Review article: the many potential roles of intestinal serotonin (5‐hydroxytryptamine, 5‐<scp>HT</scp>) signalling in inflammatory bowel disease

Coates, Matthew; Tekin, Izel; Vrana, Kent E.; Mawe, Gary M.

doi:10.1111/apt.14226

Cited by 84 publications

(72 citation statements)

References 111 publications

(223 reference statements)

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“…Additionally, the 5-HT 3 R antagonist decreased expression of proinflammatory cytokines in 5-FU administration of mice (22). Moreover, another review suggested that 5-HT 1A R, 5-HT 2A R, and 5-HT 4 R activation is likely protective against intestinal inflammation, whereas 5-HT 3 R is more likely to worsen the inflammation process (44). Therefore, 5-HT Figure 7.…”

Section: Discussionmentioning

confidence: 98%

Serotonin 3 receptor signaling regulates 5‐fluorouracil‐mediated apoptosis indirectly via TNF‐α production by enhancing serotonin release from enterochromaffin cells

et al. 2018

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Antagonists of the 5-hydroxytryptamine (serotonin) 3 receptor (5-HTR) have anti-inflammatory and anti-apoptotic activities, but the detailed, underlying mechanisms are not well understood. We focused on anti-apoptotic activities via 5-HTR signaling to clarify the underlying mechanisms. Mice were administered 5-fluorouracil (5-FU), which induced apoptosis in intestinal epithelial cells. Coadministration with 5-HTR antagonists or agonists tended to decrease or increase the number of apoptotic cells, respectively. In serotonin 3A receptor (5-HTR) null (HTR3A) mice, the number of apoptotic cells induced by 5-FU was decreased compared with that in wild-type (WT) mice. Bone marrow (BM) transplantation was performed to determine if BM-derived immune cells regulated 5-FU-induced apoptosis, but they were found to be unrelated to this process. Data from 5-HTR/enhanced green fluorescent protein reporter mice revealed that 50% of enterochromaffin (EC) cells expressed 5-HTR, but the number of apoptotic cells induced by 5-FU in the intestinal crypt organoids of HTR3A mice was not altered compared with WT mice. In contrast, plasma 5-HT concentrations in WT mice but not in HTR3A mice administered 5-FU were increased significantly. In conclusion, 5-HTR signaling may enhance 5-HT release, possibly from EC cells intravascularly, or paracrine, resulting in increases in plasma 5-HT concentration, which in turn, enhances apoptotic activities induced by 5-FU.-Mikawa, S., Kondo, M., Kaji, N., Mihara, T., Yoshitake, R., Nakagawa, T., Takamoto, M., Nishimura, R., Shimada, S., Ozaki, H., Hori, M. Serotonin 3 receptor signaling regulates 5-fluorouracil-mediated apoptosis indirectly via TNF-α production by enhancing serotonin release from enterochromaffin cells.

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Section: Discussionmentioning

confidence: 98%

Serotonin 3 receptor signaling regulates 5‐fluorouracil‐mediated apoptosis indirectly via TNF‐α production by enhancing serotonin release from enterochromaffin cells

et al. 2018

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“…The gastrointestinal mucosa harbors the largest store of 5-HT in the body (approximately 95%). 5-HT is a signaling molecule implicated in a wide number of human physiological functions, being a key neuromodulator to the whole intestinal physiology (Mawe & Hoffman, 2013), and also can influence on the development and severity of gut inflammation, particularly in the setting of IBD (Coates, Tekin, Vrana, & Mawe, 2017). On the other hand, the innate immune system also plays an essential role in intestinal homeostasis, developing several crucial regulatory mechanisms and interactions; however deregulation of The results obtained in the present study demonstrate that NOD1 activation decreases SERT activity and molecular expression, mediated by the ERK/MAPK intracellular signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

NOD1 downregulates intestinal serotonin transporter and interacts with other pattern recognition receptors

Layunta

Latorre

Forcén

et al. 2017

Journal Cellular Physiology

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Serotonin (5-HT) is an essential gastrointestinal modulator whose effects regulate the intestinal physiology. 5-HT effects depend on extracellular 5-HT bioavailability, which is controlled by the serotonin transporter (SERT) expressed in both the apical and basolateral membranes of enterocytes. SERT is a critical target for regulating 5-HT levels and consequently, modulating the intestinal physiology. The deregulation of innate immune receptors has been extensively studied in inflammatory bowel diseases (IBD), where an exacerbated defense response to commensal microbiota is observed. Interestingly, many innate immune receptors seem to affect the serotonergic system, demonstrating a new way in which microbiota could modulate the intestinal physiology. Therefore, our aim was to analyze the effects of NOD1 activation on SERT function, as well as NOD1's interaction with other immune receptors such as TLR2 and TLR4. Our results showed that NOD1 activation inhibits SERT activity and expression in Caco-2/TC7 cells through the extracellular signal-regulated kinase (ERK) signaling pathway. A negative feedback between 5-HT and NOD1 expression was also described. The results showed that TLR2 and TLR4 activation seems to regulate NOD1 expression in Caco-2/TC7 cells. To assess the extend of cross-talk between NOD1 and TLRs, NOD1 expression was measured in the intestinal tract (ileum and colon) of wild type mice and mice with individual knockouts of TLR2, and TLR4 as well as double knockout TLR2/TLR4 mice. Hence, we demonstrate that NOD1 acts on the serotonergic system decreasing SERT activity and molecular expression. Additionally, NOD1 expression seems to be modulated by 5-HT and other immune receptors as TLR2 and TLR4. This study could clarify the relation between both the intestinal serotonergic system and innate immune system, and their implications in intestinal inflammation.

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“…5-HT is recognized as a signaling molecule implicated in a wide number of physiological (gastrointestinal and non-gastrointestinal) functions [2], being also implicated in the development and maintenance of gut inflammatory pathologies, such as IBD [8]. These pathologies also involve altered intestinal innate immunity [29], which plays an important role in intestinal homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, recent works have shown that 5-HT [5], 5-HT receptors [6] and SERT [7] would play a chief role in the development of IBD. In fact, recent studies have suggested that modifications of the activity of selective serotonin receptors and reuptake transporter in the gut could be effective for controlling IBD activity and associated symptoms [8,9].…”

Section: Introductionmentioning

confidence: 99%

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Layunta

Latorre

Forcén

et al. 2018

Cell Physiol Biochem

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Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression.

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Review article: the many potential roles of intestinal serotonin (5‐hydroxytryptamine, 5‐HT) signalling in inflammatory bowel disease

Cited by 84 publications

References 111 publications

Serotonin 3 receptor signaling regulates 5‐fluorouracil‐mediated apoptosis indirectly via TNF‐α production by enhancing serotonin release from enterochromaffin cells

Serotonin 3 receptor signaling regulates 5‐fluorouracil‐mediated apoptosis indirectly via TNF‐α production by enhancing serotonin release from enterochromaffin cells

NOD1 downregulates intestinal serotonin transporter and interacts with other pattern recognition receptors

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

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