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
Barbora Waclawiková,
Paulo Cesar Telles de Souza,
Markus Schwalbe,
Constantinos G. Neochoritis,
Warner Hoornenborg,
Sieger A. Nelemans,
Siewert J. Marrink,
Sahar El Aidy
Affiliations
Barbora Waclawiková
Host-Microbe Metabolic Interactions, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, The Netherlands
Paulo Cesar Telles de Souza
Molecular Microbiology and Structural Biochemistry (MMSB - UMR 5086), CNRS & University of Lyon, Lyon, France
Markus Schwalbe
Host-Microbe Metabolic Interactions, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, The Netherlands
Constantinos G. Neochoritis
Department of Chemistry, University of Crete, Heraklion, Greece
Warner Hoornenborg
Department of Behavioral Neurosciences, Cluster Neurobiology, Groningen Institute of for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands
Sieger A. Nelemans
Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, The Netherlands
Siewert J. Marrink
Molecular Dynamics, Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, Groningen, The Netherlands
Sahar El Aidy
Host-Microbe Metabolic Interactions, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, The Netherlands
ABSTRACTIntestinal 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.
