Repurposing anti-inflammatory therapeutics for disorders of the microbiome-gut-brain axis

The microbiome-gut-brain axis (MGBA) redefines the field of anti-inflammatory therapeutics by shifting from targeting isolated immune pathways in an organ to a bidirectional, integral network, composed of gut microbiota, the peripheral immune system, barrier tissues, and neural circuits. Such reframing is predominantly pertinent for certain CNS and systemic diseases, including Alzheimer's disease and ischemic stroke. These diseases have been resistant to conventional anti-inflammatory agents that either poorly pass the blood-brain barrier or do not inhibit the upstream inflammatory drivers. Increasing evidence demonstrates that microbial communities and their metabolites modulate systemic and central immune tone, and affect barrier integrity, hence brain inflammation frequently presents with a measurable fingerprint in the gut and vice versa. Targeted microbiome therapies, metabolite replacement, and biomarker-guided patient stratification all emerge as promising new strategies when acknowledging the gut is a modifiable source. Mechanistically, the crosstalk between neuro-immune-microbial trails creates concrete therapeutic entry points. These include: (1) altering microbial enzymes that produce pro-inflammatory metabolites, (2) delivering beneficial metabolites to support homeostatic glial states, and (3) modulating afferent neural pathways like vagus nerve stimulation, which triggers the cholinergic anti-inflammatory pathway (CAP). The future of MGBA-targeted therapeutics will mostly repurpose current anti-inflammatory agents and neuromodulatory strategies into combinatorial ones that pair source control (gut-restricted drugs) with targeted central modulation (microglial modulators such as minocycline) and neural orchestration (vagus nerve stimulation, VNS). These repurposing strategies are increasingly guided by baseline inflammatory and microbiome biomarkers and may help in establishing new therapeutic paradigms for these intersecting disorders of the gut, immune system, and brain in appropriately defined patient subgroups.