Leah Stiemsma

The intestinal microbiome in early life: health and disease

Human microbial colonization begins at birth and continues to develop and modulate in species abundance for about 3 years, until the microbiota becomes adult-like. During the same time period, children experience significant developmental changes that influence their health status as well as their immune system. An ever-expanding number of articles associate several diseases with early-life imbalances of the gut microbiota, also referred to as gut microbial dysbiosis. Whether early-life dysbiosis precedes and plays a role in disease pathogenesis, or simply originates from the disease process itself is a question that is beginning to be answered in a few diseases, including IBD, obesity, and asthma. This review describes the gut microbiome structure and function during the formative first years of life, as well as the environmental factors that determine its composition. It also aims to discuss the recent advances in understanding the role of the early-life gut microbiota in the development of immune-mediated, metabolic, and neurological diseases. A greater understanding of how the early-life gut microbiota impacts our immune development could potentially lead to novel microbial-derived therapies that target disease prevention at an early age.

The hygiene hypothesis: current perspectives and future therapies.

Developed countries have experienced a steady increase in atopic disease and disorders of immune dysregulation since the 1980s. This increase parallels a decrease in infectious diseases within the same time period, while developing countries seem to exhibit the opposite effect, with less immune dysregulation and a higher prevalence of infectious disease. The “hygiene hypothesis”, proposed by Strachan in 1989, aimed to explain this peculiar generational rise in immune dysregulation. However, research over the past 10 years provides evidence connecting the commensal and symbiotic microbes (intestinal microbiota) and parasitic helminths with immune development, expanding the hygiene hypothesis into the “microflora” and “old friends” hypotheses, respectively. There is evidence that parasitic helminths and commensal microbial organisms co-evolved with the human immune system and that these organisms are vital in promoting normal immune development. Current research supports the potential for manipulation of the bacterial intestinal microbiota to treat and even prevent immune dysregulation in the form of atopic disease and other immune-mediated disorders (namely inflammatory bowel disease and type 1 diabetes). Both human and animal model research are crucial in understanding the mechanistic links between these intestinal microbes and helminth parasites, and the human immune system. Pro-, pre-, and synbiotic, as well as treatment with live helminth and excretory/secretory helminth product therapies, are all potential therapeutic options for the treatment and prevention of these diseases. In the future, therapeutics aimed at decreasing the prevalence of inflammatory bowel disease, type 1 diabetes, and atopic disorders will likely involve personalized microbiota and/or helminth treatments used early in life.

Associations between infant fungal and bacterial dysbiosis and childhood atopic wheeze in a nonindustrialized setting

Background: Asthma is the most prevalent chronic disease of childhood. Recently, we identified a critical window early in the life of both mice and Canadian infants during which gut microbial changes (dysbiosis) affect asthma development. Given geographic differences in human gut microbiota worldwide, we studied the effects of gut microbial dysbiosis on atopic wheeze in a population living in a distinct developing world environment. Objective: We sought to determine whether microbial alterations in early infancy are associated with the development of atopic wheeze in a nonindustrialized setting. Methods: We conducted a case‐control study nested within a birth cohort from rural Ecuador in which we identified 27 children with atopic wheeze and 70 healthy control subjects at 5 years of age. We analyzed bacterial and eukaryotic gut microbiota in stool samples collected at 3 months of age using 16S and 18S sequencing. Bacterial metagenomes were predicted from 16S rRNA data by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States and categorized by function with Kyoto Encyclopedia of Genes and Genomes ontology. Concentrations of fecal short‐chain fatty acids were determined by using gas chromatography. Results: As previously observed in Canadian infants, microbial dysbiosis at 3 months of age was associated with later development of atopic wheeze. However, the dysbiosis in Ecuadorian babies involved different bacterial taxa, was more pronounced, and also involved several fungal taxa. Predicted metagenomic analysis emphasized significant dysbiosis‐associated differences in genes involved in carbohydrate and taurine metabolism. Levels of the fecal short‐chain fatty acids acetate and caproate were reduced and increased, respectively, in the 3‐month stool samples of children who went on to have atopic wheeze. Conclusions: Our findings support the importance of fungal and bacterial microbiota during the first 100 days of life on the development of atopic wheeze and provide additional support for considering modulation of the gut microbiome as a primary asthma prevention strategy. Graphical abstract: Figure. No caption available.

The Role of the Microbiome in the Developmental Origins of Health and Disease

Early-life transient dysbiosis has long-lasting effects on human health, suggesting a role of the microbiome in the DOHaD. Although the prominent role of the microbiome in human health has been established, the early-life microbiome is now being recognized as a major influence on long-term human health and development. Variations in the composition and functional potential of the early-life microbiome are the result of lifestyle factors, such as mode of birth, breastfeeding, diet, and antibiotic usage. In addition, variations in the composition of the early-life microbiome have been associated with specific disease outcomes, such as asthma, obesity, and neurodevelopmental disorders. This points toward this bacterial consortium as a mediator between early lifestyle factors and health and disease. In addition, variations in the microbial intrauterine environment may predispose neonates to specific health outcomes later in life. A role of the microbiome in the Developmental Origins of Health and Disease is supported in this collective research. Highlighting the early-life critical window of susceptibility associated with microbiome development, we discuss infant microbial colonization, beginning with the maternal-to-fetal exchange of microbes in utero and up through the influence of breastfeeding in the first year of life. In addition, we review the available disease-specific evidence pointing toward the microbiome as a mechanistic mediator in the Developmental Origins of Health and Disease.

An antibiotic-altered microbiota provides fuel for the enteric foe

Antibiotic therapies disrupt the intestinal microbiota and render the host susceptible to enteric infections. A recent report by Ng et al. explores the ability of two intestinal pathogens (Salmonella enterica serovar Typhimurium and Clostridium difficile) to use this disruption to their advantage and consume host carbohydrates that would otherwise be unavailable in the presence of a normal gut microbiota.

The early life gut microbiota and atopic disease

Background Asthma is the most prevalent of all childhood diseases and accounts for the majority of hospitalizations and school absences in children [1]. Current mouse model research has identified the early life gut microbiota as a potential therapeutic target for the prevention of asthma and atopic diseases [2-4]. We hypothesize that the early life gut microbiota could play a similar preventative role against atopic disease development in humans. Methods 1262 children enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study with complete skin prick test and wheeze data at one year were grouped into four clinically relevant phenotypes: atopy + wheeze, atopy only, wheeze only, and control. Bacterial 16S rDNA from 3-month and 1-year stool samples of 319 children in these four phenotypes was extracted, amplified, and subjected to high throughput Illumina sequencing. Quantitative polymerase chain reaction (qPCR) and short chain fatty acid (SCFA) analysis were also conducted on 44 children in the two extreme phenotypes (atopy + wheeze vs. control). Results 16S sequence analysis of our sample cohort (319 subjects) identified bacterial populations that differed in abundance in the atopy + wheeze group at 3-months of age but not at 1-year of age. Additionally, significant changes in the abundance of certain bacterial genera were found in the atopy + wheeze group when compared to controls by qPCR at 3-months of age only. Changes in stool short chain fatty acid production between the atopy + wheeze group and the control group were also observed at 3months of age only. Conclusions Shifts in the relative abundance of certain gut bacterial populations and differences in the levels of stool SCFAs before 3-months of age are associated with atopy and wheeze at one year of age.

Why haven't the documented benefits of probiotics on preterm babies led to their wider acceptance and use?

Two of the most dreadful complications faced by clinicians who are involved in the medical care of premature infants are infections and necrotising enterocolitis (NEC), which entail high morbidity and carry a high risk of mortality. In North America, thousands of preterm infants die from NEC or late-onset sepsis every year, and survivors often have varying degrees of handicap for life (1). Research suggests that these complications partially arise from dysbiosis, which is an imbalance in the composition of the preterm infant’s microbiota, combined to an immature immune system (2). Probiotics have rapidly gained interest as a safe and effective way to restore a more physiological equilibrium and prevent these complications. So far, approximately 40 clinical trials, including 10 000 infants, have been published on the use of probiotics in the preterm population, and meta-analyses of these trials, including Sawh et al. (3), are largely in favour of the use of probiotics in clinical practice. In very low birthweight infants, probiotics decrease NEC and late-onset sepsis, all-cause mortality, the need for intravenous nutrition and the overall length of hospitalisation. They also have been reported to improve weight gain. Despite this accumulating evidence, many neonatal intensive care units (NICUs) do not routinely use probiotics. Why is that? We can hypothesise that this lack of endorsement stems from a lack of a precise understanding of the mode of action of probiotics. Unlike drugs, probiotics do not act by binding to a specific receptor. As live organisms, they dynamically influence the ecology of an entire microbial community, protecting the host from pathogen invasion by promoting colonisation of the gut by beneficial micro-organisms who then compete with pathogenic ones for nutrients. It has also become apparent that probiotics are essential during development, shaping the way our immune system reacts to other microbes and playing a major regulatory role during disease states. In this issue of Acta Paediatrica, Strunk et al. provide new insights into the potential effects of probiotics on the developing immune system of the preterm infant. They studied the expression of antimicrobial proteins and peptides (APP) in the gut and systemically in the blood of infants born before 33 weeks of gestation who were treated with Bifidobacterium Breve M16V during the neonatal period, compared to those who were not treated with this probiotic strain (3). APPs are a broad family of host defence proteins that are widely produced by virtually all cellular life forms. Humans express more than 100 distinct APPs, each exhibiting powerful antimicrobial properties against a wide variety of unicellular microorganisms, including many of the gram-positive and gram-negative bacteria and fungi commonly responsible for sepsis in preterm infants. Maturation of the first-line of immune defences, namely the innate immune system, in humans occurs relatively late in gestation during the third trimester (4). Similar to other innate immune functions, the capacity of very preterm infants to produce APPs is severely diminished compared to term infants and this may further contribute to their vulnerability to infections when microbes begin colonising their body a few days after birth. Strunk et al. demonstrate important changes in plasma and faecal APP levels, over the first month of life (4), and their results suggest that APPsmay play an important role in establishing a healthy gut microbiome at this age (5). Although it remains unclear how these changes may protect against late-onset sepsis and NEC, Strunk et al. have produced the first paper to examine the effect of probiotics on immune development at this critical early developmental stage. Importantly, administration of B. Breve M16V for three weeks shortly after birth did not alter the course of antimicrobial peptide maturation or the production of APPs by immune cells following in vitro stimulation using bacterial components, namely lipopolysaccharide or even whole Staphylococcus epidermidis. The authors conclude that these specific APPs were not modulated by this particular probiotic strain. However, more studies are required to understand the mode of action of probiotics during immune development and in the establishment of a healthy gut microbiota in preterm babies. Their study illustrates the inherent difficulty in studying and understanding the effects of probiotics on humans, particularly preterm infants. Similar to their findings, a large trial failed to confirm the clinical benefits from the administration of another strain of B. Breve on a large scale, which may have been due to contamination of the control group by the intervention (6). After birth, the neonatal microbiota comprises a mixture of anaerobic and facultative anaerobic bacteria, such as