Extremely premature infants who fail to grow as expected have delayed development of their microbiome


Extremely premature infants who fail to grow as expected have delayed development of their microbiome, or communities of bacteria and other micro-organisms living in the gut, according to a new study published in Scientific Reports.

Analysis of these infants’ metabolism revealed that their bodies are responding as if they were fasting, despite caloric intake similar to extremely premature infants with appropriate growth.

The study findings also suggest that the unique makeup of the microbiome in infants with growth failure might contribute to their inability to properly metabolize nutrients.

“Our identification of the distinct features within the microbiome and metabolism associated with growth failure might point to new ways to predict, prevent and treat this pervasive problem among preterm infants,” says one of the senior authors Patrick Seed, MD, Ph.D., Associate Chief Research Officer of Basic Sciences at Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago, and Research Professor of Pediatrics, Microbiology and Immunology at Northwestern University Feinberg School of Medicine.

“Currently we lack the means to identify infants at highest risk of growth failure.

The microbiome might give us the insights we need to guide individualized interventions and measure response to therapy.”

The human microbiome is estimated to consist of over a trillion bacteria in a single person, with 10 times the number of microbial cells to every human cell.

Research has established that specific microbiome characteristics play causal roles in obesity, allergy, asthma, diabetes, autoimmune disease, depression and a variety of cancers.

Studies have shown stark differences in the microbiome composition of preterm infants compared to full term infants.

Recent studies also found that childhood malnutrition is associated with persistent immaturity of the gut microbiome.

“In our study, we investigated the relationships between intestinal microbiome, metabolism and growth in preterm infants,” says Dr. Seed, who also is Division Head of Infectious Diseases at Lurie Children’s.

“The significant associations we found will need to be reproduced by more studies in the future.

We are looking to determine if the specific signatures of microbiome and metabolism maturation we discovered apply broadly to infants with and without growth failure.”

Growth failure in preterm infants is a risk factor for cognitive and motor impairment and may predispose these children to obesity, type 2 diabetes and heart disease later in life.

The study included 58 infants who were born at or before 27 weeks of pregnancy, weighing less than two pounds on average.

Growth failure in these infants was defined as weight less that the third percentile on sex-specific growth charts at 40 weeks of postmenstrual age (birth gestational age plus chronological age).

In the study, 36 infants had growth failure, while the rest had appropriate growth.

These groups had consistent differences in the microbiome and metabolism regardless of complications of prematurity, such as sepsis (blood infection), necrotizing enterocolitis (intestinal inflammation), or intestinal perforation.

Infants with growth failure had disrupted maturation of the intestinal microbiome, characterized by low bacterial diversity, dominance of certain disease-causing bacteria (Staphylococcus and Enterobacteriaceae) and low proportions of harmless bacteria (such as Veillonella).

They also displayed delayed metabolic development with features that suggest deficiencies in metabolism of glucose and other non-lipid fuels, leading to greater reliance on fatty acids.

The infants with growth failure were in a persistent physiologic state that resembled fasting.

“Our analyses of the relationship between the microbiome of infants with growth failure and the byproducts of their metabolism suggest that the unique composition of bacterial communities living in their gut might play a role in this metabolic state with similarities to fasting,” says Dr. Seed.

“This might explain why simply increasing caloric supply for infants with growth failure often does not work.

In order to develop effective treatments, we need to better understand how their inability to utilize nutrients for energy is influenced by delayed maturation of the microbiome and metabolism.”

Chronic cardiometabolic diseases are the leading cause of mortality in the US, with heart disease and diabetes costing >$500 billion a year [1,2], and affecting around 60% of individuals over their lifetime [1,3].

Many factors contribute to disease risk, including environmental exposures, diet, and genetic background.

Pathogenesis develops over decades, making risk factors that originate in childhood of particular importance for life-long disease risk.

The role of the microbiome as a disease modulator is being increasingly recognized and studied [4,5]. The human gut microbiome may act as a central regulator of metabolism, responsive to alterations in dietary intake or host physiology [6,7].

The gut microbiome expands rapidly in infants following birth [7,8] and dysbiosis in infancy or childhood may affect the long-term health of the gut microbiome.

Within the sections of this review, and as summarized in Figure 1, we evaluate several of the known determinants of microbiome composition and examine how variation in microbiome composition in children may impact lifetime risk of obesity and cardiometabolic disease.

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Figure 1
Determinants of microbiome composition, and potential mechanisms linking microbiota to disease.

Delivery Method

Extensive colonization of the infant microbiome occurs at the time of birth, and may even occur before birth.

Inoculation has stochastic components, with contribution of maternal microbiota, but also opportunistic colonization by microbiota present on other proximal individuals and in the local environment.

Gut microbiome composition is highly variable in early infancy, and of the strains that reach the infant gut, only a subset successfully colonize [7].

In a study of 25 mother–infant pairs, the development of the infant microbiome was assessed from birth to 4 months postpartum [9].

The early infant microbiome was found to contain maternal vaginal, skin, oral, and fecal strains, with variability in which site contributed the most, despite all infants being delivered vaginally.

Skin and vaginal transmission appeared to be transient, with the infant gut microbiome having greatest similarity to the maternal gut microbiome by 4 months post-birth [9].

Several studies have examined the effect of vaginal delivery compared with cesarean section in order to test the hypothesis that initial exposure to vaginal vs. skin microbiota has long-term effects on microbiome composition.

The intestinal colonization rate of infants delivered by Caesarean has been shown to be delayed [10], with lower bacterial colonization rates in infants delivered by cesarean section [11].

Lower microbial diversity has been observed in infants born by Caesarean section, an effect which may persist for at least two years [12].

However, in another sample, diversity was lower in preterm infants born vaginally compared with cesarean section [13], which could potentially be linked to the additional birth complications for preterm infants.

Caesarean section has been associated with some long-term outcomes, including overweight [11,14,15,16], although other studies have found no differences, and causality has not been established [17,18].

Preterm Birth

Preterm infants have underdeveloped intestines, which may perturb the development of healthy host–microbiota relationships early in life [19].

Preterm infants are at a much higher risk of developing complications following birth, including necrotizing enterocolitis (NEC), which may be linked to impaired gut microbiome acquisition [20].

Preterm infants who developed NEC were found to have increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes [20].

There is also evidence that altered maternal microbiome composition may be related to risk of preterm birth [21], suggesting that altered microbiome composition is both a cause and a consequence of preterm birth. Preterm infants have been shown to have differences in microbiome diversity, dependent on gestational age [22].

Dysbiosis in the preterm infant gut has been linked to delivery method, steroid use, and antibiotic use, all of which affect intestinal microbiome development [13,23,24].

Pre-Natal Microbial Colonization

Whether maternal transmission of commensal microbes to the fetus is a common occurrence remains an open question. Until relatively recently, the uterine environment was thought to be sterile.

This assumption has been challenged by several studies finding evidence of microbiota in the uterus [25], placenta [26], umbilical cord [27], and amniotic fluid [28], as well as in meconium [29], indicating that microbiota may be transmitted during fetal development.

However, data are conflicting [30,31]; microbial DNA may be detected due to contamination, presence of DNA from dead bacteria, or collection after membrane rupture [32], and thus far microbes have not been proven to be viable in utero.

While evidence supports some transmission of microbial material to the fetus, whether this is a significant contributor to a fetal microbiome, and whether this has an impact on development or outcomes, remains to be determined.

Effects of Early Infant Feeding Practices on Microbiome Development

Breast Milk and Formula Feeding

It is thought that breast milk feeding is protective against development of multiple diseases, including obesity [33], diabetes [34], and potentially also immune-mediated diseases such as asthma and allergies [35].

The mechanism whereby breast milk determines a child’s predisposition to cardiometabolic and inflammatory disease is yet to be fully determined, but may be mediated through long-term effects on gut microbiota.

In particular, as the sole source of nutrition in the first 4–6 months of life, the composition of breast milk or formula determines nutrient availability to gut microbiota in the infant, and may exert selective pressure.

A key difference between breast milk and formula is the presence of prebiotics, oligosaccharides, and antibodies, which can selectively modulate bacterial abundance [36].

Breast milk itself contains microbiota, including BifidobacteriumStreptococcus, and Lactobacillus species [37,38,39], which may contribute directly to the infant gastrointestinal microbiome.

However, there is large variability in the composition of human breast milk [40,41,42], which is modulated by maternal health status [43,44,45]. The composition of breast milk is dynamic, changing over time, and may be responsive to infant characteristics such as sex [46], or dynamic cues during illness.

Whether a “core” group of breast milk components common to most individuals are responsible for most of the protective effects remains to be determined [47]. In preterm infants, breast milk feeding appeared to mitigate some of the negative consequences of low birth weight on the development of the microbiome [48].

Studies of microbiomes in infants have focused on specific bacterial abundance, as well as diversity.

In one study, breast-fed infants were found to have greater numbers of Bifidobacterium, but the microbiome of formula-fed infants was more diverse [49]. Another study found enrichment of Actinobacteria and Firmicutes and depletion of Proteobacteria in breast-fed compared with formula-fed infants [50].

Formula feeding has been associated with altered bacterial diversity in infants [51], with the microbiota of infants fed both breast milk and formula being more similar to formula-fed infants than to exclusively breast-fed infants [33].

Formula feeding at 3 months was associated with greater risk of overweight at 12 months, defined as infants >85th percentile for weight for length [33]. In a prospective study, children who were overweight at age 7 had lower Bifidobacterium and higher Staphylococcus aureus colonization in infancy compared with matched normal weight children [52].

Breast milk-derived immunoglobulins have been shown to modulate intestinal immune function and gut microbiome composition [53], providing further evidence for mechanisms linking breast milk feeding with immunoprotection.

In a population at risk of undernutrition, lower levels of sialylated oligosaccharides in breast milk were found to be associated with stunted infant growth, and inclusion of sialylated oligosaccharides in the diet of lab animals was associated with body mass in a gut microbiome-dependent manner [54].

Although many more studies are required, these data highlight early infancy as a critical period where microbial dysbiosis may lead to overweight in later life because the microbiome may be unable to recover from dysbiosis established early in life.

Components in breast milk may shape the infant microbiome to confer lifelong protection against obesity and other metabolic diseases. However, given the large variability in breast milk composition, and the potential for interaction with genetic background, there may also be cases where breast milk promotes less favorable microbiome development.

Prebiotic and Probiotic Supplementation

The specific composition of different types of formula may modulate the microbiome. Several trials have assessed the inclusion of probiotics or prebiotics such as oligosaccharides in infant formula to more closely mimic breast milk composition [55].

Infant formula supplemented with several Bifidobacterium strains altered microbiome composition in infants, but did not affect long-term colonization [56].

There was no significant effect of oligosaccharide and Bifidobacterium supplementation on diarrhea or febrile infection, however, the microbiota of supplemented infants more closely resembled that of breast-fed infants [57].

Inclusion of lactose in hydrolyzed formula designed for infants with milk allergies promoted growth of Bifidobacterium and Lactobacillales, and increased intestinal short chain fatty acids (SCFAs) [58]. 

Lactobacillus supplementation was found to alter gut microbiome composition [59].

Current data suggest that inclusion of pre- and probiotics in formula is well-tolerated, however, whether this has beneficial effects on longer-term outcomes is not yet known.

Milk Delivery Method

Some evidence exists on different effects of direct breast feeding versus providing expressed breast milk from a bottle [60].

During breast feeding, infants are exposed to maternal skin microbiota, and also deposit saliva, which contains microbiota and pathogens that can be transmitted back to the mother, potentially eliciting changes in breast milk composition through a feedback loop [61,62]. While intriguing, this area requires further research.

Donor Breastmilk

Because of the potential benefits of breastmilk, donor milk is sometimes used when milk from the infant’s biological mother is not available.

This is particularly promoted in preterm infants.

However, whether donor milk has the same protective properties remains unclear [63].

In a randomized trial in preterm infants, donor milk did not appear to confer an advantage over formula when compared with maternal milk [64].

Donor milk is general pasteurized to reduce risk of infection and is often pooled from multiple donor sources. Pasteurization may destroy pre- and probiotics, reducing the beneficial effects of human milk.

Further, the variability in breast milk composition may result in donor milk being suboptimal for an unrelated infant. However, much more research is required to establish the potential benefits and risks of using donor milk as an alternative to formula.

Dietary Modulators of Gut Microbiome Composition throughout Childhood

The introduction of solid food is associated with a shift in the infant microbiome to more closely resemble adult profiles, however, the pediatric microbiome remains in flux for at least the first 3 years of life [7].

This suggests a period of relatively malleability and implies that diet in early childhood may have a disproportionately large impact on lifetime microbiome composition and associated health impacts.

In adults, a change in diet significantly affects the composition of their gut microbiome, with observable major shifts in microbe composition within 24 h of substantial or acute alterations to the diet, such as suddenly switching to solely plant- or animal-based foods.

A near return to the starting composition can be observed 48 h after resumption of the normal diet [6].

Data are limited on the effect of dietary intervention on the microbiome in children, but given that microbiome profiles in children after the age of 3 years closely resemble those of adults, it is likely that dietary changes can rapidly affect microbiome composition in children.

The Effect of Western Diet on the Gut Microbiome

The Western diet, high in animal protein and fat, high in refined carbohydrates, and low in plant-derived fiber, phytochemicals, and fermented foods has been associated with the relatively recent rapid rise in inflammatory-related diseases, including cardiometabolic and intestinal disease.

There is increasing evidence that this may be mediated through gut microbiota [65,66]. The Western diet has been found to decrease total bacterial load, as well as those of beneficial genera such as Bifidobacterium and Eubacterium [67].

Studies of vegetarian and vegan diets have found varying levels of differences in microbiome composition compared with the typical unrestricted Western diet, with potential negligible differences in the overall functional capacity of the microbiota [68,69,70,71].

A study investigating the impact of the Western and traditional plant-based diet in children in Thailand found differences in composition and used metagenomic prediction to identify underrepresentation in genes for butyrate biosynthetic pathways in children consuming a Western diet [72], which may modulate gut immune homeostasis [73].

Similarly, children consuming traditional diets in rural Malawi and Venezuela were found to have differences in metabolic gene content of the microbiome compared with US children consuming a Western diet [7].

In a small study of urban visitors to a traditional rainforest village, the microbiome of children was found to be more prone to change compared with a relatively stable microbiome in adults, highlighting the higher plasticity of the microbiome in children [74]. High total protein diets have been linked to increased inflammatory bowel disease (IBD) risk [75].

Pea and whey protein consumption has been linked to increased levels of commensal Bifidobacterium and Lactobacillus [76], with fermented whey protein lowering counts of potentially pathogenic species Bacteroides fragilis and Clostridium perfringens [77].

Several genera that increase in abundance from ingestion of red meat are associated with higher levels of the proatherogenic chemical trimethylamine-N-oxide (TMAO), linked to an increase in cardiovascular disease risk [78].

High protein diets in individuals <65 years of age have been related to an increase in the production of insulin-like growth factor 1, a risk factor for cancers, diabetes, and mortality [79].

High fat diets in humans have been shown to increase the relative abundance of anaerobic bacteria and Bacteroidetes, while low fat diets increase fecal Bifidobacterium counts and reduce total cholesterol and fasting glucose [80]. In mice, there was a significant effect on microbiome composition when comparing polyunsaturated fat (fish oil) to saturated fat (lard) diets [81].

Lard-fed mice had increased systemic and adipose inflammation and lowered insulin sensitivity compared to the fish oil mice. Fecal transplantation replicated the metabolic and inflammatory phenotype, demonstrating a casual effect of microbiota [81].

The intestinal microbiome of animals fed on a high fat or high sugar diet has been observed to be more vulnerable to disruption of the circadian rhythm [82].

Given the particular importance of sleep to children, the combination of a poor diet and disrupted sleep may lead to alterations in gut microbiome composition.

Plant-Derived Prebiotics

Plant-derived non-digestible carbohydrates, such as some starches and fiber, survive in the colon, where they are fermented by the colonic microbiome to produce short chain fatty acids (SCFAs) [83].

Colonic epithelial cells utilize SCFAs, particularly butyrate, for 60–70% of their energy, and they contribute to strengthening of the mucosal barrier [84].

SCFAs also regulate glucose and lipid metabolism and immune function [73,85].

Butyrate acts as a histone deacetylase inhibitor, involved in the epigenetic control of regulatory T-cell production and maintenance [86].

Western diet-associated gut dysbiosis may promote a leaky gut membrane and metabolic endotoxemia [87], leading to increased cardiometabolic disease risk.

A diet low in prebiotics decreases total bacterial load and diversity, while a high plant-based diet increases the gene richness of the microbiome and improves markers of inflammation [88,89,90].

In a study of commercially available infant cereal, different cereal types were associated with changes in microbiome composition, and differences in SCFA production in an in vitro infant gut model [91].

Other Dietary Modulators of Microbiome Composition

While the majority of diet–microbiome studies have focused broadly on Western vs. traditional diets, other dietary components have also been studied. Both undernourished and obese children in Mexico were found to have lower bacterial diversity compared with well-nourished normal-weight children [92].

There are limited data available on individual dietary effects on the microbiome in children, but evidence from adults suggest multiple diet-derived components shape microbiome composition.

Gluten-free diets have been associated with changes in microbiota, with reductions in BifidobacteriumLactobacillus, and Clostridium, and increases in other bacteria including potential opportunistic pathogens [93,94].

Artificial sweeteners have been shown to modify gut microbiota [95] and have been suggested to induce glucose intolerance through their effects on gastrointestinal microbiota [96].

Other plant components, including polyphenols, may also modulate the gut microbiome [97,98,99]. Fermented foods act as a natural source of probiotics, with fermented dairy products [100,101] and vegetables [102,103] contributing bacteria to the diet, although the extent to which these bacteria survive and colonize the gut in individuals with established microbiomes is unclear [104].

Infant probiotic supplementation trials have generally found no long-term effects of supplementation on metabolic and inflammatory markers [105,106].

The microbiome adapts to available food sources; while some profiles may be more beneficial than others, there is a complex interaction between diet, microbiota, and downstream metabolic effects, which remains to be further studied.

More information: Noelle E. Younge et al, Disrupted Maturation of the Microbiota and Metabolome among Extremely Preterm Infants with Postnatal Growth Failure, Scientific Reports (2019). DOI: 10.1038/s41598-019-44547-y

Journal information: Scientific Reports
Provided by Ann & Robert H. Lurie Children’s Hospital of Chicago


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