Translation Through the Model Organism Gap
Mouse models dominate preclinical microbiome research, with approximately 95% of published studies in rodents. Yet mice differ profoundly from humans in ways directly impacting microbiota science. Germ-free mice—bred entirely sterile—serve as the experimental blank slate for microbiota research. These animals develop severe immunological abnormalities: reduced mucus, diminished epithelial tight junctions, underdeveloped gut-associated lymphoid tissue, elevated T regulatory cells, and compromised innate immunity.
Germ-free mice differ fundamentally from conventional mice. Findings from germ-free mice, whilst mechanistically informative, poorly predict outcomes in organisms with intact microbiota. Humanised microbiome mice attempt improved translational relevance by establishing human-like microbiota. Yet even humanised mice show profound limitations: human communities often fail to stabilise, bacterial strain abundance ratios differ markedly, and the mouse intestinal environment selects for different bacterial phenotypes.
Key physiological differences directly impact outcomes: mice practice coprophagy (eating faeces), recycling microbiota through 2-3 additional passages; humans do not. Mice possess a massive cecum specialised for fermentation; humans have a relatively reduced cecum. Murine immunity differs substantially. Mouse lifespan (2-3 years) limits long-term investigation. Baseline microbiota compositions differ dramatically. DSS colitis, the most common mouse IBD model, involves toxic chemical-induced damage, poorly recapitulating IBD pathogenesis.
The translational failure rate is sobering: approximately 90% of compounds showing efficacy in rodent models fail clinical trials. For microbiota-targeted interventions specifically, failure rates exceed 70%.