Cultured Gut Microbiota from Twins Discordant for Obesity Modulate Adiposity and Metabolic Phenotypes in Mice.

摘要

Establishing whether the human gut microbiota is causally related to a given physiologic or disease phenotype is challenging. Twins discordant for obesity provide an opportunity to examine interrelationships between obesity and its associated metabolic disorders, diet, and the gut microbiota. Transplanting the intact uncultured or culturable component of fecal microbiota from each member of a discordant twin pair into separate groups of recipient germ-free (GF) mice permits the donors' communities to be replicated, differences between their properties to be identified, the impact of these differences on body composition and metabolic phenotypes to be discerned, and the effects of diet-by-microbiota interactions to be analyzed. Co-housing coprophagic mice harboring transplanted microbiota from discordant pairs provides an opportunity to determine which bacterial taxa invade the gut communities of cagemates, how invasion correlates with host phenotypes, and how invasion and microbial niche are impacted by human diets. In this thesis, separate groups of GF mice were colonized with uncultured fecal microbiota from each member of four twins pairs discordant for obesity, or with culture collections from an obese (Ob) or lean (Ln) co-twin. Animals were fed a mouse chow low in fat and rich in plant polysaccharides, or one of two diets reflecting the upper or lower tertiles of consumption of saturated fats and fruits and vegetables based on the US National Health and Nutrition Examination Survey (NHANES). Ln or Ob mice were co-housed 5 days after colonization. Body composition changes were defined by quantitative magnetic resonance. Microbiota/microbiome structure, gene expression and metabolism were assayed by 16S rRNA profiling, whole community shotgun sequencing, RNA-Seq, and mass spectrometry. Host gene expression and metabolism were also characterized. Intact uncultured and culturable bacterial component of Ob co-twins' fecal microbiota conveyed significantly greater increases in body mass and adiposity compared to Ln communities. Differences in body composition were correlated with differences in fermentation of short-chain fatty acids (increased in Ln), metabolism of branched-chain amino acids (increased in Ob), and microbial transformation of bile acid species (increased in Ln and correlated with down-regulation of host farnesoid X receptor signaling). Co-housing Ln and Ob mice prevented development of an increased adiposity and body mass phenotype in Ob cagemates and transformed their microbiota's metabolic profile to a lean-like state. Transformation correlated with invasion of members of Bacteroidales from Ln into Ob microbiota. Invasion and phenotypic rescue were diet-dependent, occurring with the diet representing the lower tertile of USA consumption of saturated fats, and upper tertile of fruits and vegetables, but not with the diet representing the upper tertile of saturated fats and lower tertile of fruit and vegetable consumption. These results disclose transmissible and modifiable effects of diet-by-microbiota interactions on host biology. Using gnotobiotic animal models to identify dietary components that promote the ability of culturable taxa from the Ln microbiota to establish themselves in Ob microbiota and shape microbial and host metabolism could provide new approaches for improving nutritional and health status.