Abstract
The human gastrointestinal tract contains the body’s largest community of microbes, comprising trillions of microorganisms collectively referred to as the gut microbiota. The gut microbiota plays a pivotal role in the development, maturation, and differentiation of the immune system and has a significant influence on both the physical and mental development of children, affecting overall health and wellbeing. Numerous factors can affect the diversity of the microbiota, such as mode of delivery in childbirth, environmental exposures, and contact with animals.Disruption or imbalance in the gut microbiota may result in dysbiosis or leaky gut syndrome. Dysbiosis has been linked to a range of diseases in both children and adults, including autism spectrum disorder, attention deficit hyperactivity disorder, asthma, and various allergies. Research indicates that the administration of probiotics may help to restore the balance of the gut microbiota, thereby improving gastrointestinal conditions such as constipation and potentially alleviating certain behavioural symptoms associated with neurodevelopmental disorders.
Introduction
The composition of gut bacteria, known as the ‘microbiota’, plays a crucial role in maintaining the health and wellbeing of children. (Sometimes used interchangeably with the term microbiome, microbiota refers to microorganisms that are found within a specific environment, whereas the microbiome refers to the collection of genomes from all these microorganisms.) There is some debate regarding the timing of bacterial colonisation in the infant gut, with some studies suggesting that this process may begin in utero via the placenta and amniotic fluid. However, it is established that the mode of delivery of a baby can affect the initial bacterial colonisation and the composition of the infant’s microbiome (Bokulich et al, 2016). Infants delivered vaginally typically acquire a microbiota resembling their mother’s vaginal flora, whereas those delivered by caesarean section are more likely to develop a microbiota similar to their mother’s skin flora (Bokulich et al, 2016).Whether a child is breastfed or formula-fed impacts the development of the microbiota. The microbiota of breastfed infants mainly comprises Lactobacillus spp., Staphylococcus spp., and Bifidobacterium spp., whereas the microbiota of formula-fed infants contains Roseburia spp., Clostridium spp., and Anaerostipes spp. (Ronan et al, 2021). When breastfeeding stops, at around 1 year of age, the microbiota evolves to be more adult-like, with microbes that degrade dietary fibres and produce short-chain fatty acids. The microbiota of infants that were formula-fed may mature faster towards an adult composition and include more organisms linked to inflammation than those of breastfed infants (Ihekweazu and Versalovic, 2018).
Research indicates that between the ages of 2–5 years, a child’s gut microbiota typically begins to stabilise into a composition resembling that of an adult (Bokulich et al, 2016; Ihekweazu and Versalovic, 2018). However, other studies suggest that development of the microbiota may continue into puberty or later (Deering et al, 2019). Environmental factors and diet during childhood are considered important influences on the composition of the microbiota. Additional factors, such as having older siblings or exposure to animals and household pets, have also been identified as potential influences on the composition of the microbiota (Milani et al, 2017).
Antibiotic treatment in early life can impact the gut microbiota by reducing bacterial diversity, altering metabolic activity, and enabling antibiotic-resistant microbial strains to establish, which can cause antibiotic-associated diarrhoea (Mukhopadhya et al, 2019). A reduced diversity of microbiota is reported to be associated with an increased risk of issues such as obesity, asthma, and allergies developing later in life (Bokulich et al, 2016).
The gut microbiota is crucial for the body’s immune, metabolic, structural, and neurological functions. The microbes affect gut development, mucosa maturation, differentiation, and immune system. Additionally, the gut microbiota influences both physical and mental health (Adak and Khan, 2019) and plays a vital role in brain development by affecting neurotransmitters like gamma-aminobutyric acid, noradrenaline, dopamine, and serotonin, with more than 90% of serotonin and 50% of dopamine being produced by the gut microbiota.
Serotonin is vital for brain development, and a decrease in levels of serotonin can impair synaptogenesis and brain connectivity, leading to long-term neurodevelopmental issues (Saeed et al, 2022). Most serotonin is produced by the gut microbiota, influencing both mood and gastrointestinal function.
Gut–brain axis and neurodevelopment
The gut microbiota plays a crucial role in various bodily functions and acts very much as an organ within the human body. There is a multidirectional relationship between the microbiota in the gut and the other body systems, forming different systemic axes, including the lung–gut axis, the skin–gut axis and the brain–gut axis (Saeed et al, 2022). An imbalance of the gut microbiota can affect the integrity of any of these axes (Figure 1).Figure 1. Diagram showing the systemic gut axis and how dysbiosis affects health. From Gebrayel et al (2022).
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The microbiota–gut–brain axis involves three pathways—endocrine/systemic, immune, and neuronal—which interact and overlap. The microbiota influences various CNS processes and neurodevelopment, including the permeability of the blood–brain barrier, synaptic pruning, neurogenesis, neuronal signalling, and behaviours like sociability, sensory function, memory, learning, and stress (Wang et al, 2023).
One of the primary pathways for gut–brain interaction involves the vagus nerve, which comprises both afferent and efferent neurons and innervates the digestive tract (Bonaz et al, 2018). The signalling from the gut microbiota to the brain via the vagus nerve is well-documented—for example, feeling ‘butterflies’ in the stomach before an important examination. The gut microbiota also produces numerous neurochemical substances such as catecholamines and serotonin. These play a crucial role in maintaining homeostasis in the body and are used by the brain to regulate basic physiological processes and mental functions such as learning.
An imbalance of the gut microbiota, known as dysbiosis, can lead to an alteration of metabolite profiles, thus influencing the enteric nerve CNS communication, brain immune function, CNS inflammation, and function and integrity of the blood–brain barrier (Ronan et al, 2021). Silva et al (2020) suggested that dysbiosis may play a role in the aetiology and development of neurodevelopment disorders and neuropsychiatric diseases.
It is believed that the gut microbiota may regulate behaviours through the production of neuroactive metabolites, suggesting that gut–brain connections could contribute to social and communication disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) (Ronan et al, 2021). Some children with neurodevelopmental disorders seem to experience pain differently to their typically developing peers. It has been proposed that the gut microbiota might influence the central perception of pain by modulating receptor expression (Defaye et al, 2019). For instance, studies on people with irritable bowel syndrome have observed that certain strains of Lactobacillus can alter the expression of mu-opioid and cannabinoid receptors in intestinal epithelial cells, producing effects similar to those of morphine (Kang et al, 2017).
Dysbiosis and ‘leaky gut’
The intestinal mucosa encounters numerous external antigens, including food antigens, food-borne pathogens, and commensal microbes present in the intestinal lumen. Hence, the intestine functions as a barrier tissue where a monolayer of intestinal epithelial cells forms a multilayered physicochemical barrier.This intestinal epithelial barrier maintains biological homeostasis by keeping external antigens out and preventing internal substances from leaking into the gut. This function relies on tight junctions formed by intestinal epithelial cells (Figure 2). Dysbiosis, or altered microbial composition, can disrupt this barrier. Dysfunction of this barrier, particularly the disruption of tight junctions, often leads to enhanced intestinal permeability, a pathological status termed ‘leaky gut syndrome’ (Kinashi and Hase, 2021).
Figure 2. Diagram showing autoimmune responses induced by dysbiosis and leaky gut syndrome. From Kinashi and Hase (2021).
