Roseburia hominis Increases Intestinal Melatonin Level by Activating p-CREB-AANAT Pathway.

Lijin Song,Jindong Zhang,Shuangjiang Liu,Qinghua Sun,Yuan Fang,Meibo He,Yujing Wang,Liping Duan

doi:10.3390/nu14010117

Abstract

Intestinal melatonin exerts diverse biological effects on the body. Our previous research showed that the abundance of the butyrate-producing bacteria, Roseburia, is positively related to the expression of colonic mucosal melatonin. However, the detailed relationship is unclear. Therefore, we aimed to explore whether Roseburia regulates intestinal melatonin and its underlying mechanisms. Male Sprague–Dawley germfree rats were orally administered with or without Roseburia hominis. R. hominis treatment significantly increased the intestinal melatonin level. The concentrations of propionate and butyrate in the intestinal contents were significantly elevated after gavage of R. hominis. Propionate or butyrate treatment increased melatonin, 5-hydroxytryptamine (5-HT), arylalkylamine N-acetyltransferase (AANAT), and phosphorylated cAMP-response element-binding protein (p-CREB) levels. When pretreated with telotristat ethyl, the inhibitor of tryptophan hydroxylase (TPH), or siRNA of Aanat, or 666-15, i.e., an inhibitor of CREB, propionate, or butyrate, could not promote melatonin production in the pheochromocytoma cell line BON-1. Metabolomics analysis showed that propionate and butyrate stimulation regulated levels of some metabolites and some metabolic pathways in BON-1 cell supernatants. In conclusion, propionate and butyrate, i.e., metabolites of R. hominis, can promote intestinal melatonin synthesis by increasing 5-HT levels and promoting p-CREB-mediated Aanat transcription, thereby offering a potential target for ameliorating intestinal diseases.

Highlights

Melatonin is generally considered a pineal hormone that can maintain circadian rhythms and regulate immune function
The results showed that the germfree rats receiving propionate gavage (GP) and germfree rats receiving butyrate gavage (GB) had higher phosphorylated CREB (p-CREB) levels in the ileum and colon tissues than the GF group (p < 0.05), while the CREB level remained relatively unchanged (Figure 5A)
We found that propionate and butyrate-producing bacteria, R. hominis, induced melatonin synthesis both in the intestinal mucosa and BON-1 cells

Summary

Introduction

Melatonin is generally considered a pineal hormone that can maintain circadian rhythms and regulate immune function. Melatonin is distributed in the gastrointestinal (GI) tract [1], fulfilling vital antioxidant and anti-inflammatory functions locally and regulating gut motility. Augmentation of the melatonin concentration in blood by oral administration may cause some adverse effects, including sleepiness, nausea, dizziness, and headaches [3]. As melatonin is a systemic hormone, it is desirable to find a way to locally induce melatonin synthesis to avoid adverse effects or the risk of hormone disturbance, which occurs when it is used for extended periods for the treatment of digestive disorders. The abundance of Roseburia, a butyrate-producing genus, is positively related to colonic mucosal melatonin level [4].

Objectives

Methods

Results

Conclusion