Safety and Modulatory Effects of Humanized Galacto-Oligosaccharides on the Gut Microbiome

Complex dietary carbohydrate structures including β(1–4) galacto-oligosaccharides (GOS) are resistant to digestion in the upper gastrointestinal (GI) tract and arrive intact to the colon where they benefit the host by selectively stimulating microbial growth. Studies have reported the beneficial impact of GOS (alone or in combination with other prebiotics) by serving as metabolic substrates for modulating the assembly of the infant gut microbiome while reducing GI infections. N-Acetyl-D-lactosamine (LacNAc, Galβ1,4GlcNAc) is found in breast milk as a free disaccharide. This compound is also found as a component of human milk oligosaccharides (HMOs), which have repeating and variably branched lactose and/or LacNAc units, often attached to sialic acid and fucose monosaccharides. Human glycosyl-hydrolases do not degrade most HMOs, indicating that these structures have evolved as natural prebiotics to drive the proper assembly of the infant healthy gut microbiota. Here, we sought to develop a novel enzymatic method for generating LacNAc-enriched GOS, which we refer to as humanized GOS (hGOS). We showed that the membrane-bound β-hexosyl transferase (rBHT) from Hamamotoa (Sporobolomyces) singularis was able to generate GOS and hGOS from lactose and N-Acetyl-glucosamine (GlcNAc). The enzyme catalyzed the regio-selective, repeated addition of galactose from lactose to GlcNAc forming the β-galactosyl linkage at the 4-position of the GlcNAc and at the 1-position of D-galactose generating, in addition to GOS, LacNAc, and Galactosyl-LacNAc trisaccharides which were produced by two sequential transgalactosylations. Humanized GOS is chemically distinct from HMOs, and its effects in vivo have yet to be determined. Thus, we evaluated its safety and demonstrated the prebiotic's ability to modulate the gut microbiome in 6-week-old C57BL/6J mice. Longitudinal analysis of gut microbiome composition of stool samples collected from mice fed a diet containing hGOS for 5 weeks showed a transient reduction in alpha diversity. Differences in microbiome community composition mostly within the Firmicutes phylum were observed between hGOS and GOS, compared to control-fed animals. In sum, our study demonstrated the biological synthesis of hGOS, and signaled its safety and ability to modulate the gut microbiome in vivo, promoting the growth of beneficial microorganisms, including Bifidobacterium and Akkermansia.

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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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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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Immune Gene Expression Covaries with Gut Microbiome Composition in Stickleback

mBio ◽

10.1128/mbio.00145-21 ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Lauren E. Fuess ◽

Stijn den Haan ◽

Fei Ling ◽

Jesse N. Weber ◽

Natalie C. Steinel ◽

...

Keyword(s):

Gene Expression ◽

Microbial Communities ◽

Gut Microbiome ◽

Alpha Diversity ◽

Host Immunity ◽

Host Gene ◽

Microbiota Composition ◽

Host Gene Expression ◽

Microbiome Composition ◽

Immune Genes

ABSTRACT Commensal microbial communities have immense effects on their vertebrate hosts, contributing to a number of physiological functions, as well as host fitness. In particular, host immunity is strongly linked to microbiota composition through poorly understood bi-directional links. Gene expression may be a potential mediator of these links between microbial communities and host function. However, few studies have investigated connections between microbiota composition and expression of host immune genes in complex systems. Here, we leverage a large study of laboratory-raised fish from the species Gasterosteus aculeatus (three-spined stickleback) to document correlations between gene expression and microbiome composition. First, we examined correlations between microbiome alpha diversity and gene expression. Our results demonstrate robust positive associations between microbial alpha diversity and expression of host immune genes. Next, we examined correlations between host gene expression and abundance of microbial taxa. We identified 15 microbial families that were highly correlated with host gene expression. These families were all tightly correlated with host expression of immune genes and processes, falling into one of three categories—those positively correlated, negatively correlated, and neutrally related to immune processes. Furthermore, we highlight several important immune processes that are commonly associated with the abundance of these taxa, including both macrophage and B cell functions. Further functional characterization of microbial taxa will help disentangle the mechanisms of the correlations described here. In sum, our study supports prevailing hypotheses of intimate links between host immunity and gut microbiome composition. IMPORTANCE Here, we document associations between host gene expression and gut microbiome composition in a nonmammalian vertebrate species. We highlight associations between expression of immune genes and both microbiome diversity and abundance of specific microbial taxa. These findings support other findings from model systems which have suggested that gut microbiome composition and host immunity are intimately linked. Furthermore, we demonstrate that these correlations are truly systemic; the gene expression detailed here was collected from an important fish immune organ (the head kidney) that is anatomically distant from the gut. This emphasizes the systemic impact of connections between gut microbiota and host immune function. Our work is a significant advancement in the understanding of immune-microbiome links in nonmodel, natural systems.

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Cruciferous Vegetable Intake Results in Differentially Modified Gut Microbiome Composition of Mice Fed a High Fat Diet or a Western Diet

Current Developments in Nutrition ◽

10.1093/cdn/nzaa062_052 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1595-1595

Author(s):

Sabrina Trudo ◽

Rosa Moreno ◽

Jeong Hoon Pan ◽

Daniel Gallaher ◽

Jae Kyeom Kim ◽

...

Keyword(s):

Gut Microbiome ◽

Vegetable Intake ◽

Body Weight Gain ◽

Alpha Diversity ◽

Western Diet ◽

Index Number ◽

Standard Diet ◽

Jaccard Distance ◽

Microbiome Composition ◽

Distinct Cluster

Abstract Objectives Cruciferous (CRU; rich in glucosinolates) and apiaceous (API; rich in furanocoumarins) vegetable intake decrease colon cancer risk markers, likely through different mechanisms. Previous reports suggest background diets influence efficacy of bioactives. Here, we determined the effects on the composition of the gut microbiome of CRU and API supplementation to different background diets, diet-induced obesity (DIO) and the total western diet (TWD). Methods C57BL/6J male mice were fed standard diet (AIN93G), DIO, DIO with 21% (w/w) CRU (DIO + CRU), DIO with 21% (w/w) API (DIO + API), TWD, TWD with CRU (TWD + CRU), or TWD with API (TWD + API). After 12 weeks, cecal contents were collected for 16S rRNA sequencing and data analyzed by mothur. Results There were no differences in body weight gain except mice fed DIO + CRU gained more than mice fed AIN-93G or TWD. Lachnospiraceae was increased by CRU supplementation to both DIO and TWD and by API supplementation to TWD. CRU increased alpha diversity [Shannon Index, number of observed Operational Taxonomic Unit (OTUs)] compared to DIO and TWD. Regarding beta diversity, DIO + CRU showed distinct cluster compared to DIO (Bray-Curtis, ANOSIM, R = 0.35, P < 0.001; Jaccard distance, R = 0.47, P < 0.001). TWD + CRU showed distinct cluster compared to TWD (Bray-Curtis, R = 0.59, P < 0.001; Jaccard distance, R = 0.62, P < 0.001). API did not change alpha diversity, but did affect beta diversities with distinct clusters between API groups and their basal diet groups (Jaccard distance, R = 0.36 and 0.31 for DIO and TWD, respectively, P < 0.05). Among top 25 discriminating features between DIO and TWD and their supplementation of API and CRU, there were 9 shared OTUs including Lachnospiraceae, Clostridium XlVa, Clostridiales, Eisenbergiella, and Clostridium IV. Akkermansia were decreased in DIO + CRU compared with DIO. In TWD panel, Bifidobacterium and Erysipelotrichaceae decreased in TWD + CRU, while Turicibacter were identified as TWD + CRU signature. Erysipelotrichaceae and Bifidobacterium differentiated AIN-93G, DIO, and TWD. Conclusions CRU supplementation of DIO and TWD altered gut microbiome composition with some differences based on background diet. API also altered composition, albeit to a lesser extent. Funding Sources University of Arkansas, Fulbright Nicaragua Fellow.

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Reintroducing B. infantis to the cesarean-born neonate: an ecologically sound alternative to “vaginal seeding”

FEMS Microbiology Letters ◽

10.1093/femsle/fnaa032 ◽

2020 ◽

Vol 367 (6) ◽

Cited By ~ 2

Author(s):

Rebbeca M Duar ◽

David Kyle ◽

Rachel M Tribe

Keyword(s):

Caesarean Section ◽

Health Outcomes ◽

Health Professionals ◽

Gut Microbiome ◽

Ecological Perspective ◽

False Sense ◽

Beneficial Impact ◽

Infant Gut Microbiome

ABSTRACT There is a burgeoning literature highlighting differences in health outcomes between babies born vaginally and by caesarean section (c-section) This has led to the suggestion that infants born by c-section may benefit from vaginal swabbing/seeding. Here, we discuss from an ecological perspective that it is gut-adapted, not vagina-adapted microbes that are likely to take up residence in the gut and have the most beneficial impact on the developing neonate. Further, we caution the practice of ‘vaginal seeding’ may be potentially unsafe and also give parents and health professionals a false sense of action in restoring the infant gut microbiome following c-section. Instead, we argue that restoring B. longum subsp. infantis, which has evolved to colonize the infant gut, is a safe and ecologically-sound approach to restoring the gut microbiome of infants born by c-section.

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Delivery mode impacts newborn gut colonization efficiency

10.1101/2020.01.29.919993 ◽

2020 ◽

Cited By ~ 2

Author(s):

Caroline Mitchell ◽

Larson Hogstrom ◽

Allison Bryant ◽

Agnes Bergerat ◽

Avital Cher ◽

...

Keyword(s):

Gut Microbiome ◽

Dominant Factor ◽

Delivery Mode ◽

Metagenomic Sequencing ◽

Vaginal Microbiome ◽

Abdominal Incision ◽

Birth Canal ◽

Microbiome Composition ◽

Gut Colonization ◽

Infant Gut Microbiome

AbstractDelivery mode is the variable with the greatest influence on the infant gut microbiome composition in the first few months of life. Children born by Cesarean section (C-section) lack species from the Bacteroides genus in their gut microbial community, and this difference can be detectable until 6-18 months of age. One hypothesis is that these differences stem from lack of exposure to the maternal vaginal microbiome, as children born by C-section do not pass through the birth canal; however, Bacteroides species are not common members of the vaginal microbiome, thus this explanation seems inadequate. Here, we set out to re-evaluate this hypothesis by collecting rectal and vaginal samples before delivery from 73 mothers with paired stool from their infants in the first two weeks of life. We compared microbial profiles of infants born by planned, pre-labor C-section to those born by emergent, post-labor surgery (where the child was in the birth canal, but eventually delivered through an abdominal incision), and found no significant differences in the microbiome between these two groups. Both groups showed the characteristic signature lack of Bacteroides species, despite their difference in exposure to the birth canal. Surprisingly, this signature was only evident in samples from week two of life, but not in the first week. Children born by C-section often had high abundance of Bacteroides in their first few days of life, but these were not stable colonizers of the infant gut, as they were not detectable by week two. Finally, we used metagenomic sequencing to compare microbial strains in maternal vaginal and rectal samples and samples from their infants; we found evidence for mother-to-child transmission of rectal rather than vaginal strains. These results challenge birth canal exposure as the dominant factor in infant gut microbiome establishment and implicate colonization efficiency rather than exposure as a dictating factor of the newborn gut microbiome composition.

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An online atlas of human plasma metabolite signatures of gut microbiome composition

10.1101/2021.12.23.21268179 ◽

2021 ◽

Author(s):

Koen F. Dekkers ◽

Sergi Sayols-Baixeras ◽

Gabriel Baldanzi ◽

Christoph Nowak ◽

Ulf Hammar ◽

...

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

High Performance ◽

Alpha Diversity ◽

Plasma Metabolites ◽

Uremic Toxin ◽

Metagenomic Sequencing ◽

Microbiome Composition ◽

Plasma Metabolite

The human gut microbiota produces a variety of small compounds, some of which enter the bloodstream and impact host health. Conversely, various exogenous nutritional and pharmaceutical compounds affect the gut microbiome composition before entering circulation. Characterization of the gut microbiota—host plasma metabolite interactions is an important step towards understanding the effects of the gut microbiota on human health. However, studies involving large and deeply phenotyped cohorts that would reveal such meaningful interactions are scarce. Here, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for detailed characterization of the fecal microbiota and plasma metabolome, respectively, of 8,584 participants invited at age 50 to 64 of the Swedish CArdioPulmonary bioImage Study (SCAPIS). After adjusting for multiple comparisons, we identified 1,008 associations between species alpha diversity and plasma metabolites, and 318,944 associations between specific gut metagenomic species and plasma metabolites. The gut microbiota explained up to 50% of the variance of individual plasma metabolites (mean of 4.7%). We present all results as the searchable association atlas "GUTSY" as a rich resource for mining associations, and exemplify the potential of the atlas by presenting novel associations between oral medication and the gut microbiome, and microbiota species strongly associated with levels of the uremic toxin p-cresol sulfate. The association atlas can be used as the basis for targeted studies of perturbation of specific bacteria and for identification of candidate plasma biomarkers of gut flora composition.

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Geographical Relationships between Long-Tailed Goral (Naemorhedus caudatus) Populations Based on Gut Microbiome Analysis

Microorganisms ◽

10.3390/microorganisms9092002 ◽

2021 ◽

Vol 9 (9) ◽

pp. 2002

Author(s):

Chang Eon Park ◽

Bum-Joon Cho ◽

Min-Ji Kim ◽

Hee Cheon Park ◽

Jae-Ho Shin

Keyword(s):

Gut Microbiome ◽

Alpha Diversity ◽

Migration Route ◽

Ecological Studies ◽

Northern Asia ◽

Microbiome Composition ◽

Microbiome Analysis ◽

Northern Regions ◽

Regional Population ◽

Relational Network

The long-tailed goral (Naemorhedus caudatus) is an endangered species found in the mountains of eastern and northern Asia. Its populations have declined for various reasons, and this species has been designated as legally protected in South Korea. Although various ecological studies have been conducted on long-tailed gorals, none have investigated the gut microbiome until now. In the present study, we compared the diversity and composition of the gut microbiome of seven populations of Korean long-tailed gorals. By analyzing the gut microbiome composition for each regional population, it was found that four phyla—Firmicutes, Actinobacteriota, Bacteroidota, and Proteobacteria—were the most dominant in all regions on average. The alpha diversity of the gut microbiome of the goral population in the northern regions was high, while that in the southern regions was low. Through the analysis of beta diversity, the seven long-tailed goral populations have been divided into three groups: the Seoraksan population, the Samcheock population, and the Wangpicheon population. It was possible to confirm the regional migration of the animals using the gut microbiome based on the site-relational network analysis. It was found that the most stable population of long-tailed gorals in Korea was the Seoraksan population, and the closely related groups were the Samcheok and Wangpicheon populations, respectively. Wangpicheon appeared to be a major point of dispersal in the migration route of Korean long-tailed gorals.

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Dysbiosis in early sepsis can be modulated by a multispecies probiotic: a randomised controlled pilot trial

Beneficial Microbes ◽

10.3920/bm2018.0067 ◽

2019 ◽

Vol 10 (3) ◽

pp. 265-278 ◽

Cited By ~ 10

Author(s):

V. Stadlbauer ◽

A. Horvath ◽

I. Komarova ◽

B. Schmerboeck ◽

N. Feldbacher ◽

...

Keyword(s):

Gut Microbiome ◽

Early Stage ◽

Pilot Trial ◽

Alpha Diversity ◽

Gut Barrier ◽

Double Blind ◽

Microbiome Composition ◽

Gut Barrier Function ◽

Probiotic Intervention ◽

Early Sepsis

The gut is hypothesised to play an important role in the development and progression of sepsis. It is however unknown whether the gut microbiome and the gut barrier function is already altered early in sepsis development and whether it is possible to modulate the microbiome in early sepsis. Therefore, a randomised, double blind, placebo-controlled pilot study to examine the alterations of the microbiome and the gut barrier in early sepsis and the influence of a concomitant probiotic intervention on dysbiosis at this early stage of the disease was conducted. Patients with early sepsis, defined as fulfilling the sepsis definition from the 2012 Surviving Sepsis Campaign guidelines but without signs of organ failure, received multispecies probiotic (Winclove 607 based on Omnibiotic® 10 AAD) for 28 days. Gut microbiome composition, function, gut barrier and bacterial translocation were studied. Patients with early sepsis had a significantly lower structural and functional alpha diversity, clustered differently and showed structural alterations on all taxonomic levels. Gut permeability was unaltered but endotoxin, endotoxin binding proteins and peptidoglycans were elevated in early sepsis patients compared to controls. Probiotic intervention successfully increased probiotic strains in stool and led to an improvement of functional diversity. Microbiome composition and function are altered in early sepsis. Probiotic intervention successfully modulates the microbiome and is therefore a promising tool for early intervention in sepsis.

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