Abstract: Melatonin, an indolic neuromodulator with putative oncostatic and proposed anti-inflammatory properties, primarily demonstrated in preclinical models, is produced at extrapineal sites-most notably in the gut. Its canonical actions are mediated by high-affinity GPCRs (MT1/MT2) and by NQO2, a cytosolic enzyme with a melatonin-binding site (historically termed "MT3"). A growing body of work highlights a bidirectional interaction between the gut microbiota and host melatonin. We integrated two lines of work: (i) three clinical cohorts-cardiac arrhythmias (n = 111; 46-75 y), epilepsy (n = 77; 20-59 y), and stage III-IV solid cancers (25-79 y)-profiled with stool 16S rRNA sequencing, SCFA measurements, and circulating melatonin/urinary 6-sulfatoxymelatonin and (ii) an age-spanning cognitive cohort with melatonin phenotyping, microbiome analyses, and exploratory immune/metabolite readouts, including a novel observation of melatonin binding on bacterial membranes. Across all three disease cohorts, we observed moderate-to-severe dysbiosis, with reduced alpha-diversity and shifted beta-structure. The core dysbiosis implicated tryptophan-active taxa (Bacteroides/Clostridiales proteolysis and indolic conversions) and depletion of SCFA-forward commensals (e.g., Faecalibacterium, Blautia, Akkermansia, and several Lactobacillus/Bifidobacterium spp.). Synthesised literature indicates that typical human gut commensals rarely secrete measurable melatonin in vitro; rather, their metabolites (SCFAs, lactate, and tryptophan derivatives) regulate host enterochromaffin serotonin/melatonin production. In arrhythmia models, dysbiosis, bile-acid remodelling, and autonomic/inflammatory tone align with melatonin-sensitive antiarrhythmic effects. Epilepsy exhibits circadian seizure patterns and tryptophan-metabolite signatures, with modest and heterogeneous responses to add-on melatonin. Cancer cohorts show broader dysbiosis consistent with melatonin's oncostatic actions. In the cognitive cohort, the absence of dysbiosis tracked with preserved learning across ages, and exploratory immunohistochemistry suggested melatonin-binding sites on bacterial membranes in ~15-17% of samples. A unifying microbiota-tryptophan-melatonin axis plausibly integrates circadian, electrophysiologic, and immune-oncologic phenotypes. Practical levers include fiber-rich diets (to drive SCFAs), light hygiene, and time-aware therapy, with indication-specific use of melatonin. Our conclusions regarding microbiota-melatonin crosstalk rely primarily on local paracrine effects within the gut mucosa (where melatonin concentrations are 10-400× plasma levels), whereas systemic chronotherapy conclusions depend on circulating melatonin amplitude and phase. This original research article presents primary data from four prospectively enrolled clinical cohorts (total n = 577).
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