A Disease-Associated Microbial and Metabolomics State in Relatives of Pediatric Inflammatory Bowel Disease Patients.
OBJECTIVE
Microbes may increase susceptibility to inflammatory bowel disease (IBD) by producing bioactive metabolites that affect immune activity and epithelial function. We undertook a family based study to identify microbial and metabolic features of IBD that may represent a predisease risk state when found in healthy first-degree relatives.


METHODS
Twenty-one families with pediatric IBD were recruited, comprising 26 Crohn's disease patients in clinical remission, 10 ulcerative colitis patients in clinical remission, and 54 healthy siblings/parents. Fecal samples were collected for 16S ribosomal RNA gene sequencing, untargeted liquid chromatography-mass spectrometry metabolomics, and calprotectin measurement. Individuals were grouped into microbial and metabolomics states using Dirichlet multinomial models. Multivariate models were used to identify microbes and metabolites associated with these states.


RESULTS
Individuals were classified into 2 microbial community types. One was associated with IBD but irrespective of disease status, had lower microbial diversity, and characteristic shifts in microbial composition including increased Enterobacteriaceae, consistent with dysbiosis. This microbial community type was associated similarly with IBD and reduced microbial diversity in an independent pediatric cohort. Individuals also clustered bioinformatically into 2 subsets with shared fecal metabolomics signatures. One metabotype was associated with IBD and was characterized by increased bile acids, taurine, and tryptophan. The IBD-associated microbial and metabolomics states were highly correlated, suggesting that they represented an integrated ecosystem. Healthy relatives with the IBD-associated microbial community type had an increased incidence of elevated fecal calprotectin.


CONCLUSIONS
Healthy first-degree relatives can have dysbiosis associated with an altered intestinal metabolome that may signify a predisease microbial susceptibility state or subclinical inflammation. Longitudinal prospective studies are required to determine whether these individuals have a clinically significant increased risk for developing IBD.
Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, California.
Jonathan P
JP
Jacobs
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, District of Columbia.
Maryam
M
Goudarzi
Pediatric Gastroenterology and Inflammatory Bowel Disease, Cedars-Sinai Medical Center, Los Angeles, California.
Namita
N
Singh
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California.
Maomeng
M
Tong
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California.
Ian H
IH
McHardy
Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, California.
Paul
P
Ruegger
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California.
Miro
M
Asadourian
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, District of Columbia.
Bo-Hyun
BH
Moon
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California.
Allyson
A
Ayson
Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, California.
James
J
Borneman
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Dermot P B
DP
McGovern
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, District of Columbia.
Albert J
AJ
Fornace
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California.
Jonathan
J
Braun
Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Department of Pediatrics, Icahn School of Medicine, Mount Sinai, New York.
Marla
M
Dubinsky
AUC, area under the curve; CD, Crohn’s disease; Family Cohort; IBD, inflammatory bowel disease; Inflammatory Bowel Disease; LC/MS, liquid chromatography/mass spectrometry; Metabolomics; Microbiome; OTU, operational taxonomic unit; PCR, polymerase chain reaction; PCoA, principal coordinates analysis; ToFMS, time-of-flight mass spectrometry; UC, ulcerative colitis; UPLC, ultra-performance liquid chromatography; rRNA, ribosomal RNA