Staphylococcus aureus is a bacterium that is naturally present in the nose and skin of healthy people but is more abundant in children with eczema, especially when it is severe. This skin disorder is also a risk factor for developing food allergies. Thus, it could be easily imagined that the link between Staphylococcus aureus and food allergies in people with eczema is related to the severity of this disorder.

Multi-step study

This hypothesis was tested by a team of researchers using data collected during the LEAP (sidenote: LEAP Learning Early About Peanut Allergy )  study which monitored 640 children who were identified as high risk for peanut allergy (based on an existing egg allergy or severe eczema, or both) from early childhood to the age of 5. The results, published in 2015, had shown that preventing peanut allergy could be achieved, paradoxically, by introducing peanut to infants who are at high-risk for developing this allergy.

S. aureus, known culprit?

In this new part of the LEAP study, the analysis of the nose and skin microbiota of the children participating in the study showed that the more significant the Staphylococcus aureus colonization was, the more severe the eczema was and the more it worsened over time. The combination of these two disorders (Staphylococcus aureus infection + eczema), regardless of severity, is often associated with an increased production of molecules as part of the allergic reaction to peanuts, chicken egg white and milk. While it generally wanes with age, egg allergy persists in about 40% of children under study; and peanut allergy appears even in children who were preventively exposed from a very young age. The presence of Staphylococcus aureus in the nose or skin could thus lead to an allergic reaction to some diseases.

Towards a new potential therapeutic avenue

According to the researchers, S. aureus could prevent the development of a natural tolerance to eggs and peanuts, which would thus trigger the allergy. They thus suggested that eradicating S. aureus in children with eczema could prevent food allergies; and argue that further work should be carried out to elucidate the role of this bacterium in the development of these two disorders.

What are the main childhood gastrointestinal disorders involving the microbiota?

I count five of them. The first two are infectious (or post-infectious) diseases related to an infestation by pathogens, and inflammatory bowel diseases, which are due to a conflict between the immune system and commensal bacteria. But intestinal microbiota is also involved in food allergies, functional disorders (irritable bowel syndrome, constipation), as well as in obesity. Whether intestinal dysbioses are the cause or the consequence of these diseases has yet to be determined. Any change in the microbiota is likely to lead to functional changes, or even organic alterations, and conversely. Simply put, we estimate that infections can generate a dysbiosis and that chronic inflammatory bowel diseases can cause, as well as be caused by, a dysbiosis. The mechanisms involved in allergies are quite unclear but they could develop even before the maturation of the immune system, while later and/or prolonged changes could be involved in gastrointestinal functional disorders or obesity..

Is France especially exposed to this type of disease?

These observations are unquestionable, but they are not specific to France. The incidence of diseases mentioned earlier has increased in the past 20 years and I believe it could be called an “epidemic”. What changed? The number of C-sections, antibiotic administration and antacids. Our dietary habits and the composition of the food we eat, especially in terms of preservatives, also play a role. All these elements are involved in the disruption of our intestinal microbiota. We should not draw simplistic conclusions, but we should bear in mind that a wide range of arguments and studies correlate these changes to a significant increase in certain childhood diseases. The challenge is even more critical in pediatrics since events that happen at birth or early childhood tend to have a lasting impact on the microbiota composition and longterm consequences on health.

How can we improve this situation and improve patient treatment?

Health professional believe that the emergency is to obtain an easier and less expensive access to intestinal microbiota metagenomics analysis methods. This could provide a qualitative comparison of the microbiota composition of the same individual at different times. Identifying changes between “baseline microbiota” and that observed during the course of a disease could help us identify pathophysiological mechanisms and develop personalized or targeted therapeutic responses. In this context, the probiotics approach seems to be effective in certain intestinal disorders and deserves to be further investigated. Some countries are starting to show interest in this topic, but France must not be left behind, especially within the European Union. Moreover, we should adopt a true “culture of prevention”, with the support from public authorities, that includes the protection of intestinal microbiota. This would contribute to limit exposure to risk factors that are likely to generate dysbioses (C-sections, antibiotics, antacids, inadequate diet, etc.) and would decrease the number of several childhood diseases.

IS PERSISTENT DIARRHEA AN INFECTIOUS DISEASE...

Persistent diarrhea is a particular form of the disease, defined as an episode lasting more than 14 days (beyond 30 days, it is called “chronic diarrhea”). The mortality rate attributed to persistent diarrhea has been determined (54% of all deaths caused by diarrhea) but its pathogenesis is still poorly understood: is it the progression of an acute episode or a disease in its own right? Through a literature review it was revealed that the majority of researchers consider persistent diarrhea to be an infectious disease associated to an intestinal colonization by pathogenic bacteria, be it followed by an acute or another episode.²⁰ This colonization could be promoted by malnutrition and other factors (especially exposure to antibiotics) susceptible to cause intestinal dysbiosis.

... OR IS IT DUE TO MICROBIAL DYSBIOSIS?

Among other etiologic hypotheses, the theory of a bacterial outbreak is gaining momentum. It was born from the observation that an abundant presence of commensal bacteria, especially Escherichia coli, disrupts lactose absorption. Connecting intestinal dysbiosis, levels of E. coli and persistent diarrhea could provide several clues to elucidate it pathogenesis. On this topic, certain probiotics have shown their efficacy to reduce the duration of acute diarrhea and persistent diarrhea in children.^21, 22

IDENTIFIED RISK FACTORS

An analysis of scientific literature provided a draft model of the disease pathogenesis. The first risk factor category includes very young age (under 1, risk x 3), malnutrition (risk x 2) and low birth weight (risk x 1.8). The second category includes an infection in the previous month (risk x 2) and a history of persistent diarrhea (risk x 3 to 6). The third category is related to eating habits (diet, breast milk substitutes...) which can multiply the risk by 4. Other factors have also been identified, including administration of antibiotics. Potential etiologies and confirmed risk factors underline the importance of a close collaboration between pediatricians, gastroenterologists, nutritionists and biologists. Interdisciplinarity could help obtain a deeper understanding of the relationships between infection, dietary habits and pathogenic and commensal microorganisms.  

The fight against infectious diarrhea is a priority of healthcare systems in developing countries, since this pathology is the second cause of child mortality in these regions. Describing the intestinal microbiota and its dysbioses are part of this fight and could help offer personalized treatments.

RISKS ASSOCIATED TO DIARRHEA

Recurrent or prolonged diarrhea episodes increase the risk of malnutrition and stunted growth. They are also associated to numerous comorbidities: cognitive disorders, cardiovascular diseases, glucose intolerance, etc. Despite a regular decrease, near 525,000 children under 5 years of age die every year in the world. Understanding the etiology of diarrhea is a health priority, but the wide variety of types and potential causes requires further investigation, especially in terms of correlation with the intestinal microbiota. A recent study focused on Vietnamese population was added to the existing body of scientific literature on infectious diarrhea. It characterized the bacterial communities of 145 children with diarrhea and 54 controls.¹⁷

ETIOLOGIC AGENTS WERE IDENTIFIED

Bacterial analysis of fecal samples revealed four major types of bacterial predominance in children with diarrhea: Bifidobacterium, Bacteroides, Streptococcus and Escherichia. The first two categories, usually asymptomatic, are close to the composition of the microbiota of control children. Predominance of Streptococcus and Escherichia in the microbiota of children who had the most severe symptoms, confirmed previous studies that associated these microorganisms with a higher risk of gastrointestinal disorders. Bacterial depletion was also observed in all categories. Nineteen taxa are concerned (mainly belonging to the Clostridiales and Erysipelotrichales orders) and especially Blautia hansenji which is known for its ability to produce SCFA¹⁹, essential to homeostasis.

INDIVIDUAL VULNERABILITIES

Age, nutritional status, intake of breast milk and etiology seem to contribute to the composition of bacterial communities during the early phase of diarrhea episodes. Streptococcus are more largely associated to young children (under 2) and bacterial infections, while Escherichia are found in older children and/or children with poor nutritional status. This extensive characterization is part of the analysis of the complex influences of infectious diarrheas on the intestinal microbiota and guides research towards new therapeutic approaches.

ASPIRATE VS. SWAB

As is the case for bronchiolitis, characterization of the airway microbiota takes on a particular importance in some pulmonary pathologies. The severity of the disease is direct y correlated with the local microbial populations. Consequently, accurate identification of the microorganisms present proves essential and requires high-quality sampling. Standard protocol (nasopharyngeal aspirate) of fers good diagnostic and prognostic efficacy. But the procedure is invasive and proves tricky to perform in children, in particular in infants. Simpler to perform and less traumatic, nasal swab is a promising alternative. Its efficacy was studied by comparing the nasopharyngeal and nasal microbiota of infants with bronchiolitis (composition / capacity to predict the severity of the inflammatory episode).¹⁶ Both sampling techniques were assessed in 815 hospitalized children; bacterial populations were characterized by amplification of 16S rRNA genes.

DIFFERENT POPULATIONS, BUT SIMILAR PREDICTABILITY

The analyses show a disparity between the microbial populations of the two areas. The nasal microbiota is composed mainly of the genera Staphylococcus (40.8%), Corynebacterium (10.4%), Moraxella (9.3%), Haemophilus (7.4%), Dolosigranulum (5.2%), Streptococcus (5%) and Enterobacter (4.7%). However, the nasopharyngeal microbiota is dominated by the genera Moraxella (30.7%), Streptococcus (30.5%) and Haemophilus (19.7%). These differences however should be put in perspective: predominance of Moraxella or Haemophilus in the nasal area is also found in the nasopharynx, making these two sites a good tool for predicting the severity of bronchiolitis. Children with a Haemophilus-dominant profile display an increased risk of requiring intensive care or prolonged hospitalization (≥ 5 days). In comparison, subjects with a Moraxella-dominant profile seem to be the least at risk. This predictive capacity is not however applicable to other bacterial genera. The nasal swab presents many practical advantages, and can therefore be considered a valid alternative to nasopharyngeal aspirate in assessing the severity of bronchiolitis in infants.

Detailed characterization of the respiratory tract microbiota demonstrates the specificity of the bacterial populations of children with cystic fibrosis. This could be a path towards identification of risk factors for pulmonary infections and better patient care.

A MORE ADVANCED TECHNOLOGY

Recent technical progress in molecular screening, sequencing and metagenomic analyses are contributing to the detailed characterization of human respiratory tract microbiota. This growing precision is accompanied by a better understanding of the complex relationships between the different populations of microorganisms and the respiratory system of their host, whether the latter is healthy or not. In this respect, cystic fibrosis is a good illustration. Pulmonary infections, which play a determining role in the pathogenesis of the disease, display changes over time. Relatively benign infections with Staphylococcus aureus and Haemophilus influenzae in early childhood, can progress to persistent infections with Gram-negative bacteria such as Pseudomonas aeruginosa, which become increasingly severe with age. This progression is accompanied by harmful changes in the respiratory tract microbiota and raises an underlying question: are these dysbioses the consequences of infectious episodes, or do they contribute to their development?

DIVERSITY ISSUE

In the absence of answer regarding causal relations, a literature review has identified the differences between a healthy respiratory microbiota and a microbiota disrupted by cystic fibrosis.¹⁴ The first is diversified and characterized by a predominance of one or two bacterial genera among the following: Staphylococcus, Dolosigranulum, Corynebacterium, Haemophilus, Streptococcus and Moraxella. The last three expose patients to a higher risk of developing acute respiratory infections. In contrast, children with cystic fibrosis have a less dense and less diversified bacterial environment, marked by the predominance of Corynebacterium and Streptococcus. This dysbiosis seems to become more pronounced with time and disease severity, and the terminal phase can be associated with the presence of only one or two pathogens.

HOW TO IMPROVE PATIENT CARE

Once a better understanding of the characteristics and progression of the respiratory tract microbiota in individuals with cystic fibrosis was obtained, the question of the interactions between dysbioses and structural and functional development of pulmonary infections arose. A detailed elucidation of the mechanisms at work could help identify the potential pathogenic or protective factors in order to strengthen prophylactic and therapeutic approaches.

IMPAIRED NEUROTRANSMISSION

Attention deficit hyperactivity disorder (ADHD) is another class of neuropathies possibly involving the human microbiota. It is associated with abnormal dopamine neurotransmission and reward processing deficits via the underlying neural circuits, in particular in the ventral striatum. The microbiota could contribute to these changes through the gut-brain axis.¹⁰ The hypothesis was explored through characterization of the intestinal microbiota of adolescents and young adults with attention deficit hyperactivity disorder, in addition to an analysis of cerebral responses to emotional stimulation.¹²

HIGHER LEVELS OF DOPAMINE PRECURSOR

Analysis of the intestinal microbiota by 16S rRNA sequencing has provided an identification of the bacterial populations in adolescents with ADHD. Functional imaging was used to compare the intestinal microbial populations and cerebral responses to stimulation of reward processes in some participants, independently of the initial diagnosis. Characterization of the microbiota revealed changes, in particular an increase in Bifidobacterium in ADHD subjects. These bacteria, which are predominant in their intestines, possess a gene encoding cyclohexadienyl dehydratase, an enzyme involved in the synthesis of phenylalanine, a dopamine precursor capable of crossing the blood-brain barrier. Consequence: an increase in brain dopamine levels leading to an increased risk of neurological disruption.

MOTIVATIONAL DEFICIT

This increased production of monoamines driven by the intestinal microbiota is correlated with a decrease in neural mechanisms of reward anticipation in the ventral striatum, another ADHD marker. This link was confirmed by imaging: subjects presenting with intestinal dysbiosis displayed “intolerance to delayed reward” (inability to tolerate deferral of a reward), considered by many experts to be the fundamental mechanism of the pathology. The intestinal microbiota thus seems to be a new factor in the etiology of attention deficit hyperactivity disorder, as its composition has a direct impact on the synthesis of cyclohexadienyl dehydratase. Whilst the possibility of dysbiosis linked to ADHD is not excluded, further investigations are required to specify the level of interactions, as well as the functional effects of microbiota on psychiatric disorders in general (OCD, phobias, anxiety disorders…).

Autistic children have distinct bacterial and fungal populations in the intestines, as well as oral dysbiosis. These two complementary research areas could help structure diagnostic approach and therapeutic care.

DISRUPTED GASTROINTESTINAL SYSTEM

Autism is a neurodevelopmental disorder that generally appears in early childhood, and is characterized by behavioral disorders: difficulties in establishing social relationships, communication problems and OCD (Obsessive Compulsive Disorders). The mechanisms of the disease remain unclear, but the recurrent presence of gastrointestinal problems in autistic children could suggest a possible link with the intestinal microbiota. Studying this hypothesis could help clarify etiology, which is currently based mainly on genetic and environmental factors.

BACTERIAL ALTERATIONS…

Some studies, such as those of an Italian team, have tried to validate the hypothesis of a dysbiosis.⁷ Fecal samples from 40 children with severe autistic disorders and 40 “neurotypical” controls led to the characterization of the bacterial populations by amplification of 16S rRNA genes. The analyses confirm the pertinence of the original hypothesis: a significant increase in the Firmicutes/Bacteroidetes ratio, traditionally associated with an increased risk of developing inflammatory disorders, was observed in autistic children. At the genus level, a depletion of Alistipes, Bilophila, Dialister, Parabacteroides and Veillonella, and an increase in Collinsella, Corynebacterium, Dorea and Lactobacillus were observed. In autistic subjects suffering from constipation (a symptom of gastrointestinal problems that is common in this pathology), an abundance of Escherichia, Shigella and Clostridium was also observed.

… AND FUNGAL ALTERATIONS

Analysis of the fungal community also demonstrated disparities between the autistic and control subjects, with the former having a twofold higher proportion of Candida. This observation must be tempered, as this type of fungus is naturally found in humans, to the point that the discrepancy is not very significant. Fungal dysbiosis seems nevertheless confirmed. It could influence bacterial development and vice versa, as the two communities develop within the same microbiota.

IS THE ORAL MICROBIOTA ALSO INVOLVED?

The intestinal microbiota is not the only one being implicated in the development of autism. Researchers are also examining the microbial populations of ENT areas, which contain a large diversity of taxa (more than 700 in the oral cavity alone) and act as a reservoir of infections for other parts of the body, including the central nervous system. Since previous works have shown oral dysbioses in patients with Parkinson’s, Alzheimer’s, MS, or migraine, researchers decided to characterize the oral microbiota of autistic children to characterize any microbial specificities.⁹

THE ORAL CAVITY, A SPECIAL ENVIRONMENT

The peculiarity of the oral cavity is that both soft tissue (mucous membranes) and hard tissue (teeth) coexist in it. Sampling of both saliva and dental plaque provided a more detailed identification of the bacterial populations of 111 samples taken from 32 autistic children and 27 controls. Like with the intestinal microbiota, large differences were observed between the two groups of participants. The oral microbial community of autistic subjects is characterized by an overall bacterial depletion and a rise in pathogens such as Haemophilus in the saliva and Streptococcus in the dental plaque, as well as a decrease, in both areas, in several commensal bacteria: Prevotella, Selenomonas, Actinomyces, Porphyromonas and Fusobacterium. The dental plaque also displays a significant decrease of all Prevotellaceae, a family capable of interacting with the immune system, and a high concentration of Rothia, a bacterium frequently associated with dental diseases in the literature.

THE MICROBIOTA: A NEW DIAGNOSTIC AND THERAPEUTIC TOOL IN PSYCHIATRY?

Thanks to the oral bacterial populations identified in autistic disorder, a diagnostic model has been developed based on the main oral biomarkers. This tool, which displayed a 96.3% efficacy rate with saliva, could prove particularly useful and relevant in modern psychiatry. This biological approach could complement the usual criteria derived mostly from DSM-5 (Diagnostic and Statistical Manual of Mental Disorders), which is based on a consensus on clinical symptoms that are difficult to measure. More extensive investigations into the microbiota of autistic children could make possible new diagnostic approaches, and the development of innovative therapeutic strategies.

EXPOSURE TO ANTIBIOTICS AND EARLY IBD

The excess weight issue underlines the complexity in elucidating the impact of dysbiosis in some medical fields. Causal relations have been more detailed in the gastroenterology field, where a link has been established between the composition of the intestinal microbiota and IBD. This connection leads researchers to increasingly take dysbioses into account when attempting to understand disorders with poorly identified etiology, especially ulcerative colitis (UC) and Crohn’s Disease in young children (under six years of age), whose global incidence is increasing regularly. As the cause of this progression cannot be found in known genetic and environmental factors, intestinal weakness associated with disruptions in the microbiota has been suggested.

TWOFOLD HIGHER RISK OF IBD AFTER INTRAPARTUM ANTIBIOTIC TREATMENT

Swedish researchers explored this hypothesis by studying a cohort of 827,239 children born between 2006 and 2013.³ This was an extensive analysis based on crosschecking the Swedish National Registers of births, patients and drug prescriptions. In total, 17% of subjects were exposed intrapartum to antibiotics (including 5% repeatedly) and 65% after birth, most of them more than once (7 out of 10). Fifty-one children were affected by Crohn’s disease or UC. Compared to the control population, children exposed to antibiotics during pregnancy had an elevated risk (aHR4 = 1.93) of developing early IBD.

FETAL IMPACT

Intrauterine exposure to antibiotics is believed to trigger a disruption of early bacterial colonization in children, characterized by a low concentration of commensal bacteria, in particular Faecalibacterium prausnitzii and Ruminococcaceae, and an increase in pathogenic bacteria. This dysbiosis could cause significant physiological changes due to the interaction between microbiota and host through production of SCFA (particularly butyrate), induction of the immune system of the intestinal mucosa, stimulation of the local nervous system and maintenance of the intestinal barrier function.⁵ These are all malfunctions which are liable to trigger inflammatory disorders.

IMPROVING ANTIBIOTIC PRESCRIPTION TO PRESERVE THE MICROBIOTA

The data mentioned above and those derived from a growing number of studies and publications show that a diversified microbiota displaying a high commensal/pathogenic bacteria ratio contributes to an adequate development in children by limiting the risk of occurrence of some diseases, especially metabolic or inflammatory. This observation should not lead to a dismissal of antibiotic therapy, whose efficacy and benefits prove invaluable in many cases, as emphasized by all healthcare providers. However, optimizing prescriptions, spectrum of the drugs employed, duration of treatment and modes of administration are good ways of limiting the impact of antibiotics and the transfer of resistance to the intestinal microbiota in order to preserve child health in the short and long term.

LITERATURE-BASED STUDY OF THE RISK OF EXCESS WEIGHT AT AN EARLY AGE

Excess weight or obesity at an early age is one of the metabolic risks associated with impairment of the intestinal microbiota that raises questions. Thirteen observational studies and meta-analyses, meeting previously defined inclusion criteria and identified from a corpus of 4,870 international publications, allowed this issue to be clarified by monitoring bodyweight in 527,504 children exposed to antibiotics in their first 24 months of life.² This work was fine-tuned by studying in detail the six-month postnatal period, as well as the doses and type of antibiotics administered.

EARLY TREATMENT OR REPEATED CYCLES: INCREASED RISK OF EXCESS WEIGHT

Analysis of the data collected revealed a slight increase in the risk of excess weight or obesity during a postnatal treatment (in the six months after birth; OR [odds ratio]: 1.20) or during repeated administration of antibiotics (more than one treatment; OR: 1.24) before two years of age. Conversely, a single treatment or one occurring after the first six months of life does not appear to impact negatively weight progression. A question remains: is this a direct causal link? Does the effect of the antibiotic cause a weight problem in children? Or it is the opposite? Is childhood obesity likely to be associated with an increased risk of infection resulting in additional antibiotic treatment courses? Those who favor the first hypothesis consider that a detrimental intestinal colonization could play a specific role, in the light of its already documented involvement in the development of metabolic disorders. In any case, the research shows that in the perinatal period antibiotics should be administered with caution.