First name
Robert
Middle name
N
Last name
Baldassano

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

Title

Venous Thromboembolism in Pediatric Inflammatory Bowel Disease: A Case-Control Study.

Year of Publication

2021

Date Published

2021 Feb 16

ISSN Number

1536-4801

Abstract

<p><strong>OBJECTIVES: </strong>Inflammatory bowel disease (IBD) is associated with increased risk of venous thromboembolism (VTE). Despite this recognized risk, there are limited data and no anticoagulation guidelines for hospitalized pediatric IBD patients. The objectives of this study were to characterize pediatric IBD patients with VTE and determine risk factors.</p>

<p><strong>METHODS: </strong>This was a nested case-control study comparing hospitalized children with IBD diagnosed with VTE to those without VTE over a decade at a large referral center. Standard descriptive statistics were used to describe the VTE group. Multivariable conditional logistic regression was used to assess risk factors.</p>

<p><strong>RESULTS: </strong>Twenty-three cases were identified. Central venous catheter (CVC) presence (OR 77.9 (95% CI: 6.9, 880.6; p &lt; 0.001)) and steroid use (OR 12.7 (95% CI: 1.3, 126.4; p = 0.012)) were independent risk factors. Median age at VTE was 17 years (IQR 13.5, 18.2), and in 48% VTE was the indication for admission. Median duration of anticoagulation was 3.8 months (IQR 2.3, 7.6), and there were no major bleeding events for patients on anticoagulation. There were no patients with known sequelae from VTE, though 22% had severe VTE that required interventions.</p>

<p><strong>CONCLUSIONS: </strong>Pediatric patients with IBD are at risk for VTE, although the absolute risk remains relatively low. The safety and efficacy of pharmacologic thromboprophylaxis needs to be further evaluated in this population with attention to risk factors, such as steroid use and presence of CVC.</p>

<p>An infographic is available for this article at:http://links.lww.com/MPG/C232.</p&gt;

DOI

10.1097/MPG.0000000000003078

Alternate Title

J Pediatr Gastroenterol Nutr

PMID

33605670

Title

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

Year of Publication

2020

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

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

Title

Changes in Hepcidin and Hemoglobin After Anti-TNF-alpha Therapy in Children and Adolescents With Crohn Disease.

Year of Publication

2018

Number of Pages

90-94

Date Published

2018 01

ISSN Number

1536-4801

Abstract

<p><strong>OBJECTIVES: </strong>Anemia is the most common systemic complication of inflammatory bowel disease, is more common in affected children than in adults, and is mediated in large part by chronic inflammation. Inflammation increases levels of the iron-regulatory protein hepcidin, which have been elevated in adults with Crohn disease.</p>

<p><strong>METHODS: </strong>We measured serum hepcidin-25 and hemoglobin (Hgb) in 40 children and adolescents with Crohn disease at baseline and 10 weeks after initiation of anti-tumor necrosis factor (TNF)-α therapy. Measures of disease activity, inflammatory markers, and cytokines were obtained in all subjects. Anemia was defined by World Health Organization criteria.</p>

<p><strong>RESULTS: </strong>At baseline hepcidin and C-reactive protein levels were correlated, and 95% of subjects were anemic. After anti-TNF-α therapy, median (interquartile range) hepcidin concentrations decreased significantly and the distribution narrowed (27.9 [16.2, 52.9] vs 23.2 [11.1, 37.7] ng/mL, P = 0.01). Mean (standard deviation) Hgb also increased significantly (10.6 ± 1.2 to 10.9 ± 1.1 g/dL, P = 0.02), and the increase was sustained at 12 months, although 90% of participants continued to meet anemia criteria at 10 weeks. Disease activity and markers of inflammation also decreased and albumin levels increased. In generalized estimating equation analyses, higher TNF-α, interleukin 6, erythrocyte sedimentation rate, and C-reactive protein were associated with higher hepcidin concentrations (P = 0.04, P = 0.03, P = 0.003, and P &lt; 0.001, respectively), and increased levels of disease activity were associated with higher hepcidin.</p>

<p><strong>CONCLUSIONS: </strong>In children with Crohn disease, anti-TNF-α therapy is associated with decreased levels of hepcidin and increased Hgb 10 weeks after induction. Improvement in anemia may be a secondary benefit for children who receive this therapy.</p>

DOI

10.1097/MPG.0000000000001650

Alternate Title

J. Pediatr. Gastroenterol. Nutr.

PMID

28604512

Title

Enthesitis is an extraintestinal manifestation of pediatric inflammatory bowel disease.

Year of Publication

2012

Date Published

2012 Jan

ISSN Number

2146-2909

Abstract

<p><strong>BACKGROUND: </strong>Enthesitis is an extra-intestinal manifestation of inflammatory bowel disease (IBD) in adults. However, little has been published about the prevalence or characteristics of enthesitis in pediatric IBD.</p>

<p><strong>METHODS: </strong>We conducted a cross-sectional study of children and young adults ages 4-21 years with IBD. Subjects were recruited among those receiving routine care in a gastroenterology clinic. All subjects underwent a clinical examination of the entheses and joints, and completed a study questionnaire.</p>

<p><strong>RESULTS: </strong>We enrolled 43 subjects, who had a median age of 16 years and a median time from IBD diagnosis of 2.7 years. 32 subjects (74%) had Crohn disease, 10 subjects (23%) had indeterminate colitis, and 1 subject (2%) had ulcerative colitis. At least one tender enthesis was present in 21% of subjects and 12% had more than 2 tender entheses. The most commonly affected entheses were located at the inferior patella, the femoral greater trochanter, and the proximal humerus. The presence of enthesitis was associated with a higher intensity of recent musculoskeletal pain (p=0.03).</p>

<p><strong>CONCLUSIONS: </strong>Enthesitis is a prevalent extra-intestinal manifestation of pediatric IBD and is associated with increased musculoskeletal pain. Future studies should evaluate the functional and long-term impact of enthesitis on children with IBD.</p>

DOI

10.5455/apr.102920121510

Alternate Title

Ann Paediatr Rheumatol

PMID

24349861

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