Potential binding modes of the gut bacterial metabolite, 5-hydroxyindole, to the intestinal L-type calcium channels and its impact on the microbiota in rats

ABSTRACT

Intestinal microbiota and microbiota-derived metabolites play a key role in regulating the host physiology. Recently, we have identified a gut-bacterial metabolite, namely 5-hydroxyindole, as a potent stimulant of intestinal motility via its modulation of L-type voltage-gated calcium channels located on the intestinal smooth muscle cells. Dysregulation of L-type voltage-gated calcium channels is associated with various gastrointestinal motility disorders, including constipation, making L-type voltage-gated calcium channels an important target for drug development. Nonetheless, the majority of currently available drugs are associated with alteration of the gut microbiota. Using 16S rRNA sequencing this study shows that, when administered orally, 5-hydroxyindole has only marginal effects on the rat cecal microbiota. Molecular dynamics simulations propose potential-binding pockets of 5-hydroxyindole in the α1 subunit of the L-type voltage-gated calcium channels and when its stimulatory effect on the rat colonic contractility was compared to 16 different analogues, ex-vivo, 5-hydroxyindole stood as the most potent enhancer of the intestinal contractility. Overall, the present findings imply a potential role of microbiota-derived metabolites as candidate therapeutics for targeted treatment of slow intestinal motility-related disorders including constipation.

KEYWORDS:

• Microbiota
• molecular dynamics
• motility
• L-type calcium channels
• indole derivatives

Data availability

All sequencing data is available at PRJNA800624.

Acknowledgments

We thank Amber Bullock, Host-Microbe Interactions group, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, The Netherlands and Prof. Dr. Gertjan van Dijk, Department of Behavioral Neurosciences, Cluster Neurobiology, Groningen Institute of for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands, for their help with the collection of the cecal samples.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

B.W. and S.E.A. conceptualized and designed the study. B.W. performed the organ bath experiments and analysis of the data. B.W. and M.S. performed the analysis of the 16S rRNA sequencing data. P.C.T.S. designed and performed the CG MD simulations and analysis of the data. W. H. and S.A.N. assisted with the organ bath experiments. S.E.A. assisted with analysis of the data. B.W., PC.T.S. and S.E.A. wrote the original manuscript that was reviewed by M.S., C.N., W.H., S.A.N and S.J.M. Funding was acquired by S.E.A.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2022.2154544

Additional information

Funding

This work was supported by the Rosalind Frankline Fellowship-University of Groningen