Microbiota as a therapeutic target for metabolic inflammation: Promise or illusion?

Abstract

Metabolic inflammation is a chronic, low-grade immune state associated with nutrient excess and contributes substantially to obesity, insulin resistance, and type 2 diabetes. The gut microbiota has emerged as a pivotal regulator of these metabolic pathways through its influence on energy harvest, intestinal barrier integrity, and immune signaling. However, despite strong mechanistic evidence, clinical outcomes of microbiota-targeted therapies remain inconsistent. This PRISMA-informed structured review evaluates the translational validity of microbiota modulation as a therapeutic approach to metabolic inflammation, emphasizing the need for precision-driven strategies. To improve methodological transparency, a PRISMA-informed structured review with explicit search strategy and eligibility criteria was adopted. A synthesis of human trials on next-generation probiotics, postbiotics, prebiotics, and fecal microbiota transplantation (FMT) reveals that significant benefits occur only under specific conditions such as biomarker-gated participant selection, metabolite target attainment, and sustained microbial engraftment. When these criteria are met, interventions improve insulin sensitivity, glycated hemoglobin, and inflammatory markers. Without these precision criteria, outcomes remain modest and transient. Here we highlight a clinical-precision framework linking mechanistic biomarkers such as short-chain fatty acids, bile-acid ratios, and lipopolysaccharide-binding protein to measurable therapeutic endpoints. Emerging directions, including engineered probiotics, postbiotic metabolites, and AI-guided personalized nutrition, hold promise for achieving durable metabolic benefits. Overall, this work underscores that the microbiota’s therapeutic potential lies not in broad modulation but in mechanistically precise, biomarker-based interventions capable of delivering durable metabolic benefits. • Precision biomarkers improve outcomes of microbiota-based therapies. • Clinical benefit requires biomarker gating, metabolite targets, engraftment. • SCFA and bile-acid modulation enhance insulin sensitivity and inflammation. • Next-gen probiotics and diet co-therapy drive precision microbiome care. • A translation checklist guides reproducible microbiota clinical trials.