Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study.
Necrotizing enterocolitis (NEC) is an inflammatory disease of the newborn bowel, primarily affecting premature infants. Early intestinal colonization has been implicated in the pathogenesis of NEC. The objective of this prospective case-control study was to evaluate differences in the intestinal microbiota between infants who developed NEC and unaffected controls prior to disease onset. We conducted longitudinal analysis of the 16S rRNA genes of 312 samples obtained from 12 NEC cases and 26 age-matched controls with a median frequency of 7 samples per subject and median sampling interval of 3 days. We found that the microbiome undergoes dynamic development during the first two months of life with day of life being the major factor contributing to the colonization process. Depending on when the infant was diagnosed with NEC (i.e. early vs. late onset), the pattern of microbial progression was different for cases and controls. The difference in the microbiota was most overt in early onset NEC cases and controls. In proximity to NEC onset, the abundances of Clostridium sensu stricto from Clostridia class were significantly higher in early onset NEC subjects comparing to controls. In late onset NEC, Escherichia/Shigella among Gammaproteobacteria, showed an increasing pattern prior to disease onset, and was significantly higher in cases than controls six days before NEC onset. Cronobacter from Gammaproteobacteria was also significantly higher in late onset NEC cases than controls 1-3 days prior to NEC onset. Thus, the specific infectious agent associated with NEC may vary by the age of infant at disease onset. We found that intravenously administered antibiotics may have an impact on the microbial diversity present in fecal material. Longitudinal analysis at multiple time points was an important strategy utilized in this study, allowing us to appreciate the dynamics of the premature infant intestinal microbiome while approaching NEC at various points.
The Genome Institute, Washington University, St. Louis, MO, United States of America; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States of America.
Yanjiao
Y
Zhou
Cooper Medical School of Rowan University, Camden, NJ, United States of America.
Gururaj
G
Shan
The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.
Erica
E
Sodergren
The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States of America.
George
G
Weinstock
Department of Pediatrics, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA, United States of America; Harvard Medical School, Boston, MA, United States of America.
W Allan
WA
Walker
Department of Newborn Medicine, Brigham and Women's Hospital, Boston, MA, United States of America; Department of Nursing, Brigham and Women's Hospital, Boston, MA, United States of America; Harvard Medical School, Boston, MA, United States of America.
Katherine E
KE
Gregory
D016022:Case-Control Studies; D020345:Enterocolitis, Necrotizing / Q000382:microbiology*; D005243:Feces / Q000382:microbiology*; D005260:Female; D000069196:Gastrointestinal Microbiome; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000382:microbiology*; D007422:Intestines / Q000382:microbiology*; D008137:Longitudinal Studies; D008297:Male; D012336:RNA, Ribosomal, 16S
D012336:RNA, Ribosomal, 16S