(157e) Improving the Residence Time of Probiotics in the Gut through Functional Metagenomics

The human large intestine houses trillions of microorganisms which collectively form the highly diverse microbial community known as the gut microbiota.  The gut microbiota is becoming increasingly recognized as an organ, performing many functions critical to the maintenance of health, including extraction of nutrients, production of vitamins, and defense against pathogens.  Like an organ, pathologies in the structure of the gut microbiota (termed “dysbioses”) can have significant negative impacts to the human host, including obesity, malnutrition, cancer, and death.  However, the gut microbiota is currently unique among the organs in that it is highly engineerable, enabling improvement of function through the substitution of beneficial microbes for less desirable ones.  Towards this goal, probiotics are orally ingested microorganisms which improve gut health through provision of additional metabolic functions or through competition for niche space with pathogens.  Unfortunately, current probiotic strains have short residence times in the gut, necessitating continual administration for treatment of chronic conditions.  In order to improve the gut residence time of the important probiotic E. coli Nissle, we extracted tens of gigabases of metagenomic DNA from several highly distinct gut microbial communities and selected colonization-enhancing gene fragments via passage in both gnotobiotic and conventional mice.  Bioinformatic and biochemical analyses of these fragments indicated mechanisms of improved colonization, and integration of these colonization factors into probiotic E. coli Nissle significantly improved overall gut residence time.  Subsequently, these fragments were tested in combination to investigate synergistic and antagonistic effects between colonization factors.  Taken together, this work has the potential to significantly improve our understanding and use of probiotics while laying an important foundation for engineering the human gut microbiota.