Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease

Abstract Serotonin (5-hydroxytryptamine [5-HT]) is an intestinal neuromodulator that regulates several essential enteric physiological functions such as absorption or secretion of fluids, and peristaltic reflexes. Availability of the intestinal 5-HT is dependent on serotonin transporter (SERT), whic...

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Autores principales:	Ahmad Qasem, Abed Elrahman Naser, Saleh A. Naser
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2b581d68cdc2408e8698a517bf9bfa00
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spelling	oai:doaj.org-article:2b581d68cdc2408e8698a517bf9bfa002021-11-21T12:22:57ZEnteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease10.1038/s41598-021-02050-32045-2322https://doaj.org/article/2b581d68cdc2408e8698a517bf9bfa002021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02050-3https://doaj.org/toc/2045-2322Abstract Serotonin (5-hydroxytryptamine [5-HT]) is an intestinal neuromodulator that regulates several essential enteric physiological functions such as absorption or secretion of fluids, and peristaltic reflexes. Availability of the intestinal 5-HT is dependent on serotonin transporter (SERT), which uptakes 5-HT and facilitates its degradation. Interestingly, Toll-like receptor 2 (TLR-2) is co-localized with 5-HT, which suggests a possible impact of neuroendocrine cells in the inflammatory response through TLR-2 activation. Serum 5-HT levels were measured in 80 Crohn’s disease (CD) patients and 40 healthy control subjects. Additionally, fully differentiated Caco-2 monolayers were infected with Mycobacteria paratuberculosis (MAP), L. monocytogenes, or M. smegmatis in the presence of exogenous 5-HT at different concentrations. Cells were subsequently harvested and used for measuring SERT activity, RNA isolation followed by RT-PCR, protein quantification, and tissue damage markers (DHE, LDH, GSH and MDA). TLR-2 intracellular signaling pathways were assessed by pre-incubating Caco-2 monolayers with selective blockers of ERK, cAMP/PKA, p38 MAPK, and 5-HT3 receptors. MAP-infected CD patients (N = 40) had higher serum 5-HT levels (462.95 ± 8.55 ng/mL, N = 40) than those without MAP infection (385.33 ± 10.3 ng/mL, N = 40). TLR-2 activation by enteropathogenic bacteria inhibited SERT activity in the presence of exogenous 5-HT by up to 50%. These effects were increasing gradually over 72 h, and MAP infection had the greatest effect on SERT inhibition when cells were exposed to 5-HT in a concentration dependent manner. Additionally, inhibition of SERT activity was accompanied with higher levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-8) and oxidative stress markers (DHE, LDH and MDA), whereas SERT expression and protein level were downregulated. Consequently, inhibition of TLR-2 and p38 MAPK signaling or blocking 5-HT3 receptors restored SERT activity and reduced the production of pro-inflammatory cytokines, as reflected by the downregulation of oxidative stress and tissue damage markers. The involvement of TLR-2 in the intestinal pathology might be concluded not only from its innate immune role, but also from its effect on modulating the intestinal serotonergic response. Ultimately, regulating the intestinal serotonergic system can be therapeutically exploited to mitigate other enteropathogenic infections, which will help in understanding the gut-microbiome-brain connection.Ahmad QasemAbed Elrahman NaserSaleh A. NaserNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ahmad Qasem Abed Elrahman Naser Saleh A. Naser Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease
description	Abstract Serotonin (5-hydroxytryptamine [5-HT]) is an intestinal neuromodulator that regulates several essential enteric physiological functions such as absorption or secretion of fluids, and peristaltic reflexes. Availability of the intestinal 5-HT is dependent on serotonin transporter (SERT), which uptakes 5-HT and facilitates its degradation. Interestingly, Toll-like receptor 2 (TLR-2) is co-localized with 5-HT, which suggests a possible impact of neuroendocrine cells in the inflammatory response through TLR-2 activation. Serum 5-HT levels were measured in 80 Crohn’s disease (CD) patients and 40 healthy control subjects. Additionally, fully differentiated Caco-2 monolayers were infected with Mycobacteria paratuberculosis (MAP), L. monocytogenes, or M. smegmatis in the presence of exogenous 5-HT at different concentrations. Cells were subsequently harvested and used for measuring SERT activity, RNA isolation followed by RT-PCR, protein quantification, and tissue damage markers (DHE, LDH, GSH and MDA). TLR-2 intracellular signaling pathways were assessed by pre-incubating Caco-2 monolayers with selective blockers of ERK, cAMP/PKA, p38 MAPK, and 5-HT3 receptors. MAP-infected CD patients (N = 40) had higher serum 5-HT levels (462.95 ± 8.55 ng/mL, N = 40) than those without MAP infection (385.33 ± 10.3 ng/mL, N = 40). TLR-2 activation by enteropathogenic bacteria inhibited SERT activity in the presence of exogenous 5-HT by up to 50%. These effects were increasing gradually over 72 h, and MAP infection had the greatest effect on SERT inhibition when cells were exposed to 5-HT in a concentration dependent manner. Additionally, inhibition of SERT activity was accompanied with higher levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-8) and oxidative stress markers (DHE, LDH and MDA), whereas SERT expression and protein level were downregulated. Consequently, inhibition of TLR-2 and p38 MAPK signaling or blocking 5-HT3 receptors restored SERT activity and reduced the production of pro-inflammatory cytokines, as reflected by the downregulation of oxidative stress and tissue damage markers. The involvement of TLR-2 in the intestinal pathology might be concluded not only from its innate immune role, but also from its effect on modulating the intestinal serotonergic response. Ultimately, regulating the intestinal serotonergic system can be therapeutically exploited to mitigate other enteropathogenic infections, which will help in understanding the gut-microbiome-brain connection.
format	article
author	Ahmad Qasem Abed Elrahman Naser Saleh A. Naser
author_facet	Ahmad Qasem Abed Elrahman Naser Saleh A. Naser
author_sort	Ahmad Qasem
title	Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease
title_short	Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease
title_full	Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease
title_fullStr	Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease
title_full_unstemmed	Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease
title_sort	enteropathogenic infections modulate intestinal serotonin transporter (sert) function by activating toll-like receptor 2 (tlr-2) in crohn’s disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2b581d68cdc2408e8698a517bf9bfa00
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Enteropathogenic infections modulate intestinal serotonin transporter (SERT) function by activating Toll-like receptor 2 (TLR-2) in Crohn’s disease

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