Could Alterations in the Infant Gut Microbiota Explain the Development of Noncommunicable Diseases from the DOHaD Perspective?

Abstract

Obesity and its complications are a global public health problem with increasing childhood prevalence. The developmental origins of health and disease (DOHaD) theory explain the maintenance of health or disease development throughout life, related to early life exposures. Although it arises from epidemiological observations, its support for epigenetics is strong. In this chapter, we address the importance of maternal diet in prenatal development, as well as the establishment of the infant microbiota and its postnatal regulating factors. According to the DOHaD theory, breastfeeding and other environmental factors are modulators or enhancers of the epigenetic mechanisms, which explain the increased incidence of noncommunicable diseases. We will discuss the molecular mechanisms related to the microbiota products, their effects on gene expression, and the pathophysiology of the disease. Finally, we will raise the areas of opportunity in childhood for preventive purposes, including the potential role of the use of prebiotics, probiotics, synbiotics, and postbiotics in early life.

1. Introduction

Obesity and chronic noncommunicable diseases, such as diabetes and cardiovascular disease, lead to the main causes of disability and premature mortality worldwide. In recent decades, the prevalence of obesity in the world has increased exponentially in children and adolescents, going from 0.7% to 5.6% in boys and from 0.9% to 7.8% in girls, between 1975 and 2016 [1]. Simultaneously, the incidence of type 2 diabetes (T2D) in the youth increased from 9 to 12.5 cases per 100,000 between 2003 and 2012 [2]. Additionally to the increase in obesity and diabetes, the development of unhealthy habits, such as inadequate diet and sedentary lifestyle in young people, have contributed to the development of cardiovascular diseases (CVD) at an early age [3]. Data from the National Health and Nutrition Examination Survey (NHANES) estimated a prevalence of ischemic heart disease of 0.5–0.6% in the United States for the period 2011–2014 in young adults between 20 and 39 years old. This trend is increasing, and it is expected that by 2030, 43.9% of the US adult population will have some type of cardiovascular disease [4].

The attempts to prevent or palliate the current wave of obesity and the following noncommunicable diseases should be funded at the beginning of human life. An interesting hypothesis is proposed: The Developmental Origins of Health and Disease (DOHaD) that is derived from the Barker hypothesis, which proposed that nutrition during the intrauterine period and exposure to infections after birth determine susceptibility to disease and death from coronary artery disease. This hypothesis has evolved, and currently, critical periods have been identified in fetal life and early childhood, which will determine growth, metabolism, neurogenesis, and future disease risk, expanding the hypothesis to other disorders, such as obesity, diabetes, cardiovascular disease, allergies, and neurological alterations, throughout the life. The DOHaD concept is based on epigenetics and explains the possibility of variations in the programming of the fetus and the infant through the modification of environmental factors, such as diet and infections, in these window periods [5].

Another main component involved in the early life stages is the gut microbiota, defined as the microbial ecosystem that colonizes the gastrointestinal tract, depending on perinatal and environmental factors, such as diet. Its balance is associated with health and its imbalance with the presence of various diseases, although the mechanisms involved have not been fully elucidated; and as with the DOHaD theory, window periods have been identified where its modulation is possible, especially in the perinatal period and up to preschool age [5, 6]. Thus, the aim of this chapter is to discuss the role of the perinatal maternal and infant diet and the gut microbiota to explain the development of chronic noncommunicable diseases from the DOHaD perspective, as key factors in the modulation of epigenetic programming mechanisms, to identify the areas of opportunity for preventive purposes in early childhood.

2. Establishment of the first gut microbiota and its modulating factors

Gut microbiota establishment is determined by several perinatal factors, including gestational pathologies, type of birth, type of feeding, prenatal and perinatal use of antibiotics, complementary feeding, and environmental pollutants [7]. From gestation to the first 2 years of life, these events influence the establishment of the microbiota. Hence, it affects the metabolic and immune response and has a subsequent impact on human health [8].

In the last century, the paradigm dictated that the womb was a sterile environment and that the first microbiota colonized the newborn at the birth time [9]. Even though this is yet a discussion topic, there is evidence pointing toward prenatal exposure to microbes [10]. Despite these, reports of low bacterial abundance and diversity and, in most cases, the lack of culturable bacteria leads to a reasonable doubt about whether it is an established microbiota or only transient exposure to DNA or microbial products that is occurring in the womb [11].

The first major event in microbial colonization for the newborn occurs at birth. Type of birth determines the first gut microbiota composition. Vaginally delivered infant’s fecal microbiota is enriched with Bifidobacterium, Bacteroides, Clostridium, and Lactobacillus genus. On the other hand, cesarean section is related to a higher abundance of Firmicutes and a lower abundance of Actinobacteria and Bacteroidetes [12]. In the first case, inoculum came mainly from vaginal maternal microbiota, whilst in the second case proceeded from skin and environment, presenting a high abundance of Staphylococcus, Streptococcus, or Propionibacteria [13]. These abundance differences decreased approximately at 6 months of age [12]. Depending on the birth way, different bacterial communities have a competitive advantage, thus first colonizers in infants born by cesarean section delay the establishment of other specific bacterial taxa [14].

First microbiota evolves to adapt to the biochemical environment and in a dependent way on the nutrient availability in the gut [14]. In this sense, whether the infant is breastfed or not, impacts the gut microbiota composition. Ho et al. [15], in a meta-analysis study, found higher bacterial diversity and abundance of Bacteroidetes and Firmicutes in non-exclusively breastfed infants compared to those exclusively breastfed at 6 months of age. At the genus level, Bacteroides, Eubacterium, Veillonella, and Megasphaera are more abundant in non-exclusively breastfed infants. Bäckhed et al. [13] also described differences at genus level between the microbiota of exclusively breastfeed and bottle-feed infants at 4 months of age. The first ones had a microbiota predominated by several species of Lactobacillus, whilst the second ones had a high abundance of Clostridium difficile, Granulicatella adiacens, Citrobacter spp., Enterobacter cloacae, and Bilophila wadsworthia.

Breastfeeding meets all the infant macro and micronutrient requirements during the first 6 months, besides human milk oligosaccharides have a probiotic effect promoting a healthy gut microbiota. Also, human milk provides bioactive compounds that favor immune development, such as immunoglobulins, leukocytes, and antimicrobial peptides. Moreover, human milk harbors its own microbiota, the genera with potential probiotic use as Lactobacillus, Bifidobacterium, and Streptococcus have been identified as its members [16].

Before 6 months of age, microbial metabolic pathways related to carbohydrate metabolism are higher in non-exclusively breastfed infants [15]. Once other foods aside from breast milk are introduced into the infant diet, functional shifts toward polysaccharides and protein metabolism occur in gut microbiota. However, these changes are not noticeable until breastfeeding cessation. Microbiota composition turns to an adult-like profile with a high abundance of Bacteroides, Bilophila, Roseburia, Clostridium, and Anaerostipes; but if exclusive breastfeeding continues, Lactobacillus and Bifidobacterium are higher in gut microbiota at 12 months of age [13].

The evidence on prenatal and perinatal factors influencing the composition of the gut microbiota highlights the importance of microbial colonization as a critical process in early human life. Healthy microbiota is indispensable for immune system shaping and development, and its metabolites promote the integrity of the intestinal mucosa.

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 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.

4. Microbiota products and their local and systemic effects

The main physiological effects observed in the host by gut microbiota could be explained by their metabolite production. There are different products identified and the most studied are short-chain fatty acids (SCFA), where acetate, butyrate, and propionate are the most common and with the most known effects [36]. Other metabolites include trimethylamine-N-oxide (TMAO), obtained from compounds containing choline [37, 38]; secondary bile acids [39]; free anthocyanidins and protocatechuic acid, derived from flavonoid anthocyanins [38], and indolepropionic acid, produced from tryptophan [40]. The ones with beneficial effects on host health are SCFA, anthocyanidins, and indole compounds, and we are going to focus on the first ones.

SCFAs are produced in the bowel lumen by fermentation of dietary fiber [41] by anaerobic bacteria such as Eubacterium, Roseburia, Faecalibacterium, Coprococcus, and Bifidobacterium [38, 39]. Acetate is predominant, representing 60–75% of the SCFA generated [36] and it is produced via acetyl-CoA and the Wood-Ljungdahl pathway [38]. Propionate can be synthesized by succinate, acrylate, and propanediol pathways, and butyrate by the phosphotransbutyrylase/butyrate kinase, accounting for 25% and 15%, respectively [36, 38].

These molecules exercise their effects by direct or indirect pathways [37]. Direct mechanisms include local or systemic effects, where the microbiota-gut-brain axis is the most studied systemic example [42]; and indirect ways include the effects of these metabolites in other microbes that could modify their function [37].

4.1 Local effects

SCFAs are associated with the maintenance of gut epithelium integrity and protection of the intestinal barrier [36, 37]. Their principal mechanism is as an energy source for enterocytes, but also butyrate and indole derivatives have been associated with aryl hydrocarbon receptor (AhR) ligands, a nuclear receptor whose activation is reported to modulate cell proliferation, immune response, gene expression, and epithelial barrier function [43]. This association with a healthy intestinal epithelium had been explained by the “Warburg effect” or “butyrate paradox.” Briefly, fiber-rich diets, associated with an increase in SCFA-producing bacteria, induce normal colonocyte proliferation and apoptosis in neoplastic cells, when metabolism is promoted by glucose [37, 38].

Furthermore, butyrate is important for the maintenance of intestinal barrier integrity because increases the expression of tight junction proteins, such as claudin-1, claudin-7, zonula occludens-1 (ZO-1), and ZO-2 [36, 38, 44]. Also, SCFAs can modulate mucin glycoprotein in the mucus layer [45], induce epithelial cell production of RegIIIγ and β-defensins, antimicrobial peptides [46], and reduce luminal pH [36]. All these functions help to avoid the proliferation of pathogenic bacteria and reduce the translocation of molecules to the systemic circulation.

4.2 Systemic effects

Besides local effects, microbiota metabolites can travel across the intestinal epithelium to systemic circulation or the central nervous system. This can impact different cells via extracellular receptors previously known as G protein-coupled receptors (GPRs) 43, 41, 81, 109A, and 91 [37]. For instance, propionate has a high affinity to GPR41, now called free fatty acid receptor 3 (Ffar3), which modulates cyclic adenosine monophosphate (cAMP); and to GPR43, now Ffar2, which increases the activity of calcium/protein kinase C (PKC) [36]. Butyrate also has activity on GPR 41 and is the only ligand of GPR109A, now hydrocarboxylic acid receptor 2 (HCA2), which also increases cAMP. Depending on the stimulated cells, effects can be seen in the endocrine, immune, and neurologic systems. For example, activation of the HCA2 receptor in dendritic cells and macrophages is associated with stimulation of T cells into the Treg phenotype [47, 48].

SCFAs also act as inhibitors of histone deacetylases (HDACs). When N-acetyl lysine on DNA histones loses its acetyl group, a more tightly wrapped double chain is formed. HDACs are enzymes that remove this acetyl group, altering DNA transcription by limiting access to transcriptional factors [37]. SCFAs can modify the transcription of a broad range of genes by inhibiting HDACs. Besides, butyrate can act as a ligand of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) to modulate the transcription of genes associated with lipolysis and adipogenesis [38, 49]. These different pathways help understand the systemic effects that SCFA can have in several organs, depending on which receptor is activated and the dominant SCFA.

4.3 Role of SCFA in inflammation and immune response

The most beneficial effects of SCFAs are associated with an anti-inflammatory profile. They help to regulate cytokine expression, promoting the production of IL-10, and subsequently, differentiation of Treg cells by the Ffar2 mechanism [36, 37]. Besides, due to their capacity for inhibiting HDACs, SCFAs can impede the activation of nuclear factor-kappa β (NF-κB) [38], a protein complex mainly associated with inflammation. When its RelA/p65 subunit is acetylated, NF-κB can increase gene expression of pro-inflammatory cytokines, such as IL17, IL-1b, IL-6, and IL-12 [50], and enhance transcription of growth factors, adhesion molecules, and immune receptors [36]. Altogether, when the production of pro-inflammatory cytokines is reduced and Treg cells are predominant, the immune response is more regulated, and the risk of inflammatory pathologies is decreased.

SCFAs can suppress the NLRP3 inflammasome and promote an adequate immunologic response by directing T cell differentiation in appropriate phenotypes [36]. For example, reducing systemic inflammation in allergic reactions by modification of T helper type 2 cell numbers [37]. Besides, SCFAs are associated with decreased IL-8 in macrophages and neutrophils, TNF-α in mononuclear cells, and nitric oxide synthase in monocytes [51]. Similarly, butyrate can reduce prostaglandin synthesis by inhibiting COX-2 transcription [50]. All these effects help support the anti-inflammatory profile associated with a fiber-rich diet.

Moreover, SCFAs can influence humoral response. In plasmatic cells, acetate can increase retinoic acid conversion from vitamin A, facilitating response to CD4+ T cell and IgA production [47, 52]. Besides, butyrate and propionate favor antigen affinity inhibiting somatic hypermutation and enhancing class-switch DNA recombination in B cells [53]. SCFAs also influence the proliferation and migration of immune cells, not only as energy sources but through MPAK signal transduction and cascades associated with Ffar2 and Ffar3 receptors [51]. HDACs inhibition activity modulates lymphocyte function, increasing Th1, Th17, and innate lymphoid cells2 (ILC2) and ILC3 [47]. In summary, SCFAs not only allow a more balanced immune response but a more efficient and effective one.

SCFAs have proved to impact immune system development in early life. Exposure to SCFAs during the weaning period is associated with a tolerogenic phenotype and lower risk of inflammatory pathologies later in life, improving CD25+ Treg cells, humoral response, and gut epithelium integrity; confirming microbiota’s role in immune system development [54].

4.4 Microbiota-gut-brain axis

Microbiota and their metabolites participate in the bidirectional communication between gut and brain, called the microbiota-gut-brain axis [42]. When SCFAs translocate from intestinal epithelium, they can travel by system circulation, immune system, or enteric-cerebral nervous pathway to provoke changes in distal organs [37, 49].

In the nervous system, butyrate is associated with an increase in cholinergic neurons in the gastrointestinal tract to facilitate motility, propionate with sympathetic activation to greater energy expenditure, and acetate with satiety by hypothalamic stimulation [55]. Similarly, along the gastrointestinal tract, there are enteroendocrine cells (EECs) that sense luminal content and release hormones in the systemic circulation. SCFAs can increase the release of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), affecting appetite signals and influencing weight control [49]. Therefore, SCFAs can modify autonomic functions and behavior, separately from CNS influence [56].

Another mechanism by which SCFAs alter neurological functions is by direct communication through the vagus nerve and enteric nervous system. SCFAs can alter the expression of GABA receptors [49], production of endothelial nitric oxide, anti-inflammatory and pro-inflammatory components in cerebral microcirculation [55], and increase neurogenesis [56]. Likewise, microbiota’s metabolites are associated especially with microglia maturation and function, involving Toll-like receptors (TLRs) [49] and blood–brain barrier integrity [55]. These effects on CNS immune cells explain why SCFAs are associated with less risk of neuroinflammatory disorders.

There are still many mechanisms to be elucidated that could explain all the beneficial effects that microbiota’s metabolites in eubiosis could have on host health. However, so far, our diet and early life events are one of the most important interventions to secure a healthy immune and neurologic system, through microbiota modulation.

5. Dysbiosis and early noncommunicable diseases

Throughout life, the structure of the intestinal microbiota can be affected by different factors, such as diet, drugs, the host’s immune system, and even the intestinal mucosa itself. Changes in the microbiota can be transient or long-lasting. However, most of the time, alterations in multiple factors are required to generate changes in the microbiota that become harmful to health. This is because the microbiota has resilience, also known as the ability to adapt, to some extent, to changes in the availability of nutrients or environmental conditions [57]. However, when negative conditions are maintained over time, for example, when breastfeeding is not provided or when there is an inadequate dietary pattern or lifestyle in the early years of life, a persistent imbalance of bacterial communities is generated, known as dysbiosis [58].

In addition, some elements have been identified that can amplify or drive changes in the microbiota, making the imbalance more evident and leading directly to dysbiosis. Among them are an increase in the richness of bacteriophages with lytic action in the intestinal environment [59] and the secretion of bacteriocins as a bacterial competition strategy in the intestinal ecosystem. Both situations are enhanced when there is some type of stress [60]. For example, oxidative stress also leads to dysbiosis by promoting the increase of specific bacterial communities and causing the activation of the immune system, as well as the development of subclinical inflammation [57]. This, together with the local and systemic effects of imbalanced SCFAs, described in Section 4 of this chapter, links dysbiosis with the pathophysiological processes of some noncommunicable metabolic diseases, such as obesity, T2D, and CVD [58], as is shown in Figure 1.

Figure 1.

Perinatal determinants of the first microbiota and effects of protective or harmful interventions for child health through life. BMI: Body mass index, SCFA: Short-chain fatty acids, TMAO: Trimethylamine-n-oxide, T2D: Type 2 diabetes, ACVD: Atheroesclerotic cardiovascular disease.

5.1 Obesity

Different studies have confirmed that there is an imbalance in the intestinal microbiota of obese children when compared to healthy children with normal weight. In general, an increase in the Firmicutes/Bacteroidetes (F/B) ratio has been described in some populations [61]; while in others, no differences have been found at the phylum level [62]. In the systematic review by Indiani et al. [63], the results of seven high-quality studies were analyzed and a significant association of Firmicutes with body mass index (BMI) was identified. At the genus and species levels, there is greater consensus regarding the increase in abundance of some Bacteroides species, such as B. fragilis [64, 65] and B. eggerthii [62]. Other studies have also detected microorganisms such as Methanobrevibacter smithii, Akkermansia muciniphyla, Desulfovibrionaceae, Bifidobacteriaceae, and Enterobacteriaceae associated with obesity in specific populations, but more studies are needed to increase the evidence of these associations in children [63]. Furthermore, it is generally considered that members of the Bacteroidetes family are the best predictors of the BMI z-score than the phylum analysis [66].

The specific mechanisms by which these associations could explain the early development of obesity from the DOHaD perspective are diverse. In the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort [67], 935 mother-infant dyads were followed from pregnancy through the first 3 years. Their results explain the intergenerational transmission of overweight and obesity, where having an obese mother and being born by cesarean section increases the risk 5 times for obesity at 1 and 3 years. In this model, the abundance of some specific families of Firmicutes, such as Lachnospiraceae, were sequentially associated with the development of obesity. This association increased in children with obese mothers and was even higher in those born by cesarean section.

Bacteria belonging to the phylum Firmicutes are mostly SCFA producers, such as butyrate and acetate. This supports the findings of Riva et al. [66], who found a higher production of SCFA in children with obesity, suggesting a higher fermentative activity. Consequently, when this occurs, energy harvest is increased, which favors a positive energy balance, and contributes to overweight and obesity. Despite this, it depends on the type of SCFA. For example, acetate that is absorbed in the intestine can serve as a substrate for de novo lipogenesis in the liver, which contributes to the accumulation of adipose tissue [68] and compromises the integrity of the intestinal barrier, increasing paracellular permeability and inducing inflammation due to bacterial translocation [6]. In contrast, others SCFA, such as butyrate and propionate, which are dominant products in eubiosis, have a protective effect against obesity. Among the proposed mechanisms, its role in reducing cholesterol synthesis, improving insulin sensitivity, inducing fatty acid oxidation, and leptin gene expression stand out [69].

In obese Canadian children [70], prebiotic supplementation for 16 weeks was associated with a normalized rate of weight gain, decreased percent body fat, and changes in gut microbiota structure, characterized by the increase of Bifidobacterium spp. This highlights the role of the microbiota in obesity and the impact that a high-fiber diet could have on its prevention and treatment in childhood.

5.2 Type 2 diabetes

There is increasing evidence of the role of the microbiota in the development of type 2 diabetes (T2D) in youth. In a murine study [71], it was found that during pregnancy, maternal gut microbiota provides protection against obesity and diabetes, through mechanisms related to the SCFA receptors GRP41 and GRP43, which are part of the FFAR family of receptors. This axis participates in the prenatal development of the metabolic and neural systems, driving the development of enteroendocrine cells and pancreatic beta cells. In this way, the deficiency in the signaling of this pathway caused sympathetic dysfunction, compromising energy metabolism, and inducing hyperglycemia.

As in children with obesity, adult patients with T2D have heterogeneous results regarding the F/B ratio [72, 73]. In a study conducted in China [74], it was found that when separating patients with T2D according to the presence or absence of chronic complications, the group without chronic complications presented a higher F/B ratio than those with complications, at the expense of increased Proteobacteria in the latter. Furthermore, some opportunistic pathogens have been identified as part of the microbiota of T2D patients, such as Bacteroides caccae, Clostridium hathewayi, Clostridium ramosum, Clostridium symbiosum, Eggerthella tarda, and Escherichia coli [75]. Thus, in general, in patients with T2D, there is a depletion of butyrate-producing bacteria such as Prevotella and Bifidobacterium. Also, decreased levels of Akkermansia muciniphila have been related to mucosal damage and induction of inflammation by activation of the immune system in the lamina propria [74, 75].

Seeking to integrate the previous observations, different mechanisms have been proposed that link the microbiota with the regulation of glycemia. Among them is the production of SCFA due to its effects already described and the increase in the secretion of incretins such as GLP-1 and its role in the differentiation of enteroendocrine cells. In addition, there is evidence regarding their participation in the metabolism of bile acids (BA) and the consequent induction of local and peripheral signals, and the regulation of adipose tissue by promoting white adipose tissue browning and by acting as a trigger for metabolic inflammation [76].

5.3 Cardiovascular disease

The microbiota and its metabolites also modulate the risk and progression of atherosclerosis. Changes in the microbiota diversity and structure have been described in people with atherosclerotic cardiovascular disease (ACVD). As cardiovascular disease is a complication of obesity as well as diabetes, the identified mechanisms coincide with those we have described for these diseases. For example, in a study with 218 patients with ACVD [77], an increased abundance of Enterobacteriaceae and Streptococcus spp. was found, with a decrease in butyrate-producing bacteria such as Prevotella copri and Alistepes Shahii, when compared with the fecal microbiota from 187 healthy controls. Thus, among the associated mechanisms stand out the induction of inflammation, the alteration of lipid metabolism and glucose homeostasis, as well as bacterial translocation. These findings are secondary to alterations in the F/B ratio and in the profile of metabolites such as SCFAs, TMAOs, and BA [78]. In the pathophysiology of ACVD, TMAOs, in particular, have been linked to increased foam cell activation, prothrombotic platelet response, and reverse cholesterol transport, raising the risk of myocardial infarction, stroke, and death [78].

Given that both cardiovascular disease and T2D have a pre-pathogenic period that can last for decades, and because overweight development usually begins in childhood, the perinatal period and early childhood represent a window of ​​opportunity for their prevention and risk modulation.

6. Areas of opportunity in fetal and lactating periods

There are different ways to gauge the window of opportunity during pregnancy and lactation periods. Firstly, the mother’s diet and physical activity during the preconceptional and pregnancy periods can induce favorable epigenetic modifications in early life. Second, the delivery way influences the intestinal microbiota composition of the newborn, where the advantage is vaginal delivery, followed by breastfeeding. At this point is quite important the physical contact between mother and child. Exclusive breastfeeding in the first 6 months, depending on the mother’s diet, can stimulate the best epigenetic activity to keep a normal growth rate, avoiding a rapid development by direct action or through the intestinal microbiota functionality. After 6 months, a proper food introduction is essential for promoting present and future child’s health, and for inducing a favorable intestinal microbiota balance.

As previously described, DNA methylation is crucial for processes epigenetically regulated. In the early embryogenic stage, most parental gametic methylation signs are erased before the acquisition of marks at implantation and beyond. Just after conception, the external environment influences early embryonic events, which are crucial for the DOHaD concept [79]. Therefore, the mother’s diet, energy balance, composition as well as her nutritional status, and physical condition are determinant during the periconceptional period [80]. Depending on the nutrient balance and richness of the women’s diet in methyl donor compounds, epigenetics modulation will promote normal growth to prevent accelerated fetal growth.

Dietary recommendations during pregnancy are related to amounts of energy, macro-, and micronutrients, such as vitamins and minerals. Dietary reference intake is 340 extra calories during the 2nd pregnancy trimester and 452 for the third one [81]. Pregnant women require a diverse diet, including fruits, vegetables, legumes, nuts, seeds, grains, and tubers, as well as animal-origin products such as dairy, meat, poultry, fish, and eggs. In contrast, pregnant women should avoid some raw seafood, alcohol, and caffeine.

Often health-related practices of a particular cultural group, based on its beliefs, negatively or positively affect the science-based dietary recommendations. For instance, Western diet patterns can fulfill the extra calories for pregnancy, mainly with animal-based products and supplements of vitamins and minerals. Although animal-origin foods contain enough choline, during pregnancy the folate requirement is 600 ug/d and the fiber recommendation is high (28–30 g/d), so supplements are needed [81]. Plant origin fiber is the best recommendation because fruits and vegetables contain in addition to fiber, some very important compounds with antioxidant activity, as well the methyl donor compounds such as betaine and folates, present in leafy green vegetables, broccoli, beans, and peas.

In addition to a diverse and balanced diet, during pregnancy physical activity is necessary for improving glucose tolerance and insulin activity, preventing excessive weight gain. The mother’s emotional well-being is important for the fetus, and fitness promotes an easier delivery.

The delivery mode defines the structure of the neonatal microbiota with an advantage of vaginal delivery over C-section delivery, and it is a key factor for the right development of the immune system [82]. The vaginal microbiota is the source of bacterial colonization for the neonate, with implications for the neonate and the mother’s health. Before delivery, the vaginal microbiota is mainly dominated by Lactobacillus, and just after delivery, it becomes diverse and similar to the neonatal oral microbiota [83].

In some cases, vaginal delivery is not possible, and C-section is done; additionally, because of strong causes, such as illness and drug treatments, feeding is through milk formulas. Apparently, the window of opportunity is lost, but there are other techniques to ensure healthy microbiota, for example, the use of probiotics, prebiotics, synbiotics, and postbiotics (PPSP) either by the mother or by the newborn. Prebiotics are nondigestible components of food that selectively promote the growth of beneficial bacteria in the intestine; while probiotics are live microorganisms that, administered in adequate amounts, confer a health benefit. On the other hand, synbiotics are a combination of prebiotics and probiotics, while postbiotics are an emerging option, which are soluble products or metabolites (such as SCFA) of commensal bacteria or bacterial components that provide benefits to the host [84]. The use of a combination of strains principally Bifidobacterium with or without prebiotics led to an increasing population of bifidobacteria in the newborn microbiota, close to the one of vaginal delivery. Although the effect is larger in breastfeeding children, due to the prebiotic effect of breast milk, even in mixed or formula feeding, there is an additional effect if the intervention begins just after birth [82].

There are still hospitals that pull apart the newborn from the mother if there was a C-section delivery, premature birth, or another reason associated with the mother or newborn’s health. Independently of the delivery mode, skin-to-skin contact between mother and child just after the first hour of life improves the possibility of exclusive breastfeeding in the lactation period. This technique helps to reduce neonatal morbidity due to multiple benefits; for instance, stabilizes cardiopulmonary function, and reduces the risk of hypoglycemia, hypothermia, and infections. After delivery, the effect on the mother is a reduction in anxiety and postpartum bleeding [85]. Everywhere, the neonatal intensive care units should promote family participative care, assisting skin-to-skin contact between the mother and newborn as soon as possible, for the establishment of breastfeeding [86].

Regarding general dietary recommendations during breastfeeding, there are higher requirements for carbohydrates and energy intake of up to 500 extra calories, from the beginning to 6 months of lactation. In addition, choline, dietary fiber, and water intake should be higher during the breastfeeding period than during pregnancy [81]. Besides a balanced diet with animal and vegetable sources, mothers should avoid some raw seafood, alcohol, smoking, and caffeine. It is very important to have the best diet for the mother and child’s well-being. Installation of breastfeeding is mandatory to induce a good balance of the child’s intestinal microbiota, for appropriate immune system development and general child health.

Once and again, microbiota appears in this chapter. It is because the community of different microorganisms in the intestinal tract produces metabolites and cell detritus involved in human metabolic functions. Furthermore, the microbiota influences the immune and central nervous systems; as such, the inhibition of the feeding activity promotes neurons, which ultimately decreases appetite [87]. Therefore, microbiota in dysbiosis could be implicated in metabolic disorders, such as obesity.

A strategy to help the infant to maintain the balance and achieve the stability of its microbiota is to make a correct introduction of solid foods in its diet or complementary feeding. It starts when breast milk or formula composition is not sufficient to accomplish the nutritional requirements of infants, usually from six to 23 months. Breastfeeding can continue at the same time as complementary feeding; the focus is to provide nutrients enough to meet the nutritional requirements of infants. A complementary feeding that is carried out in a staggered manner allows the microbiota to adapt and enrich itself in diversity; thus, it becomes more stable. The problem is that if neglected, complementary feeding has the potential to contribute to childhood overweight and obesity [88].

PPSPs have shown beneficial potential for treating overweight and obesity in children. The proposed mechanism is the modulation of the structure of the microbiota, the profile of microbial metabolites, and the improvement of the intestinal barrier mechanism [84, 89]. In patients with T2D, the use of PPSP decreases fasting blood glucose, total cholesterol, triglycerides, and insulinemia, as demonstrated in the meta-analysis by Bock et al. [90]. However, more studies are still needed to define its role in the prevention and/or treatment of chronic noncommunicable diseases, especially during pregnancy and early childhood.

The task to accomplish a good approach to raising a healthy child across the life course looks so difficult, but any effort pays off with profit. A well-planned pregnancy followed by a balanced and diverse diet, a vaginal delivery with immediate breastfeeding, skin-to-skin contact between mother and newborn, and basic care for the first months is crucial for the metabolic programming of the baby. However, also a carefully complementary feeding from 6 to 24 months, as well as an adequate lifestyle, will help maintain eubiosis, the proper maturation, and functioning of the immune system, and reduce the risk of developing early chronic diseases.

7. Conclusion

There is evidence that demonstrates the relationship between alterations in the intestinal microbiota and the risk of developing chronic noncommunicable diseases throughout life, such as obesity, T2D, and stroke. The involved mechanisms derive from the local and systemic effect of microbiota products, such as SCFAs, indoles, anthocyanins, TMAOs, and BA, as modulators of the inflammatory response and lipid metabolism, among others. Perinatal and early childhood factors modulate the first microbiota and early metabolic programming by epigenetic mechanisms. Thus, the intestinal microbiota is an additional component to the epigenetic mechanisms that strengthen the DOHaD theory and that should be considered in the establishment of preventive measures in the first 1000 days of life.

Conflict of interest

The authors declare no conflict of interest.