Date Published: July 6, 2017
Publisher: Public Library of Science
Author(s): Tomokazu Hata, Yasunari Asano, Kazufumi Yoshihara, Tae Kimura-Todani, Noriyuki Miyata, Xue-Ting Zhang, Shu Takakura, Yuji Aiba, Yasuhiro Koga, Nobuyuki Sudo, Yvette Tache.
Gut lumen serotonin (5-hydroxytryptamine: 5-HT) contributes to several gastrointestinal functions such as peristaltic reflexes. 5-HT is released from enterochromaffin (EC) cells in response to a number of stimuli, including signals from the gut microbiota. However, the specific mechanism by which the gut microbiota regulates 5-HT levels in the gut lumen has not yet been clarified. Our previous work with gnotobiotic mice showed that free catecholamines can be produced by the deconjugation of conjugated catecholamines; hence, we speculated that deconjugation by bacterial enzymes may be one of the mechanisms whereby gut microbes can produce free 5-HT in the gut lumen. In this study, we tested this hypothesis using germ-free (GF) mice and gnotobiotic mice recolonized with specific pathogen-free (SPF) fecal flora (EX-GF). The 5-HT levels in the lumens of the cecum and colon were significantly lower in the GF mice than in the EX-GF mice. Moreover, these levels were rapidly increased, within only 3 days after exposure to SPF microbiota. The majority of 5-HT was in an unconjugated, free form in the EX-GF mice, whereas approximately 50% of the 5-HT was found in the conjugated form in the GF mice. These results further support the current view that the gut microbiota plays a crucial role in promoting the production of biologically active, free 5-HT. The deconjugation of glucuronide-conjugated 5-HT by bacterial enzymes is likely one of the mechanisms contributing to free 5-HT production in the gut lumen.
Enterochromaffin (EC) cells are located within the gut epithelia and store the largest pool of serotonin (5-hydroxytryptamine: 5-HT) in the body [1–3]. Thus, a significant amount of 5-HT is released into the gut lumen in response to various stimuli [1, 4–7]. For example, EC cells release 5-HT into the lumen in response to mechanical stimuli on the side of the gut mucosa, which enhances peristaltic reflexes [5, 8, 9]. Similarly, nutrients (e.g., short-chain fatty acids [SCFAs] and glucose), as well as acids and bases have been reported to induce the release of 5-HT from EC cells [10–12].
Recent research via animal experiments and human studies suggests that the gut microbiota plays a crucial role in 5-HT synthesis and its regulation in the gut lumen. In support of this interaction, the present study showed that EX-GF mice, which were GF mice reconstituted with SPF microbiota, had higher levels of luminal 5-HT in the cecum and colon, as well as whole-colon 5-HT levels compared with the GF mice. These direct effects were confirmed with direct exposure experiments, in which 5-HT levels in the gut lumen of GF mice rapidly and markedly increased within 3 days after oral administration of SPF mouse feces. In contrast, the mRNA expression levels of Tph1, an important molecule involved in the 5-HT synthesis pathway, showed a transient decrease at 3 days after the exposure, and returned to the basal level 21 days later. The majority of 5-HT was in the free form in the EX-GF mice, whereas more than 50% of the 5-HT was in the glucuronide-conjugated form in the GF mice, indicating the critical role of gut microbes in the production of biologically active, free 5-HT.