That gut instinct! Novel insights in the interplay between the microbiota, serotonin metabolism and gut function

The gut microbiota-derived metabolites are evident to have a substantial effect on the regulation of various host functions. Despite the vast number of studies dissecting the host-microbiota interactions over the last years, enormous efforts are still needed to fully unravel the underlying mechanisms of this crosstalk, thereby potentiating the application of microbiota-targeted therapies in clinical practice and in a personalized manner.This thesis investigates the interplay between the microbiota, serotonin metabolism, and gut function. We showed that a wide range of gut microbiota can convert, the serotonin precursor, 5-hydroxytryptophan into an indole derivative. This bacterial product showed a potent stimulatory effect on the intestinal motility via activation of calcium channels, and a marginal effect on the microbiota composition. Besides, we uncovered the bacterial metabolization of serotonin and how this process impacts both the bacteria and its host. The outcome of this thesis has brought new insight in the physiological role of bacteria-derived indoles and may help the design of novel microbiota-based therapeutics targeting gut motility

5-hydroxyindole and analogs thereof as stimulants of gut motility

The invention relates to 5-hydroxyindole (5-HI) and analogs thereof, and to their medical use, such as the treatment of conditions associated with reduced gut motility. Provided is a method for the treatment of a condition associated with reduced gut motility, comprising administering to a subject in need thereof a pharmaceutically effective amount of 5-HI or an analog thereof having the capability to increase gut motility

Gut microbiota-motility interregulation:Insights from in vivo, ex vivo and in silico studies

The human gastrointestinal tract is home to trillions of microbes. Gut microbial communities have a significant regulatory role in the intestinal physiology, such as gut motility. Microbial effect on gut motility is often evoked by bioactive molecules from various sources, including microbial break down of carbohydrates, fibers or proteins. In turn, gut motility regulates the colonization within the microbial ecosystem. However, the underlying mechanisms of such regulation remain obscure. Deciphering the inter-regulatory mechanisms of the microbiota and bowel function is crucial for the prevention and treatment of gut dysmotility, a comorbidity associated with many diseases. In this review, we present an overview of the current knowledge on the impact of gut microbiota and its products on bowel motility. We discuss the currently available techniques employed to assess the changes in the intestinal motility. Further, we highlight the open challenges, and incorporate biophysical elements of microbes-motility interplay, in an attempt to lay the foundation for describing long-term impacts of microbial metabolite-induced changes in gut motility

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

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

Gut bacteria-derived 5-hydroxyindole is a potent stimulant of intestinal motility via its action on L-type calcium channels.

Microbial conversion of dietary or drug substrates into small bioactive molecules represents a regulatory mechanism by which the gut microbiota alters intestinal physiology. Here, we show that a wide variety of gut bacteria can metabolize the dietary supplement and antidepressant 5-hydroxytryptophan (5-HTP) to 5-hydroxyindole (5-HI) via the tryptophanase (TnaA) enzyme. Oral administration of 5-HTP results in detection of 5-HI in fecal samples of healthy volunteers with interindividual variation. The production of 5-HI is inhibited upon pH reduction in in vitro studies. When administered orally in rats, 5-HI significantly accelerates the total gut transit time (TGTT). Deciphering the underlying mechanisms of action reveals that 5-HI accelerates gut contractility via activation of L-type calcium channels located on the colonic smooth muscle cells. Moreover, 5-HI stimulation of a cell line model of intestinal enterochromaffin cells results in significant increase in serotonin production. Together, our findings support a role for bacterial metabolism in altering gut motility and lay the foundation for microbiota-targeted interventions

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

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