ABSTRACT
Early life gut microbiome composition has been correlated with childhood obesity, though microbial functional contributions to disease origins remain unclear. Here, using an infant birth cohort (n = 349) we identify a distinct fecal microbiota composition in 1-month-old infants with the lowest rate of exclusive breastfeeding, that relates with higher relative risk for obesity and overweight phenotypes at two years. Higher-risk infant fecal microbiomes exhibited accelerated taxonomic and functional maturation and broad-ranging metabolic reprogramming, including reduced concentrations of neuro-endocrine signals. In vitro, exposure of enterocytes to fecal extracts from higher-risk infants led to upregulation of genes associated with obesity and with expansion of nutrient sensing enteroendocrine progenitor cells. Fecal extracts from higher-risk infants also promoted enterocyte barrier dysfunction. These data implicate dysregulation of infant microbiome functional development, and more specifically promotion of enteroendocrine signaling and epithelial barrier impairment in the early-life developmental origins of childhood obesity.
Acknowledgments
We thank the participants in the WHEALS study. We also thank E. Rackaityte, A.R. Panzer, C. Ha, M. Bacino and X.H. Lim for their thoughtful critique of this manuscript.
Disclosure statement
S.V.L. is a cofounder, consultant and serves on the board of directors of Siolta Therapeutics Inc.
Author contributions
G.J.M.Y. designed the study, performed research, analyzed the data and wrote the manuscript; C.E.P. performed research, analyzed data, and contributed to manuscript writing, A.R.S. and K.E.F. contributed to data analysis and manuscript development; K.M. assisted with data analysis; D.T.N. assisted in performing research; K.J.W. and C.C.J. provided resources. A.C.B. designed and supervised the epidemiology study, provided resources and contributed to manuscript development; S.V.L. designed and supervised the study, contributed to data analysis and wrote the manuscript. A.M.L, D.R.O., A.G.R. and all other authors discussed the results and edited the manuscript.
Data availability statement
All raw sequences are deposited in the European Nucleotide Archive (Study PRJEB52295 and PRJEB13896) and in the SRA Bioproject PRJNA648818. All additional datasets and materials are available from the corresponding author upon reasonable request.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2290661