Understanding the distinct roles of core and low-abundant human gut microbiota in host metabolism and inflammatory disease using defined microbial consortia in germ-free mice

The human gut microbiota, composed of trillions of microorganisms, plays a pivotal role in shaping host physiology, including metabolism, immune development, and disease susceptibility. Within this complex ecosystem, core microbiota, species consistently found across individuals, are thought to support homeostasis, while low-abundant taxa, though less represented, may exert disproportionately strong effects. Yet, the distinct contributions of these groups remain unclear. In this study, we developed two defined, culturable human gut microbial consortia: CoreCom, consisting of highly prevalent taxa identified from global metagenomic datasets, and LowCom, comprising rare but potentially functional species from the same culture library. Germ-free (GF) mice were colonized with these consortia individually or in combination to systematically evaluate their colonization dynamics, functions, and impact on host physiology. Chapter 1 characterized CoreCom assembly in GF mice using longitudinal 16S and metagenomic analyses. We found that CoreCom stably colonized the host and supported key immunomodulatory functions resembling those of complex human microbiota. Chapter 2 explored microbial influence on host metabolism. Surprisingly, LowCom-colonized mice showed increased weight gain and adiposity, even under a standard chow diet, effects not seen in CoreCom mice, suggesting that rare taxa can drive metabolic phenotypes. In Chapter 3, we assessed microbial contributions to intestinal inflammation using a DSS-induced colitis model. CoreCom protected against epithelial damage and inflammation, while LowCom exacerbated colitis, potentially due to its high Firmicutes content and pro-inflammatory traits. Together, this work demonstrates distinct, non-redundant roles of core and low-abundant gut microbes and introduces a minimal human-derived microbiota platform for future mechanistic studies.