Effect of Environmental Exposures on the Gut Microbiota from Early Infancy to Two Years of Age

The gut microbiota undergoes rapid changes during infancy in response to early-life exposures. We have investigated how the infant gut bacterial community matures over time and how exposures such as human milk and antibiotic treatment alter gut microbiota development. We used the LonGP program to create predictive models to determine the contribution of exposures on infant gut bacterial abundances from one month to two years of age. These models indicate that infant antibiotic use, human milk intake, maternal pre-pregnancy BMI, and sample shipping time were associated with changes in gut microbiome composition. In most infants, Bacteroides, Lachnospiraceae unclassified, Faecalibacterium, Akkermansia, and Phascolarctobacterium abundance increased rapidly after 6 months, while Escherichia, Bifidobacterium, Veillonella, and Streptococcus decreased in abundance over time. Individual, time-varying, random effects explained most of the variation in the LonGP models. Multivariate association with linear models (MaAsLin) displayed partial agreement with LonGP in the predicted trajectories over time and in relation to significant factors such as human milk intake. Multiple factors influence the dynamic changes in bacterial composition of the infant gut. Within-individual differences dominate the temporal variations in the infant gut microbiome, suggesting individual temporal variability is an important feature to consider in studies with a longitudinal sampling design.

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Can we modulate the breastfed infant gut microbiota through maternal diet?

FEMS Microbiology Reviews ◽

10.1093/femsre/fuab011 ◽

2021 ◽

Author(s):

Azhar S Sindi ◽

Donna T Geddes ◽

Mary E Wlodek ◽

Beverly S Muhlhausler ◽

Matthew S Payne ◽

...

Keyword(s):

Gut Microbiota ◽

Human Milk ◽

Gut Microbiome ◽

Animal Studies ◽

Maternal Diet ◽

Breastfed Infant ◽

Microbial Composition ◽

Infant Gut Microbiome ◽

And Function ◽

Microbiome Data

Abstract Initial colonisation of the infant gut is robustly influenced by regular ingestion of human milk, a substance that contains microbes, microbial metabolites, immune proteins, and oligosaccharides. Numerous factors have been identified as potential determinants of the human milk and infant gut microbiota, including maternal diet; however, there is limited data on the influence of maternal diet during lactation on either of these. Here, we review the processes thought to contribute to human milk and infant gut bacterial colonisation and provide a basis for considering the role of maternal dietary patterns during lactation in shaping infant gut microbial composition and function. Although only one observational study has directly investigated the influence of maternal diet during lactation on the infant gut microbiome, data from animal studies suggests that modulation of the maternal gut microbiota, via diet or probiotics, may influence the mammary or milk microbiota. Additionally, evidence from human studies suggests that the maternal diet during pregnancy may affect the gut microbiota of the breastfed infant. Together, there is a plausible hypothesis that maternal diet during lactation may influence the infant gut microbiota. If substantiated in further studies, this may present a potential window of opportunity for modulating the infant gut microbiome in early life.

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Consumption of Lysozyme-Rich Milk Can Alter Microbial Fecal Populations

Applied and Environmental Microbiology ◽

10.1128/aem.00956-12 ◽

2012 ◽

Vol 78 (17) ◽

pp. 6153-6160 ◽

Cited By ~ 56

Author(s):

Elizabeth A. Maga ◽

Prerak T. Desai ◽

Bart C. Weimer ◽

Nguyet Dao ◽

Dietmar Kültz ◽

...

Keyword(s):

Human Milk ◽

Gut Microbiome ◽

16S Rrna Gene Sequencing ◽

Fecal Microbiota ◽

Rrna Gene ◽

Gut Health ◽

Content Type ◽

Microbiome Composition ◽

The Impact ◽

Over Time

ABSTRACTHuman milk contains antimicrobial factors such as lysozyme and lactoferrin that are thought to contribute to the development of an intestinal microbiota beneficial to host health. However, these factors are lacking in the milk of dairy animals. Here we report the establishment of an animal model to allow the dissection of the role of milk components in gut microbiota modulation and subsequent changes in overall and intestinal health. Using milk from transgenic goats expressing human lysozyme at 68%, the level found in human milk and young pigs as feeding subjects, the fecal microbiota was analyzed over time using 16S rRNA gene sequencing and the G2 Phylochip. The two methods yielded similar results, with the G2 Phylochip giving more comprehensive information by detecting more OTUs. Total community populations remained similar within the feeding groups, and community member diversity was changed significantly upon consumption of lysozyme milk. Levels ofFirmicutes(Clostridia) declined whereas those ofBacteroidetesincreased over time in response to the consumption of lysozyme-rich milk. The proportions of these major phyla were significantly different (P< 0.05) from the proportions seen with control-fed animals after 14 days of feeding. Within phyla, the abundance of bacteria associated with gut health (BifidobacteriaceaeandLactobacillaceae) increased and the abundance of those associated with disease (Mycobacteriaceae,Streptococcaceae,Campylobacterales) decreased with consumption of lysozyme milk. This study demonstrated that a single component of the diet with bioactivity changed the gut microbiome composition. Additionally, this model enabled the direct examination of the impact of lysozyme on beneficial microbe enrichment versus detrimental microbe reduction in the gut microbiome community.

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The Role of Human Milk in Decreasing Necrotizing Enterocolitis Through Modulation of the Infant Gut Microbiome: A Scoping Review

Journal of Human Lactation ◽

10.1177/0890334420950260 ◽

2020 ◽

Vol 36 (4) ◽

pp. 647-656

Author(s):

Jessica A. Davis ◽

Kelley Baumgartel ◽

Michael J. Morowitz ◽

Vivianna Giangrasso ◽

Jill R. Demirci

Keyword(s):

Human Milk ◽

Necrotizing Enterocolitis ◽

Scoping Review ◽

Gut Microbiome ◽

Human Infants ◽

Microbiome Composition ◽

Infant Diet ◽

Infant Gut Microbiome ◽

State Of The Science

Background Necrotizing enterocolitis is associated with a high incidence of morbidity and mortality in premature infants. Human milk minimizes necrotizing enterocolitis risk, although the mechanism of protection is not thoroughly understood. Increasingly, dysbiosis of the infant gut microbiome, which is affected by infant diet, is hypothesized to play a role in necrotizing enterocolitis pathophysiology. Research aim The aim of this scoping review was to summarize the state of the science regarding the hypothesis that the gut microbiome composition is a mediator of the relationship between human milk and decreased incidence of necrotizing enterocolitis within a sample of human infants. Methods Electronic databases and reference lists were searched for peer-reviewed primary research articles addressing the link between human milk, gut microbiome composition, and subsequent incidence of necrotizing enterocolitis among human infants. Results A total of four studies met criteria for inclusion in this review. Of these, evidence supporting the link between human milk, gut microbiome composition, and necrotizing enterocolitis was found in two (50%) studies. Conclusion Some evidence linking all three variables is provided in this review. Given the small number of available studies, and the limitations of those studies, more research is urgently needed to thoroughly understand the protection against necrotizing enterocolitis gained through the provision of human milk.

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Infant gut microbiome composition is associated with non-social fear behavior in a pilot study

Nature Communications ◽

10.1038/s41467-021-23281-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Alexander L. Carlson ◽

Kai Xia ◽

M. Andrea Azcarate-Peril ◽

Samuel P. Rosin ◽

Jason P. Fine ◽

...

Keyword(s):

Pilot Study ◽

Gut Microbiome ◽

Brain Structures ◽

Experimental Manipulation ◽

Human Infant ◽

Microbiome Composition ◽

Social Fear ◽

Infant Gut Microbiome ◽

First Year Of Life ◽

Fear Behavior

AbstractExperimental manipulation of gut microbes in animal models alters fear behavior and relevant neurocircuitry. In humans, the first year of life is a key period for brain development, the emergence of fearfulness, and the establishment of the gut microbiome. Variation in the infant gut microbiome has previously been linked to cognitive development, but its relationship with fear behavior and neurocircuitry is unknown. In this pilot study of 34 infants, we find that 1-year gut microbiome composition (Weighted Unifrac; lower abundance of Bacteroides, increased abundance of Veillonella, Dialister, and Clostridiales) is significantly associated with increased fear behavior during a non-social fear paradigm. Infants with increased richness and reduced evenness of the 1-month microbiome also display increased non-social fear. This study indicates associations of the human infant gut microbiome with fear behavior and possible relationships with fear-related brain structures on the basis of a small cohort. As such, it represents an important step in understanding the role of the gut microbiome in the development of human fear behaviors, but requires further validation with a larger number of participants.

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Interaction between Host MicroRNAs and the Gut Microbiota in Colorectal Cancer

mSystems ◽

10.1128/msystems.00205-17 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 35

Author(s):

Ce Yuan ◽

Michael B. Burns ◽

Subbaya Subramanian ◽

Ran Blekhman

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Gut Microbiota ◽

Mirna Expression ◽

Gut Microbiome ◽

Noncoding Rna ◽

Microbial Community Composition ◽

Host Cells ◽

Microbiome Composition ◽

Small Noncoding Rna

ABSTRACT Although variation in gut microbiome composition has been linked with colorectal cancer (CRC), the factors that mediate the interactions between CRC tumors and the microbiome are poorly understood. MicroRNAs (miRNAs) are known to regulate CRC progression and are associated with patient survival outcomes. In addition, recent studies suggested that host miRNAs can also regulate bacterial growth and influence the composition of the gut microbiome. Here, we investigated the association between miRNA expression and microbiome composition in human CRC tumor and normal tissues. We identified 76 miRNAs as differentially expressed (DE) in tissue from CRC tumors and normal tissue, including the known oncogenic miRNAs miR-182, miR-503, and mir-17~92 cluster. These DE miRNAs were correlated with the relative abundances of several bacterial taxa, including Firmicutes , Bacteroidetes , and Proteobacteria . Bacteria correlated with DE miRNAs were enriched with distinct predicted metabolic categories. Additionally, we found that miRNAs that correlated with CRC-associated bacteria are predicted to regulate targets that are relevant for host-microbiome interactions and highlight a possible role for miRNA-driven glycan production in the recruitment of pathogenic microbial taxa. Our work characterized a global relationship between microbial community composition and miRNA expression in human CRC tissues. IMPORTANCE Recent studies have found an association between colorectal cancer (CRC) and the gut microbiota. One potential mechanism by which the microbiota can influence host physiology is through affecting gene expression in host cells. MicroRNAs (miRNAs) are small noncoding RNA molecules that can regulate gene expression and have important roles in cancer development. Here, we investigated the link between the gut microbiota and the expression of miRNA in CRC. We found that dozens of miRNAs are differentially regulated in CRC tumors and adjacent normal colon and that these miRNAs are correlated with the abundance of microbes in the tumor microenvironment. Moreover, we found that microbes that have been previously associated with CRC are correlated with miRNAs that regulate genes related to interactions with microbes. Notably, these miRNAs likely regulate glycan production, which is important for the recruitment of pathogenic microbial taxa to the tumor. This work provides a first systems-level map of the association between microbes and host miRNAs in the context of CRC and provides targets for further experimental validation and potential interventions.

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The sugar composition of the fibre in selected plant foods modulates weaning infants’ gut microbiome composition and fermentation metabolites in vitro

Scientific Reports ◽

10.1038/s41598-021-88445-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shanthi G. Parkar ◽

Jovyn K. T. Frost ◽

Doug Rosendale ◽

Halina M. Stoklosinski ◽

Carel M. H. Jobsis ◽

...

Keyword(s):

Gut Microbiome ◽

Gas Production ◽

Sugar Composition ◽

Microbiome Composition ◽

Fibre Concentration ◽

Microbiome Profile ◽

Infant Gut Microbiome ◽

Immune Health ◽

Faecal Bacteria

AbstractEight plant-based foods: oat flour and pureed apple, blackcurrant, carrot, gold- and green-fleshed kiwifruit, pumpkin, sweetcorn, were pre-digested and fermented with pooled inocula of weaning infants’ faecal bacteria in an in vitro hindgut model. Inulin and water were included as controls. The pre-digested foods were analysed for digestion-resistant fibre-derived sugar composition and standardised to the same total fibre concentration prior to fermentation. The food-microbiome interactions were then characterised by measuring microbial acid and gas metabolites, microbial glycosidase activity and determining microbiome structure. At the physiologically relevant time of 10 h of fermentation, the xyloglucan-rich apple and blackcurrant favoured a propiogenic metabolic and microbiome profile with no measurable gas production. Glucose-rich, xyloglucan-poor pumpkin caused the greatest increases in lactate and acetate (indicative of high fermentability) commensurate with increased bifidobacteria. Glucose-rich, xyloglucan-poor oats and sweetcorn, and arabinogalactan-rich carrot also increased lactate and acetate, and were more stimulatory of clostridial families, which are indicative of increased microbial diversity and gut and immune health. Inulin favoured a probiotic-driven consortium, while water supported a proteolytic microbiome. This study shows that the fibre-derived sugar composition of complementary foods may shape infant gut microbiome structure and metabolic activity, at least in vitro.

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Iron-containing micronutrient powders modify the effect of oral antibiotics on the infant gut microbiome and increase post-antibiotic diarrhoea risk: a controlled study in Kenya

Gut ◽

10.1136/gutjnl-2018-317399 ◽

2018 ◽

Vol 68 (4) ◽

pp. 645-653 ◽

Cited By ~ 9

Author(s):

Daniela Paganini ◽

Mary A Uyoga ◽

Guus A M Kortman ◽

Colin I Cercamondi ◽

Hans C Winkler ◽

...

Keyword(s):

Gut Microbiome ◽

Community Dwelling ◽

Controlled Study ◽

Faecal Calprotectin ◽

Microbiome Composition ◽

E Coli ◽

Increase Risk ◽

Infant Gut Microbiome ◽

Registration Number ◽

Antibiotic Efficacy

ObjectiveMany African infants receiving iron fortificants also receive antibiotics. Antibiotic efficacy against enteropathogens may be modified by high colonic iron concentrations. In this study, we evaluated the effect of antibiotics on the infant gut microbiome and diarrhoea when given with or without iron-containing micronutrient powders (MNPs).DesignIn a controlled intervention trial, four groups of community-dwelling infants (n=28; aged 8–10 months) received either: (A) antibiotics for 5 days and iron-MNPs for 40 days (Fe+Ab+); (B) antibiotics and no-iron-MNPs (Fe−Ab+); (C) no antibiotics and iron-MNPs (Fe+Ab−); or (D) no antibiotics and no-iron-MNPs (Fe−Ab−). We collected a faecal sample before the first antibiotic dose (D0) and after 5, 10, 20 and 40 days (D5–D40) to assess the gut microbiome composition by 16S profiling, enteropathogens by quantitative PCR, faecal calprotectin and pH and assessed morbidity over the 40-day study period.ResultsIn Fe+Ab+, there was a decrease in Bifidobacterium abundances (p<0.05), but no decrease in Fe−Ab+. In Fe−Ab+, there was a decrease in abundances of pathogenic Escherichia coli (p<0.05), but no decrease in Fe+Ab+. In Fe−Ab+, there was a decrease in pH (p<0.05), but no decrease in Fe+Ab+. Longitudinal prevalence of diarrhoea was higher in Fe+Ab+ (19.6%) compared with Fe−Ab+ (12.4%) (p=0.04) and compared with Fe+Ab− (5.2%) (p=0.00).ConclusionOur findings need confirmation in a larger study but suggest that, in African infants, iron fortification modifies the response to broad-spectrum antibiotics: iron may reduce their efficacy against potential enteropathogens, particularly pathogenic E. coli, and may increase risk for diarrhoea.Trial registration numberNCT02118402; Pre-results.

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Underdevelopment of the gut microbiota and bacteria species as non-invasive markers of prediction in children with autism spectrum disorder

Gut ◽

10.1136/gutjnl-2020-324015 ◽

2021 ◽

pp. gutjnl-2020-324015

Author(s):

Yating Wan ◽

Tao Zuo ◽

Zhilu Xu ◽

Fen Zhang ◽

Hui Zhan ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Gut Microbiota ◽

Gut Microbiome ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Chinese Children ◽

Chronological Age ◽

Microbiome Composition ◽

Children With Asd ◽

Faecal Microbiome

ObjectiveThe gut microbiota has been suggested to play a role in autism spectrum disorder (ASD). We postulate that children with ASD harbour an altered developmental profile of the gut microbiota distinct from that of typically developing (TD) children. Here, we aimed to characterise compositional and functional alterations in gut microbiome in association with age in children with ASD and to identify novel faecal bacterial markers for predicting ASD.DesignWe performed deep metagenomic sequencing in faecal samples of 146 Chinese children (72 ASD and 74 TD children). We compared gut microbial composition and functions between children with ASD and TD children. Candidate bacteria markers were identified and validated by metagenomic analysis. Gut microbiota development in relation to chronological age was assessed using random forest model.ResultsASD and chronological age had the most significant and largest impacts on children’s faecal microbiome while diet showed no correlation. Children with ASD had significant alterations in faecal microbiome composition compared with TD children characterised by increased bacterial richness (p=0.021) and altered microbiome composition (p<0.05). Five bacterial species were identified to distinguish gut microbes in ASD and TD children, with areas under the receiver operating curve (AUC) of 82.6% and 76.2% in the discovery cohort and validation cohort, respectively. Multiple neurotransmitter biosynthesis related pathways in the gut microbiome were depleted in children with ASD compared with TD children (p<0.05). Developing dynamics of growth-associated gut bacteria (age-discriminatory species) seen in TD children were lost in children with ASD across the early-life age spectrum.ConclusionsGut microbiome in Chinese children with ASD was altered in composition, ecological network and functionality compared with TD children. We identified novel bacterial markers for prediction of ASD and demonstrated persistent underdevelopment of the gut microbiota in children with ASD which lagged behind their respective age-matched peers.

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Maximizing Nutrient Availability for the Breastfed Infant Through Colonization with B. Infantis EVC001 (FS04-04-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz048.fs04-04-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Tracy Shafizadeh ◽

Steve Frese ◽

Giorgio Casaburi

Keyword(s):

Human Milk ◽

Nutrient Availability ◽

Gut Microbiome ◽

Bifidobacterium Longum ◽

Developed Countries ◽

Breastfed Infant ◽

Control Group ◽

Term Infants ◽

Fecal Samples ◽

Infant Gut Microbiome

Abstract Objectives Human breastmilk contains complete nutrient composition required for the developing infant, including human milk oligosaccharides (HMO). These complex carbohydrates are indigestible by the infant alone, and require digestion by gut microbes, namely Bifidobacterium longum subsp. infantis (B. infantis). However, decades of C-section delivery, formula feeding and increasing exposure to antibiotics have contributed the loss of this critical infant-associated gut bacterium in developed countries. Therefore, restoring B. infantis to the infant gut was hypothesized to improve the nutritional utilization of human breastmilk in healthy term infants. Methods In an open trial, healthy, exclusively breastfed term infants were fed 1.8 × 1010 CFU B. infantis EVC001 daily from day 7–27 postnatal (n = 34; EVC001-fed), or breastmilk alone (n = 32; control group). Fecal samples, milk samples, and weekly self-reported data were collected and analyzed for infant gut microbiome composition and function, human milk oligosaccharide composition, and fecal metabolites. 16S rRNA sequencing and shotgun metagenome sequencing provided characterization of microbial communities from birth through 60 days postnatal. Results Infants fed B. infantis EVC001 were uniformly colonized with this organism at 1011 CFU/g feces, while infants in the control group had a median total Bifidobacterium level below 10^5 CFU/g feces, despite exclusive breastfeeding. Mass spectrometry of fecal samples from B. infantis EVC001-fed infants showed that the resulting microbial community produced higher concentrations of lactate and acetate and lower excretion of HMO, while control infants showed significantly lower ability to capture and utilize these carbohydrates from human milk. Importantly, HMO content of breastmilk was not significantly different between groups and no difference was found in the gut microbiome of infants based on secretor status of mothers (presence or absence of 2’FL in breastmilk). Further, these changes were associated with reductions in taxa that have been associated with negative health outcomes including colic, asthma, eczema and allergy. Conclusions Overall, colonization with B. infantis is observed to be an effective way to restore maximal function of the infant gut microbiome to improve nutrient availability in the breastfed infant. Funding Sources This study was funded by Evolve BioSystems, Inc.

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The Effects of Glucosamine and Chondroitin Sulfate on Gut Microbial Composition: A Systematic Review of Evidence from Animal and Human Studies

Nutrients ◽

10.3390/nu11020294 ◽

2019 ◽

Vol 11 (2) ◽

pp. 294 ◽

Cited By ~ 8

Author(s):

Anna Shmagel ◽

Ryan Demmer ◽

Daniel Knights ◽

Mary Butler ◽

Lisa Langsetmo ◽

...

Keyword(s):

Systematic Review ◽

Gut Microbiota ◽

Chondroitin Sulfate ◽

Gut Microbiome ◽

Human Studies ◽

Journal Articles ◽

Microbial Composition ◽

Microbiome Composition ◽

Search Terms ◽

Quality Evidence

Oral glucosamine sulfate (GS) and chondroitin sulfate (CS), while widely marketed as joint-protective supplements, have limited intestinal absorption and are predominantly utilized by gut microbiota. Hence the effects of these supplements on the gut microbiome are of great interest, and may clarify their mode of action, or explain heterogeneity in therapeutic responses. We conducted a systematic review of animal and human studies reporting the effects of GS or CS on gut microbial composition. We searched MEDLINE, EMBASE, and Scopus databases for journal articles in English from database inception until July 2018, using search terms microbiome, microflora, intestinal microbiota/flora, gut microbiota/flora and glucosamine or chondroitin. Eight original articles reported the effects of GS or CS on microbiome composition in adult humans (four articles) or animals (four articles). Studies varied significantly in design, supplementation protocols, and microbiome assessment methods. There was moderate-quality evidence for an association between CS exposure and increased abundance of genus Bacteroides in the murine and human gut, and low-quality evidence for an association between CS exposure and an increase in Desulfovibrio piger species, an increase in Bacteroidales S24-7 family, and a decrease in Lactobacillus. We discuss the possible metabolic implications of these changes for the host. For GS, evidence of effects on gut microbiome was limited to one low-quality study. This review highlights the importance of considering the potential influence of oral CS supplements on gut microbiota when evaluating their effects and safety for the host.

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