Exploring the role of the gut microbiome in pediatric gastrointestinal and neurological health

Introduction

The human body is a superorganism, an intricate biological system made up of human cells and a vast number of commensal, symbiotic, and pathogenic microorganisms. The most densely populated microbiome is the gut microbiome, which is located in the gastrointestinal (GI) tract, and contains trillions of bacteria, archaea, viruses, and fungi. In the past 20 years, our understanding of the role of the microbiome has shifted. Once thought to be solely involved in digestion, it is now recognized as a key regulator of human physiology, including immune function, metabolism, and brain development. This review highlights the key role of the gut microbiome in the most dynamic and vulnerable stage of life, childhood (1).

The formation of the gut microbiome is not random; rather, it is a stepwise, programmed process that starts at birth. The first microbial inoculum is strongly dependent on the delivery method; infants born vaginally are colonized by microbes similar to those of the maternal vagina and feces, while those born by cesarean section are colonized by skin and environmental microbes (2). This initial community is then sequentially influenced by diet—breast milk serves as an important source of prebiotic human milk oligosaccharides (HMOs) and specific bacteria—antibiotic exposure—which can induce profound and sometimes lasting changes in composition—and a variety of other environmental factors. This early-life collection pathway can affect long-term health, a concept that is commonly referred to as the hygiene hypothesis or developmental origins of health and disease (DOHaD) (3).

The gut microbiome influences brain function through the gut-brain axis (GBA), a complex two-way communication system involving neural, hormonal, and immune pathways (4). The gut microbiome is a major regulator of this axis. It also produces a vast array of neuro-active and immuno-active compounds, including short-chain fatty acids (SCFAs), such as butyrate, a microbial fermentation product of dietary fibers that strengthens the blood-brain barrier (BBB) and exerts anti-inflammatory effects; as well as various neurotransmitters, including serotonin and gamma-aminobutyric acid (GABA), such as serotonin (90% of which is produced in the gut) and GABA; and metabolites that modulate the activation of microglia, the cells of the brain’s immune system (5).

When the precarious development of the microbiome is upset, microbial imbalance (i.e., dysbiosis) may ensue. This is characterized by a loss of beneficial microbes, reduced microbial diversity, and an increase in pathobionts (potentially harmful microbes). In pediatrics, dysbiosis has been shown to be mechanistically associated with numerous diseases. Inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC) are well-known GI diseases that are closely linked to dysbiotic patterns of microbial life, which increase inflammation and counteract intestinal barrier functions (6).

More dramatically, it is now established that gut dysbiosis is related to neurodevelopmental disorders. Children diagnosed with autism spectrum disorder (ASD) typically suffer GI symptoms and possess a unique composition of gut microbiota that is proportionate to the level of severity of their behavioral symptoms (1). Similarly, the microbiome is altered in attention-deficit/hyperactivity disorder (ADHD), anxiety, and other mood disorders, leading to the conclusion that the microbiome is a regulator of emotion, cognition, and behavior (7).

Malnutrition, including both undernutrition and overnutrition, is a principal cause of dysbiosis, which has dire consequences for the planet. Both protein-energy malnutrition (PEM) and micronutrient deficiencies directly affect the gut environment, leading to a loss of microbiota diversity, decreased SCFA production, and an alteration in gut integrity. This allows bacterial endotoxins to translocate into the circulation, resulting in systemic inflammation that can impair nutrient absorption, causing a vicious cycle and impairing neural growth via neuroinflammatory mechanisms (8).

The results of malnutrition-induced gut dysbiosis—meaning impaired nutrient absorption, inflammation, and disrupted neurodevelopment. and can include impaired cognitive function, impaired growth, and an increased incidence of infection. Thus, an understanding of the complex interplay between the gut microbiome, nutrition, and the GBA is critical for improving pediatric health outcomes. This review includes a thorough analysis of the manner in which the gut microbiome affects both the GI and neurological health of children. It also discusses the insidious consequences of malnutrition-induced dysbiosis and the exciting possibilities for treatment modalities. Various modalities, such as probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), and the emerging field of precision nutrition, which tailors dietary recommendations to an individual’s microbiome and genetic predisposition, offer promising methods for restoring microbial homeostasis and thus eliminating disease, resulting in optimal growth and functioning in children worldwide (9).

The GBA: definition and pediatric relevance

The central nervous system and the enteric nervous system of the GI tract are connected via the intricate, two-way GBA. This system allows for constant communication between the gut and the brain, enabling emotional and cognitive centers to influence intestinal functioning (e.g., motility, secretion, and permeability) and the afferent signals of the gut to influence brain activity, which in turn affects mood, behavior, and cognition (10). The GBA is crucial because early-life development of the brain, immune system, and microbiome occurs simultaneously. This axis serves as a multi-system interface, and communication occurs via three parallel and interacting pathways.

In the neural pathway, the vagus nerve functions as the major neural superhighway of the GBA. This cranial nerve provides a direct physical link between the brainstem and the GI tract. Gut microbes and enteroendocrine cells residing in the lining of the intestines produce neurotransmitters and metabolites (e.g., serotonin, GABA, and SCFAs) that activate vagal afferent fibers. These signals are directed to the brain affecting parts of the brain that deal with stress, emotion, and appetite, including the hypothalamus, amygdala, and nucleus tractus solitarius (11).

In the immune pathway, the gut microbiome is critical in training and regulating the host immune system. A diverse microbiome in a healthy state induces a state of anti-inflammatory tolerance. However, dysbiosis may compromise the integrity of the intestinal barrier, resulting in a “leaky gut”. This causes bacterial lipopolysaccharides (LPSs) or other immunogenic compounds to translocate to the systemic circulation, resulting in a low-grade inflammatory response. Pro-inflammatory cytokines [e.g., tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-6] may also cross the BBB or stimulate the surrounding vascular structures, resulting in neuroinflammation. Persisting neuroinflammation has been implicated in the pathophysiology of various neurodevelopment and psychiatric disorders (12).

In the neuroendocrine/hormonal pathway, enteroendocrine cells are scattered throughout the epithelium of the gut and serve as specialized sensory cells that respond to nutritional and microbial stimuli by secreting more than 20 different hormones into the bloodstream. One of the most important hormones is serotonin (5-HT). The gut produces more than 90% of the body’s serotonin. It is a vital controller of mood, sleep, and thought in the brain, and peristalsis and secretion in the gut. The main stress hormone is cortisol, which is secreted by the hypothalamic-pituitary-adrenal axis (13).

This complex interaction enables the gut microbiome to affect the brain and the brain to affect the gut. As Figure 1 shows, the GBA has important elements such as the vagus nerve, which conveys information between the gut and the brain, and microbial metabolites such as SCFAs and neurotransmitters such as serotonin and GABA, which are essential in the regulation of mood, cognition, and gut motility. Moreover, immune pathways in the gut play a role in neuroinflammation and BBB integrity, further emphasizing the role of gut health in neurological outcomes.

Figure 1 Two-way communication between the brain and the gut microbiome. Diagram showing the major mediators in the two-way communication between the brain and the gut microbiome are the vagus nerve and the enteric nervous system, which connect to the central nervous system, and allow microbial signals in the gut to affect the brain. The microbiota synthesizes neurotransmitters such as serotonin and GABA, which influence mood and cognition. The immune signaling pathways are also depicted showing the effects of gut-derived cytokines and short-chain fatty acids on neuroinflammation and the blood-brain barrier. This illustration highlights the two-way relationship between the brain and the gut, which is essential in gastrointestinal and neurological wellbeing. GABA, gamma-aminobutyric acid; SCFA, short-chain fatty acid.

The relevance of the gut-brain axis in pediatric development

Due to the simultaneous and rapid development of the brain, immune system, and gut microbiome in early life, the GBA is of paramount importance in pediatrics. This period represents a critical window of vulnerability and opportunity.

In terms of neurodevelopment, the microbial metabolites and immune signals relayed via the GBA are crucial for normal brain development, including synaptogenesis, myelination, and the maturation of stress-response systems. Early-life disruptions to this signaling (e.g., through antibiotic use, infection, or malnutrition) can have long-lasting effects on cognitive function and emotional regulation (14).

In terms of the manifestation of disorders, the GBA provides a plausible biological framework for understanding the frequent comorbidity of GI disorders (e.g., IBD and abdominal pain) with neuropsychiatric conditions (e.g., ASD, ADHD, and anxiety) in children. Aberrant signaling along any of the three pathways can contribute to the symptoms of both gut and brain disorders, making the GBA a prime therapeutic target for intervention (15).

Effect of early-life exposures

In infants, the early colonization and development of the intestinal microflora are modulated by environmental exposures that occur in early life in a phase known as the “critical period”. During this time, the microbial flora is very plastic and its composition may exert long-lasting effects on immunity, the metabolic processes of the body, brain function, and overall health later in life (16).

One important factor is the mode of delivery. Infants born vaginally are immediately exposed to maternal vaginal and fecal bacteria, most of which are non-pathogenic species belonging to the genera of Lactobacillus, Bifidobacterium, and Bacteroides. Babies born by surgical delivery (cesarean section) have skin bacteria from the mother and hospital microflora, including Staphylococcus, Corynebacterium, and Propionibacterium. This may influence immune mechanisms and metabolic disorders, such as asthma, allergic diseases, and obesity, particularly when combined with antibiotic treatment in infancy and variations in breastfeeding (17).

Diet type in infancy is a further important determinant of the structure of the intestinal flora. Breast milk has special bioactive ingredients, particularly HMOs, which favor the growth of beneficial non-pathogenic bacteria in the large intestine (e.g., Bifidobacterium and Bacteroides), leading to a well-structured gut microflora. The use of lactose-free formula or regular formula in infancy may be necessary; however, it results in reduced microbial flora diversity, an increase in flora known as pathobionts, including some Clostridium species and Escherichia coli, and a poorly developed gut barrier (18).

Studies have shown that exposure to antibiotics in the early days of life changes its structure so that there is less of it, and delays its maturity. The most significant effects of this occur during the early postnatal months, resulting in a greater susceptibility to infections, allergies, and obesity (19).

Other environmental factors, such as place of residence, lifestyle (urban versus rural), and social level, also play an important role in shaping the gut microflora. Children who are raised on farms or have pets have more varied intestinal flora and are less prone to allergies, which supports the hygiene hypothesis. Maternal health during pregnancy, including diet and exposure to stress, can affect an infant’s immune system and intestinal flora (20).

Malnutrition and GI dysfunction

Malnutrition, including PEM and micronutrient deficiencies, triggers a vicious cycle of GI dysfunction that continues and intensifies nutritional deficiencies. The gut microbiome is highly susceptible to dietary deficiencies, as it depends on diet to sustain itself and carry out its functions. Protein and micronutrient deficiencies directly affect the gut environment, resulting in a state of severe dysbiosis with reduced microbial diversity, a loss of key beneficial taxa such as Bifidobacterium and Faecalibacterium prausnitzii, and the overgrowth of proteobacteria and other potential pathobionts (21).

Link to malnutrition: the connection between malnutrition, GI dysfunction, and neurological development

Malnutrition causes major disturbances in the GI system, leading to changes in the gut microflora that produce significant GI disturbances. The GI tract is home to trillions of organisms important for digestion, immune regulation, and metabolism. Malnutrition causes significant changes in the gut flora, often resulting in dysbiosis, which is defined as an imbalance of the flora that leads to both acute and chronic GI dysfunction (22).

A major consequence of malnutrition is damage to gut barrier function integrity. Intestinal epithelium integrity is essential in nutrient absorption and gut homeostasis. Malnutrition can compromise this barrier, increasing its permeability, leading to the translocation of harmful microbes into the bloodstream that will worsen systemic inflammation and nutritional absorption. This leads to a cycle whereby the child’s nutrient absorption ability is impaired. This is particularly damaging in children because the developing GI tract is more vulnerable to long-term damage.

Malnutrition related to protein and micronutrient deficiencies also commonly leads to a loss of flora variety. Beneficial bacteria such as Bifidobacterium and Lactobacillus decrease while pathogenic microbes increase. Animal model and human population studies (23). have shown that malnutrition can cause increased intestinal permeability, commonly known as “leaky gut.” This condition allows for the passage of poisons and pathogens into the blood stream, and leads to increased systemic inflammation. Increased intestinal permeability has also been shown to be associated with impairment of immune responses. This will affect common GI symptoms of diarrhea, bloating, and malabsorption in malnourished children (23-25).

Effect of malnutrition on the gut microbiome

Chronic malnutrition in children is characterized by reduced gut microbial diversity, which is necessary for appropriate immune responses. Children suffering from PEM have higher concentrations of opportunistic enteric pathogens, including Enterobacteriaceae and Clostridium, which are associated with inflammatory changes and impaired immune function (26).

Malnutrition also affects microbial metabolites, including those necessary for the production of SCFAs, which are necessary for proper gut health. The fermentation of dietary fiber by the microbiota results in the production of SCFAs, including butyrate, acetate, and propionate. These metabolites affect gut-barrier function and inflammatory responses, and may even influence brain activity. However, this rarely occurs in malnutritional states, where low SCFAs lead to dysfunctional gut barrier function, systemic inflammation status, etc. (27). As Figure 2 shows, probiotics and firmicutes reduce microbial diversity and gut-barrier function, and increase inflammation, producing a cascade of both GI and systemic metabolic dysfunction; thus, a balanced microbiome is a prerequisite for maintaining health.

Figure 2 Mechanistic comparison of a healthy gut microbiome vs. dysbiosis. Graphic of a healthy gut microbiome with commensal bacteria (e.g., Lactobacillus and Bifidobacterium), and a dysbiotic microbiome with pathogenic bacteria that may over proliferate. Dysbiosis results in reduced microbial diversity, a loss of gut barrier integrity, and inflammation with a predominance of Proteobacteria and Firmicutes, which is associated with gastrointestinal and neurological dysfunction. ATP, ; SCFA, short-chain fatty acid.

Malnutrition and neurological development

Malnutrition significantly affects the developing brain through the GBA. Altering the gut microbiome causes systemic and central inflammation, which can affect major brain functions. Increased intestinal permeability and LPS translocation can affect the brain, resulting in the release of pro-inflammatory cytokines that can cross the BBB and activate the microglial cells, which can induce a state of chronic inflammation. This state of chronic inflammation can affect the processes of synaptogenesis, myelination, and neurogenesis in critical brain areas, including the hippocampus and prefrontal cortex, which are vital for learning and memory, and executive function, respectively (28).

Additionally, malnutrition can also affect the concentration of important neurotransmitters, including serotonin, dopamine, and GABA, which are critical for cognitive and emotional processing. These processes can lead to cognitive and attention deficits later in life, resulting in an increased risk of neurodevelopmental disorders such as ASD and ADHD, which are both linked to cognitive deficits (29-31).

Nutrients such as iron, zinc, omega-3 fatty acids, and choline are vital for proper neuronal development. These nutrients assist in synaptogenesis processes and synaptic plasticity, which are important for the structural formation and functional operations of the brain. Together, neuroinflammation, neurotransmitter dysregulation, and nutritional deficiencies can lead to cognitive deficits such as decreased intelligence quotient (IQ), learning disabilities, and behavioral deficits that can persist throughout life (32).

The effects of malnutrition extend beyond the GI system and localized effects on the brain, especially during critical neurodevelopmental periods. Altered gut microbiome populations can directly affect neurodevelopment via the GBA. Studies have shown that neurochemical variations due to malnutrition, such as changes in serotonin, dopamine, and GABA, greatly affect cognitive and emotional development. Decreased levels of serotonin cause deficits in mental and emotional processing functions, and increase the incidence of neurodevelopmental disorders. Animal studies of malnutrition have reported decreases in important neurochemicals and increases in inflammatory markers in the brain, resulting in marked deficits in behavior and cognitive function (33).

Linking malnutrition, gut dysbiosis, and cognitive impairments

There is increasing evidence of links between malnutrition, gut dysbiosis, and cognitive impairment. Malnutrition increases the risk of delays in neurodevelopment, mainly due to its effects on the gut-brain pathway. Gut dysbiosis (secondary to malnutrition and deficiency states) disrupts normal brain function by altering gut-brain communication. For example, a study comparing malnourished and non-malnourished children reported a significant correlation between cognitive test results and the level of gut-related endotoxins in the blood. The malnourished children had inferior cognitive scores and higher blood levels of endotoxins, indicating that malnutrition resulted in “leaky gut”, which in turn resulted in a persistent systemic inflammatory response, leading to cognitive impairment. A decrease in beneficial gut flora (e.g., Bifidobacterium and Lactobacillus) may also contribute to cognitive impairment, as these flora are needed for the production of neuroprotective neurochemicals (34).

Additionally, malnutrition and proteobacterium changes in the gut flora also influence the BBB. The BBB is a protective mechanism that helps to regulate the permeability of molecules into the central nervous system. In malnutrition, the dysbiotic condition could compromise the BBB, making it leakier or less selective, and allowing toxic substances (e.g., toxins and inflammatory mediators) to penetrate the brain, resulting in further neurodevelopmental impairment (35).

Therapeutic implications: restoring gut health for cognitive and GI improvement

The gut microbiome could serve as a therapeutic target for conditions of GI dysfunction and neurological impairment related to malnutrition. Restoring the microbial balance could provide a therapeutic avenue for improving GI function and cognitive development in malnourished children. Probiotics, prebiotics, and nutritional interventions designed for gut health may restore GI function and enhance cognitive development. Nutritional interventions related to the restoration of protein, micronutrient, and fiber intake may restore the diversity of the microbiome and production of essential metabolites.

Clinical work on FMT in malnourished children with GI dysbiosis is in its infancy; however, early findings suggest that FMT can restore a balanced gut microbiota and decrease the effects of malnutrition on both GI and neurologic function. The effects of malnutrition are considered key factors in both GI dysfunction and defective neurological development. The gut microbiome plays a critical role in preventing or mitigating malnutrition-related deficits by modulating immune responses, affecting nutrient metabolism, and participating in neurologic development. In terms of malnutrition, gut dysbiosis induces or promotes GI symptoms and cognitive deficits, resulting in a cycle that hinders both recovery and development. An understanding of how malnutrition disrupts the GBA may lead to the development of novel microbiome-targeted therapies to improve the GI and neurologic function of children suffering from malnutrition.

PEM and micronutrient deficiencies lead to gut dysbiosis, a state of microbial imbalance that further disrupts gut and brain function (36-38). As Figure 3 shows, dysbiosis leads to a loss of GI barrier integrity, resulting in “leaky gut” and the circulation of harmful factors such as bacterial endotoxins. This activates the immune system, exacerbates neuroinflammation, interferes with nutrient absorption, and worsens any GI dysfunction. Figure 3 provides a summary of how the cycle of worsening dysbiosis and GI barrier dysfunction, inflammation, and malabsorption negatively affects neuro-development outcomes for malnourished children.

Figure 3 Mechanistic visualization of the consequences of malnutrition. Malnutrition (i.e., protein-energy malnutrition and micronutrient deficiencies) leads to gut microbe imbalance (dysbiosis) and the “loss” of beneficial microbes; dysbiosis impairs gut barrier integrity and increases gut permeability, leading to the uncontrolled translocation, of noxious, pro-inflammatory molecules. Immune activation and the resulting neuroinflammation create a feedback loop that further impairs nutrient absorption and worsens gastrointestinal dysfunction.

Precision nutrition

Precision nutrition is a personalized approach in which dietary plans are tailored to each individual’s unique biology, lifestyle, and environment rather than based on universal food concepts (food pattern). This approach recognizes individual patterns of interaction between diet, genetics, the microbiome, metabolism, and other health parameters, and explains differences in the dietary responses of individuals. It has important applications in the field of malnutrition, as clinicians can profile gut microbiomes with sequencing techniques to identify various patterns of dysbiosis instead of good players versus bad players. Clinicians can then work with patients on various strategies, including dietary prebiotics and probiotics.

Genomic data may also be applied to micronutrient supplementation for individuals with genetic polymorphisms in nutrient metabolism pathways. The ultimate goal of precision nutrition is to move from a reactive model of treatment to a proactive model in which preventative strategies are devised that promote optimum gut health and maximal nutrient absorption, thereby decreasing the incidence of developmental delays that can occur in childhood malnutrition and allowing for the application of successful integrative therapeutic measures in the long term that may or may not alter mortality and long-term health statistics (39).

Precision nutrition for GI dysfunction due to malnutrition in children

Precision nutrition employs a novel personalized approach, using individualized dietary treatment regimens based on each individual’s genetic, microbiomics, and environmental profiles. It holds significant promise for the treatment of GI dysfunction associated with malnutrition in children. Unlike traditional nutritional regimens that use unhelpful, standard nutritional advice, precision nutrition uses nutritional recommendations tailored to the individual circumstances of each child, improving health outcomes by identifying any underlying etiologic factors, including the dysregulation of gut health resulting from malnutrition. Studies have shown that precision nutrition is more effective in treating malnourished children than inclusive diet regimens (40).

Role of precision nutrition in GI health restoration

Nutritional regimens should be individualized to restore normal microbiota and dysbiotic conditions resulting from malnutrition. Microbiome-directed complementary foods significantly alter the gut microbiota and are associated with improved growth in children with malnutrition. These nutritional regimens benefit the growth of beneficial bacteria such as Lactobacillus and Bifidobacterium, which are essential for restoring normal gut milieu for gut barrier function and nutrient absorption (41).

Improvement of nutrient absorption

To restore hypoabsorption due to nutrient deficiency, dietary recommendations should be individualized. Fiber can improve the production of SCFAs in the gut, which are needed to maintain gut barrier integrity and improve nutrient absorption. SCFAs, which are produced through the fermentation of dietary fiber, are also important for gut health and proper immune system activity (41).

Reduction of inflammatory conditions

Precision nutrition can also be used to select nutrients that modify the inflammatory pathways and thus reduce systemic inflammation in malnourished children with nutrient deficiencies. Omega-3 fatty acids, which are generally lacking in children from low-income families, exert anti-inflammatory effects and improve gut health and immune function by reducing pro-inflammatory cytokines (42).

Neurodevelopmental support

Adequate nutrition is critical for brain function. Precision nutrition ensures a sufficient supply of essential fatty acids and micronutrients for adequate cognitive development. Omega-3 fatty acids have been shown to improve the cognitive performance of children with malnutrition-related developmental delays (43).

Barriers and difficulties

Despite its promise, many barriers limit the implementation of precision nutrition in resource-challenged areas. The cost of microbiome and genetic profiling is prohibitive, limiting access to individualized interventions for malnourished children. In addition, due to its complexity, highly skilled trained personnel are required to interpret and understand microbiome and genetic data. The implementation of therapeutics in practice is limited. Cultural acceptance of such nutritional recommendations is also lacking; interventions have to be accepted locally to have any effect on local and customary food habits (44). Future research should prioritize the development of affordable diagnostic tools for microbiome and genetic profiling to ensure precision nutrition is accessible in resource-poor areas. Longitudinal studies need to be conducted to examine the long-term effects of precision nutrition on growth, development, and health outcomes in malnourished children. Further, epidemiological models incorporating precision nutrition could deliver personalized population-based dietary interventions aimed at addressing the problem of pediatric malnutrition as a global issue (45,46).

Emerging precision nutrition tools

Advances in genetic sequencing, and microbiome and metabolic testing are increasing the feasibility of precision nutrition interventions. Tools such as whole-genome and metagenomic sequencing allow clinicians to identify biomarkers that can predict an individual’s response to diet and guide highly personalized nutritional recommendations. Additionally, wearable health applications are making it easier to track data on diet, exercise, and other health variables in real time, enabling the implementation of quick adaptive dietary interventions (47) (Figure 4). This personalized approach targets certain dysbiotic patterns in the gut microbiome to improve the proliferation of beneficial microorganisms and to restore microbial diversity. As the diagram shows, this has implications for how these targeted interventions improve gut health, nutrient absorption, inflammatory responses, and ultimately health outcomes.

Figure 4 Mechanistic evaluation of tailored interventions for gut health. Mechanistically, tailored interventions can be evaluated by microbiome assay, genetic testing, and other relevant metrics in the environment. Precision nutrition for gut health has been shown to restore dysbiotic dietary patterns, increase micro-biome biodiversity, and ultimately improve gut health and absorption, and reduce intestinal inflammation.

Therapeutic interventions

Microbiome-targeted interventions that promote the repopulation of healthy gut microbes have emerged as appealing adjuncts to traditional nutritional rehabilitation for malnutrition. A probiotic is defined as a live microorganism that, when consumed in adequate amounts, confers a health benefit on the host organism. Gut probiotics often target a few specific strains within the genera Lactobacillus and Bifidobacterium. In randomized control trials of undernourished children, specific probiotic strains have been shown to improve gut barrier functions, decrease the duration of infectious diarrhea, and increase growth outcomes (albeit these improvements have been modest).

Probiotics exert their benefits through the competitive exclusion of pathogenic microbes and interactions with the local immune system. Prebiotics are non-digestible food components that promote the growth of beneficial gut microbes by selectively stimulating the growth or activities of good bacteria. Prebiotics can use foods containing fructooligosaccharides (FOSs), galactooligosaccharides, and HMOs as a substrate, arising from the fermentation process they promote of SCFA-producing bacteria, affecting the composition of the microbial community and helping to rebuild the gut barrier from the inside out, as well as being an essential food source for bacterial probiotics (48).

Synbiotics are products that contain a combination of probiotic and prebiotic foods that generate a synergistic effect (e.g., synbiotics may stimulate the survival and colonization of microbes by supplying needed substrates). Clinical studies have shown that this method of intervention is more effective in producing greater variability and weight gain in malnourished children compared with each component alone (i.e., either a probiotic or a prebiotic alone) (49).

The most intricate dysfunction of the gut microbiome has been observed in patients presenting with recurrent Clostridioides difficile infections. FMT transfers a carefully screened, entire microbial community of bacteria from a healthy individual to “reset” a microbiome. FMT has been shown to be highly effective in the treatment of Clostridioides difficile infections, but its use in the treatment of pediatric malnutrition remains experimental. It is an important approach for the reconstitution of a functional microbiome; however, careful consideration must be given to its safety, efficacy, long-term outcomes, and any ethical issues before its use (50).

Probiotic trials in NEC

Probiotics have been widely studied as a potential therapeutic intervention for NEC, a condition in preterm infants characterized by inflammation and injury to the intestine. Some studies have reported favorable results; however, other studies have raised concerns related to the ambiguous results of probiotic trials for NEC (51).

Inconsistent results

The findings of various clinical studies indicate that certain probiotics may reduce the incidence of NEC in premature infants, and certain strains of Lactobacillus and Bifidobacterium may help promote intestinal health and prevent inflammation of the intestine. However, other studies have failed to replicate these results, raising questions as to the effectiveness of probiotics in such ill-fated groups of subjects. Some studies have reported deleterious effects associated with probiotics, such as sepsis caused by the inoculation of non-sterile probiotic products (52).

Confounding results

Differences in study design, including variations in probiotic medications and dosages, and variations in study duration (e.g., weeks vs. months), have produced confusion in the results. The small size of the patient populations in many of these studies also limits the generalizability of the results. Further, methodical errors, such as a failure to use standardized diagnostic criteria for NEC and differences in the treatment of infants at different study sites, make any evaluation of the results difficult. Thus, great caution must be exercised in interpreting public opinions on the use of probiotic interventions in the treatment of NEC, especially in infants. Probiotics may have many potential uses, but their application in particular incidence should be analyzed, and more carefully controlled studies are needed to establish their efficacy and safety (53).

Therapeutic approaches for mitigating the effect of malnutrition on brain development

The gut microbiome plays a significant role in brain development, and microbiome dysregulation can contribute to neurodevelopmental defects and neurological deficits. Microbiome-targeted therapies, such as probiotics, prebiotics, and other supplements, offer novel therapeutic approaches for ameliorating these disorders. Such treatments are capable of restoring GI barrier function, reducing inflammation, and improving cognitive function, particularly in children diagnosed with ASD, ADHD, cognitive delays, and similar disorders associated with malnutrition (54).

Global gaps in therapeutic effectiveness

Microbiome-targeted therapies encounter substantial obstacles and problems in low- and middle-income countries (LMICs). Such therapies, particularly the novel approaches identified in the literature, may be successful in high-income countries (HICs), but their effectiveness in LMICs may be limited for environmental, nutritional, and epidemiological reasons.

Different prelude pathophysiology

Environmental enteric dysfunction is a common pathophysiology in LMICs. It results in a loss of gut health, and nutrient mal-resorption due to constant exposure to fecal pathogens. Environmental enteric dysfunction produces intestinal permeability, which prevents pro- or prebiotics from colonizing or stimulating the growth of beneficial bacteria. Nutrient absorption is compromised, rendering dietary manipulation ineffective. Most of the therapies described in HICs are ineducable in these environmental situations, as the increased intestinal permeability and total malfunction of the absorptive function of the intestines creates a barrier to nutritional rehabilitation (55).

Nutritional status and food substrates

The effectiveness of microbiome-targeted therapies is strongly influenced by the nutritional status of the host. For example, prebiotics have a low likelihood of promoting the growth of probiotic bacteria in severely malnourished children, who do not have an adequate protein and micronutrient intake to encourage the growth of bacteria. Similarly, synbiotics (a combination of both probiotics and prebiotics) are ineffectual in the malnourished gut, where the catabolic state of the host profile inhibits the metabolic interaction of the two. Thus, therapeutic plans need to be designed that are specifically tailored to the nutritional context of each child (56,57).

Probiotics, prebiotics, and synbiotics in restoring microbiome homeostasis

To restore the gut health of malnourished children, therapeutic techniques need to be used that are capable of restoring normal homeostatic balance in the microbiome. Probiotics, prebiotics, and synbiotics are leading therapeutic strategies for accomplishing these goals. These techniques aim to restore homeostatic balance in living microbiota, and promote nutrient absorption and decreased inflammation both in the GI tract and brain. Probiotics promote the re-establishment of beneficial bacteria, prebiotics provide nutrients to these bacteria, encouraging their growth, and synbiotics attempt to join the beneficial elements of both to ensure maximum therapeutic effectiveness. FMT is a more aggressive approach for achieving substantial changes in the microbiome. It provides an input of healthy microbiota from a healthy donor to reset the gut ecosystem.

Combinations of these therapies seek to improve the functional status of the gut, promote the nutrient absorption, decrease systemic inflammatory status, potentially improve the recovery of malnourished children, and enhance the cognitive and GI health of individuals (32,58). Therapeutic modalities that aim to restore gut health, such as probiotics, prebiotics, synbiotics, or FMT (Figure 5), seek to restore balance to the microbiome, increase microbial diversity, and enhance gut function. Probiotics restore key beneficial bacteria; prebiotics provide nourishment, while synbiotics incorporate both for a greater combined effect. FMT resets the gut’s ecosystem via the transfer of healthy microbiota from a donor. These methods ultimately enhance gut function and nutrient absorption, and decrease inflammation for both GI and neurological health.

Figure 5 Mechanistic representation of therapeutic strategies for restoring gut health. summary of the therapeutic strategies—probiotics, prebiotics, synbiotics, and FMT—that restore microbial homeostasis by using these mechanisms of action. Probiotics provide beneficial bacteria, prebiotics feed the beneficial bacteria, and synbiotics combine their respective components to promote microbial growth. FMT re-establishes the microbiome by providing healthy bacteria. All of these procedures help promote nutrient absorption, decrease inflammation, and alleviate gastrointestinal and neurologic symptoms to promote gut and brain health. FMT, fecal microbiota transplantation.

Clinical applications and efficacy

Several clinical trials have shown the therapeutic effects of probiotics, prebiotics, and synbiotics in malnourished children. Probiotic supplementation has been shown to have significant effects on GI function, to reduce the incidence of diarrhea, and to improve nutrient absorption in malnourished infants and children. A meta-analysis of randomized controlled trials showed that probiotics decreased the incidence of diarrhea and improved the growth of malnourished children with PEM (59). Similarly, prebiotics have also been shown to exert favorable effects on gut health and improve the microbial diversity of children with malnutrition. Prebiotic supplementation positively increases levels of beneficial bacteria, stimulates the immune response, and improves nutrient absorption. Thus, prebiotics may be an effective intervention strategy for improving aspects of gut health and promoting recovery from malnutrition. Synbiotics (both probiotics and prebiotics) have also been shown to exert synergistic effects on both GI health outcomes and immune health in malnourished children. A number of studies have shown that synbiotics are effective in restoring gut microbial diversity, and in improving the values of SCFA products, nutrient absorption, and the growth and cognitive outcomes of malnourished children (60-65). Table 1 summarizes these findings.

Microbiome modulation for adult brain health

The gut microbiome affects brain function and mental health through the GBA, which is important in the field of nutritional psychiatry. Diets rich in fermented foods, such as butyrate, improve BBB function, decrease neuroinflammation, and enhance neuroplasticity, which in turn increase brain-derived neurotrophic factor, which is necessary for learning and memory (66).

The microbiome also affects tryptophan metabolism, transporting it to either the serotonin pathway where it improves mood and cognition, or the kynurenine pathway where it produces neurotoxic metabolic products, leading to depression and anxiety. The presence of omega-3 fatty acids and polyphenols, both of which are derived from plants, negatively affects systemic and neuroinflammation, and not only helps to maintain brain health but also decreases cognitive decline due to unhealthy diets such as the western diet (62,67).

Pediatric disease and the microbiome

There is increasing evidence that dysbiosis in the gut microbiome is related to the pathogenesis of a number of pediatric disease processes. In terms of ASD, children have abnormal microbiomes that are characterized not only by lower diversity but also the absence of SCFA-producing organisms, which is correlated with their GI complaints and behavioral dysfunction (68). Experimental studies, in which the microbiomes of children with ASD were deposited into gnotobiotic mice, induced ASD-like behaviors, suggesting a potential causal relationship between the microbiome and the disease process. A similar situation was observed in ADHD, where in similar microbiome populations, improvements in behavior and attention were observed with dietary changes and probiotics. In terms of IBD, which includes Crohn’s disease and ulcerative colitis, chronic dysbiosis with a loss of beneficial microbiota and the proliferation of pro-inflammatory microorganisms results in gut barrier dysfunction and the activation of defense mechanisms. The microbiome also plays a role in childhood obesity. An obesogenic microbiome can promote excessive energy extraction, low-grade inflammation, and insulin resistance, leading to an increase in caloric intake, weight gain, and the induction of metabolic dysfunction (69,70). These findings suggest that microbiome modulation could also be beneficial in pediatric diseases.

Overview of malnutrition

Malnutrition includes various nutrition disorders, but it is primarily classified into two types: undernutrition and overnutrition. This review largely focused on undernutrition, a global health problem with devastating consequences for children. Undernutrition includes PEM, micronutrient malnutrition, or both. PEM occurs in two main forms (i.e., impetigo and kwashiorkor), each of which has certain characteristics. Marasmus is an extreme and chronic deficiency of energy and protein, associated with muscle and fat wasting, growth stunting, and a wizened appearance. Conversely, kwashiorkor indicates a protein deficiency, characterized by peripheral oedema, hepatomegaly, skin lesions, and depigmented hair. This typically occurs during the transition between pre- and post-weaning.

Micronutrient deficiency can have similarly devastating effects and is called “hidden hunger”. Iron deficiency is the most common cause of anemia and affects the development of intellect and may result in immune response failure. Vitamin A deficiency leads to a failure of the epithelial covering and impairment of the immune response. It can result in xerophthalmia cause blindness. Vitamin E is used as an anti-oxidant, and vitamin D is involved in the metabolism of calcium and bone mineralization. A deficiency in this vitamin leads to rickets. Iodine deficiency causes a defect in the production of thyroid hormone, leading to mental retardation and conditions such as goiter or cretinism. These micronutrient deficiencies often occur alongside PEM, compounding their impact on the health of children (71,72).

The critical windows of development in pediatric health

The first 1,000 days of life (from conception to 2 years) are very important in human development, particularly brain neurodevelopment. During this time, important processes occur, such as neuronal development, synaptogenesis, myelination, and neural circuit formation, which sustain cognitions and emotions throughout the lifespan. Any disruptions during this time, such as malnutrition or environmental enteropathies, drastically affect brain functions, such as neuroplasticity. The gut plays an important role in supporting child development by aiding in digestion, immune modulation, and vital metabolite synthesis. Any disruption in these processes in early life interferes with digestion, brain development, neuroplasticity, and ultimately brain functions and cognitive abilities in daily life (73).

Effects of malnutrition on the gut microbiome and brain development

Malnutrition, especially during infancy and early childhood, alters the gut microbiome, resulting in dysbiosis, affecting both gut health and brain development. PEM and disturbed micronutrient status result in decreased diversity of the microbial flora, resulting in an increase in pathogenic flora and a decrease in beneficial bacteria such as Lactobacillus and Bifidobacterium, which are necessary to maintain gut integrity, immune integrity, and SCFA synthesis (74).

Malnutrition also affects the immune system. Immune system dysregulation and chronic inflammation are of great importance to brain development, especially in areas related to learning, memory, and executive functions. Decreases in the production of beneficial metabolites, such as SCFAs, which help to lower neuroinflammation and aid in neurogenesis in normally nourished individuals, also harm cognitive and behavioral development. In malnourished children, the diminished production of SCFA compounds also contributes to lasting deficits in brain function (75). The role of gut bacteria in fermenting dietary fibers and the resulting output of SCFA products enhances gut barrier function, decreasing inflammation, and improving brain health by preventing breaches of the BBB and aiding in neurogenesis (Figure 6).

Figure 6 Mechanistic illustration of SCFA production and related effects. Gut bacteria ferments fibers in the diet to produce SCFAs (e.g., butyrate, acetate, and propionate), which benefit gut health by improving barrier function and decreasing inflammation. SCFAs also serve to reinforce the blood-brain barrier and aid in neurogenesis; thus, SCFAs are vital for gastrointestinal health and neurological health. SCFAs, short-chain fatty acids.

Effects of malnutrition, disease, and the gut microbiota on brain development

The first 1,000 days of life are a critical period for brain development. Disturbances in this period, including malnutrition and chronic disease, can have significant adverse effects on both gut health and neurodevelopment. PEM and micronutrient deficiency give rise to dysbiosis, characterized by decreased microbial diversity and increased pathogenic bacteria, impaired gut integrity, and neuroinflammation. This inflammation, as well as immune dysregulation, interferes with brain development, especially in areas that are responsible for learning and cognition. Chronic diseases, including IBD, aggravate the phenomena described above by creating a chronic inflammatory environment that interferes with brain development (76). The gut microbiota plays a fundamental role in maintaining gut health and brain function. Abnormalities in this area, resulting from malnutrition or disease, like mucosal atrophy, limit the ability of the gut to absorb vital nutrients, maintaining further nutrient deficiencies. Additionally, chronic low-grade inflammation induced by pro-inflammatory cytokines, such as TNF-α and IL-6, interferes with gut barrier function and contributes to deficits in nutrient absorption, compromising both GI and brain function (77,78).

The microbiome and the gut: key mechanisms

The gut microbiome is critical for maintaining GI homeostasis. The microbiome influences gut health through many mechanisms, including the maintenance of the intestinal barrier function, digestion, and nutrient absorption. One of the first ways the microbiome influences the gut is through the intestinal barrier function. The gut epithelial cells are tightly connected to one another to prevent damaging substances from leaching into the bloodstream. When the microbiome is dysbiotic (characterized by an imbalance of favorable to harmful microbes), the integrity of the intestinal barrier is compromised, leading to “leaky gut” syndrome. In this state, harmful bacteria, toxins, and antigens can leak into the bloodstream, inducing inflammation and an immune response (79-81).

Regional differences in the microbiome of the GI tract

The microbiota differs between the small intestine and colon due to variations in oxygen gradient, pH, and transit time. The oxygen gradient is higher and the transit time is quicker in the small intestine, leading to less diverse microbiota. Conversely, the colon, which is anaerobic and has a longer transit time, has a more complex micro-biotic population. Given these differences, consideration must be given to the methods used to sample the microbiota. Stool samples reflect the micro-biotic population of the colon, while duodenum samples can only be taken by endoscopy, which is more invasive. The sampling methods highlight the challenge of adequately characterizing the whole microbiome along the entire GI tract (82).

The microbiome and the brain: neurodevelopmental mechanisms

Functional brain activity uses the gut microbiome through the GBA, a network of communication between the gut and brain via the vagus nerve, immune pathways, and microbial metabolites. The vagus nerve directly connects the brain and the gut. Gut microbes affect the signals passed along this nerve, influencing brain functions, including emotional control, learning, and memory. Recent research suggests gut microbes influence brain centers involved in stress and mood, including the hippocampus and prefrontal cortex, and exposures to microbial colons in early life may be associated with the subsequent development of conditions such as autism and anxiety disorders in children (58). The microbiome also produces specific microbial metabolites, including SCFAs, which influence neurotransmitters, such as serotonin and GABA. Dysbiosis, or gut bacteria imbalance, may ultimately lead to reduced SCFA production, which may lead to neurodevelopmental problems due to the decreased production of serotonin and GABA, which may lead to psychiatric disorders such as anxiety and ASD (83).

The gut microbiome and development of the immune system

The gut microbiome is essential in the development of both innate and adaptive immunity, particularly in the early stages of life. A healthy microbiome enables the immune system to identify pathogenic organisms and harmful antigens, and promotes immune tolerance. Healthy early childhood colonization of a balanced microbial environment also provides the basis for the development of T regulatory cells and T helper 17 cells, which are critical in the modulation of immune responses. However, gut dysbiosis ultimately leads to decreased immune function and maladaptive immune responses, and an increased risk of allergic diseases, autoimmunity, and IBD. This dysregulation may also provide a basis for neuroinflammation, which in turn can affect neurological development and behavior, thus implicating immune imbalance in cognitive disorders and emotional disorders (84).

The microbiome interacts with Toll-like receptor (TLR) proteins. The immune system uses TLRs to recognize microbial components and activate immune functions. The microbiome is critical for modulating TLRs, the associated inflammatory pathways, and immune tolerance. An ecological imbalance of the normal microbiota (i.e., dysbiosis) leads to inappropriate TLR activation, resulting in chronic inflammation, impaired immune system function, and chronic inflammatory diseases such as autoimmune diseases and IBD (85).

Effect of early-life gut microbiome on long-term health

The effect of the gut microbiome on a child’s health is not limited to infancy. The microbiome affects GI health and brain development in infancy, and exerts lasting effects on immune function, metabolic health, and the risk of chronic disease that persist well into childhood and beyond. Altered microbiome composition during early childhood is associated with increased risks of obesity, diabetes, and cardiovascular disease later in life. Children who experience microbiome dysbiosis in infancy and early childhood are at greater risk of these diseases as they grow older (86).

The infant microbiome also affects neurodevelopment. An altered microbiome during infancy has been associated with altered microbial diversity and has been shown to exert negative effects on cognitive function and behaviors, as observed in conditions such as ASD and ADHD. Thus, favorable and comprehensive interventions need to be established to restore a healthy microbiome early in life to mitigate any long-term health effects (87).

Limitations of microbiome research

Platform variability

One of the major challenges facing microbiome research is the variability between sequencing platforms, especially the variability between 16S ribosomal ribonucleic acid (rRNA) sequencing and whole-genome shotgun sequencing. The 16S sequencing of rRNA genes targets some areas of the bacterial genome; however, its taxonomic resolution is limited, and it cannot catalog the vast diversity of the microbiome. Conversely, whole-genome sequencing offers a more complete picture but is usually expensive and technically challenging. Due to these methodological differences, it is difficult to compare or draw conclusions from the published data (88).

Sample bias

Another challenge facing microbiome research is sample bias. Many microbiome studies use stool samples, but microbiome composition can differ significantly depending on the sampling site. For example, the composition of gut microbiota may differ significantly among mucosal samples, stool samples, and different areas of the GI tract. Additionally, the timing and methodology of sample collection can introduce potential biases; for example, the time of day, diet, or recent antibiotic use can all modify the composition of these microbial communities. All these factors hinder the interpretation of results and limit the generalizability of findings (89).

No standardization

Another major challenge facing microbiome research is the lack of standardization. Variations in study design, data collection, and data analysis techniques make replicating studies and comparing the results of different research groups difficult. For example, differences in DNA extraction protocols, the depth of sequencing, and data processing pipelines can introduce variability, decreasing the reliability of findings. Thus, protocols and methodologies need to be standardized to improve the reproducibility and robustness of microbiome research (90).

Cross-sectional vs. longitudinal issues

To date, most studies of the microbiome have been cross-sectional, and thus present a snapshot of microbial composition at a single point in time. However, this type of study design cannot establish causation or monitor change over time. Thus, longitudinal studies that monitor participants over extended periods need to be conducted to assess the dynamic nature of the microbiome and its long-term effects on health. It is very difficult to conclude whether changes observed in the microbiome are the cause of the disease or condition being evaluated or simply a consequence of it (91).

Variability across platforms

A key challenge facing microbiome research is inconsistencies across sequencing platforms, especially 16S rRNA sequencing and whole-genome shotgun sequencing. Due to its low cost and its ability to detect the presence of bacteria in the sample, 16S rRNA sequencing is the predominant technology. However, 16S rRNA sequencing lacks taxonomic sensitivity and can only assess a fraction of the diversity of the microbiome. Conversely, whole-genome sequencing provides a better overview of the microbiome, as it provides species-level resolution and insights into the functional nature of the microbiota; however, it is expensive and requires much greater computational capabilities. Methodological differences can lead to contradictory results, making comparisons across studies difficult and limiting our ability to draw general conclusions. Differences in sequencing depth can also affect variability because there are disadvantages in the detection of rare species. Thus, methodologies should be standardized across studies to allow for comparison and ensure the reproducibility of microbiome data (69).

Microbiome variability and the persistence of changes

The microbiome exhibits both resilience and persistence to its modification. It will usually revert to its original state after slight insults. However, more permanent and significant disturbances, such as antibiotic exposure and significant early environmental changes, may produce permanent changes in the microbiome (92). In certain instances, the microbiome can return to its normal condition after transient dietary changes or slight disturbances, at least in children.

Persistence

The use of antibiotics, early environmental exposures, diet, and the mode of delivery can result in permanent microbiome modifications that have long-term health effects. For example, broad-spectrum antibiotics can reduce microbiota diversity, and early exposures may modify depreciation or metabolic health (93).

Brain dysfunction via gut dysbiosis

A malnourished, dysbiotic gut can alter neurologic function through several GBA pathways, producing a perfect storm of neurodevelopmental dysfunction. This is affected by dysregulated vagal-nerve signaling, as the vagus nerve conveys signals from the gut to the brain stem. The gut microbiome and enteroendocrine cells produce neurotransmitters, including serotonin and GABA, and metabolites, including SCFAs, which regulate vagal tone.

SCFA-producing organisms are reduced in the dysbiotic gut of malnourished children, impairing this form of signaling, which in turn can affect mood, stress receptors, and cognitive function by modulating the locus coeruleus and amygdala (93). This inflammation activates pro-inflammatory cytokines, which cross the BBB and activate microglia in the brain, producing neuroinflammation, which impairs critical neurodevelopmental processes, such as neurogenesis, myelination, and synaptic pruning, especially in areas such as the hippocampus and prefrontal cortex, leading to cognitive and behavioral dysfunction (94).

A generalized imbalance of neurochemicals also contributes to these. The gut microbiome also produces significant amounts of neuro-active metabolites, such as serotonin, dopamine, and GABA. Neuro-active chemical intermediate production is altered in the dysbiotic gut, affecting tryptophan metabolism, such that tryptophan is diverted away from the production of serotonin toward the production of the potentially neurotoxic chemical pathway of kynurenine, producing quinolinic acid, an excitotoxin that impairs neurodevelopment. Such neuro-physiologic chemical signaling imbalances contribute to cognitive delays, depressive disorders, and aberrant behaviors in malnourished children (95).

Challenges and controversies in gut-brain-microbiome research in pediatric populations

Developmental variability in the microbiome in children

Due to variables, including the pattern of birth, diet, and antibiotic exposure, the developing microbiome of children differs from that of adults. Thus, it is difficult to generalize findings from research on adults to children. Longitudinal studies need to be conducted to examine how the early-life microbiome affects brain health over time (96).

Lack of standardization in microbiome analysis

Due to a lack of standard methods for performing DNA extraction, sequencing, and bioinformatics, it is difficult to compare results between studies and thus draw reliable conclusions (97).

Short- vs. long-term effects

Most studies have examined the short-term effects of microbiome-targeted interventions, such as mood changes, while little is known about the long-term effects of such interventions on brain health and cognitive development; thus, further research is required (98).

Ethical and practical concerns

Research involving children, particularly very young children, faces ethical challenges, including those related to obtaining informed consent and the difficulties inherent in obtaining samples to study the microbiome (99).

Individual variability in responses to microbiome interventions

Because each child’s microbiome differs, it is difficult to apply a single technique universally. A more effective approach is the personalized use of interventions based on existing profiles of the microbiome. However, the implementation of this approach requires sophisticated technology (100).

Limited research in non-bacterial components of the microbiota

Most studies on the microbiome have focused on the bacteria; however, other components, such as viruses, fungi, and archaea, influence gut brain health; thus, more comprehensive research needs to be conducted (101).

Personalized nutrition and microbiome analysis in pediatric malnutrition

Personalized nutrition in pediatric care

Personalized nutrition tailors treatments to an individual’s genome and microbiome, enhancing the efficacy of nutrition therapy in the treatment of malnutrition in children of all ages. This treatment seeks to improve both nutrition and the microbiome, particularly when the microbiome is abnormal, as it is in malnutrition. Nutritional therapy focuses on both intake and the improvement of microbial imbalances, which can deleteriously affect nutrient absorption and immune function in children (102).

Role of microbiome analysis in personalized treatment

Nutrition analysis of the microbiome helps to reveal any microbial imbalances that are causing malnutrition. Gut microbiome analysis enables clinicians to target the treatment of malnutrition by designing diets that alter the gut microbiome so that the nutrients ingested can be more easily absorbed and eventually used in the GI tract. Prebiotics contained in foods such as FOSs promote prebiotic microbes such as Bifidobacterium and Lactobacillus that help maintain healthy gut function (103).

Nutritional interventions to target and restore specific microbiome imbalances

Nutritional interventions employ targeted treatment modalities to restore a more favorable balance in the gut microbiome via the use of prebiotics such as the FOSs and probiotics to modify the ratio of the gut fermentation of certain dietary fibers that produce SCFAs, which are important for GI health and absorptive processes. As part of the treatment of malnourished children, omega-3 fatty acids, particularly docosahexaenoic acid and eicosapentaenoic acid, have also been found to positively augment and modify the microbiome, resulting in decreased inflammation (104). Recent meta-analyses and systematic reviews have shown that omega-3 supplementation in children can result in cognitive benefits, including improved memory, attention, and executive function. A study has also highlighted (105) positive effects on neurodevelopment in children with autism and general cognitive development.

Multi-omics approaches in personalized nutrition

Using genomics, metabolomics, and microbiome analyses in personalized nutrition provides a holistic framework for addressing pediatric malnutrition. In multi-omics frameworks, data reveal complex interactions among genes, the microbiome, and lifestyle factors that can enhance adherence to dietary interventions (106).

Future research directions

Microbiome research in pediatrics is at a crossroads, and several critical areas require attention. Longitudinal and mechanistic studies need to be conducted to examine the development of the microbiome from infanthood to childhood, taking into account cultural and geographic variations worldwide. These studies should move beyond mere correlation and seek to establish causation using meta-omics approaches (metagenomics, metabolomics, and proteomics) and better define clinical phenotypes to extend our understanding of the effects of the microbiome on health and disease. This will be affected particularly through diet and food interventions (107).

Microbiome diagnostics represents a critical research area, as it could aid in the identification and validation of clinically significant microbial biomarkers. Biomarkers such as individual taxa, bodies of functional gene classes, and metabolic markers (e.g., SCFA or Bil acid ratios) may have diagnostic relevance. For example, such metabolic markers could assist in the diagnosis of diseases (e.g., IBD or ASD) or the diagnosis of severe malnutrition, could be used to monitor treatment effects, and could ultimately lead to pre-intervention treatments and individualized patient care (108).

However, the future aim is precision nutrition. Generic diet recommendations based on the general population should be replaced with individualized recommendations based on the microbiome, host genetics (nutrigenomics), immune competence, and lifestyle. Advanced tools (e.g., machine learning techniques) will be required to predict individual responses to foods and supplements, thus enabling the individualized tailoring of dietary interventions to both prevent and treat diseases (109).

Promising avenues for early diagnosis, individualized treatment, and preventative measures include the multi-omics approach, microbiome-directed therapies, precision nutrition, and longitudinal tracking. Such strategies can strengthen children’s immune systems, and improve their health and cognitive and physical development (Figure 7). Microbial consortia designed for specific physiological end points, targeted phage biology to eliminate pathobionts, and personalized prebiotics, probiotics, or psychobiotics will open new avenues (110).

Figure 7 Future directions for pediatric gut and brain health. Novel targeted pathways for improving pediatric gut and brain health include multi-omics approaches, microbiome-directed interventions, precision nutrition, and longitudinal tracking. Each of these approaches can inform an early diagnosis, personalized care, and preventative approaches that seek to support healthy growth, optimal cognitive development, and immune function in children.

Conclusions

The gut microbiome is no longer an ignored organ, it is now well-recognized as a core component of pediatric health and disease. This review described the complex interplay between the gut microbiota, the GI system, and the brain (the GBA), and how this communication is fundamentally driven by early-life exposures and nutritional status. Malnutrition—in all its forms—initiates a vicious cycle of dysbiosis, intestinal inflammation, impaired nutrient absorption, and neuroinflammation, which together can significantly affect physical growth and cognitive development. Although this is a bleak synopsis, it does offer a glimmer of hope. The microbiome can be modulated and therapeutic interventions can have significant effects. The routine use of probiotics, prebiotics, or synbiotics, dietary modification, and even emerging approaches such as precision nutrition all represent promising avenues for breaking the malnutrition and disorder cycle. The microbiome can be altered, and altering the microbiome ecosystem in a healthy and functional way could improve nutrient absorption, systemic inflammation, and ultimately healthy neurodevelopment. To fully realize this potential, multidisciplinary collaboration is required. Variability, and safety, ethical, and regulatory challenges need to be addressed before any interventions can be implemented. Pediatric medicine needs to adopt a more holistic approach to child health that includes the microbiome (i.e., the microbial self) to establish a foundation for wellbeing through targeted, evidence-based, personalized interventions.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-608/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-608/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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(English Language Editor: L. Huleatt)