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.
Highlights
IntroductionThe gut microbiota produces a wide range of small bioactive molecules derived from various substrates, including dietary precursors and medications [1,2]
The gastrointestinal (GI) tract is home to trillions of microbes
Chromatograms revealed the formation of an unknown peak (Fig 1A), which was further identified by Liquid Chromatography-Mass Spectrometry (LC-MS) to be 5-HI (S1A Fig)
Summary
The gut microbiota produces a wide range of small bioactive molecules derived from various substrates, including dietary precursors and medications [1,2]. Such microbial conversion represents a significant regulatory mechanism by which gut microbes can alter intestinal host physiology, including gut motility [3,4]. Tryptamine produced by bacterial decarboxylation of dietary tryptophan accelerates GI transit by activating epithelial G-protein coupled receptor, serotonin receptor 4, and increasing anion-dependent fluid secretion in the proximal colon of mice [5]. Gut microbiota-derived molecules appear to functionally link the microbiota activity to the host gut motility.
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