Melatonin Biosynthesis, Receptors, and the Microbiota-Tryptophan-Melatonin Axis: A Shared Dysbiosis Signature Across Cardiac Arrhythmias, Epilepsy, Malignant Proliferation, and Cognitive Trajectories.

All three disease cohorts demonstrated moderate-to-severe dysbiosis with reduced alpha-diversity and shifted beta-diversity structure.

• The study enrolled cardiac arrhythmia (n=111; ages 46-75), epilepsy (n=77; ages 20-59), and stage III-IV solid cancer (ages 25-79) cohorts
• Total study population across four prospectively enrolled clinical cohorts was n=577
• Dysbiosis was characterized by reduced alpha-diversity and shifted beta-structure across all disease groups
• Profiling was performed using stool 16S rRNA sequencing, SCFA measurements, and circulating melatonin/urinary 6-sulfatoxymelatonin

The core dysbiosis signature across disease cohorts implicated tryptophan-active taxa and depletion of SCFA-producing commensals.

• Tryptophan-active taxa implicated included Bacteroides/Clostridiales proteolysis and indolic conversions
• Depleted SCFA-forward commensals included Faecalibacterium, Blautia, Akkermansia, and several Lactobacillus/Bifidobacterium species
• This pattern was consistent across cardiac arrhythmia, epilepsy, and cancer cohorts

In the cognitive cohort, absence of dysbiosis tracked with preserved learning across ages.

• The cognitive cohort included melatonin phenotyping, microbiome analyses, and exploratory immune/metabolite readouts
• Subjects without dysbiosis showed preserved learning performance across age groups
• The cognitive cohort was part of the age-spanning component of the study

Exploratory immunohistochemistry suggested melatonin-binding sites on bacterial membranes in approximately 15-17% of samples.

• This was described as a 'novel observation of melatonin binding on bacterial membranes'
• Melatonin-binding sites were observed on bacterial membranes in '~15-17% of samples'
• This finding was detected in the cognitive cohort as part of exploratory immune/metabolite readouts
• This observation is described as exploratory in nature

Gut mucosal melatonin concentrations are 10-400 times higher than plasma levels, indicating primarily local paracrine effects.

• The paper states 'microbiota-melatonin crosstalk rely primarily on local paracrine effects within the gut mucosa (where melatonin concentrations are 10-400× plasma levels)'
• Systemic chronotherapy conclusions depend on circulating melatonin amplitude and phase
• Melatonin is produced at extrapineal sites, most notably in the gut
• This distinction between local mucosal and systemic circulating melatonin is noted as a limitation for interpreting findings

Typical human gut commensals rarely secrete measurable melatonin in vitro; rather, their metabolites regulate host enterochromaffin serotonin/melatonin production.

• Synthesized literature indicates gut bacteria do not directly produce melatonin in measurable amounts
• Bacterial metabolites including SCFAs, lactate, and tryptophan derivatives regulate host enterochromaffin serotonin/melatonin production
• This indirect regulatory mechanism rather than direct bacterial melatonin secretion is described as the primary pathway of microbiota-melatonin interaction

Melatonin's canonical actions are mediated by high-affinity GPCRs (MT1/MT2) and by NQO2, a cytosolic enzyme with a melatonin-binding site historically termed 'MT3'.

• MT1 and MT2 are described as high-affinity GPCRs mediating canonical melatonin actions
• NQO2 is described as 'a cytosolic enzyme with a melatonin-binding site (historically termed MT3)'
• Melatonin is characterized as 'an indolic neuromodulator with putative oncostatic and proposed anti-inflammatory properties, primarily demonstrated in preclinical models'

Epilepsy exhibits circadian seizure patterns and tryptophan-metabolite signatures, with modest and heterogeneous responses to add-on melatonin treatment.

• The epilepsy cohort comprised n=77 subjects aged 20-59 years
• Circadian seizure patterns were identified in the epilepsy cohort
• Tryptophan-metabolite signatures were detected in epilepsy subjects
• Melatonin as add-on therapy showed 'modest and heterogeneous responses'

In arrhythmia models, dysbiosis, bile-acid remodelling, and autonomic/inflammatory tone align with melatonin-sensitive antiarrhythmic effects.

• The arrhythmia cohort comprised n=111 subjects aged 46-75 years
• Bile-acid remodelling was identified as part of the dysbiosis signature in arrhythmia patients
• Autonomic and inflammatory tone changes were observed alongside dysbiosis in arrhythmia patients
• These features were described as aligning with 'melatonin-sensitive antiarrhythmic effects'

Cancer cohorts showed broader dysbiosis consistent with melatonin's oncostatic actions.

• Cancer cohort included stage III-IV solid cancers in patients aged 25-79 years
• Cancer cohort showed broader dysbiosis compared to other disease groups
• Findings were described as consistent with melatonin's oncostatic actions
• Melatonin's oncostatic properties are characterized as 'putative' and 'primarily demonstrated in preclinical models'

Practical interventions identified for modulating the microbiota-tryptophan-melatonin axis include fiber-rich diets, light hygiene, and time-aware therapy.

• Fiber-rich diets are recommended to drive SCFA production
• Light hygiene is identified as a lever to modulate melatonin signaling
• Time-aware therapy is recommended with indication-specific use of melatonin
• These recommendations are based on the bidirectional interaction between gut microbiota and host melatonin