Microbial metabolites in chemotherapy-induced cognitive impairment: from mechanistic associations to pharmacological target validation

Chemotherapy-induced cognitive impairment (CICI) encompasses heterogeneous changes in memory, attention, executive function and processing speed. Microbial metabolites offer experimentally tractable candidates because their exposure, dose–response relationships and host-target engagement can be measured. This review evaluates short-chain fatty acids (SCFAs), microbial indoles and host kynurenine metabolism, and microbially modified bile acids, while considering microbial inflammatory products as distinct modifiers of the intestinal–brain environment. Evidence is assessed against five criteria: CICI specificity, temporal sequence, selective causal manipulation, host-target engagement and oncological compatibility. Clinical microbiome associations and probiotic intervention findings support further investigation, but do not establish mediation by an individual metabolite. Selected chemotherapy models provide cognitive and molecular intervention evidence, although its strength varies by agent, metabolic pathway and behavioral endpoint. Changes in metabolite concentrations may reflect altered diet, epithelial absorption, host metabolism or clearance as well as microbial production. Translation therefore requires regimen-specific longitudinal sampling, compartment- appropriate exposure measurements, selective pathway perturbation and domain-specific cognitive assessment with controls for sickness and motor impairment. Cognitive protection must also be evaluated alongside chemotherapy exposure, tumor control and infectious safety. This framework distinguishes biomarkers of treatment-associated injury from causal mediators and identifies the evidence needed to develop metabolite-guided pharmacological interventions.