Three overarching themes from the review emerged: 1) intestinal microbiota and immuno-inflammatory regulation, 2) intestinal microbiota and Metabolic balance, and 3) intestinal microbiota and nervous system: gut-brain axis.
Intestinal Microbiota and Immuno-inflammatory Regulation
The host-microbiota interaction is considered to be strongly linked to the development, maturation, and function of the immune system in the host, not only locally, but also systemically through local colonization, metabolites, and signaling. Changes in the composition of the intestinal microbiota are now recognized to dysregulate the immune system toward hypersensitive and/or hyper-inflammatory states in early childhood, and this may be associated with atopic/allergic diseases and other inflammatory diseases in children (Stiemsma & Michels, 2018; Versalovic, 2013). Of the 25 articles, 12 articles discussed this theme. Five examined the link between intestinal microbiota and atopic dermatitis and/or eczema in children, six studied asthma in children, two looked at IBD, and one focused on juvenile idiopathic arthritis (JIA).
There has been recent recognition of the evidence that early life dysbiosis of the human intestinal microbiota is associated with different types of immune-inflammatory diseases in children (Arrieta et al., 2015; Arvonen et al., 2016; Shaw et al., 2016; Stiemsma & Michels, 2018; Versalovic, 2013). A literature review by Slattery and colleagues (2016) reported that a markedly altered abundance of Faecalibacterium prausnitzii in the microbiota of children with atopic dermatitis might be related to inflammatory process. Similarly, Arrieta and colleagues (2015) revealed that the relative abundance of the intestinal bacterial genera, Faecalibacterium, Lachnospira, Veillonella, and Rothia, was significantly decreased in children at risk of asthma. Stokholm (2018) found an association between decreased Faecalibacterium, Bifidobacterium, Roseburia, Alistipes, Lachnospiraceae, and Ruminococcus in fecal samples of infants and toddlers who were born to asthmatic mothers and asthma at age 5 years. Additionally, Versalovic (2013) discussed the relative deficiency of Faecalibacterium in IBD.
Slattery and colleagues (2016) and Stiemsma and Michels (2018) both explained a potential mechanism of the disease process may be altered production of short chain fatty acids, metabolites of Butyrate-producing bacteria, including Faecalibacterium, also known as potent anti-inflammatory agents. Moreover, Arrieta and colleagues (2015) looked into the role of Faecalibacterium, Lachnospira, Veillonella, and Rothia in asthma susceptibility by an experiment using germ-free (GF) mice and concluded that GF mice with these four bacterial taxa ameliorated airway inflammation compared to GF mice without bacterial supplementation.
Along with the above, some reported similar findings. Arvonen and colleagues (2016) described that the decreased portion of the Firmicutes phylum and increased Bacteroidetes phylum were significant in children with JIA, and Shaw and colleagues (2016) found Coprococcus and Adlercreutzia were significantly de creased in children with IBD. Although their findings of specific species were different, there is also a suggestion of Butyrate-producing bacteria as the key players in both findings.
Additionally, Stiemsma and colleagues (2016) featured that the significant shift to less Lachnospira and more Clostridium neonatale at 3 months was associated with the increased risk of asthma at 4 years of age; this significance at 1 year of age was not as strong as at 3 months. Consistent with this result (Stiemsma et al., 2016), several researchers also emphasized the early infancy critical window of intestinal dysbiosis in developing/preventing chronic immune-inflammatory diseases in later childhood (Arrieta et al, 2015; Stiemsma & Michels, 2018; Stokholm et al., 2018). In articles by Arvonen and colleagues (2016) and Stiemsma and colleagues (2016), an increased susceptibility to inflammatory health conditions by the negative impact of antibiotics use on intestinal microbiota compositions during this specific critical window was considered. Comparatively, protective effects of breastfeeding in JIA, atopic diseases and the effects of probiotics, prebiotics in preventing and decreasing severity of atopic dermatitis, asthma, and JIA were also noted (Arvonen et al., 2016; Foolad et al., 2013; Hendaus et al., 2016; Slattery et al., 2016; West et al., 2017). Furthermore, West and colleagues (2017) discussed the beneficial administrating methods of probiotics. They referred to a meta-analysis of 29 studies and identified there was a benefit of probiotics for eczema reduction when administered in the last trimester of pregnancy, when administered during breast-feeding, or when administered to infants and/or mothers.
Finally, although there is rapidly accumulating evidence, there are still inconsistent reports trying to identify precise factors and mechanisms of the dysbiosis by which the microbiota might contribute to chronic immune-inflammatory disease in children. Studies regarding the involvement of up/down regulation of T regulatory cells, T helper 1 cells, T helper 2 cells, interferons (IFN), and interleukins in mechanisms of the interactions between intestinal microbiota and immune system seem to be promising (Arvonen et al, 2016; Hendaus et al., 2016; West et al., 2017). However, in-depth discussion is beyond the scope of the present review.
Intestinal Microbiota and Metabolic Balance
There have been appealing reports about the relationship between individuals' differences in their intestinal microbiota and weight gain, adiposis, glucose tolerance, and consequent metabolic syndrome, such as obesity, fatty liver, cardiovascular disease, and diabetes mellitus, reflecting great concerns for increasing metabolic syndrome in children and adolescents (Belei et al., 2017; Forbes et al., 2018; Nobili et al., 2018; Stiemsma & Michels, 2018). Of the 25 articles reviewed, eight articles featured this theme.
Belei and colleagues (2017) and Nobili and colleagues (2018) both investigated the relationship between non-alcoholic fatty liver disease (NAFLD) and the intestinal bacterial compositions. Belei and colleagues (2017) disclosed that about 60% of the children who were positive for intestinal bacterial overgrowth had NAFLD, while none of the children who were negative for intestinal bacterial over growth had NAFLD. They also noted this intestinal bacterial overgrowth was associated with elevated aminotransferases and hypertension. Interestingly, it has long been known that GF mice can eat more and gain less weight than regular mice (Davis, 2016), and this initially provoked the researchers' questions for the role of intestinal microbiota in malnutrition and obesity.
A landmark study by Ridaura and colleagues (2013) showed that obesity can be a microbiota transmissible trait. In this study, stool samples were taken from paired human twins (one was obese; the other was lean) and supplemented to GF mice. Later, the GF mice that got stool from the obese twin gained more weight even though they were fed the same diet. It is remarkable that the finding by Belei and colleagues (2017) in human children resembles the fact in mice. At the genomic level, Nobili and colleagues (2018) noted increased Lactobacillus spp. in children with NAFLD and/or obese compared to the controls, while Bifidobacterium spp. were more abundant in the controls. This suggested a protective role of these microorganisms against the featuring diseases.
Forbes and colleagues (2018) also found that a potential protecting influence of Bifidobacterium spp could start from birth. Researchers examined the link between fecal microbiota of breastfed and formula-fed infants at 3 to 4 months and their overweight status at 12 months. Their results revealed that increasing exclusivity of breastfeeding was associated with increasing abundance of Bifidobacteriaceae and Enterobacteriaceae and decreasing Lachnospiraceae, Veillonellaceae, and Ruminococcaceae. In contrast, the lower abundance of Bifidobacteriaceae and the higher abundance of Lachnospiraceae at 3 to 4 months were strongly associated with increase in risk of overweight by 12 months. They also mentioned the association between over-richness of microbiota and the risk of overweight by 12 months, which concurs previous findings (Belei et al., 2018; Davis, 2016).
It is well known that human breast milk is a gold liquid for infants, containing ideal nutrients, digestive enzymes, hormones, immune properties, and probiotics/microbiome. However, beyond that, human breast milk contains a large portion of complex sugars – oligosaccharides. In fact, the human body cannot digest oligosaccharides, but Bifidobacterial species can. Amazingly, breast milk provides oligosaccharides for these intestinal bacteria, which eventually promote their beneficial function on infants' intestines. As a result, during the period of intestinal microbiota establishment in early infancy, Bifidobacterial species grow well on human milk oligosaccharides (Thomson et al., 2018). It is an awe-inspiring mystery of nature how our body was made as a balanced ecosystem by coexisting with these microorganisms.
Some researchers studied the association between the impact of antibiotics exposure on the composition of intestinal microbiota and overweight in children (Gerber et al, 2016; Saari et al., 2015; Stiemsma & Michels, 2018). Gerber and colleagues (2016) and Saari and colleagues (2015) both addressed that the risk of overweight and weight gain were significantly associated with the earlier life antibiotic exposure and the higher number of antibiotic courses in the first 12 months of age. Although Saari and colleagues (2015) reported this significance was greater when the first antibiotic exposure took place at younger than 6 months of age, Gerber and colleagues (2016) did not find this association. Intriguingly, both studies described a dose dependence in the significance of increasing risk of overweight and weight gain. Moreover, Saari and colleagues (2015) reported the association of the higher risk, especially in children who were exposed to macrolides, broad spectrum antibiotics at less than 6 months of age. This also reminds us of the previously discussed early infancy critical window of intestinal dysbiosis in disease development. Thus, these results bring attention to the importance of the choice of antibiotics in early infancy. For instance, avoidance from repeated exposure and favored use of narrow-spectrum antibiotics when possible should be considered. Additionally, probiotics for preventing and treating antibiotic-associated diarrhea may be worth discussing prior to antibiotics administration in otherwise healthy children (AAP, 2010; Guo et al., 2019).
Furthermore, findings from a study by Rampelli and colleagues (2018) exploring changes in microbiota structures of participants for over age 5 years were also thought-provoking. While some participants became obese, others remained normal weight in 4 years. Rampelli and colleagues (2018) found an increase in the abundance of Proteobacteria and a decrease in Clostridiaceae and Ruminococcaceae after the onset of obesity. Again, as can be similarly seen in the previous theme, members of Butyrate-producing bacteria families to which Faecalibacterium and Coprococcus belong were decreased in unhealthy, diseased states. Interestingly, their findings show that differences in food consumption lead to different microbiota diversity structures. For example, higher consumption of fish, seeds, and whole grain bread was associated with the diversity structures seen more in the normal group while a higher consumption of dairy products, pizza, sausages, and sweetened drinks and other carbohydrates was associated with the structures seen more in the obese group. This highlights an evidence of the impact of daily diet on microbiota compositions influencing the disease process either positively or negatively. Finally, Slattery and colleagues (2016) referred to several studies investigating the protective effects of probiotics in overweight, obesity, and obesity-related NAFLD by administration of Lactobacillus rhamanosus GG, although results were inconsistent.
Intestinal Microbiota and Nervous System: Gut-brain Axis
Echoing the increasing evidence to support early-life microbial compositional changes in stress response and anxiety and the growing attention to the possible association between variations in the intestinal microbiota and aspects of social behavior and mental health, 10 of 25 articles were identified as focusing on this theme. McVey Neufeld and colleagues (2016) reviewed their own mice studies and studies of others and explained gut-brain axis as complex interactions by three systems: the enteric nervous system (ENS), the central nervous system (CNS), and the immune system. According to McVey Neufeld and colleagues (2016), the GF mice showed typical characteristics, such as unusually reduced anxiety-like behaviors, cognitive dysfunction, social deficits, microglia activation deficits, and changes in brain-derived neurotrophic factor (BDNF) expression. It is reasonably presumed that the absence of microbes during the development period dramatically affected the brain-gut axis and the CNS circuitry and neuro-wiring. Additionally, there are many similarities in the immune system and nervous system. Some molecular components (e.g., cytokines) are shared by both systems. In fact, the comorbidity of gastrointestinal problems and inflammatory problems in children with cognitive, behavioral, and/or mental problems is fairly common (Navarro et al., 2016).
Jiang and colleagues (2018) investigated the intestinal microbiota profiles of children with attention deficit hyperactivity disorder (ADHD) and noted Faecalibacterium, Dialister, and Sutterella were abundant in healthy controls and less so in ADHD group. Further, the abundance of Faecalibacterium was negatively associated with parental reports of ADHD symptoms. Comparatively, in the study by Krajmalnik-Brown and colleagues (2015) on autism spectrum disorders (ASD) with gastrointestinal (GI) symptoms, a distinguishing microbiome in ASD was associated with lower abundance of the bacterial genera Prevotella, Coprococcus, and unclassified Veillonellaceae, and an overall less diverse gut microbiome. Although they studied different cognitive, behavioral problems, both studies shared findings of microbiome changes in intestinal Butyrate-producing communities, which are also consistent with findings of several studies as previously discussed. However, Inoue and colleagues (2016) contrarily revealed that the abundance of genus Faecalibacterium was significantly higher in the fecal microbiota of infants with ASD, although their sample size was notably limited when compared with others.
Featuring the protective effect of probiotics in childhood ASD and ADHD, Navarro and colleagues (2016) and Pärtty and colleagues (2015) conducted a review and a study, respectively. Impressively, Pärtty and colleagues (2015) reported that at 13 years of age, ADHD or ASD was diagnosed in 17.1% children in the placebo group and none in the probiotic supplementation group. They further looked into participants' microbiota compositions and found that the numbers of Bifidobacterium species bacteria in feces during the first 6 months of life was lower in affected children. Moreover, at 18 months and 24 months, Bacteroides and Lactobacillus-Enterococcus group bacteria and Clostridium histolyticum group were also lower among affected children; however, at age 13 years, there were no statistically significant differences in gut microbiota composition.
Findings above repeatedly illustrated the possible key influence of Butyrate-producing microorganism communities and the critical window in infancy and early childhood for both the development of intestinal microbiota community and the development of the neurological system and their interactions. Navarro and colleagues (2015) also supported the evidence for the role of probiotics in ASD with GI problems, noting potential benefits due to the underlying systemic inflammation. Moreover, in a mouse study, the above-mentioned GF mice with cognitive dysfunction, social deficits showed mitigation of these deficits after the microbiota supplementation. In addition, antibiotic-treated mice displayed the similar immature function of the CNS to that of GF mice, as well as the probiotics effects above (McVey Neufeld et al., 2016; Stiemsma & Michels, 2018).
On the other hand, some researchers argued there is another critical window for neurological development and intestinal microbiota interactions in adolescence because there are active physiological neuron development, myelination, and synaptic pruning during this period. Additionally, increasing stress, unhealthy lifestyle, and substance exposure are also common in the same period. Interestingly, the peak age of onset for mood and mental disorders is around 14 years, which may suggest a strong link to the currently discussed critical window in the adolescence period (McVey Neufeld et al., 2016). A study by Herpertz-Dahlmann and colleagues (2017) revealed that patients with anorexia nervosa displayed a significantly reduced intestinal microbiota diversity in the state of a low body mass index (BMI) and an increased diversity after gaining weight, although it remained lower than in healthy controls. Further, differences in the abundance and diversity of bacterial groups were significantly associated with eating disorder psychopathology and depression scores. Finally, al though researchers started to have a better understanding of this fascinating theme, these complex interactions are still under studied, especially with human subjects.
In summary, the evidence of the association between dysbiosis of the intestinal microbiota and common childhood diseases was confirmed by the current literature review. Dysbiosis may also be linked to the likelihood causation of the development of disease status, although other factors from genetics and extra environment should be also considered. Specifically, findings repeatedly suggested the protective function of Bifidobacteria and Butyrate-producing intestinal microbiota in the development of common childhood chronic health problems across the three themes. Bifidobacteria seems to be the key player for the sufficient establishment of intestinal microbiota community and the effective energy metabolism in the very limited microbiota nature of newborns and young infants.
Other consistent findings throughout the three themes were the critical windows of significant interactions between the intestinal microbiota and developing organs/physiologic systems of the children. Notably, the early infancy critical window of intestinal dysbiosis was linked to the development of asthma, atopic disease, obesity, ASD and ADHD. The adolescent critical window might be related to the development of mood, mental disorders, and disruption of cognitive functions.
Moreover, the consumption of probiotics and prebiotics was prevalent and considered safe strategies to restore intestinal homeostasis and enhance protective bacteria. Despite their potential benefits, inconsistent results of their effects in preventing and alleviating the severity of the featured diseases were seen in the reviewed studies. In addition, the appropriate dosage and choice of species, and timing and duration of administration have been limitedly examined.
Pediatr Nurs. 2020;46(3):125-137. © 2020 Jannetti Publications, Inc.