Metabolites produced by the gut microbiota may affect host physiology both directly and indirectly. Tryptophan is an essential amino acid and a precursor to several such metabolites. Tryptamine is important example of a bacterially-produced, tryptophan-derived metabolite with previously unknown functions in the gastrointestinal tract.
A new study, published in Cell Host & Microbe and led by Dr. Purna C. Kashyap and his team at the Mayo Clinic Center for Individualized Medicine, sheds some light on the function of bacterially-produced tryptamine in the gut by showing that it increases colonic fluid secretion in mice through activation of serotonin receptor-4, thus accelerating gastrointestinal transit.
Previous research has suggested that tryptamine production in the gut is likely a product of tryptophan metabolism by bacteria, with two specific species – Ruminococcus gnavus and Clostridium sporogenes – possessing the ability to express tryptophan decarboxylase, the enzyme which catalyzes tryptamine production. In order to determine the physiological effect of this bacterially-produced tryptamine, Dr. Kashyap and his team designed a series of experiments using a system that measures the transport of ions across various epithelial tissues.
The team found that tryptamine increases fluid secretion in the proximal colon of both humanized (HM) and conventionally raised (CR) mice, irrespective of sex. Researchers were clued into the mechanism by which this modulation occurs by the structural similarity of tryptamine to serotonin (5-HT), and the fact that tryptamine is a ligand for several serotonin receptors (5-HTRs). The involvement of serotonin receptors in tryptamine function was confirmed by showing that tryptamine-induced increases in ion secretion are absent in mice lacking the serotonin receptor-4 (5-HT4R).
The serotonin receptor-4 (5-HT4R), one of the serotonin receptors found in the colonic epithelium, is a G-protein-coupled receptor (GPCR); hence it’s activation increases the amount of the intracellular signaling messenger cyclic adenosine monophosphate (cAMP). To support their assertion that tryptamine increases both ion and fluid secretion, researchers measured cAMP levels in germ-free and humanized mouse colonoids following incubation with tryptamine with or without pre-treatment of a 5HT4R antagonist. Researchers found that there was a significant increase in the absolute concentration of cAMP in both GF and HM colonoids incubated with tryptamine alone. This tryptamine-dependent increase in cAMP was not observed in GF or HM colonoids pre-treated with the 5-HT4R antagonist. These findings show that tryptamine increases both ionic flux and fluid secretion across the colonic epithelium in mice; a secretory effect that is dependent on 5-HT4R activation.
In order to evaluate the potential of bacterially-derived tryptamine in vivo, the team inserted the gene encoding tryptophan decarboxylase (from R. gnavus) into Bacteroides thetaiotaomicron, a common commensal bacteria that effectively colonizes the gut. It was found that, in mice, engineered B. thetaiotaomicron produced gut-localized tryptamine in vivo, which was able to successfully accelerate whole-gut transit by increasing anion-dependent fluid secretion in the proximal colon. There was no significant increase in serum tryptophan or tryptamine concentrations following colonization with B. thetaiotaomicron.
“This is an exciting example of an aspect of host physiology (colonic secretion and gastrointestinal transit) that falls under the control of a bacterial metabolite”, scientists say. The team is now evaluating the potential of tryptamine as a biotherapeutic for diseases characterized by chronic constipation such as constipation-predominant Irritable Bowel Syndrome (IBS-C).
In the discussion, researchers highlight that some of the most effective therapeutics for IBS-C have been 5-HT4R agonists, though success of these agents has been limited by their tendency to produce adverse systemic effects. The ability of engineered B. thetaiotaomicron to increase luminal tryptamine without affecting systemic concentrations provides an exciting way to overcome these barriers. Of course, ongoing challenges associated with functional, long-term establishment of probiotic strains in complex human communities needs to be overcome before functional supplementation may become a reality.
Bhattarai Y, Williams BB, Battaglioli EJ, et al. Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. Cell Host Microbe. 2018; 23(6):775-85. doi: 10.1016/j.chom.2018.05.004.