ReviewRole of Gut Microbiota and Gut-Brain and Gut Liver Axes in Physiological Regulation of Inflammation, Energy Balance, and Metabolism

Early nutrition and gut microbiome: interrelationship between bacterial metabolism, immune system, brain structure, and neurodevelopment

Published Online:https://doi.org/10.1152/ajpendo.00188.2019

Abstract

Disturbances of diet during pregnancy and early postnatal life may impact colonization of gut microbiota during early life, which could influence infant health, leading to potential long-lasting consequences later in life. This is a nonsystematic review that explores the recent scientific literature to provide a general perspective of this broad topic. Several studies have shown that gut microbiota composition is related to changes in metabolism, energy balance, and immune system disturbances through interaction between microbiota metabolites and host receptors by the gut-brain axis. Moreover, recent clinical studies suggest that an intestinal dysbiosis in gut microbiota may result in cognitive disorders and behavioral problems. Furthermore, recent research in the field of brain imaging focused on the study of the relationship between gut microbial ecology and large-scale brain networks, which will help to decipher the influence of the microbiome on brain function and potentially will serve to identify multiple mediators of the gut-brain axis. Thus, knowledge about optimal nutrition by modulating gut microbiota-brain axis activity will allow a better understanding of the molecular mechanisms involved in the crosstalk between gut microbiota and the developing brain during critical windows. In addition, this knowledge will open new avenues for developing novel microbiota-modulating based diet interventions during pregnancy and early life to prevent metabolic disorders, as well as neurodevelopmental deficits and brain functional disorders.

INTRODUCTION

The first 1,000 days of life between conception and a child’s second birthday, offer a unique window of opportunity to improve lifelong health. It is well known that maternal disorders such as malnutrition, obesity. or gestational diabetes during pregnancy will determine “early metabolic programing” of their offspring, which adapts the fetus to the adverse intrauterine environment, in some cases maximizing an immediate chance for survival (96). These complex interactions that exist between maternal nutrition and metabolic status, together with a wide range of factors influence the intestinal microbiota and its establishment, including maternal metabolic state, delivery, and feeding mode, among others, which are particularly powerful during this period of rapid change (19, 75).

The child's brain grows rapidly and has a high demand for energy, proteins, essential fatty acids, and key micronutrients such as iron, folate, zinc, and iodine (29, 65). On one hand, nutrient deficiencies during this critical period may have long-term and irreversible effects on brain development (13, 15). For instance, iodine deficiency during pregnancy results in damage to the developing brain, which is further aggravated by hypothyroidism in the fetus (3, 122). On the other hand, human epidemiologic studies have shown that prenatal and lactational exposure to maternal obesity and to a high-fat diet is associated with later neurodevelopmental and psychiatric disorders in the offspring (45). Since obesity is associated to a chronic low-grade inflammatory state (49), the link between inflammation and infants’ neurodevelopment is being extensively studied (103). Inflammation during development may cause widespread injury to the brain by interfering with the normal balance of cytokine signaling and therefore developmental processes. The specific consequences of systemic inflammation on brain development appear to change with the type of insult and the period of gestation affected; for example, autism spectrum disorders appear to be related to insults occurring in the first trimester of pregnancy, while schizophrenia appears to be more prevalent when the inflammatory insult occurs in the second trimester (125). Many other factors also contribute to the process of brain growth and maturation, including genetics, maternal and fetal environments, and the exposure to other environmental insults, such as drugs and toxins (30).

In the last few years, intestinal microbiota have emerged as a new factor that influences neurodevelopment through the “gut-brain axis”. Nutrition alterations alterations or intestinal diseases may determine a dysbiosis of the gut microbiota community, inducing physiological and immunological changes favoring inflammation. This inflammation will contribute to intestinal barrier loss, causing translocation of pathogenic bacteria components to the systemic circulation from the intestinal mucosa. These components activate the innate immune system, which produces proinflammatory cytokines, leading to an impairment of the central nervous system (CNS) development and function. Although the role of the gut microbiota on the infant’s neurodevelopment is not well understood, increasing evidence suggests that the gut microbiota play a key role in this axis (17).

To perform the present review of the literature, PubMed and Google Scholar databases were explored to update the information about how external factors, such as nutrients or maternal metabolic state, may influence gut microbiota composition and metabolism on the offspring, showing the recent knowledge about the different mechanisms potentially involved in the gut-brain axis functioning. The selected papers were those reporting randomized clinical trials, cohort, and epidemiological studies mainly in humans (specially focused on infants and children), most published in the last 10 years and reporting associations between gut microbiota community and functionality with brain structure and function. Furthermore, some experimental animal studies of special interest have been included.

FACTORS THAT INFLUENCE THE COLONIZATION OF GUT MICROBIOTA

In the last year, several studies have shown that obesity may become a self-perpetuating problem during fetal programing (63, 117). Although the mechanisms behind this association are not fully delineated, one possible way to explain this influence is the transmission of obesogenic microbes from mother to the offspring (82); this hypothesis also takes into account other factors like maternal obesity etiology, unbalanced weight gain during pregnancy, environmental factors, or socioeconomic status (23, 55). Moreover, recent findings have reported the presence of bacteria in amniotic fluid and placenta and their potential role on infant gut colonization (115, 141). Collado et al. (24) collected maternal feces, placenta, amniotic fluid, colostrum, meconium, and infant feces samples from 15 mother-infant pairs. They observed that the placenta and amniotic fluid harbored a distinct microbiota characterized by low richness, low diversity, and predominance of Proteobacteria. However, the results are controversial, since there is no convincing evidence of the existence of a “reproducible preterm placental microbiome,” being the bacterial DNA found indistinguishable from contaminated controls (83, 85, 105).

Maternal Metabolic Environment

Even though the exact mechanism linking gut microbiota to obesity is far from being very well understood, maternal obesity during pregnancy has been associated with alterations in the composition and function of the intestinal microbial community in their offspring. Recently, Cerdó et al. (20) investigated differences in the gut microbial composition and potential functions encoded by the microbiome of infants at 18 mo of age, when the transition from early infant feeding to solid family foods is established, according to mothers’ body mass index. They observed that Firmicutes was significantly enriched in infants born to normal weight mothers, whereas Bacteroidetes was significantly enriched in infants born to obese women. Regarding functionality, the microbiome of infants born to normal weight mothers was characterized by a significant enrichment in the abundances of “pentose phosphate pathway,” “lysine biosynthesis,” “glycerolipid metabolism,” and “C5-branched dibasic acid metabolism.” Notably, the microbiome of infants born to obese mothers was significantly enriched in “streptomycin biosynthesis,” “sulfur metabolism,” “taurine and hypotaurine metabolism,” and “lipopolysaccharide biosynthesis” (20). In addition, Stanislawski et al. (124) found that maternal overweight/obesity and excessive gestational weight gain were associated with differences in the maternal gut microbiota at the time of delivery. However, these changes were associated with only limited compositional differences in their infants. Thus, understanding the relationship between the gut microbiota and obesity in mothers and their infants may offer opportunities for obesity prevention strategies.

Gestational diabetes has been suggested as a factor that interacts with the infant micronutrient status, gut microbiota, and with the offspring’s neurodevelopment (95, 118). On one hand, a study carried out by Kuang et al. (76) found a connection between gut microbiota and gestational diabetes. They compared the gut microbiota composition of 81 healthy pregnant women versus 43 pregnant women with gestational diabetes mellitus (GDM). The gut microbiota of GDM patients was rich in Bacteroides spp., Parabacteroides distasonis, and the family Enterobacteriaceae, which were previously reported as specific features of gut microbiota dysbiosis (8). On the other hand, Bassols et al. (5a) found a distinct microbiota profile in placenta in women with GDM, where bacteria belonging to Pseudomonadales order and Acinetobacter genus showed lower relative abundance compared with healthy women. Furthermore, Wang et al. (142), in addition to finding differences regarding composition, observed lower evenness but more depletion of Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs and higher abundance of some viruses (e.g., herpesvirus and mastadenovirus) in the meconium microbiota of neonates associated with GDM.

The broad public health problem of obesity requires further knowledge since it may be an important predictor of psychological problems in adulthood, adult intelligence quotient, and problems in executive function and aging (79, 136). A study carried out by Huang et al. (64) found that maternal prepregnancy obesity was associated with lower child intelligence quotient, and excessive weight gain accelerated this association. These results are in agreement with other studies, where prenatal maternal severe obesity predicted poorer neurodevelopment, worse problem-solving and fine motor skills and poorer executive functioning in areas of attention, inhibitory control, and working memory (25, 93). Furthermore, during the last years it has been reported that children born to mothers with diabetes are at risk of neurodevelopmental alterations (39, 80, 118). A recent study carried out by Torres-Espínola et al. (137), found that children born to mothers with gestational diabetes had impaired scores in gross motor development domains and also in expressive language and composite language scores. These results are in agreement with other studies (39, 53), where the authors concluded that gestational diabetes hinders expressive language in the offspring during middle childhood and is associated with lower offspring cognition.

Prenatal Nutrition

During pregnancy, a deficiency or an excess in certain nutrients will result in an altered nutrient transport through the placenta, changing offspring physiology and metabolism (35, 78). In this period, nutrition modulates disease risk by inducing gene-environment interactions in fetal homeostasis, leading to persistent changes in key signaling pathways (58). Some studies have reported that these changes during pregnancy may be associated with alterations in gut microbiota and neurodevelopment in the offspring (102) (Fig. 1).

Fig. 1.

Fig. 1.Potential links between mother during and after pregnancy and offspring gut microbiota and neurodevelopment. Prenatal and postnatal diet influence fetal microbial population, via microbiota of the mother, driving to an early innate immune system development and neurodevelopment of the infant. [Reprinted with permission from Cerdó (16).]


Nonetheless, the mechanisms regulating these adaptations are unclear (72). It is worth mentioning that gut microbiota are essential for metabolizing indigestible polysaccharides, producing essential nutrients and regulating fat storage among other functions. Moreover, it has been proposed the existence of a brain-gut microbiota axis influencing each other (17, 32), even though the critical periods where the dietary supply of specific nutrients can influence brain maturation function, are still unknown (50). Consequently, it is advisable to follow a healthy, balanced diet during pregnancy and the breastfeeding period, based on the “Balance of Good Health” model. In particular, it is recommended throughout pregnancy that women should try to consume plenty of iron‐ and folate‐rich foods and a daily supplement of vitamin D (10 µg/day) (26). In addition, it is very important to stay physically active to promote general health and well‐being and also to help in the prevention of excessive maternal weight gain, one of the main factors influencing the establishment of the offspring intestinal microbiota (20).

Type of Delivery

Microbial contact according to type of delivery imprints the offspring microbiota and immune system with a remarkably wide diversity of bacteria, being reflected by a high interindividual diversity in the neonatal gut microbiota composition (4, 99).

From the mid-1980s, it has been well known that the transmission route by cesarean section (C-section) has an impact on the infant gut microbiota, which is different from vaginal delivery (6). Recent studies have demonstrated that children born by C-section show a lower microbiota diversity and delayed Bacteroidetes colonization versus children born by vaginal mode (66). Furthermore, Martin et al. (92) showed that children born through vaginal delivery exhibit similar strains in their gut microbiota to the maternal gut and vaginal microbiota, while infants born by C-section have a gut community more similar to bacteria from mother’s skin or the hospital environment. Vaginally delivered infants carry facultative anaerobic Enterobacteriaceae that probably are transmitted directly from mother to child through feces (36). Moreover, these children born vaginally share a significantly higher proportion of gut microbiota 16S rRNA gene sequences with their own mother than with other mothers for up to 2 yr of age, particularly within the Bacteroidetes and Firmicutes phyla (66). As an alternative to the problems that the C-section carries with respect to intestinal microbial colonization, a pilot study showed that a sterile gauze, first inoculated in the mother’s vagina and then rubbed over the skin and mouth of C-section-born babies, could partially restore the neonate’s microbiome to one similar to a vaginally born baby by 1 mo of age (41). However, this method does not account for the fecal and skin microbes that also pass to the infant at the time of vaginal birth; further concerns have been raised about passing potential maternal pathogens to the infant (28). Nevertheless, such studies have brought to light many public health issues associated with maternal and infant health, as well as healthcare costs and the promise of microbiome management (22).

After birth, first colonizers are facultative anaerobes, which create a new environment that promotes the colonization of strict anaerobes such as Bacteroides, Clostridium, and Bifidobacterium spp. (109). Neonatal gut microbiota is constantly changing. It starts with low diversity and relative dominance of the phyla Proteobacteria and Actinobacteria and increases after birth; afterward it changes to a more diverse gut microbiota, with Firmicutes and Bacteroidetes emerging and dominating (44). Moreover, a recent study in fecal samples of healthy infants showed that the maturation of the gut microbiota is a nonrandom process where two mutually exclusive modules of functional families, built around Bifidobacteriaceae in children at 6 mo old and Lachnospiraceae in children at 18 mo old, maintain their function metabolically speaking, even though the type of bacteria change through time (18).

Given all the above, maternal environment will influence its offspring’s phenotype independently of the offspring's genotype. So, not only genetics will influence on the offspring, but also the mother’s lifestyle habits before and during pregnancy, as well as her lifestyle habits after pregnancy.

Postnatal Nutrition

Several studies have shown the importance of the type of feeding in the establishment of intestinal microbiota during the first year of life (70). Human milk is a dynamic fluid that changes in composition from colostrum to mature milk and varies within feeds, diurnally, and between mothers (5). Colostrum contains high amounts of IgA, lactoferrin, leukocytes, and epidermal growth factor that from 5 days to 2 weeks postpartum will change to transitional milk characterized by a lower concentration of some immunoglobulins and nutrients such as fat-soluble vitamins, polysaccharides, and sugars linked to proteins. After this period, human milk is considered fully mature and it remains stable in composition over the course of lactation (14, 52, 77). Human milk has important influence on gut microbiota establishment and functional development. In fact, human milk is an excellent source of potentially beneficial and commensal bacteria, including Staphylococci, Streptococci, lactic acid bacteria, and Bifidobacteria (67).

From a viral point of view, the change in bacteriophages over time reflects alterations in their bacterial hosts (106). Le Thomas et al. (81) report on a 38-day-old infant who developed pleuropneumonia due to a Staphylococcus aureus strain responsible for familial furunculosis, which was acquired by maternal breastfeeding. However, it is noteworthy to mention that the most abundant viral sequences in a healthy infant have not been detected in either breast milk or formula (11). Consequently, the origin of the phages in the human gut remains to be identified clearly, therefore more studies are required in this field.

Human milk provides other components such as milk fat globule membrane, which has shown to be essential for brain development (17), and human milk oligosaccharides that have immune modulatory capacity and have been related to gut microbiota and brain development and health (12). Nowadays, a formula that provides exactly the same benefits than human milk has not yet been developed. However, many infants cannot be breastfed for different reasons and they have to be fed with infant formulas (21). Infant formula’s properties are being discussed, since several studies have found that formula feeding provides greater weight gain and increases the risk of obesity, hypertension, diabetes, and less gut microbiota diversity in comparison to human milk (132).

In recent years, new technological advances have made possible the supplementation of infant formulas with bovine milk fat globule membrane and certain probiotics like Bifidobacterium and Lactobacillus species (133, 144, 145). Although the quality has improved in the past few years, artificial milk is not as nutritious nor is the quality as good as human breast milk.

Thus, the World Health Organization recommends exclusive breastfeeding for 6 mo, followed by the introduction of complementary feeding alongside breast milk (74). Recently, the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) suggested possible adverse effects on the microbiota when large amounts of iron are provided in a form not easily absorbed. Thus, this committee recommends that dietary iron supply should be between 0.9 and 1.3 mg·kg−1·day−1 from 6 to 12 mo and 0.5 and 0.8 mg·kg−1·day−1 from 1 to 3 yr of age (40). Furthermore, breast milk provides important immune factors, which have an essential role in gut microbiota development (89) and may be involved in different neurodevelopmental outcomes regarding infant formulas.

Long-chain polyunsaturated fatty acids (LC-PUFAs), highlighting docosahexaenoic acid (DHA), play an important role in brain development (84, 98). However, it is well known that DHA status tends to decline during the complementary feeding period, because the intake of human milk or LC-PUFA supplemented formulas decreases (50). European Food Safety Authority (EFSA) Dietetic Products, Nutrition and Allergies Panel recommends a suitable intake of DHA of 100 mg/day for 7- to 24-mo-old infants and young children (46). However, in a recent systematic review, it was shown that the mean DHA intake in the European Union was lower than the EFSA recommendation in 74% of the countries, which is a matter of concern in pregnant and lactating women and in infants, children, and adolescents (120). A recent research in mice has shown that n-3 PUFAs interventions induced subtle changes in the offspring during early life and adolescent behavior, since omega-3 deficient (O3−) animals displayed impaired communication, social, and depression-related behavior and omega-3 supplemented (O3+) animals displayed enhanced cognition. Furthermore, there was a change in the ratio Firmicutes: Bacteroidetes in O3− mice, with a blunted systemic LPS responsiveness. Contrastingly, O3+ mice displayed greater fecal Bifidobacterium and Lactobacillus abundance and dampened hypothalamic-pituitary-adrenal (HPA)-axis activity (108).

On the other hand, consumption of sugar-sweetened beverages and free sugars in children is too high at the present and increases the risk for dental caries and overweight/obesity, giving rise to a diet poor in nutrients, leading to overeating, diminished release of hormones such as glucagon-like peptide-1, impaired blood glucose regulation, and increasing cardiovascular risk (51). Additionally, the use of these artificial sweeteners has become a topic of interest. Artificial sweeteners provide a sweet flavor and usually no or very low energy. Under European regulations by the European Food Safety Authority (Council Directive 89/398/EEC), artificial sweeteners cannot be added to infant formulas, follow-on formulas, cereals, baby foods, or dietary foods for very young children for special medical purposes, unless it is expressly indicated (57). As a matter of fact, it has been proposed that they may be particularly problematic in gut microbiota community, altering the metabolic pathways of the bacteria, contributing to impaired glucose regulation (56). It is noteworthy that there is no nutritional requirement for free sugars in infants, children, and adolescents. For this reason, the ESPGHAN Committee on Nutrition recently recommended reducing and minimizing the intake of free sugars, with a desirable upper limit of <5% of the total daily energy intake in children and adolescents aged 2–18 yr. In infants and toddlers who are less than 2 yr of age, intakes should be even lower (51).

There is limited evidence that excessive intake of proteins during the first 2 yr of life increases later risk for obesity (86). Thus, it is very important to control the amount of proteins in infant formulas, reducing their content to be similar to breast milk. It is not well established to what extent the level of protein intake may impact gut microbiota establishment and maturation during the first years of life; nevertheless, it has been demonstrated that babies fed with infant formulas with a high amount of proteins show a high risk of developing obesity during childhood (60). EFSA recommends that the minimum level of protein in cows’ milk-based infant formulas and follow-on formulas should remain at 1.8 g/100 kcal (47). On the European market, artificial formulas have a very wide amount of proteins, up to 6.7 g/100 kcal with a median of 2.6 g/100 kcal, although it is not mentioned whether the protein source is animal or plant, being the content is lower than regular cow’s milk (4.8 g/100 kcal) (62). However, the EFSA recommends that the upper limit for protein content of follow-on formulas should be reduced from 3.0 to 2.5 g/100 kcal. Therefore, it has been suggested to lower the protein content of artificial formulas to a median of 1.6 g/100 kcal for animal-based protein products (121). Therefore, it is necessary to carry out more studies that allow for exact determination of the optimal amount of nutrients for a favorable neurodevelopment, as well as for an adequate establishment and development of gut microbiota, to preserve offspring’s health.

GUT MICROBIOTA AND METABOLISM/ENERGY BALANCE

A major challenge in microbial ecology is to identify its functional members and understand how their functional and phylogenetic dynamics ultimately influence human physiology and health. Even though the exact mechanism linking gut microbiota to obesity is far from being understood, maternal obesity during pregnancy has been associated with alterations in the composition and function of the intestine microbial community. Recently, Gosalbes et al. (59) employed metatranscriptomic sequencing analyses to study gene expression in the gut microbiota metabolism of infants during the first years of life and their mothers. They have shown that hallmarks of aerobic metabolism disappear from the microbial metatranscriptome as development proceeds, while the expression of functions related to carbohydrate transport and metabolism increase and diversify, approaching to what has been observed in a control group of nonpregnant women. Furthermore, butyrate synthesis enzymes were overexpressed at 3 mo of age, even though most butyrate-producing organisms were still rare. In late pregnancy, the microbiota readjusts the expression of carbohydrate-related functions in a manner consistent with a high availability of glucose. On the other hand, several studies in animals have shown that germ-free mice, which received a transplantation of human microbiota from the third trimester of pregnancy, displayed symptoms of metabolic syndrome, reducing glucose tolerance and increasing adiposity and inflammation (54). These effects may be mediated by key gut microbial metabolites, such as short-chain fatty acids, which were previously shown to be associated with these metabolic changes during pregnancy (101).

After delivery, the initial stages of microbiota colonization and maturation in the gut are critically important, because it has been shown that early dysbiosis may affect human health later in life, which could alter the host metabolism (107). Although a high number of papers has described community membership in gut microbiota (42, 119), few studies have attempted to provide insight into the dynamics of functional and metabolic processes associated to gut microbial evolution and maturation (71, 128). Recently, a study using metaproteome analysis showed that early gut microbiota acquires a significant capacity to transport bicarbonate, ion metals, amino acids, and inorganic oxides during the first 6 mo of life and that the role of host and dietary glycan degradation, central carbon metabolism, and short chain fatty acid fermentation reflects the progression to a mature profile in the gut microbiota, providing insights into the metabolic strategies of gut microbiota taxa (18).

Since obesity, inflammation, and immune system are closely related, emerging evidence points to the fact that gut microbiota metabolism changes intestinal permeability and inappropriate immune responses predispose to alterations in neurodevelopment (Tables 1 and 2). Soto et al. (123) have shown that mice with a diet-induced obesity presented anxiety and depression, which were associated with decreased insulin signaling and increased inflammation in the nucleus accumbens and amygdala. After treatment with antibiotics, changes in gut microbiota reflected an improvement in insulin signaling in the brain, reducing signs of these behaviors. On other hand, Wang et al. (143) observed that children with autism spectrum disorders (ASD) presented altered glutamate metabolites, along with a decline in 2-keto-glutaramic acid and an abundance of microbiota associated with glutamate metabolism. Recent preclinical findings suggest that alterations in gut microbiota metabolism increase microglia activation in the brain and the levels of proinflammatory cytokines in the cerebrospinal fluid, giving way to neurological disorders (2).

Table 1. Overview of studies focused on the effects of human gut microbiota on neurodevelopment/brain functioning in randomized controlled clinical trials

Study (Reference)Cohort PopulationKey Findings & Conclusions
Wang et al. (2019) (143)92 children with ASD and 42 age-matched children exhibiting typical developmentAltered glutamate metabolites were found in the ASD group, along with a decline in 2-keto-glutaramic acid and an abundance of microbiota associated with glutamate metabolism.
Pärtty et al. (2015) (100)75 infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed up for 13 yrAt 13 yr old, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group. The mean amounts of Bifidobacterium species bacteria in feces during the first 6 mo of life were lower in affected children than in healthy ones. Probiotic supplementation in early life may reduce the risk of neuropsychiatric disorders development later in childhood.
Martin et al. (2009) (91)30 human subjects; 40 g of dark chocolate/day/14 days; classified in low and high anxiety traits with validated psychological questionnaires.Dark chocolate reduced urinary excretion of cortisol and catecholamines and partially normalized stress-related differences in energy metabolism and gut microbial activities. 40 g of dark chocolate/day/14 days modifies host and gut microbial metabolism of free living and healthy human subjects. Nevertheless, these results have to be taken with caution due to the small sample size.
Tillisch et al.
(2017) (130)
40 women supplied fecal samples for 16S rRNA profiling.Two bacterial genus-based clusters were identified, one with greater Bacteroides abundance (n = 33), one with greater Prevotella abundance (n = 7). The Prevotella group showed less hippocampal activity viewing negative valences images. For gray matter, the Bacteroides cluster showed greater prominence in the cerebellum, frontal regions, and the hippocampus.
Tillisch et al.
(2013) (129)
Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given fermented milk product with probiotic FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 wk.FMPP intake was associated with reduced task-related response of a distributed functional network containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity.
Aarts et al.
(2017) (1)
96 participants, of whom 19 had been diagnosed with ADHD and 77 were healthy.A nominal increase in the Bifidobacterium genus was observed in ADHD cases. The observed increase was linked to significantly enhanced 16S-based predicted bacterial gene functionality encoding cyclohexadienyl dehydratase in control cases. These results show increases in gut microbiome predicted function of dopamine precursor synthesis between ADHD cases and controls.

ASD, autism spectrum disorders; ADHD, attention deficit-hyperactivity disorder; AS, Asperger syndrome; FMPP, fermented milk product with probiotic.

Table 2. Overview of studies focused on the effects of gut microbiota on animals’ neurodevelopment

Study (Reference)Cohort PopulationKey Findings & Conclusions
Robertson et al. (2017) (108)C57BL/6 male offspring mice with control, O3+ or O3− diets (n = 10 per group)Neurobehavioral development related to cognitive, anxiety, and social behaviors is highly dependent upon in utero and lifelong n-3 PUFA availability. Neurobehavioral changes induced by altering n-3 PUFA status are closely associated with comprehensive alterations in gut microbiota composition, HPA axis activity and inflammation.
Soto et al. (2018) (123)6-wk-old male C57BL/6J mice maintained on either a normal or a high-fat diet for 6 wk. During the last 2 wk, some of the HFD mice were treated with vancomycin or metronidazoleDiet-induced obesity causes anxiety and depression, decreasing insulin signaling and increasing inflammation in the nucleus accumbens and amygdala. Treatment with antibiotics alters gut microbiota community controlling brain insulin signaling and metabolite levels, leading to altered behavior.
Davari et al. (2013) (34)40 male Wistar rats at 45 days of age assigned to four groups (controls vs diabetes)Probiotics administration considerably improved the impaired spatial memory in the diabetic animals. Probiotics efficiently reversed deteriorated brain functions in cognitive performances levels and their proposed synaptic mechanisms in diabetes mellitus.
Bravo et al. (2011) (10)Adult male BALB/c mice (n = 36)Chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain, with increases in cortical regions and concomitant reductions in expression in the hippocampus, amygdala, and locus ceruleus. Neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain.
Vinolo et al. (2011) (139)Male Wistar rats (sample size not available)Propionate and butyrate diminished TNF-α, CINC-2αβ and NO production by LPS-stimulated neutrophils. Products of cyclooxygenase and 5-lipoxygenase are not involved in the effects of SCFAs. Propionate and butyrate inhibit HDAC activity and NF-κB activation, which might be involved in the attenuation of the LPS response.
Sudo et al. (2004) (127)SPF and gnotobiotic mice (n = 18–24 per group)Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. Commensal microbiota affects postnatal development of the HPA stress response in mice with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhancing the response to stress.

ACTH, adrenocorticotropic hormone; CINC-2αβ, cytokine-induced neutrophil chemoattractant-2; GF mice, germ-free mice; HDAC, histone deacetylase; HFD, feeding a high-fat diet; HPA, hypothalamic-pituitary-adrenal; LPS, lipopolysaccharide; NF-κB, nuclear factor κB; NO, nitric oxide; OR, omega-3; PUFA, polyunsaturated fatty acid; SPF, specific pathogen free; TNF, tumor necrosis factor.

MICROBIOTA AND BRAIN DEVELOPMENT

Microbiota-Brain Axis

In recent years, an increasing interest about the importance of gut microbiota in the development of different psychiatric diseases such as autism (135), schizophrenia (37), attention deficit-hyperactivity disorder (ADHD) (100) or depression (33), has been shown. So far, the influence of the mother gut microbiota on the cognitive or behavioral development of the offspring has not been thoroughly studied (94). Neurodevelopment will be influenced by the genetic predisposition of the individual and by the influence of external factors (social, environmental, lifestyle) and dietary factors (diet, probiotics, prebiotics) (Table 2). The intestinal microbiota community will be affected by these factors and it will influence the functions and development of brain activity. There are several evidences showing mutual mechanisms between central nervous system (CNS) and gut microbiota community, which involve the vagus nerve, the hypothalamic-pituitary-adrenal (HPA) axis modulation and the immune system (Fig. 2).

Fig. 2.

Fig. 2.Gut-brain axis pathway. Direct and indirect pathways support the bidirectional interactions between the gut microbiota and the central nervous system: cytokine balance and microglia activation (immune pathway), cortisol (endocrine pathway), and vagus nerve and enteric nervous system (neural pathway). In addition, short-chain fatty acids (SCFAs) are neuroactive bacterial metabolites of dietary fiber fermentation that can also modulate brain and behavior. HPA, hypothalamic-pituitary-adrenal. [Reprinted with permission from Cerdó (16).]


Vagus Nerve

The vagus nerve predominantly supplies the thoracic and abdominal cavities (7). It is the major modulatory communication pathway between gut microbiota and brain. Evidence of this communication has been demonstrated in studies with vagotomized mice. These mice did not present neurochemical and behavioral effects (10). Moreover, the vagus nerve does not project directly into the lumen, and its activation is partly dependent on the secretion of chemical signals such as peptide YY, glucagon-like peptide 1, or cholecystokinin by specialized endocrine cells in the intestinal tract (110). These gastrointestinal peptides play a role in the regulation of energy intake in humans. Short-chain fatty acid (SCFAs) produced by gut microbiota induce secretion of these peptides, via protein-coupled receptor (GPR) activation, on enteroendocrine cells and subsequent vagal afferent signaling (43).

The vagus nerve is able to sense the microbiota metabolites through its afferents and to transfer this gut information to the CNS, where it will generate an adapted or inappropriate response (9). A cholinergic anti-inflammatory pathway has been described through vagus nervous fibers. This pathway is able to dampen peripheral inflammation and to decrease intestinal permeability, very likely modulating microbiota composition (90). These researches show that the vagus nerve is a potential target with anti-inflammatory properties, in addition to being a way of interest to study the signaling processes during the first months of life, helping to understand the functioning of the brain-microbiota-brain axis during infant development.

HPA Axis

Hypothalamic-pituitary-adrenal (HPA) axis activity is governed by the secretion of adrenocorticotrophic hormone-releasing factor and vasopressin from the hypothalamus, which in turns activates the secretion of adrenocorticotrophic hormone (ACTH) from the pituitary, which finally stimulates the secretion of glucocorticoids (cortisol) from the adrenal cortex (61). Cortisol levels are increased in response to stress (104). Furthermore, high levels of proinflammatory cytokines influence the activation of HPA axis, which activate the production of cortisol (38). Recently, a study assessing the effect of a combination of Lactobacillus helveticus and Bifidobacterium longum on humans showed that both species had beneficial psychological effects with a decrease in serum cortisol (34). Interestingly, a study of 77 human patients with irritable bowel syndrome, with an abnormal IL-10/IL-12 ratio, indicative of a pro-inflammatory state, showed that Bifidobacterium infantis 35624 feeding produced a normalization of the interleukins ratio (97).

In addition, Martin et al. (91) observed in human subjects with high anxiety trait that the consumption of 40 g of dark chocolate reduced levels of urinary excretion of the stress hormone cortisol and catecholamines. Also, they observed partially normalized stress-related differences in energy metabolism (glycine, citrate, trans-aconitate, proline, β-alanine) and gut microbial activities (hippurate and p-cresol sulfate). Nevertheless, these results have to be taken with caution due to the small sample size. Other studies in animals showed a mono-association with B.infantis, a representative inhabitant of the neonate gut, and a reduction in the HPA stress response of germ-free mice. This effect was also observed with the reconstitution of germ-free mice with feces from specific-pathogen-free mice (127).

Therefore, the commensal microbiota, influenced by diet, plays a crucial role against the development of stress-related disorders, such as anxiety and depression, altering the development of the HPA axis. These new concepts are very suggestive for future studies; it is necessary to confirm the microbial content of the gut during infancy and early childhood, which constitute critical periods for the development of an appropriate stress response later in life. Moreover, it is necessary to identify the narrow window in early life during which the microbial colonization must occur to ensure the normal development of the HPA axis.

Host Immunity

Gut microbiota provides a broad variety of metabolites from the anaerobic fermentation of exogenous undigested dietary components that reach the colon, as well as endogenous compounds that are generated by microorganisms and the host. These metabolites access the single layer of epithelial cells that makes up the gut mucosal interface and interacts with host cells, influencing immune responses and disease risk (111).

One of the most abundant substrates for bacteria in the colon is the undigested carbohydrates complex, which are metabolized during the fermentation to produce SCFAs. This includes acetic acid, butyric acid and propionic acid, which are important energy sources not only for the gut microbiota itself, but also for intestinal epithelial cells (27). Although their effects on host physiology and immune system are not fully understood, they act as local substrates for energy production and are involved in diverse regulatory functions. Several studies have identified the SCFA as inhibitors of histone deacetylases, a crucial regulator of the inactivated nuclear factor-κB activity and pro-inflammatory innate immune responses (138, 139). Furthermore, Erny et al. (48) found in germ-free that the GPR43 expressed by microglia for the maintenance of its homeostasis, requires SCFAs produced by the gut microbiota.

The intestinal tract contains high levels of polyamines, which are derived from the diet and from de novo production by host and microbial cells (88). Polyamine metabolism has a central role in regulating immunity and must be tightly controlled by the host. Arginase 1 and nitric oxide synthase compete for arginine to produce either polyamines or nitric oxide, respectively, and are important enzymes that balance effector immune responses (147). Several studies have suggested that host-microbial polyamine synthesis is an important function of the gut microbiome that is acquired early in life and is necessary for postnatal development of the gastrointestinal tract (31, 87). Kibe et al. (69) showed that the administration of arginine in combination with Bifidobacterium animalis subsp. lactis LKM512 in mice resulted in increased levels of circulating and colonic polyamines, decreasing levels of TNF and IL-6 in the colon.

In most neurological disorders, the immune system, through inflammation, appears to play an important role in the development and/or progression of the disease. The gut bacterium Lactobacillus reuteri is known to produce indole-3-aldehyde from dietary tryptophan, which can modulate the inflammatory status of human astrocytes, with important consequences for neuroinflammation (112, 146). Regarding the incidence of the general inflammatory condition on dementia in humans, Koyama et al. (73) carried out a meta-analysis, where they demonstrated that high levels of peripheral inflammatory markers are related to a slight increase in the risk of dementia in the broad sense, not to Alzheimer disease.

These findings raise the hypothesis that manipulating the diet and providing beneficial bacteria may favorably alter colonic metabolism to benefit host’s health. In addition, more studies in humans should be carried out, since most of the current results are based on animal models; these studies will lead to evaluating the potential beneficial effects of gut microbiota on children’s immune system, and its association with food choices and consumption, and eating behavior. These approaches would help in the discovery of new health status biomarkers during the first years of life.

Gut Microbiota and Brain Structure and Function

Although much of the progress in understanding the influences of the microbiota-gut-brain axis in mental disorders has been based on the composition and function of gut microbiota, work is now moving toward brain function investigation using neuroimaging. Despite this progress, few studies have established direct links between gut microbiota and brain function. A recent report (130) showed that 40 healthy women could be classified into two bacterial genus-based clusters based on their gut microbiota composition, one with greater Bacteroides abundance (n = 33) and the other with greater Prevotella abundance (n = 7). The results of functional magnetic resonance imaging showed that the Prevotella group had less hippocampal activity viewing negative valences images. White and gray matter imaging discriminated the two clusters, with an accuracy of 66.7% and 87.2%, respectively. The Prevotella cluster was associated with differences in emotional, attentional, and sensory processing regions. For gray matter, the Bacteroides cluster showed greater prominence in the cerebellum, frontal regions, and the hippocampus. Interestingly, another study informed that the consumption of a fermented milk product with probiotic for 4 wk by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks (129). These studies support the concept of gut microbiota-brain interactions in healthy adults. Nevertheless, few studies have been carried out in children, and none explaining early programing of such axes, despite several evidence of early programing of neurological disorders such as ADHD, autism, or other cognitive and behavioral problems. Aarts et al. (1) observed in children with ADHD an increase of 16S-based predicted bacterial gene functionality encoding cyclohexadienyl dehydratase. This enzyme is involved in the synthesis of phenylalanine, a precursor of dopamine. This increase in microbiome function relates to decreased neural responses to reward anticipation, which constitutes one of the hallmarks of ADHD.

Although the current knowledge in the field of brain imaging includes an approach to connect gut microbial ecology with large-scale brain networks, further examination of the interaction between early life gut microbes, brain, and later health is needed to inform preclinical reports that early life microbial modulation may affect mood and behavior later in life.

FUTURE PERSPECTIVES AND CONCLUSIONS

The relationship between behavior disorders and gut microbiota metabolism is the subject of a growing number of studies. Some microorganisms are thought to produce substances derived from their metabolism that can cross the blood-brain barrier and are therefore likely to be involved in central nervous system impairments. A better understanding of these interactions would help to clarify the etiology of some psychiatric disorders that are still poorly understood. Alternative approaches that comprise a holistic view of the gut microbiota, which implies studying not only bacteria, but also fungal species, and viruses are needed to develop new therapies based on the manipulation of the gut ecosystem to promote an optimal neurodevelopment and prevent mental diseases.

Fungal dysbiosis could influence bacterial development metabolism and vice versa, being able to affect the development of certain diseases. Strati et al. (126) studied 40 children with severe autistic disorders versus 40 controls and they observed disparities in fungal community between both study groups. The autistic group presented a twofold higher proportion of Candida compared with the control group. Functional analysis of fungal community during early life is needed to understand the relationship of intestinal microbiota and neurodevelopment.

On the other hand, the human gut harbors plant-derived viruses, giant viruses, and abundant bacteriophages. New metagenomic methods have allowed reconstitution of the entire viral genomes from the genetic material spread in the human gut, opening new perspectives on the understanding of the gut virome composition and potential clinical applications (116). Zuo et al. (148) investigated enteric virome alterations in Clostridium difficile infection (CDI) and the association between viral transfer and clinical outcome in patients with CDI. They observed that the treatment response in fecal microbiota transplantation (FMT) was associated with a high colonization level of donor-derived Caudovirales taxa in the recipient. They concluded that Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI. From the above mentioned, it results that clinical practice in the foreseeable future could be based on donor selection according to virome characteristics in FMT practice.

Recently, the use of phytobiotics has emerged as a potential alternative to the use of antibiotics. Phytobiotics are preparations of plant origin, as well as their chemical constituents that positively affect the microbiota of the gastrointestinal tract. They have secretomotoric and secretolytic properties, which can enhance the immune system of the host and decrease pathogens (68). Phytobiotics have gained more interest as potential alternatives to antimicrobials, showing also their antioxidant, immunomodulatory, and therapeutic effects against various diseases and disorders (113, 114, 134, 140). However, despite the many beneficial properties of phytobiotics, more research evidence on a molecular basis is needed to find out the molecular mechanism of action in various animals and human models to validate the usefulness of these preparations as potential therapeutic agents.

In conclusion, progress continues to be made in deciphering mechanisms by which the microbiota impact metabolism and how the role of diet, as a modifiable factor, likely holds the key to exploit our increasing understanding of the microbiota to prevent disease and improve health. Furthermore, it has been shown that gut microbiota are involved through many metabolites and several pathways with the brain development from early life. The role of gut microbiota in the maturation of the neuroendocrine axis that controls stress and regulates emotions has been clearly established. Finally, the identification of biomarkers of gut microbiota-brain axis dysfunction during early life, the use of neuroimaging, and the identification of critical windows will facilitate the development of novel specific and personalized therapeutic interventions to prevent mental diseases and behavioral problems later in life. Among the limitations of this review were the few studies found related to brain structure and brain function and gut microbiota in humans, the lack of systematization of the search, and the lack of analysis of the articles included.

GRANTS

Supported by funds from European Union 7th FP KBBE.2013.2.2-02—MyNewGut Project (“Factors influencing the human gut microbiome and its effect on the development of diet-related diseases and brain development,” Grant Agreement 613979) and from Spanish Ministry of Economy and Competitiveness—GD-Brain Project (SAF2015-69265-c2.2).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

T.C. and C.C. conceived and designed research; T.C. prepared figures; T.C. drafted manuscript; T.C., E.D., and C.C. edited and revised manuscript; T.C., E.D., and C.C. approved final version of manuscript.

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AUTHOR NOTES

  • Address for reprint requests and other correspondence: C. Campoy, Dept. of Paediatrics, School of Medicine, Univ. of Granada, Avda. de la Investigación, 11, 18016 Granada, Spain (e-mail: ).