers JC. Diet induced epigenetic changes and their implications for health. Acta Physiol 2011; 202: 103-18. Publisher Full Text

29. Lavebratt C, Almgren M, Ekstrom TJ. Epigenetic regulation in obesity. Int J Obes 2012; 36: 757-65. Publisher Full Text

30. Jimenez-Chillaron JC, Diaz R, Martinez D, Pentinat T, Ramon-Krauel M, Ribo S, et al. The role of nutrition on epigenetic modifications and their implications on health. Biochimie 2012; 94: 2242-63. PubMed Abstract | Publisher Full Text

31. Feil R, Fraga MF. Epigenetic and the environment: emerging patterns and implications. Net Rev Genet 2012; 13: 97-109.

32. Chinnery PF, Elliott HR, Hudson G, Samuels DC, Relton CL. Epigenetics, epidemiology and mitochondrial DNA diseases. Int J Epidemiol 2012; 41: 177-87. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

33. Kidd PM. Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. Altern Med Rev 2005; 10: 268-93. PubMed Abstract

34. Nicolson GL. Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Altern Ther Health Med 2014; 20: 18-25. PubMed Abstract

35. Macfabe D. Autism: metabolism, mitochondria and the microbiome. Glob Adv Health Med 2013; 2: 52-66. PubMed Abstract | Publisher Full Text

36. Wallace DC. The epigenome and the mitochondrion: bioenergetics and the environment. Gen Dev 2010; 24: 1571-3. Publisher Full Text

37. Huang JY, Hirschey MD, Shimazu T, Ho L, Verdin E. Mitochondrial sirtuins. Biochim Biophys Acta 2010; 1804: 1645-51. PubMed Abstract | Publisher Full Text

38. Bellizzi D, D'Aquila P, Giordano M, Montesanto A, Passarino G. Global DNA methylation levels are modulated by mitochondrial DNA variants. Epigenomics 2012; 4: 17-27. doi: 10.2217/epi.11.109. PubMed Abstract | Publisher Full Text

39. Soballe B, Poole RK. Microbial ubiquinones: multiple roles in respiration, gene regulation and oxidative stress management. Microbiology 1999; 145: 1817-30. PubMed Abstract | Publisher Full Text

40. Herrmann G, Jayamani E, Mai G, Buckel W. Energy conservation via electron-transferring flavoprotein in anaerobic bacteria. J Bacteriol 2008; 190: 784-91. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

41. Musso G, Gambino R, Cassader M. Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr Opin Lipidol 2010; 21: 76-83. PubMed Abstract | Publisher Full Text

42. Wallace DC, Fan W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion 2010; 10: 12-31. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

43. Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Ann Rev Pathol 2010; 5: 297-348. Publisher Full Text

44. Naviaux RK. Mitochondrial control of epigenetics. Cancer Biol Ther 2008; 7: 1191-3. PubMed Abstract | Publisher Full Text

45. Kobza K, Sarath G, Zempleni J. Prokaryotic BirA ligase biotinylates K4, K9, K18 and K23 in histone H3. BMB Rep 2008; 41: 310-5. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

46. Smiraglia DJ, Kulawiec M, Bistulfi GL, Gupta SG, Singh KK. A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther 2008; 7: 1182-90. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

47. Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS. Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol 2009; 5: 401-8. PubMed Abstract | Publisher Full Text

48. Cooney CA. Maternal nutrition: nutrients and control of expression. In: Kaput J, Rodriquez RL, eds. Nutritional genomics: discovering the path to personalized nutrition. Chapter 10. By John Wiley & sons, Inc., Hoboken, New Jersey; 2006, pp. 219-54.

49. Dolinoy DC, Weidman JR, Jirtle RL. Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 2007; 23: 297-307. PubMed Abstract | Publisher Full Text

50. Miller RL. Prenatal maternal diet affects asthma risk in offspring. J Clin Invest 2008; 118: 3265-8. PubMed Abstract | PubMed Central Full Text

51. Mathers JC, McKay JA. Epigenetics - potential contribution to fetal programming. Adv Exp Med Biol 2009; 646: 119-23. PubMed Abstract

52. Raghunath M, Venu L, Padmavathi I, Kishore YD, Ganeshan M, Kumar A, et al. Modulation of macronutrient metabolism in the offspring by maternal micronutrient deficiency in experimental animals. Indian J Med Res 2009; 130: 655-65. PubMed Abstract

53. Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Backhed HK, et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 2012; 150: 470-80. doi: 10.1016/j.cell.2012.07.008. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

54. Attig L, Gabory A, Junien C. Nutritional developmental epigenomics: immediate and long-lasting effects. Proc Nutr Soc 2010; 69: 221-31. PubMed Abstract | Publisher Full Text

55. Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Am Rev Nutr 2002; 22: 283-307. Publisher Full Text

56. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505: 559-63. doi: 10.1038/nature12820. PubMed Abstract | Publisher Full Text

57. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004; 558: 263-75. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

58. Midtvedt T. Microbial functional activities. In: Hanson LA & Yolken RS, eds. Probiotics, other nutritional factors and intestinal microflora. Nutrition Workshop Series vol 42. Pennsylvania, USA: Nestec Ltd and Lippincott-Raven Publiishers; 1999. p. 79-96.

59. Dolinoy DC. The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations of the fetal epigenome. Nutr Rev 2008; 66: 7-11. Publisher Full Text

60. Delage B, Dashwood RH. Dietary manipulation of histone structure and function. Ann Rev Nutr 2008; 28: 347-66. Publisher Full Text

61. Li Y, Tollefsbol TO. Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem 2010; 17: 2141-51. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

62. Li CC, Cropley JE, Cowley MJ, Preiss T, Martin DL, Suter CM. A sustained dietary change increases epigenetic variation in isogenic mice. PLoS Genet 2011; 7: e10011380.

63. Shenderov BA. Probiotic (symbiotic) bacterial languages. Anaerobe 2011; 17: 490-5. PubMed Abstract | Publisher Full Text

64. Sommer F, Backhed F. The gut microbiota-masters of host development and physiology. Nat Rev Microbiol 2013; 11: 227-38. doi: 10.1038/nrmicro2974. PubMed Abstract | Publisher Full Text

65. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes 2005; 54: 1899-906. PubMed Abstract | Publisher Full Text

66. Faulk C, Dolinoy DC. Timing is everything. The when and how of environmentally induced changes in the epigenome of animals. Epigenetics 2011; 6: 791-7. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

67. Simon C. Nutritional programming of disease: unraveling the mechanism. J Anat 2009; 215: 36-51. Publisher Full Text

68. Oberleas D. A new perspective of trace element deficiencies. Trace Elem Med 2003; N1-3: 3-8.

69. Badretdinova LM, Badretdinov RR, Shenderov BA. Sanatorium & spa treatment of osteoarthritis: current condition and perspectives. Ekaterinburg: Publishing House AMB; 2012, 208 p. [In Russian].

70. Midtvedt AC, Midtvedt T. Production of short chain fatty acid by the intestinal microflora during the first 2 years of human life. J Pediatr Gastroenterol Nutr 1992; 15: 395-403. PubMed Abstract | Publisher Full Text

71. Midtvedt AC, Midtvedt T. Conversion of cholesterol to coprostanol by the intestinal microflora during the first two years of human life. J Pediatr Gastroenterol Nutr 1993; 17: 161-8. PubMed Abstract | Publisher Full Text

72. Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev 2006; 82: 485-91. PubMed Abstract | Publisher Full Text

73. Simmons R. Epigenetics and maternal nutrition: Nature v. nurture. Proc Nutr Soc 2011; 70: 73-81. PubMed Abstract | Publisher Full Text

74. Landecker H. Food as exposure: nutritional epigenetics and new metabolism. Biosocieties 2011; 6: 167-94. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

75. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 2010; 467: 963-66. PubMed Abstract | Publisher Full Text

76. Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 2010; 143: 1084-96. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

77. Park LK, Friso S, Choi SW. Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc 2012; 71: 75-83. PubMed Abstract | Publisher Full Text

78. Shenderov BA, Aleshkin VA. Functional dairy foods in human epigenetic regulation. IDF world dairy summit. 4-8 November 2012. Cape Town. Abstract Book. Poster 0121.

79. Shenderov B. Metabiotics: novel idea or natural development of probiotic conception. Microb Ecol Health Dis 2013; 24: 20399.

80. Carlin J, George R, Reves TM. Methyl donor supplementation blocks the adverse effects of maternal high fat diet on offspring physiology. PLoS One 2013; 8: e63549. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

81. Christophersen OA, Haug A. Animal products, diseases and drugs: a plea for better integration between agricultural sciences, human nutrition and human pharmacology. Lipid Health Dis 2011; 10: 16-38. Publisher Full Text

82. Sonnenburg JL, Fischbach MA. Community health care: therapeutic opportunities in the human microbiome. Sci Trans Med 2011; 3: 78ps12. Publisher Full Text

83. White RA, Bjornholt JV, Baird DD, Midtvedt T, Harris JR, Pagano M, et al. Novel developmental analysis identify longitudinal patterns of early gut microbiota that affect infant growth. PLoS Comput Biol 2013; 9: e1003042. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

84. Kau AL, Ahern PB, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature 2011; 474: 327-36. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

85. Hannas BR, Lambright CS, Furr J, Evans N, Foster PMD, Gray EL, et al. Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: a targeted RT-PCR array approach for defining relative potency. Toxicol Sci 2012; 125: 544-57. doi: 10.1093/toxsci/kfr315. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

86. Vandegehuchte MB, Janssen CR. Epigenetics in an ecotoxicological context. Mutat Res 2014 Apr. 764-765: 36-45. doi: 10.1016/j.mrgentox.2013.08.008. Publisher Full Text

87. Huen K, Yousefi P, Bradman A, Yan L, Harley KG, Kogut K, et al. Effects of age, sex and persistent organic pollutants on DNA methylation in children. Environ Mol Mutagen 2014; 55: 209-22. doi: 10.1002/em.21845. PubMed Abstract | Publisher Full Text

88. Fudvoye J, Bourguignon JP, Parent AS. Endocrine- disrupting chemicals and human growth and maturation: a focus on early critical windows of exposure. Vitam Horm 2014; 94: 1-25. doi: 10.1016/B978-0-12-800095-3.00001-8. PubMed Abstract | Publisher Full Text

89. Hou L, Zhang X, Wang D, Baccarelli A. Environmental chemical exposure and human epigenetics. Int J Epidemiol 2012; 41: 79-105. doi: 10.1093/ije/dyr154. PubMed Abstract | PubMed Central Full Text | Publisher Full Text

90. Siama R, Ballester F, Casas M, Cordier S, Eggesbo M, Iniquez C, et al. Epidemiological tools to study the influence of environmental factors on fecundity and pregnancy - related outcomes. Epidemiol Rev 2014; 36: 148-64. doi: 10.1093/epirev/mxt011. Publisher Full Text

91. Critical Reviews in Food Science and Nutrition (2013). Nutrition and health claims as marketing tools, Critical Reviews in Food Science and Nutrition. doi: 10.1080/10408398.2012.754738. Publisher Full Text

92. Luoto R, Ruuskanen O, Waris M, Kalliomäki M, Salminen S, Isolauri E. Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: a randomized placebo-controlled trial. J Allergy Clin Immunol 2014; 133: 405-13. doi: 10.1016/j.jaci.2013.08.020. PubMed Abstract | Publisher Full Text

93. Rijkers GT, Bengmark S, Enck P, Haller D, Herz U, Kalliomaki M, et al. Guidelines for substantiating the evidence for beneficial effects of probiotics: current status and recommendations for future research. J Nutr 2010; 140: 671-8. Publisher Full Text