Sniffing Out Paediatric Gastrointestinal Diseases: The Potential of Volatile Organic Compounds as Biomarkers for Disease

ABSTRACT The diagnostic work-up and follow-up of paediatric functional gastrointestinal disorders and organic conditions usually includes invasive tests, carrying a high burden on patients. There is a place, therefore, for novel, noninvasive disease-specific biomarkers. Volatile organic compounds (VOCs), originating from (patho)physiological metabolic processes in the human body, are excreted as waste products through all conceivable bodily excrements. The spectrum of VOCs harbours a magnificent source of information, with the potential to serve as noninvasive diagnostic biomarkers and to monitor disease activity. VOC analysis has been studied in children and infants with a variety of gastrointestinal diseases, including inflammatory bowel disease, liver diseases, irritable bowel syndrome, necrotizing enterocolitis and infectious diarrhoea. Most of these studies, although limited in sample size, show that patients can be discriminated from controls based on their VOC profiles, underscoring the potential of VOC analysis in diagnosis and follow-up. Currently, however, the application of VOC analysis in clinical practice is limited; substantial challenges, including methodological, biological, and analytical problems, still need to be met. In this review we provide an overview of the available literature on the potential of VOCs as biomarkers for paediatric gastrointestinal diseases. We discuss the available techniques to analyse VOCs and provide topics for VOC-related research, which need to be addressed before VOC diagnostics can be implemented in daily clinical practice.

[1]  M. Benninga,et al.  Epidemiology of Pediatric Functional Abdominal Pain Disorders: A Meta-Analysis , 2015, PloS one.

[2]  Ben de Lacy Costello,et al.  Analysis of Faecal Volatile Organic Compounds in Preterm Infants Who Develop Necrotising Enterocolitis: A Pilot Study , 2009, Journal of pediatric gastroenterology and nutrition.

[3]  Douglas B. Kell,et al.  Statistical strategies for avoiding false discoveries in metabolomics and related experiments , 2007, Metabolomics.

[4]  C. Probert,et al.  A novel method for rapidly diagnosing the causes of diarrhoea , 2003, Gut.

[5]  Lawrence A. David,et al.  Diet rapidly and reproducibly alters the human gut microbiome , 2013, Nature.

[6]  R. Dweik,et al.  Metabolomic analysis of breath volatile organic compounds reveals unique breathprints in children with inflammatory bowel disease: a pilot study , 2014, Alimentary pharmacology & therapeutics.

[7]  David C. Wilson,et al.  Faecal Calprotectin in Suspected Paediatric Inflammatory Bowel Disease , 2015, Journal of pediatric gastroenterology and nutrition.

[8]  R. Dweik,et al.  Analysis of Exhaled Volatile Organic Compounds Reveals New Biomarkers for Irritable Bowel Syndrome: ACG Fellow Award: 1827 , 2014 .

[9]  David Smith,et al.  Selected ion flow tube mass spectrometry (SIFT-MS) for on-line trace gas analysis. , 2005, Mass spectrometry reviews.

[10]  Daniel J. C. Berkhout,et al.  Early Detection of Necrotizing Enterocolitis by Fecal Volatile Organic Compounds Analysis. , 2015, The Journal of pediatrics.

[11]  Masoumeh Sikaroodi,et al.  The Approach to Sample Acquisition and Its Impact on the Derived Human Fecal Microbiome and VOC Metabolome , 2013, PloS one.

[12]  David Moher,et al.  The STARD Statement for Reporting Studies of Diagnostic Accuracy: Explanation and Elaboration , 2003, Annals of Internal Medicine [serial online].

[13]  P. Sterk,et al.  Breathomics in lung disease. , 2015, Chest.

[14]  Alan D. Lopez,et al.  The Global Burden of Disease Study , 2003 .

[15]  Subrata Ghosh,et al.  Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. , 2012, Gastroenterology.

[16]  E. Zoetendal,et al.  Intestinal microbiota in functional bowel disorders: a Rome foundation report , 2012, Gut.

[17]  Peter J. Sterk,et al.  Volatile Metabolites of Pathogens: A Systematic Review , 2013, PLoS pathogens.

[18]  Peter J Sterk,et al.  Exhaled Molecular Fingerprinting in Diagnosis and Monitoring: Validating Volatile Promises. , 2015, Trends in molecular medicine.

[19]  R. Sartor Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis. , 2010, Gastroenterology.

[20]  D. Manuel,et al.  Changing Age Demographics of Inflammatory Bowel Disease in Ontario, Canada: A Population-based Cohort Study of Epidemiology Trends , 2014, Inflammatory bowel diseases.

[21]  E. Yasugi,et al.  Phospholipid turnover in the inflamed intestinal mucosa: Arachidonic acid-rich phosphatidyl/plasmenyl-ethanolamine in the mucosa in inflammatory bowel disease , 1999, Journal of Gastroenterology.

[22]  N. Alkhouri,et al.  Nonalcoholic fatty liver disease in children: recent practice guidelines, where do they take us? , 2014, Current pediatric reviews.

[23]  Jeffrey B. Schwimmer,et al.  Prevalence of Fatty Liver in Children and Adolescents , 2006, Pediatrics.

[24]  H. Lehmann,et al.  Chronic Abdominal Pain in Children: A Clinical Report of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition: American Academy of Pediatrics Subcommittee on Chronic Abdominal Pain and NASPGHAN Committee on Abdominal Pain , 2005, Journal of pediatric gastroenterology and nutrition.

[25]  C Harmston,et al.  Review article: next generation diagnostic modalities in gastroenterology – gas phase volatile compound biomarker detection , 2014, Alimentary pharmacology & therapeutics.

[26]  Se Jin Song,et al.  The treatment-naive microbiome in new-onset Crohn's disease. , 2014, Cell host & microbe.

[27]  Kenneth K Wang,et al.  Diagnosing gastrointestinal illnesses using fecal headspace volatile organic compounds. , 2016, World journal of gastroenterology.

[28]  Alan D. Lopez,et al.  Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2014, The Lancet.

[29]  M. Walsh,et al.  Causes and timing of death in extremely premature infants from 2000 through 2011. , 2015, The New England journal of medicine.

[30]  Claude Gravel,et al.  Adeno-associated Virus–mediated Delivery of a Recombinant Single-chain Antibody Against Misfolded Superoxide Dismutase for Treatment of Amyotrophic Lateral Sclerosis , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  M. Tarlow,et al.  Diagnosis of rotavirus gastroenteritis by smell. , 1987, Archives of disease in childhood.

[32]  N. Bârsan,et al.  Electronic nose: current status and future trends. , 2008, Chemical reviews.

[33]  Bogusław Buszewski,et al.  Human exhaled air analytics: biomarkers of diseases. , 2007, Biomedical chromatography : BMC.

[34]  R. Dweik,et al.  Analysis of breath volatile organic compounds in children with chronic liver disease compared to healthy controls , 2015, Journal of breath research.

[35]  L. Freitag,et al.  Ion mobility spectrometry for the detection of volatile organic compounds in exhaled breath of patients with lung cancer: results of a pilot study , 2009, Thorax.

[36]  J. Frick,et al.  Microbiota in pediatric inflammatory bowel disease. , 2010, The Journal of pediatrics.

[37]  James A Covington,et al.  The Interplay of the Gut Microbiome, Bile Acids, and Volatile Organic Compounds , 2015, Gastroenterology research and practice.

[38]  Raed A. Dweik,et al.  Analysis of breath volatile organic compounds as a noninvasive tool to diagnose nonalcoholic fatty liver disease in children , 2014, European journal of gastroenterology & hepatology.

[39]  H. Haick,et al.  Nanomaterial-based sensors for detection of disease by volatile organic compounds. , 2013, Nanomedicine.

[40]  B. de Lacy Costello,et al.  A review of the volatiles from the healthy human body , 2014, Journal of breath research.

[41]  Marc A Benninga,et al.  Faecal gas analysis by electronic nose as novel, non-invasive method for assessment of active and quiescent paediatric inflammatory bowel disease: Proof of principle study. , 2014, Journal of Crohn's & colitis.

[42]  T. Konno,et al.  A long-term survey of rotavirus infection in Japanese children with acute gastroenteritis. , 1978, The Journal of infectious diseases.

[43]  Jamie Perin,et al.  Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000 , 2012, The Lancet.

[44]  M. Wei,et al.  Volatile Organic Compounds as Novel Markers for the Detection of Bacterial Infections , 2014 .

[45]  G. Gibson,et al.  Gut microbial activity, implications for health and disease: the potential role of metabolite analysis. , 2012, Journal of proteome research.

[46]  S. Hazen,et al.  Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls , 2015, Pediatric obesity.

[47]  C. Moorehead All rights reserved , 1997 .

[48]  F. Bushman,et al.  Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes , 2011, Science.

[49]  G. Collins,et al.  New Guideline for the Reporting of Studies Developing, Validating, or Updating a Multivariable Clinical Prediction Model: The TRIPOD Statement , 2015, Advances in anatomic pathology.

[50]  J. Versalovic,et al.  Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome , 2015, Alimentary pharmacology & therapeutics.

[51]  M. McEwan,et al.  Rapid monitoring of volatile organic compounds: a comparison between gas chromatography/mass spectrometry and selected ion flow tube mass spectrometry. , 2014, Rapid communications in mass spectrometry : RCM.