**3. Maternal diet and its relationship with epigenetics and infant microbiota**

Maternal diet is key for offspring development and future disease risk, and this is mediated by epigenetic modifications. In the gestational stage, maternal diet

influences offspring epigenetics directly, after birth this influence continues through breastfeeding. Breast milk composition contributes to epigenetics directly as well as through the gut microbiota, which also modulates infant health and development.

During pregnancy, maternal nutrition is a determinant for in utero development, birth weight, and future disease risk. This has been confirmed in studies on the Dutch famine (1944–1945), a period of severe shortage of food in the Netherlands, which have shown that maternal undernutrition during gestation had lasting consequences on the offspring's health. Also, prenatal exposure to the Dutch famine had transgenerational effects highlighting the influence of maternal nutrition over offspring epigenetics [17].

Epigenetic modifications are heritable biochemical markers in the genome that will not change its sequence but will determine gene expression, adapting to diverse environmental factors [18]. There are several epigenetic mechanisms, including DNA methylation, histone modification, and miRNA. DNA methylation is the most studied mechanism, and it relies on one-carbon metabolism. This pathway consists of two cycles, one dependent and one independent of folate. In the first cycle, folate acts as a methyl donor where homocysteine is re-methylated to form methionine. In the second cycle, betaine, and its precursor choline, act as methyl donors. Through this pathway, methionine is turned into S-Adenosylmethionine, the universal methyl donor, which will contribute to DNA methylation [19]. Therefore, DNA methylation depends on methyl donor supply, such as folate, choline, and betaine.

Dietary sources of methyl donors vary according to culture and geographic region. The best sources in Western diets are meat, dairy, and grains; while, in Mediterranean diets, fish, legumes, whole grains, and vegetables are the main sources [20]. According to Taylor *et al.* [21], in Australian preschool children's diet, grains and dairy products were the main sources of folate and choline. Redruello Requejo *et al.* [19] found that the most common sources of one-carbon donors in Spanish pregnant women were animal-source foods, grains, and vegetables. Additionally, culture influences maternal diet in pregnancy and lactation, increasing or decreasing methyl donor intake.

In the gestational stage, offspring's DNA methylation patterns are formed, and maternal intake of methyl donors contributes to proper development and growth. Pauwels *et al.* [22] found that maternal intake of folate, choline, and betaine in the periconceptional stage was associated with methylation of genes related to growth (IGF2), metabolism (RXRA), and appetite (LEP) in 6 months old infants. Insulin-like growth factor II (IGF2) contributes to cell growth and differentiation. According to Xiao *et al.* [23], newborns with fetal growth restriction had a decreased DNA methylation of IGF2. The gene LEP is responsible for leptin production, a hormone that signals appetite regulation and energy expenditure, and LEP methylation is associated with weight gain in the first 10 years of life [24].

There are strong interactions between maternal dietary intake and offspring DNA methylation and health. A high maternal betaine status during pregnancy is associated with lower offspring adiposity; in contrast, a low maternal folate status is associated with a future risk of childhood overweight and obesity [25, 26]. These findings highlight the impact of maternal nutrition during gestation on the offspring's metabolic health.

After birth, the maternal diet continues, influencing DNA methylation through breastfeeding. Therefore, breastfed infants have higher DNA methylation in childhood, compared with formula-fed children [18]. In addition, Briollais *et al*. [27] found that exclusively breastfed infants had more DNA methylation variations, and *Could Alterations in the Infant Gut Microbiota Explain the Development of Noncommunicable… DOI: http://dx.doi.org/10.5772/intechopen.105168*

these were associated with slower BMI growth in the first 6 years of life. The study by Sherwood *et al*. [24] confirmed these findings, where breastfeeding was associated with methylation of LEP and BMI trajectories in childhood. Differently from infant formulas, some breast milk components influence offspring DNA methylation, appetite, and growth; and these components are partly determined by maternal diet.

Compounds such as lipids, oligosaccharides, B vitamins, and betaine, are influenced by dietary intake [28]. Changes in breast milk content will have an impact on infant health, growth, and the development of gut microbiota. Fat and energy content in breast milk is associated with adipose tissue gain in breastfed infants [29]. Additionally, the intake of methyl donors through breast milk could have a direct effect on DNA methylation or could modulate epigenetic modifications via the infant gut microbiota. In two different populations, it was found that betaine concentration in breast milk was associated with infant growth in the first years of life, and betaine concentration was related with the abundance of *Akkermansia municiphila* in the infant's gut, a specie associated with infant growth [30, 31]. Although the evidence is limited, it opens the possibility for the infant gut microbiota to be a modulator of epigenetic modifications.

The development of the gut microbiota occurs in early life, and breast milk has the optimal composition for promoting its proper establishment. For instance, a study that evaluated the fecal microbiota of exclusive breastfed and formula-fed infants found that formula-fed children had a rapid maturation of the gut microbiota, which is associated with future obesity risk [32]. In addition, different types of breastfeeding have an impact on the gut microbiota, breastfed infants with skin-to-skin contact have a healthier microbiota than those fed from a bottle [33].

Many aspects of health are determined by the early gut microbiota, including infant growth. Children with a rapid maturation of the gut microbiota and a high abundance of *Bacteroides* spp. have rapid growth in the first year of life [31]. According to Forbes *et al.* [32], children that were weaned before 6 months old had a rapid maturation of gut microbiota and a greater risk of being overweight at 1 year old. In contrast, the abundance of *Bifidobacterium* and *Akkermansia* at 1-month-old was associated with proper growth in the first year of life [31]. Growth velocity in infancy is a determinant for future metabolic health, and these effects of the gut microbiota on infant growth could be mediated by epigenetic modifications.

The gut microbiota produces a great number of metabolites that participate in epigenetic regulations. Butyrate and propionate produced by *Akkermansia muciniphila* and other species modulate cell transcriptional factors and genes related to lipid metabolism in a murine model [34]. In addition, the effect of Bifidobacterium on infant growth could be mediated by epigenetics, since this genus produces folate, a methyl donor for DNA methylation [35]. Changes in the concentration of the microbiota metabolites could influence post-translational changes in DNA and histones. Therefore, gut microbiota alterations could negatively affect the epigenetic regulation in enterocytes and other cell groups, which in turn will influence infant metabolic health [35].

Epigenetics play a big role in determining infant development and health, and from conception to the postnatal stage, the maternal diet is key for supplying nutrients and components that are necessary for epigenetic regulation. During lactation, breast milk influences epigenetics directly or through the gut microbiota. There is a need for more evidence to elucidate the interactions between breast milk composition, infant gut microbiota, and epigenetic modifications; and to emphasize the importance of maternal diet to ensure proper offspring development, health, and minimize future disease risk.
