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

Abstract

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.

Enteric Microbiota-Mediated Serotonergic Signaling in Pathogenesis of Irritable Bowel Syndrome

“…Other reports showed that colonization with gut microbiota increases gut motility in ex-GF animals in conjunction with an elevated luminal 5-HT level, while administration of pharmacologic antagonists of 5-HT 4 receptors resulted in recovery GI transit in GF rodents [ 105 , 124 , 138 ]. In addition, gut bacteria-derived 5-hydroxyindole, a major 5-HT metabolite, translocates through intestinal smooth muscle cells and directly accelerates colonic motility via the activation of L-type calcium channels [ 139 ]. Moreover, BTBR mice, a mouse model of ASD, showed an impaired serotonergic pathway with the downregulation of Tph1 and upregulation of Sert in the gut, which was associated with a reduction in 5-HT-producing Blautia bacteria [ 140 ].…”

Oral Administration of the Gut-bacterial Metabolite 5-hydroxyindole and Its Subsequent Acceleration of Gut Motility Have Marginal Effects on the Rat Microbiota

“…5-hydroxyindole has a marginal effect on the richness and composition of the cecal microbiota in wild-type Groningen rats Recently, we showed that a daily oral administration of the gut microbiota-produced 5-hydroxyindole (30 mg/kg) to wild-type Groningen (WTG) rats for 11 days results in a signi cant decrease of the total gut transit time (TGTT) [7].…”

“…Because the gut transit time was signi cantly affected in the 5-hydroxyindole-treated group [7], the TGTT was tested for its association with the abundance of genera using Spearman correlations. The correlation analysis revealed nine genera to be associated with the TGTT covariate (Spearman, P value < 0.05); Figure 1D; Table 2; Table D in Supplementary Table 1).…”

“…All animal procedures were approved by the Groningen University Committee of Animal experiments (approval number: AVD1050020197786) and were performed in adherence to the NIH Guide for the Care and Use of Laboratory Animals. Wild-type Groningen (WTG) male rats were orally administered either 30 mg/kg 5hydroxyindole (H31859, Sigma) (n = 10) or vehicle (10% sucrose) (n = 6) for a period of 11 days and after measurement of total gut transit time (TGTT) (more detailed protocol can be found in [7]), the rats were anesthetized with iso urane, killed and the whole cecum from every rat was collected and snap-frozen in a liquid nitrogen and stored in -80°C until further procedure. DNA isolation DNA isolation followed a previously proposed protocol by Yu and Morrison (2004).…”

“…Such microbial conversion represents a signi cant regulatory mechanism by which gut microbes can alter intestinal host physiology, including gastrointestinal motility [3][4][5][6]. Recently, we have identi ed 5-hydroxyindole, a product of gut microbial conversion of the dietary supplement and antidepressant 5-hydroxytryptophan, as a potent accelerator of the gastrointestinal motility via its activation of L-type calcium channels located on the colonic smooth muscle cells and possibly also through its induction of serotonin production from enterochroma n cells [7]. These ndings propose 5-hydroxyindole as a potentially safe treatment for gastrointestinal slow motility disorders.…”