TY - JOUR
T1 - Leveraging Human Microbiome Features to Diagnose and Stratify Children with Irritable Bowel Syndrome
AU - Hollister, Emily B.
AU - Oezguen, Numan
AU - Chumpitazi, Bruno P.
AU - Luna, Ruth Ann
AU - Weidler, Erica M.
AU - Rubio-Gonzales, Michelle
AU - Dahdouli, Mahmoud
AU - Cope, Julia L.
AU - Mistretta, Toni Ann
AU - Raza, Sabeen
AU - Metcalf, Ginger A.
AU - Muzny, Donna M.
AU - Gibbs, Richard A.
AU - Petrosino, Joseph F.
AU - Heitkemper, Margaret
AU - Savidge, Tor C.
AU - Shulman, Robert J.
AU - Versalovic, James
N1 - Funding Information:
Supported by the National Institute of Diabetes and Digestive and Kidney Diseases grants UH2DK093990 (J.V.) and UH3DK083990 (J.V.), R21DK096323-01 (T.C.S.), K23DK101688 (B.P.C.) and R03DK117219 (B.P.C.); the National Center for Complementary and Integrative Medicine grant RO1AT004326 (J.V.); the National Cancer Institute grant U01CA170930 (J.V.); the National Human Genome Research Institute grant U54HG004973 (R.A.G.); the National Institute of Nursing Research grants R01NR05337 (R.J.S.), R01NR013497 (R.J.S.), and RC2NR011959 (R.J.S. and M.H.); the National Institute of Allergy and Infectious Diseases grants U011AI24290-01 (T.C.S.) and R01AI10091401 (T.C.S.); the Autism Speaks Gastrointestinal and Neurobehavioral Processes grant 9455 (R.A.L.); the Baylor College of Medicine Caroline Weiss Law Fund for Research in Molecular Medicine (B.P.C.); and Daffy's Foundation (R.J.S.). Shared resources that helped advance this project were also supported, in part, by NIH grant P30 DK56338 (Texas Medical Center Digestive Diseases Center). We thank Rebecca Cappello and Elizabeth Menard for contributions to subject screening, recruitment, and sample processing; Wen Y. Chong for contributions to subject screening and sample processing; Yue Shang, Delphine Saulnier, and Tulin Ayvaz for contributions to specimen extraction and sequence library preparation; Nadim Ajami for contributions to specimen management and sequencing, as well as critical feedback on the manuscript; Kevin Riehle and Aleks Milosavljevic for data analysis support; and Karen Prince for contributions to the development and preparation of figures. R.J.S. M.H. and J.V. designed the study; R.J.S. J.V. T.C.S. J.F.P. and R.A.G. managed the project; E.M.W. and M.R.-G. recruited subjects and collected subject data; R.A.L. M.R.-G. S.R. G.A.M. and D.M.M. performed sample processing and sequencing; E.B.H. N.O. B.P.C. E.M.W. M.D. J.L.C. and T.-A.M. analyzed the data; E.B.H. B.P.C. N.O. R.A.L. T.C.S. R.J.S. and J.V. wrote and edited the manuscript; all authors commented on the manuscript and approved the final draft.
Publisher Copyright:
© 2019 American Society for Investigative Pathology and the Association for Molecular Pathology
PY - 2019/5
Y1 - 2019/5
N2 - Accurate diagnosis and stratification of children with irritable bowel syndrome (IBS) remain challenging. Given the central role of recurrent abdominal pain in IBS, we evaluated the relationships of pediatric IBS and abdominal pain with intestinal microbes and fecal metabolites using a comprehensive clinical characterization and multiomics strategy. Using rigorous clinical phenotyping, we identified preadolescent children (aged 7 to 12 years) with Rome III IBS (n = 23) and healthy controls (n = 22) and characterized their fecal microbial communities using whole-genome shotgun metagenomics and global unbiased fecal metabolomic profiling. Correlation-based approaches and machine learning algorithms identified associations between microbes, metabolites, and abdominal pain. IBS cases differed from controls with respect to key bacterial taxa (eg, Flavonifractor plautii and Lachnospiraceae bacterium 7_1_58FAA), metagenomic functions (eg, carbohydrate metabolism and amino acid metabolism), and higher-order metabolites (eg, secondary bile acids, sterols, and steroid-like compounds). Significant associations between abdominal pain frequency and severity and intestinal microbial features were identified. A random forest classifier built on metagenomic and metabolic markers successfully distinguished IBS cases from controls (area under the curve, 0.93). Leveraging multiple lines of evidence, intestinal microbes, genes/pathways, and metabolites were associated with IBS, and these features were capable of distinguishing children with IBS from healthy children. These multi-omics features, and their links to childhood IBS coupled with nutritional interventions, may lead to new microbiome-guided diagnostic and therapeutic strategies.
AB - Accurate diagnosis and stratification of children with irritable bowel syndrome (IBS) remain challenging. Given the central role of recurrent abdominal pain in IBS, we evaluated the relationships of pediatric IBS and abdominal pain with intestinal microbes and fecal metabolites using a comprehensive clinical characterization and multiomics strategy. Using rigorous clinical phenotyping, we identified preadolescent children (aged 7 to 12 years) with Rome III IBS (n = 23) and healthy controls (n = 22) and characterized their fecal microbial communities using whole-genome shotgun metagenomics and global unbiased fecal metabolomic profiling. Correlation-based approaches and machine learning algorithms identified associations between microbes, metabolites, and abdominal pain. IBS cases differed from controls with respect to key bacterial taxa (eg, Flavonifractor plautii and Lachnospiraceae bacterium 7_1_58FAA), metagenomic functions (eg, carbohydrate metabolism and amino acid metabolism), and higher-order metabolites (eg, secondary bile acids, sterols, and steroid-like compounds). Significant associations between abdominal pain frequency and severity and intestinal microbial features were identified. A random forest classifier built on metagenomic and metabolic markers successfully distinguished IBS cases from controls (area under the curve, 0.93). Leveraging multiple lines of evidence, intestinal microbes, genes/pathways, and metabolites were associated with IBS, and these features were capable of distinguishing children with IBS from healthy children. These multi-omics features, and their links to childhood IBS coupled with nutritional interventions, may lead to new microbiome-guided diagnostic and therapeutic strategies.
UR - http://www.scopus.com/inward/record.url?scp=85064535878&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064535878&partnerID=8YFLogxK
U2 - 10.1016/j.jmoldx.2019.01.006
DO - 10.1016/j.jmoldx.2019.01.006
M3 - Article
C2 - 31005411
AN - SCOPUS:85064535878
SN - 1525-1578
VL - 21
SP - 449
EP - 461
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 3
ER -