UC Davis

The human gut microbiota is intimately linked to our overall health by performing various functions that augment our metabolic, immunologic and physiologic characteristics. A key commensal taxon that resides within the infant gut is the genus Bifidobacterium. For over a century bifidobacteria have been studied in the context of the infant gut microbiota with continual discoveries describing their mutualistic relationship with the host. Diet is a major determinant of bifidobacteria colonization during infancy by which human milk feeding enriches for Bifidobacterium through the prebiotic effect of human milk oligosaccharides. In contrast, conventional formulas typically lack prebiotic structures consumed specifically by bifidobacteria. As such, the microbiota of human milk-fed compared with formula-fed infants assemble into distinct community states leading to disparate effects on the infant’s metabolic and immunologic parameters. However, there are still knowledge gaps regarding the beneficial health effects conferred by Bifidobacterium species and the molecular basis of their enrichment in the gut. Through leveraging the strengths of different experimental designs centered on bifidobacteria, this body of work seeks to characterize the metabolic interactions of the host-Bifidobacterium relationship and better understand their role in the human gut microbiome. The first chapter provides an overview of the relationship between bifidobacteria and the host including factors affecting early gut colonization by Bifidobacterium and their metabolic interactions. Cell culture of Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), an infant gut isolate, grown in 2’-fucosyllactose (2’-FL) or lactose reveal that the fermentation product profiles are substrate specific. The second chapter focuses on developing a mouse model of HMO driven bifidobacteria colonization in which a synbiotic of B. pseudocatenulatum and 2’-FL enable persistent populations of bifidobacteria. Comparing local and systemic differences in microbial derived metabolites in these mice provide insight into the dynamics of gut microbial perturbations that occur via persistent, rather than transient, enrichment of Bifidobacterium. Lastly, a prospective observational study in preterm infants supplemented with B. longum subsp. infantis (B. infantis) or Lactobacillus reuteri (L. reuteri) was conducted to contrast the changes in metabolite profiles in the gut from these probiotics and assess gut inflammation in relationship to these treatments. The results of these studies have provided important insights pertaining to the modulation of host metabolism in the presence of bifidobacteria. Fermentation products excreted in cell culture are driven by the starting substrate, in this case 2’-FL, which are observed to increase in the intestine and circulation in mice colonized with the probiotic. Furthermore, absorption of 1,2-propanediol produced by Bifidobacterium pseudocatenulatum in the gut is enriched in tissues including liver and brain. This novel finding demonstrates that modulation of the gut microbiome has the potential to influence peripheral tissue metabolism with the possibility of altering brain biochemistry independently of the gut-brain axis. In preterm infants, metabolites in the gut lumen are consistent with a Bifidobacterium-enriched microbiota showing significant increases in several fermentation products produced by bifidobacteria. Additionally, gut inflammation is reduced in preterm infants provided bifidobacteria and is associated with the anti-inflammatory metabolite indole-3-lactate. Together, these studies demonstrate the potential of pre- and probiotics, i.e. 2’-FL and bifidobacteria, to enrich the gut microbiota with commensal microorganisms and impact host metabolism.