First name
Kyle
Last name
Bittinger

Title

Early stool microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation.

Year of Publication

2021

Number of Pages

e29384

Date Published

2021 Oct 28

ISSN Number

1545-5017

Abstract

<p><strong>BACKGROUND: </strong>The contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pretransplant are needed.</p>

<p><strong>METHODS: </strong>We sought to describe the pretransplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pretransplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations.</p>

<p><strong>RESULTS: </strong>We profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4&nbsp;days before transplant. Pretransplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae, and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication, or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition.</p>

<p><strong>DISCUSSION: </strong>Stool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome changes are imperative to identify causal associations and to inform rational design of interventions.</p>

DOI

10.1002/pbc.29384

Alternate Title

Pediatr Blood Cancer

PMID

34709713
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Title

Decreased Intestinal Microbiome Diversity in Pediatric Sepsis: A Conceptual Framework for Intestinal Dysbiosis to Influence Immunometabolic Function.

Year of Publication

2021

Number of Pages

e0360

Date Published

2021 Mar

ISSN Number

2639-8028

Abstract

<p><b>Objectives: </b>The intestinal microbiome can modulate immune function through production of microbial-derived short-chain fatty acids. We explored whether intestinal dysbiosis in children with sepsis leads to changes in microbial-derived short-chain fatty acids in plasma and stool that are associated with immunometabolic dysfunction in peripheral blood mononuclear cells.</p><p><b>Design: </b>Prospective observational pilot study.</p><p><b>Setting: </b>Single academic PICU.</p><p><b>Patients: </b>Forty-three children with sepsis/septic shock and 44 healthy controls.</p><p><b>Measurements and Main Results: </b>Stool and plasma samples were serially collected for sepsis patients; stool was collected once for controls. The intestinal microbiome was assessed using 16S ribosomal RNA sequencing and alpha- and beta-diversity were determined. We measured short-chain fatty acids using liquid chromatography, peripheral blood mononuclear cell mitochondrial respiration using high-resolution respirometry, and immune function using ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor-α. Sepsis patients exhibited reduced microbial diversity compared with healthy controls, with lower alpha- and beta-diversity. Reduced microbial diversity among sepsis patients (mainly from lower abundance of commensal obligate anaerobes) was associated with increased acetic and propionic acid and decreased butyric, isobutyric, and caproic acid. Decreased levels of plasma butyric acid were further associated with lower peripheral blood mononuclear cell mitochondrial respiration, which in turn, was associated with lower lipopolysaccharide-stimulated tumor necrosis factor-α. However, neither intestinal dysbiosis nor specific patterns of short-chain fatty acids were associated with lipopolysaccharide-stimulated tumor necrosis factor-α.</p><p><b>Conclusions: </b>Intestinal dysbiosis was associated with altered short-chain fatty acid metabolites in children with sepsis, but these findings were not linked directly to mitochondrial or immunologic changes. More detailed mechanistic studies are needed to test the role of microbial-derived short-chain fatty acids in the progression of sepsis.</p>

DOI

10.1097/CCE.0000000000000360

Alternate Title

Crit Care Explor

PMID

33786436
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Title

Gut Microbiome Profile After Pancreatectomy in Infants With Congenital Hyperinsulinism.

Year of Publication

2021

Number of Pages

89-92

Date Published

2021 Jan 01

ISSN Number

1536-4828

Abstract

<p><strong>OBJECTIVES: </strong>The objective of this study was to characterize gut microbiome profiles of infants with congenital hyperinsulinism (HI) who underwent near-total or partial pancreatectomy for hypoglycemia management, as compared with healthy controls.</p>

<p><strong>METHODS: </strong>A prospective observational cohort study was performed. Subjects were infants (0-6 months) with HI who underwent removal of pancreatic tissue for management of intractable hypoglycemia from February 2017 to February 2018 at the Children's Hospital of Philadelphia. Fecal samples were collected postoperatively, on full enteral nutrition. The gut microbiome of HI subjects was analyzed and compared with age-matched samples from healthy infants.</p>

<p><strong>RESULTS: </strong>Seven subjects with ≥50% pancreatectomy and 6 with &lt;50% pancreatectomy were included. α (within-sample) diversity was lowest among infants with ≥50% pancreatectomy (richness: false discovery rate, 0.003; Shannon index: false discovery rate, 0.01). β (between-sample) diversity (Bray-Curtis dissimilarity, P = 0.02; Jaccard distance, P = 0.001) differed across groups (≥ or &lt;50% pancreatectomy, controls). Bifidobacteria and Klebsiella species were least abundant among infants with ≥50% pancreatectomy but did not differ between infants with &lt;50% pancreatectomy and historical controls.</p>

<p><strong>CONCLUSIONS: </strong>Infants with HI who underwent ≥50% pancreatectomy differed from age-matched infants in gut microbiome profile, whereas those with &lt;50% pancreatectomy more closely resembled control profiles. The durability of this difference should be investigated.</p>

DOI

10.1097/MPA.0000000000001708

Alternate Title

Pancreas

PMID

33370028
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Title

Multi-omic Analysis of the Interaction between Clostridioides difficile Infection and Pediatric Inflammatory Bowel Disease.

Year of Publication

2020

Number of Pages

Date Published

2020 Aug 11

ISSN Number

1934-6069

Abstract

<p>Children with inflammatory bowel diseases (IBD) are particularly vulnerable to infection with Clostridioides difficile (CDI). IBD and IBD&nbsp;+ CDI have overlapping symptoms but respond to distinctive treatments, highlighting the need for diagnostic biomarkers. Here, we studied pediatric patients with IBD and IBD&nbsp;+ CDI, comparing longitudinal data on the gut microbiome, metabolome, and other measures. The microbiome is dysbiotic and heterogeneous in both disease states, but the metabolome reveals disease-specific patterns. The IBD group shows increased concentrations of markers of inflammation and tissue damage compared with healthy controls, and metabolic changes associate with susceptibility to CDI. In IBD&nbsp;+ CDI, we detect both metabolites associated with inflammation/tissue damage and fermentation products produced by C.&nbsp;difficile. The most discriminating metabolite found is isocaproyltaurine, a covalent conjugate of a distinctive C.&nbsp;difficile fermentation product (isocaproate) and an amino acid associated with tissue damage (taurine), which may be useful as a joint marker of the two disease processes.</p>

DOI

10.1016/j.chom.2020.07.020

Alternate Title

Cell Host Microbe

PMID

32822584
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Title

The stepwise assembly of the neonatal virome is modulated by breastfeeding.

Year of Publication

2020

Number of Pages

470-474

Date Published

2020 May

ISSN Number

1476-4687

Abstract

<p>The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which-in some cases-leads to gastrointestinal disorders. Here we show that the assembly of the viral community in neonates takes place in distinct steps. Fluorescent staining of virus-like particles purified from infant meconium or early stool samples shows few or no particles, but by one month of life particle numbers increase to 10 per gram, and these numbers seem to persist throughout life. We investigated the origin of these viral populations using shotgun metagenomic sequencing of virus-enriched preparations and whole microbial communities, followed by targeted microbiological analyses. Results indicate that, early after birth, pioneer bacteria colonize the infant gut and by one month prophages induced from these bacteria provide the predominant population of virus-like particles. By four months of life, identifiable viruses that replicate in human cells become more prominent. Multiple human viruses were more abundant in stool samples from babies who were exclusively fed on&nbsp;formula milk compared with those fed partially or fully on breast milk, paralleling reports that breast milk can be protective against viral infections. Bacteriophage populations also differed depending on whether or not the infant was breastfed. We show that the colonization of the infant gut is stepwise, first mainly by temperate bacteriophages induced from pioneer bacteria, and later by viruses that replicate in human cells; this second phase is modulated by breastfeeding.</p>

DOI

10.1038/s41586-020-2192-1

Alternate Title

Nature

PMID

32461640
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Title

Perturbations of the Gut Microbiome and Metabolome in Children with Calcium Oxalate Kidney Stone Disease.

Year of Publication

2020

Number of Pages

Date Published

2020 May 07

ISSN Number

1533-3450

Abstract

<p><strong>BACKGROUND: </strong>The relationship between the composition and function of gut microbial communities and early-onset calcium oxalate kidney stone disease is unknown.</p>

<p><strong>METHODS: </strong>We conducted a case-control study of 88 individuals aged 4-18 years, which included 44 individuals with kidney stones containing ≥50% calcium oxalate and 44 controls matched for age, sex, and race. Shotgun metagenomic sequencing and untargeted metabolomics were performed on stool samples.</p>

<p><strong>RESULTS: </strong>Participants who were kidney stone formers had a significantly less diverse gut microbiome compared with controls. Among bacterial taxa with a prevalence &gt;0.1%, 31 taxa were less abundant among individuals with nephrolithiasis. These included seven taxa that produce butyrate and three taxa that degrade oxalate. The lower abundance of these bacteria was reflected in decreased abundance of the gene encoding butyryl-coA dehydrogenase (=0.02). The relative abundance of these bacteria was correlated with the levels of 18 fecal metabolites, and levels of these metabolites differed in individuals with kidney stones compared with controls. The oxalate-degrading bacterial taxa identified as decreased in those who were kidney stone formers were components of a larger abundance correlation network that included and several species. The microbial () diversity was associated with age of stone onset, first decreasing and then increasing with age. For the individuals who were stone formers, we found the lowest diversity among individuals who first formed stones at age 9-14 years, whereas controls displayed no age-related differences in diversity.</p>

<p><strong>CONCLUSIONS: </strong>Loss of gut bacteria, particularly loss of those that produce butyrate and degrade oxalate, associates with perturbations of the metabolome that may be upstream determinants of early-onset calcium oxalate kidney stone disease.</p>

DOI

10.1681/ASN.2019101131

Alternate Title

J. Am. Soc. Nephrol.

PMID

32381601
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Title

Bacterial colonization reprograms the neonatal gut metabolome.

Year of Publication

2020

Number of Pages

Date Published

2020 Apr 13

ISSN Number

2058-5276

Abstract

<p>Initial microbial colonization and later succession in the gut of human infants are linked to health and disease later in life. The timing of the appearance of the first gut microbiome, and the consequences for the early life metabolome, are just starting to be defined. Here, we evaluated the gut microbiome, proteome and metabolome in 88 African-American newborns using faecal samples collected in the first few days of life. Gut bacteria became detectable using molecular methods by 16 h after birth. Detailed analysis of the three most common species, Escherichia coli, Enterococcus faecalis and Bacteroides vulgatus, did not suggest a genomic signature for neonatal gut colonization. The appearance of bacteria was associated with reduced abundance of approximately 50 human proteins, decreased levels of free amino acids and an increase in products of bacterial fermentation, including acetate and succinate. Using flux balance modelling and in vitro experiments, we provide evidence that fermentation of amino acids provides a mechanism for the initial growth of E. coli, the most common early colonizer, under anaerobic conditions. These results provide a deep characterization of the first microbes in the human gut and show how the biochemical environment is altered by their appearance.</p>

DOI

10.1038/s41564-020-0694-0

Alternate Title

Nat Microbiol

PMID

32284564
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