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Multi-Compartment Profiling of Bacterial and Host Metabolites Identifies Intestinal Dysbiosis and Its Functional Consequences in the Critically Ill Child

Wijeyesekera, Anisha PhD1; Wagner, Josef PhD2; De Goffau, Marcus PhD1; Thurston, Sarah MSc3; Rodrigues Sabino, Adilson PhD4; Zaher, Sara MSc3; White, Deborah RN3; Ridout, Jenna RN5; Peters, Mark J. FRCPCH, PhD6,7; Ramnarayan, Padmanabhan FRCPCH, MD6,8; Branco, Ricardo G. FRCPCH, PhD5; Torok, M. Estee FRCPCH, PhD3,5; Valla, Frederic MD9; Meyer, Rosan PhD10; Klein, Nigel FRCPCH, PhD6,7; Frost, Gary PhD10; Parkhill, Julian PhD2; Holmes, Elaine PhD10; Pathan, Nazima FRCPCH, PhD3,5

doi: 10.1097/CCM.0000000000003841
Online Clinical Investigation: PDF Only
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Objectives: Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children.

Design: Prospective multicenter cohort study.

Setting: Three U.K.-based PICUs.

Patients: Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55).

Interventions: Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls.

Measurements and Main Results: Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = –0.2; p = 0.037).

Conclusions: Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. Profiling of bacterial metabolites in fecal and urine samples may support identification and treatment of intestinal dysbiosis in critical illness.

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1Department of Human Microbiome Studies, University of Reading, Berkshire, United Kingdom.

2Wellcome Sanger Institute, Cambridge, Cambridgeshire, United Kingdom.

3Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.

4Federal University of Alagoas, Maceio, Brazil.

5Paediatric Intensive Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.

6Paediatric Intensive Care Unit, Great Ormond Street Hospital, London, United Kingdom.

7UCL Institute of Child Health, Respiratory, Critical Care and Anaesthesia Section, London, United Kingdom.

8St Mary’s Hospital, London, United Kingdom.

9Hospices Civils de Lyon, Pediatric Intensive Care, Hôpital Femme Mère Enfant, Lyon-Bron, France.

10Imperial College London, London, United Kingdom.

Drs. Wijeyesekera and Wagner contributed equally.

Dr. Wijeyesekera developed and supervised the metabolic profiling strategy, undertook data analysis, and wrote the article. Dr. Wagner developed and supervised the microbial profiling strategy, undertook data analysis, and wrote the article. Dr. De Goffau analyzed the microbial data and co-wrote the article. Ms. Thurston undertook sample processing and data analysis. Drs. Rodrigues Sabino and Zaher, Ms. White, Ms. Ridout, and Dr. Valla undertook sample processing, data collection, and analysis. Dr. Meyer undertook data analysis. Drs. Peters, Branco, Torok, Meyer, and Klein contributed to protocol development, supervised data analysis, and co-wrote the article. Dr. Parkhill developed the microbial profiling protocol, supervised all aspects of the microbial data analysis, and co-wrote the article. Drs. Frost and Holmes developed the metabolic profiling protocol, supervised all aspects of the metabolic data analysis, and co-wrote the article. Dr. Pathan conceived and supervised the study and wrote the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Aspects of the work were funded by an Imperial College Biomedical Research Centre award (to Drs. Holmes and Pathan), the Evelyn Trust (to Drs. Parkhill and Pathan), a Wellcome Trust Core Informatics Award (to Dr. Parkhill), Great Ormond Street Hospital Children’s Charity (to Drs. Peters and Ramnarayan), and a Levi-Montalcini award from the European Society of Intensive Care Medicine (to Dr. Pathan). The research was supported by the National Institute for Health Research Biomedical Research Centres based at Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Great Ormond Street Hospital NHS Foundation Trust, Imperial College Healthcare NHS Trust, and Imperial College London.

Dr. Rodrigues Sabino’s institution received funding from National Institute for Health Research Imperial Biomedical Research Centre Institute of Translational Medicine and Therapeutics Call for Experimental Medicine Proposals. Dr. Valla received funding from Baxter and Nutricia. Dr. Meyer received funding from academic lectures for Danone, Nestle and Mead Johnson, and from the Mead Johnson Allergy Advisory Board. Dr. Frost’s institution received funding from Nestle and Heptares, and he received support for article research from Research Councils UK and Bill & Melinda Gates Foundation. Drs. Frost, Parkhill, and Pathan received support for article research from Wellcome Trust/Charity Open Access Fund. Dr. Parkhill’s institution received funding from Wellcome Trust, and he received funding from Next Gen Diagnostics Llc. Dr. Pathan’s institution received funding from European Society of Intensive Care Medicine, Evelyn Trust, and Wellcome Trust. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Nazima Pathan, FRCPCH, PhD, Department of Paediatrics, University of Cambridge, Level 8, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom. E-mail: np409@cam.ac.uk

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