Co-cultivation is a powerful approach to produce a robust functionally designed synthetic consortium as a live biotherapeutic product (LBP)

TLDR

Fecal microbiota transplants have proven effective but carry risks, prompting the development of defined microbial consortia as safer, targeted microbiome therapeutics, though strain selection and scalable production remain challenging. The study proposes a bottom‑up, ecology‑ and biotechnology‑driven method that uses continuous co‑cultivation to construct robust, functionally designed microbial consortia for therapeutic use. Nine strains were chosen to replicate key carbohydrate‑fermentation pathways of the healthy human gut microbiota and assembled into a consortium. Co‑culturing produced a stable, reproducible consortium with distinct growth and metabolism, matching FMT efficacy in a DSS colitis mouse model while a mixed inoculum failed, and the approach proved robust across additional consortia designs.

Abstract

The success of fecal microbiota transplants (FMT) has provided the necessary proof-of-concept for microbiome therapeutics. Yet, feces-based therapies have many associated risks and uncertainties, and hence defined microbial consortia that modify the microbiome in a targeted manner have emerged as a promising safer alternative to FMT. The development of such live biotherapeutic products has important challenges, including the selection of appropriate strains and the controlled production of the consortia at scale. Here, we report on an ecology- and biotechnology-based approach to microbial consortium construction that overcomes these issues. We selected nine strains that form a consortium to emulate the central metabolic pathways of carbohydrate fermentation in the healthy human gut microbiota. Continuous co-culturing of the bacteria produces a stable and reproducible consortium whose growth and metabolic activity are distinct from an equivalent mix of individually cultured strains. Further, we showed that our function-based consortium is as effective as FMT in counteracting dysbiosis in a dextran sodium sulfate mouse model of acute colitis, while an equivalent mix of strains failed to match FMT. Finally, we showed robustness and general applicability of our approach by designing and producing additional stable consortia of controlled composition. We propose that combining a bottom-up functional design with continuous co-cultivation is a powerful strategy to produce robust functionally designed synthetic consortia for therapeutic use.