The human microbiome at translational crossroads: an ecological and causal perspective.

Abstract

Abstract: The human microbiome has emerged as a central focus of biomedical research, driven by interest in its translational potential for chronic diseases. Although compelling associations link microbial alterations to gastrointestinal, metabolic, neuropsychiatric and systemic conditions, successful clinical translation remains limited. This perspective contends that the principal barrier is not biological relevance but the application of reductionist thinking to an inherently complex ecological system, compounded by an incomplete understanding of causality. This review examines the gradient of causal confidence across gut-organ axes, from established roles in digestive disorders to less established distal associations, as well as highlights the epistemological challenges underlying microbiome research. A critical appraisal of current strategies, including probiotics, live biotherapeutics and faecal microbiota transplantation, suggests that progress requires ecological reasoning, causal rigour and systems-level integration. Moving from association to intervention demands approaches that account for host-microbiome complexity rather than oversimplified microbial targeting.