Did you know that most of the microbes in your gut have never been grown in the lab and some might be the key to preventing chronic diseases? The human gut microbiome is a vast and diverse ecosystem, home to approximately 40 trillion microbes spanning all domains of life. These microorganisms play essential roles in digestion, immune regulation, and protection against external pathogens. However, understanding the microbiome’s complexity remains a significant challenge due to its highly individualised nature - only about 20% of microbial species are shared across the population. Identifying microbiome signatures linked to health and disease is a major focus of research in this field.
The Microbiome Function and Diversity Group, University of Cambridge
Dr. Alexandre Almeida, from the Microbiome Function and Diversity Group at the University of Cambridge’s Department of Veterinary Medicine, specialises in large-scale metagenomic approaches to study the microbiome. At the Festival of Genomics & Biodata 2025, he highlighted his work that focuses on the discovery of hidden and misunderstood microbial species. Many of these remain uncultured and thus difficult to study using traditional cultivation techniques. To overcome this, researchers employ metagenomics, which allows for a more comprehensive analysis of microbial diversity without the need for cultivation.
Genome-resolved metagenomics is a powerful tool that involves collecting DNA sequences from microbial communities and analysing them using reference-based approaches or de novo assembly. This method enables the identification of new microbial species by grouping sequences based on shared genomic characteristics.
The Unified Human Gastrointestinal Genome catalogue
The development of the Unified Human Gastrointestinal Genome (UHGG) catalogue contains nearly 300,000 genomes, representing approximately 4,500 microbial species and 170 million genes. With enhanced resolution, researchers can now obtain more accurate microbiome analyses and gain deeper insights into microbial functions.
One of the key findings from this catalogue is that about 60% of gut microbial species remain uncultured, highlighting a vast, uncharted microbial world. These discoveries challenge previous assumptions about gut microbiome composition and emphasise the need to investigate the functions of these unknown species in human health.
Can the uncultured microbiome predict disease?
To better understand the clinical relevance of the uncultured microbiome, Dr. Almeida’s team analysed 11,000 publicly available gut microbiome samples from 39 countries, covering 13 diseases, including obesity, Crohn’s disease, and colorectal cancer. They aimed to determine whether uncultured microbes were broadly associated with these diseases. By aligning microbiome samples to the UHGG catalogue, they estimated the prevalence and abundance of uncultured species.
Key findings include:
- 32% of species in each sample were uncultured, though they accounted for only 16% of relative microbial abundance.
- Machine learning models were developed to quantify species accurately, accounting for study variations. These models successfully classified disease states, with varying accuracy depending on the disease.
- The gut microbiome showed strong disease-specific patterns; only 26% of disease biomarkers were shared across multiple conditions, whereas healthy microbiomes had more overlap.
- Higher proportions of uncultured bacteria were found in healthy microbiomes, possibly due to their sensitivity to oxygen and inflammation, which are elevated in disease states.
Functional insights and priority targets
The study also investigated the functional differences between health- and disease-associated microbes. In diseased microbiomes, stress response pathways (e.g., oxidative and osmotic stress) were enriched, whereas healthy microbiomes exhibited enriched colonisation and immune regulation functions.
To identify priority targets within uncultured bacteria, researchers analysed genera with high proportions of uncultured species and strong associations with health or disease. One such genus, CAG170, emerged as a key health-associated group. Despite being poorly understood, its members were highly correlated with health and appeared to play a stabilising role in the gut microbiome.
CAG170: a keystone health biomarker
CAG170 has only been successfully cultured once, requiring arginine in the growth medium. Functional analysis revealed that species in this genus show depleted biosynthesis of arginine but enriched folate biosynthesis, suggesting a potential link to overall health. Folate is crucial for various physiological functions, potentially explaining the association between CAG170 and healthy microbiomes.
Moreover, longitudinal data from the Human Microbiome Project 2 indicated that higher abundance of CAG170 correlated inversely with dysbiosis, reinforcing its role as a keystone species in maintaining a stable and healthy gut microbiome.
Conclusions
Dr. Almeida’s research underscores the importance of uncultured gut microbes in shaping health outcomes. Key takeaways include:
- Over 300 uncultured species are associated with at least one disease.
- Microbiome patterns are largely disease-specific, while healthy microbiomes share more common microbial signatures.
- Uncultured bacteria are overrepresented in healthy microbiomes, suggesting they may contribute to maintaining gut stability.
- Functional traits related to gut colonisation and immune regulation are enriched in healthy microbiomes.
- CAG170 is a novel keystone biomarker of health, with only one species of the genus successfully cultured so far.
Future research will aim to cultivate and functionally characterise more uncultured species, further illuminating their roles in human health and disease. By expanding our understanding of the microbiome’s hidden diversity, we move closer to unlocking new therapeutic and diagnostic opportunities for microbiome-related diseases.