Similar Datasets
Project description:The serotonin neurotransmitter modulates virulence of enteric pathogens
| PRJNA604962 | ENA
Project description:The gut-brain axis is crucial to microbial-host interactions. The neurotransmitter serotonin is primarily synthesized in the gastrointestinal (GI) tract, where it is secreted into the lumen and subsequently removed by the serotonin transporter, SERT. Here, we show that serotonin decreases virulence gene expression by enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium, a murine model for EHEC. The membrane-bound histidine sensor kinase, CpxA, is a bacterial serotonin receptor. Serotonin induces dephosphorylation of CpxA, which inactivates the transcriptional factor CpxR controlling expression of virulence genes, notably those within the locus of enterocyte effacement (LEE). Increasing intestinal serotonin by genetically or pharmacologically inhibiting SERT decreases LEE expression and reduces C. rodentium loads. Conversely, inhibiting serotonin synthesis increases pathogenesis and decreases host survival. As other enteric bacteria contain CpxA, this signal exploitation may be engaged by other pathogens. Additionally, repurposing serotonin agonists to inhibit CpxA may represent a potential therapeutic intervention for enteric bacteria.
| S-EPMC7351610 | biostudies-literature
Project description:Serotonergic neurons have multiple roles, including regulating mood and behavior1,2, yet it remains unclear which of these phenotypes are caused by serotonin produced by the central versus the peripheral nervous system. Neuronal serotonin is produced by the enzyme tryptophan hydroxylase 2 (Tph2)3. Mice that lack Tph2 exhibit decreased gut motility4 and several behavioral disorders, including decreased anxiety-like behavior and increased aggression5. To clarify the specific role of peripheral serotonergic circuits, here we engineered mice with intact Tph2 in central neurons but lacking Tph2 in peripheral neurons (Tph2fl/fl; Hand2-Cre). We discovered that PSN contribute to gut motility and are important in the control of anxiety-like behavior but do not contribute to impulsive aggression. Thus, central and peripheral serotonergic neurons have different roles in behavioral regulation. Intriguingly, animals lacking peripheral neuronal Tph2 had deficiencies in enteric immune cells, including reduced abundance of dendritic cells (DC) and IgA+ B cells in the small intestine and elevated susceptibility to oral Salmonella infection. Mechanistic studies suggest that serotonin produced by PSN promotes activation of DC through the 5-HT7 receptor, thereby facilitating DC-mediated differentiation of IgA+ B cells. Our findings highlight the importance of serotonin produced by peripheral neurons for control of behavior and gut defense and suggest that these circuits could be valuable targets for therapeutics.
2024-09-04 | GSE227333 | GEO
Project description:Serotonergic neurons have multiple roles, including regulating mood and behavior1,2, yet it remains unclear which of these phenotypes are caused by serotonin produced by the central versus the peripheral nervous system. Neuronal serotonin is produced by the enzyme tryptophan hydroxylase 2 (Tph2). Mice that lack Tph2 exhibit decreased gut motility4 and several behavioral disorders, including decreased anxiety-like behavior and increased aggression5. To clarify the specific role of peripheral serotonergic circuits, here we engineered mice with intact Tph2 in central neurons but lacking Tph2 in peripheral neurons (Tph2fl/fl; Hand2-Cre). We discovered that PSN contribute to gut motility and are important in the control of anxiety-like behavior but do not contribute to impulsive aggression. Thus, central and peripheral serotonergic neurons have different roles in behavioral regulation. Intriguingly, animals lacking peripheral neuronal Tph2 had deficiencies in enteric immune cells, including reduced abundance of dendritic cells (DC) and IgA+ B cells in the small intestine and elevated susceptibility to oral Salmonella infection. Mechanistic studies suggest that serotonin produced by PSN promotes activation of DC through the 5-HT7 receptor, thereby facilitating DC-mediated differentiation of IgA+ B cells. Our findings highlight the importance of serotonin produced by peripheral neurons for control of behavior and gut defense and suggest that these circuits could be valuable targets for therapeutics.
2024-09-04 | GSE227216 | GEO
Project description:Serotonergic neurons have multiple roles, including regulating mood and behavior1,2, yet it remains unclear which of these phenotypes are caused by serotonin produced by the central versus the peripheral nervous system. Neuronal serotonin is produced by the enzyme tryptophan hydroxylase 2 (Tph2). Mice that lack Tph2 exhibit decreased gut motility4 and several behavioral disorders, including decreased anxiety-like behavior and increased aggression5. To clarify the specific role of peripheral serotonergic circuits, here we engineered mice with intact Tph2 in central neurons but lacking Tph2 in peripheral neurons (Tph2fl/fl; Hand2-Cre). We discovered that PSN contribute to gut motility and are important in the control of anxiety-like behavior but do not contribute to impulsive aggression. Thus, central and peripheral serotonergic neurons have different roles in behavioral regulation. Intriguingly, animals lacking peripheral neuronal Tph2 had deficiencies in enteric immune cells, including reduced abundance of dendritic cells (DC) and IgA+ B cells in the small intestine and elevated susceptibility to oral Salmonella infection. Mechanistic studies suggest that serotonin produced by PSN promotes activation of DC through the 5-HT7 receptor, thereby facilitating DC-mediated differentiation of IgA+ B cells. Our findings highlight the importance of serotonin produced by peripheral neurons for control of behavior and gut defense and suggest that these circuits could be valuable targets for therapeutics.
2024-09-04 | GSE227208 | GEO
Project description:Serotonergic neurons have multiple roles, including regulating mood and behavior1,2, yet it remains unclear which of these phenotypes are caused by serotonin produced by the central versus the peripheral nervous system. Neuronal serotonin is produced by the enzyme tryptophan hydroxylase 2 (Tph2)3. Mice that lack Tph2 exhibit decreased gut motility4 and several behavioral disorders, including decreased anxiety-like behavior and increased aggression5. To clarify the specific role of peripheral serotonergic circuits, here we engineered mice with intact Tph2 in central neurons but lacking Tph2 in peripheral neurons (Tph2fl/fl; Hand2-Cre). We discovered that PSN contribute to gut motility and are important in the control of anxiety-like behavior but do not contribute to impulsive aggression. Thus, central and peripheral serotonergic neurons have different roles in behavioral regulation. Intriguingly, animals lacking peripheral neuronal Tph2 had deficiencies in enteric immune cells, including reduced abundance of dendritic cells (DC) and IgA+ B cells in the small intestine and elevated susceptibility to oral Salmonella infection. Mechanistic studies suggest that serotonin produced by PSN promotes activation of DC through the 5-HT7 receptor, thereby facilitating DC-mediated differentiation of IgA+ B cells. Our findings highlight the importance of serotonin produced by peripheral neurons for control of behavior and gut defense and suggest that these circuits could be valuable targets for therapeutics.
2024-09-04 | GSE227338 | GEO
Project description:Serotonergic neurons have multiple roles, including regulating mood and behavior1,2, yet it remains unclear which of these phenotypes are caused by serotonin produced by the central versus the peripheral nervous system. Neuronal serotonin is produced by the enzyme tryptophan hydroxylase 2 (Tph2). Mice that lack Tph2 exhibit decreased gut motility4 and several behavioral disorders, including decreased anxiety-like behavior and increased aggression5. To clarify the specific role of peripheral serotonergic circuits, here we engineered mice with intact Tph2 in central neurons but lacking Tph2 in peripheral neurons (Tph2fl/fl; Hand2-Cre). We discovered that PSN contribute to gut motility and are important in the control of anxiety-like behavior but do not contribute to impulsive aggression. Thus, central and peripheral serotonergic neurons have different roles in behavioral regulation. Intriguingly, animals lacking peripheral neuronal Tph2 had deficiencies in enteric immune cells, including reduced abundance of dendritic cells (DC) and IgA+ B cells in the small intestine and elevated susceptibility to oral Salmonella infection. Mechanistic studies suggest that serotonin produced by PSN promotes activation of DC through the 5-HT7 receptor, thereby facilitating DC-mediated differentiation of IgA+ B cells. Our findings highlight the importance of serotonin produced by peripheral neurons for control of behavior and gut defense and suggest that these circuits could be valuable targets for therapeutics.
2024-09-04 | GSE227217 | GEO
Project description:Serotonergic neurons have multiple roles, including regulating mood and behavior1,2, yet it remains unclear which of these phenotypes are caused by serotonin produced by the central versus the peripheral nervous system. Neuronal serotonin is produced by the enzyme tryptophan hydroxylase 2 (Tph2). Mice that lack Tph2 exhibit decreased gut motility4 and several behavioral disorders, including decreased anxiety-like behavior and increased aggression5. To clarify the specific role of peripheral serotonergic circuits, here we engineered mice with intact Tph2 in central neurons but lacking Tph2 in peripheral neurons (Tph2fl/fl; Hand2-Cre). We discovered that PSN contribute to gut motility and are important in the control of anxiety-like behavior but do not contribute to impulsive aggression. Thus, central and peripheral serotonergic neurons have different roles in behavioral regulation. Intriguingly, animals lacking peripheral neuronal Tph2 had deficiencies in enteric immune cells, including reduced abundance of dendritic cells (DC) and IgA+ B cells in the small intestine and elevated susceptibility to oral Salmonella infection. Mechanistic studies suggest that serotonin produced by PSN promotes activation of DC through the 5-HT7 receptor, thereby facilitating DC-mediated differentiation of IgA+ B cells. Our findings highlight the importance of serotonin produced by peripheral neurons for control of behavior and gut defense and suggest that these circuits could be valuable targets for therapeutics.
2024-09-04 | GSE227125 | GEO
Project description:Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.
| S-EPMC7606741 | biostudies-literature
Project description:The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.
2019-05-15 | PXD013750 | Pride