# Exploring the Interplay Between Gut Microbiota and the Melatonergic Pathway in Hormone Receptor-Positive Breast Cancer

## TL;DR

This study explores how gut bacteria and melatonin production are linked in hormone receptor-positive breast cancer patients, suggesting gut dysbiosis and disrupted melatonin synthesis may contribute to disease progression.

## Contribution

The study identifies novel associations between gut microbiota composition, melatonin pathway disruption, and intestinal permeability in hormone receptor-positive breast cancer.

## Key findings

- HR+ BC patients showed gut dysbiosis with reduced Bifidobacterium longum and increased Bacteroides eggerthii.
- Elevated NAS/melatonin ratio and disrupted melatonin synthesis enzymes were observed in BC patients.
- Increased fecal βGD activity and serum zonulin suggest higher intestinal permeability in BC patients.

## Abstract

Emerging evidence suggests a bidirectional relationship between gut microbiota, melatonin synthesis, and breast cancer (BC) development in hormone receptor-positive patients (HR+HER2+ and HR+HER2-). This study investigated alterations in gut microbiota composition, the serum serotonin–N-acetylserotonin (NAS)–melatonin axis, fecal short-chain fatty acids (SCFAs) and beta-glucuronidase (βGD) activity, and serum zonulin in HR+ BC patients compared to healthy controls. Blood and fecal samples were analyzed using mass spectrometry for serotonin, NAS, melatonin, and SCFAs; ELISA for AANAT, ASMT, 14-3-3 protein, and zonulin; fluorometric assay for βGD activity; and 16S rRNA sequencing for gut microbiota composition. HR+ BC patients exhibited gut dysbiosis with reduced Bifidobacterium longum and increased Bacteroides eggerthii, alongside elevated fecal βGD activity, SCFA levels (e.g., isovaleric acid), and serum zonulin, indicating increased intestinal permeability. Serum serotonin and N-acetylserotonin (NAS) levels were elevated, while melatonin levels were reduced, with a higher NAS/melatonin ratio in BC patients. AANAT levels were increased, and ASMT levels were decreased, suggesting disrupted melatonin synthesis. Bifidobacterium longum positively correlated with melatonin and negatively with βGD activity, while Bacteroides eggerthii showed a positive correlation with βGD activity. These findings suggested that gut microbiota alterations, disrupted melatonin synthesis, microbial metabolism, and intestinal permeability may contribute to BC pathophysiology. The NAS/melatonin ratio could represent a potential biomarker, necessitating further mechanistic studies to confirm causality and explore therapeutic interventions.