Identifying the ecological forces driving global divergence in infant microbiome assembly - infants worldwide are born sterile and acquire their microbiomes through a process of ecological…

The National Institute of General Medical Sciences awarded The Regents of the University of Colorado $386,994 on August 5, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to identify ecological forces driving global divergence in infant microbiome assembly.

The recipient will conduct multi-omics profiling of global infant cohorts to identify correlations between microbiome composition and ecological pressures including human milk oligosaccharides (HMOs) and early diet, maternal IgA antibodies, keystone bacterial taxa that reshape gut pH and oxygen tension, and dispersal limitations from reduced microbial exposures. The work employs a reverse-translation pipeline combining observational studies in human infants with controlled high-throughput anaerobic fermentation experiments to test how diet, IgA, keystone taxa, and inoculum diversity shape microbial succession, followed by validation in gnotobiotic mouse models to assess impacts on murine immune development.

Work is performed in Boulder, Colorado, with a period of performance extending through April 30, 2031.

Identifying the ecological forces driving global divergence in infant microbiome assembly - infants worldwide are born sterile and acquire their microbiomes through a process of ecological succession that stabilizes around age three. Our prior work demonstrates that early microbiome succession diverges between global populations in ways that reflect global variations in immune disease rates, indicating that some patterns of assembly may provide stronger support for human immune system development than others. Here, we aim to identify the ecological forces that drive infant microbiomes to assemble along distinct trajectories. We will test how four ecological processes contribute to this process: positive pressures (hmos and early diet), negative pressures (IGA antibodies), keystone species (those that reshape GUT PH and oxygen tension), and dispersal limitations (reduced microbial exposures). To accomplish this, we will employ a reverse-translation pipeline that grounds experiments in processes relevant to human infants and uses reductionist experimental models to establish causality. We will first perform multi-omics profiling of global infant cohorts to identify correlations and generate hypotheses. These include measuring HMO levels and infant diet composition to determine the ideal food sources of different microbes, measuring maternal IGA specificity to find differences in IGA binding patterns, identifying keystone taxa linked to major changes in GUT PH and oxygen tension, and assessing rates of vertical VS. Non-maternal microbial transmission. We will next use high-throughput anaerobic fermentation to manipulate these ecological pressures under controlled conditions, directly testing how diet, IGA, keystone taxa, and inoculum diversity shape microbial succession. Finally, we will use gnotobiotic mouse models to validate robust effects in vivo, assess impact on murine immune development, and test whether manipulating these ecological drivers can redirect microbiome assembly toward immune- protective states. This project tackles the central question of why immune diseases are far more common in industrialized infants by studying the ecological forces that shape early microbiome assembly. Its novelty lies in shifting from intra-population to inter-population comparisons, leveraging naturally large effect sizes to gain greater contrast between microbiomes, and employing a creative reverse-translation pipeline. The results will establish core principles of early-life succession, identify actionable microbial and immunologic levers, and lay the foundation for preventive interventions. Future work will focus on establishing therapeutic strategies, potentially including diet, IGA-based strategies, probiotics, or lifestyle modifications, that can be used in low-risk clinical trials aimed at steering infant microbiomes toward immune-protective states and restore immune health to pre-industrial levels.