Interplay between gut microbial composition and the melatonergic pathway: implications for hormonal receptor-positive breast cancer development

Abstract Background This study aimed to investigate the intricate relationship between the gut microbiota and serum melatonin levels in hormonal receptor-positive breast cancer (BC) patients, focusing on alterations in microbial composition, the melatonergic pathway, and their implications for BC development. Methods Serum and fecal samples were obtained from hormonal receptor-positive BC patients and healthy controls. Mass spectrometry was used to measure the serum levels of serotonin, N-acetylserotonin (NAS), and melatonin and the fecal levels of short-chain fatty acids (SCFAs). Beta-glucuronidase (βGD) activity was quantified using a fluorometric assay kit, while arylalkylamine N-acetyltransferase (AANAT), acetylserotonin-O-methyltransferase (ASMT), and zonulin were assessed via ELISA. The gut microbiota composition was evaluated using 16S rRNA sequencing. Results We identified significant alterations in the gut microbiota composition and melatonin production of BC patients compared to healthy controls. This dysbiosis is characterized by heightened serum serotonin, N-acetylserotonin (NAS), and fecal β-glucuronidase (βGD) activity, concomitant with diminished serum melatonin levels in BC patients. Moreover, increased fecal levels of isovaleric acid (IVA) and isobutyric acid (IBA), coupled with increased serum zonulin levels, highlight intestinal permeability alterations that could facilitate the translocation of gut bacteria and inflammatory compounds, predisposing individuals to cancer development. Notably, we observed reduced gut microbiota diversity and significant shifts in predominant bacterial taxa, with Bacteroides eggerthii enrichment and a reduction in beneficial Bifidobacterium longum positively associated with serum melatonin levels, suggesting potential roles in BC development. Dysregulation of the serotonin-NAS-melatonin axis, along with perturbed expression of enzymes involved in the melatonergic pathway, underscores their implications in BC. Finally, we propose the NAS/melatonin ratio as a potential diagnostic biomarker for discriminating hormonal receptor-positive BC patients from healthy individuals, offering promising avenues for clinical management strategies. Conclusions Overall, our findings shed valuable light on the contributions of the gut microbiota and the melatonergic pathway to the development of hormonal receptor-positive BC, warranting further research into potential therapeutic targets.