THE HUMAN microbiome, particularly the gut microbiota, has been linked to conditions ranging from obesity, diabetes, and cardiovascular disease to autism, inflammatory bowel disease, and neurodegenerative disorders. Yet much of the evidence in humans remains correlative, and reliable clinical translation has been elusive. In a recent perspective, experts highlight why translating microbiome findings into consistent clinical benefit has proven challenging.
Why Microbiome Interventions Often Underperform in Humans
Despite strong mechanistic evidence from animal models, interventions such as faecal microbiota transplantation (FMT), prebiotics, probiotics, and postbiotics frequently produce modest or inconsistent effects in clinical trials. A key reason is inter-individual variability: genetics, diet, medications, comorbidities, and baseline microbiota composition shape responses, making outcomes unpredictable.
Ecological complexity further limits impact. Gut microbial communities are resilient and functionally redundant, so introduced microbes or isolated metabolites may fail to engraft, be outcompeted, or have minimal effect. Moreover, some microbial compounds act differently depending on host physiology or disease state, emphasising the context-dependent nature of microbiome interventions.
Trial Design and Regulatory Hurdles
Clinical trials are often heterogeneous in duration, endpoints, formulation, and inclusion criteria. Many studies are short-term despite targeting chronic conditions, and validated biomarkers for microbial function or treatment response remain scarce. Regulatory ambiguity, where microbiota-based products fall between food, drug, or biologic classifications, adds further practical barriers, affecting standardisation, quality control, and trial comparability.
Moving Toward Precision and Systems-Based Approaches
The perspective suggests several paths forward. FMT could benefit from functional donor–recipient matching, while prebiotic interventions may need tailoring to individual baseline microbiomes. Probiotics may require a pharmacological approach with defined strains and mechanisms, and postbiotics should be standardised as bioactive compounds with measurable host effects. Integrating multi-omics profiling and AI may help design personalised, function-focused interventions rather than one-size-fits-all approaches.
Looking Ahead
While clinical translation of the human microbiome has been slower than early expectations suggested, precision and systems-based strategies offer a pathway forward. By accounting for individual variability, ecological complexity, and functional interactions, future microbiome research may deliver actionable insights and more consistent health benefits.
Reference
Van Hul M, Cani PD. From microbiome to metabolism: bridging a two-decade translational gap. Cell Metab. 2026;38(1):14-32.
