This Genome Watch article discusses the dominance of uncultivated microorganisms in natural ecosystems and how the consequent genome-driven insights could guide the rational design of synthetic microbial communities.

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In recent years, there has been growing recognition that microbial communities, rather than individual strains, are the key functional units that drive many important biological processes in the environment as well as society, including waste management, digestive health and disease modulation. As a result, the rational design of microbial consortia has emerged as a strategy in both basic and applied microbiology. Unlike monocultures, engineered consortia can coordinate diverse metabolic activities through interspecies interactions, thus stabilizing the system and providing more resilience and fitness in a given environment. This shift in perspective is opening up promising new avenues for addressing challenges that no single organism could tackle alone.

Further promoting this shift is the continued expansion of genome-resolved microbiome data. In early 2025, a global survey of more than 1.5 million microbial genomes from public datasets confirmed that cultivated taxa represent less than 10% of the total phylogenetic diversity described to date, highlighting the central role of metagenome-assembled genomes (MAGs) in shaping our understanding of microbial life1. Strikingly, the study also revealed that only about one-third of known cultivated species are recovered as MAGs, which suggests a sharp ecological divide: the most abundant microorganisms in natural ecosystems remain uncultivated, while most cultivated microorganisms seem to be rare or absent in the same environments.

Credit: Neil Smith/Springer Nature Limited

This insight is profoundly reshaping how we approach the design of synthetic communities. By tapping into the wealth of genomic information from MAGs, particularly from dominant, uncultivated lineages, we are gaining access to the true functional core of microbial ecosystems. MAGs enable us to reconstruct genome-scale metabolic networks, uncover patterns of metabolic interdependence and identify taxa that are consistently co-abundant across environments. This enables the rational selection of community members not just for their individual traits, but for their ecological roles, complementary functions and potential for stable coexistence. These genome-driven insights are now being translated into applications, as synthetic biology and microbial ecology converge around a shared goal: the rational design of communities that harness the principles of natural microbial ecosystems.

In the medical domain, engineered consortia are emerging as powerful tools for precision therapeutics. For example, van der Lelie et al.2 developed a defined bacterial consortium that successfully treated chronic immune-mediated colitis in mice. Designed to deliver therapeutic functions while remaining stable through time based on predicted metabolic interdependencies, this consortium represents a promising alternative to faecal microbiota transplants, which suffer from effect variability and safety concerns. Beyond medicine, rationally designed microbial communities are being applied in the environmental and industrial settings. In waste management, microbial consortia have proven more resilient and functionally robust than single-strain systems, particularly in processes such as fermentation and bioconversion. CO2 recycling, for example, relies on multispecies communities leading the transformation of carbon into energy carriers, thus moving towards the reduction of greenhouse gas emissions and climate change mitigation. Challenges such as community drift and genetic instability remain key concerns that could be addressed using the ecological data brought by the observed dominance of MAGs3.

Together, these developments highlight the rising importance of the rational design of consortia as a unifying framework across biotechnology, health and environmental science. Genome-resolved approaches are not only expanding our catalogue of microbial diversity, but they are providing the foundation for the next generation of stable, scalable and purpose-built microbial communities.