Intestinal Microbiota of Childhood: Dysbiosis and Diseases

Adult humans harbor ∼10¹⁴ bacteria in the gut, comprising >1,000 species, with ∼160 species per person per fecal sample,[1] and this ecosystem plays an important role in human health. While the area of gut microbiology in relation to human diseases is not new and has received medical interest for more than 100 years, technological advancements in the last decade have allowed us to investigate it in a more sophisticated manner. A novel approach is characterized by culture-independent techniques such as amplification of the 16S rRNA gene, which encodes several conserved regions that are exclusive to all bacteria.[2] In parallel with the prevailing use of these techniques, the number of articles published in this field is growing rapidly. A search of PubMed for English-language articles using the key words “gut microbiota” found ∼6,000 articles, among which more than 95% were published after 2005.

The infant gut undergoes important developmental stages that are entirely dependent on microbial colonization. This development of gut microbiota is considered to begin not at birth but in the fetal period, as meconium is not as sterile as previously assumed.[3] The composition of the microbiota in childhood depends on numerous factors including sanitization, mode of delivery (cesarean section or vaginal delivery), maturity at birth (preterm or term birth), infant diet (breastfeeding or formula feeding, and introduction of solid foods), antibiotic usage during infancy, immunization, and geography.[1] [2] These factors that can alter the microbiota are being studied as potential drivers of the increasing trend in immune-mediated diseases. An ever-expanding number of studies have reported that changes in the composition and activities of gut microbiota can play a significant role in the development of many gastrointestinal as well as nonintestinal diseases.[1] [2] Dysbiosis is defined as changes in the composition of the gut microbiota and may be associated with several clinical conditions, including obesity and metabolic diseases,[4] autoimmune diseases,[5] allergy-related diseases,[6] acute and chronic intestinal inflammation,[7] irritable bowel syndrome,[8] necrotizing enterocolitis (NEC),[9] and autistic-spectrum disorders.[10] Furthermore, a recent review correlates the possible role of dysbiosis with sudden infant death syndrome.[11] Although the precise mechanisms in the relationship between dysbiosis and disease development remain unknown, it has been hypothesized that there is a “critical window” early in life during which the microbiota can be disrupted in a way that may favor the development of disease later in life, based on an early Japanese study.[12]

The aim of this special issue entitled “Intestinal Microbiota of Childhood: Dysbiosis and Diseases” is to summarize the latest studies of childhood intestinal microbiota. It also discusses the increasing evidence indicating that changes in microbiota during early life affect the development of intestinal and extra-intestinal diseases.

This special issue begins with an excellent overview entitled “Early-Life Gut Microbial Composition” by Nagpal and Yamashiro. They summarize the current understanding of acquisition of particular microbial arrays during early life, mainly the first 1,000 days. They also review recent findings about the gut–brain axis, a multicomponent bidirectional signaling system between the gut and the brain.

The following review article, entitled “Antibiotics Usage and Intestinal Microbiota” by Tsuji and Kaneko, focuses on antibiotic-associated diarrhea (AAD). Among many factors that influence and disrupt the development of the gut microbiota in children, increasing use of broad-spectrum antibiotics in infants in the western world gives rise to disruption of the overall ecology of the gut microbiota and alters the abundance of resident gut bacteria. Both of these factors play an important role in the development of AAD, which is mainly caused by Clostridium difficile. Tsuji and Kaneko summarizes the current understanding of AAD, including preventative treatment using probiotics, which are defined as microorganisms that have a beneficial effect on the body, particularly by maintaining the balance in the composition of the intestinal microbiota.

The next five articles discuss increasing evidence indicating that changes in microbiota during early life affect the development of intestinal and extra-intestinal diseases.

Despite overall decreases in mortality and morbidity in very low birth weight infants in recent decades, NEC, a devastating condition with high mortality, develops in 5 to 6% of these infants. Lin reviews the critical role of gut microbiota in the pathogenesis of NEC, along with possible therapeutic strategies using probiotics.

Inflammatory bowel diseases (IBDs) include Crohn disease and ulcerative colitis, both of which are chronic, incurable inflammatory conditions affecting the gastrointestinal tract. Although the precise cause of these common conditions is currently unknown, it is clear that the intestinal microbiota is a critical element in the development of gut inflammation. Day reviews the current findings on the characteristics of intestinal microbiota with regard to changes in IBD.

Obesity is a worldwide epidemic threat in both industrialized and developing countries. Yamashiro and colleagues discuss how gut dysbiosis in infants, caused by multiple factors including maternal obesity, contributes to obesity and obesity-related disorders in later life.

Allergic diseases have seen a rapid increase in prevalence during the past 30 years. Atopic dermatitis, food allergy, allergic rhinitis, and asthma are a quartet of conditions that are often seen sequentially. There is mounting evidence that imbalances in the gut microbiome plays a role in the pathogenesis of allergic diseases. Dissanayake and Shimojo review the current knowledge about the role of intestinal microbiota in the development of asthma and atopy.

Finally, Sudo focuses on the signaling pathway between the gut microbiota and the brain in terms of the effects of commensal microbiota on the hypothalamic–pituitary–adrenal axis response and behavioral characteristics, and further considers the possible link between gut microbiota and childhood mental health.

I believe that this special issue gives an excellent overview of the state of the art in childhood intestinal microbiota and hope that it prompts pediatricians worldwide, regardless of their subspecialties, to study the appropriate timing of interventions and the complex interactions between the infant immune system and the gut microbiota.

• References

• 1 Rodríguez JM, Murphy K, Stanton C , et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis 2015; 26: 26050
• 2 Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The intestinal microbiome in early life: health and disease. Front Immunol 2014; 5: 427
• 3 DiGiulio DB, Romero R, Amogan HP , et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS ONE 2008; 3 (8) e3056
• 4 Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444 (7122) 1027-1031
• 5 Van Praet JT, Donovan E, Vanassche I , et al. Commensal microbiota influence systemic autoimmune responses. EMBO J 2015; 34 (4) 466-474
• 6 Atarashi K, Tanoue T, Shima T , et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331 (6015) 337-341
• 7 Gevers D, Kugathasan S, Denson LA , et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 2014; 15 (3) 382-392
• 8 Simrén M. IBS with intestinal microbial dysbiosis: a new and clinically relevant subgroup?. Gut 2014; 63 (11) 1685-1686
• 9 Torrazza RM, Ukhanova M, Wang X , et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS ONE 2013; 8 (12) e83304
• 10 Hsiao EY, McBride SW, Hsien S , et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013; 155 (7) 1451-1463
• 11 Goldwater PN. Gut microbiota and immunity: possible role in sudden infant death syndrome. Front Immunol 2015; 6: 269
• 12 Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 1997; 159 (4) 1739-1745