Project Summary/Abstract
The gut microbiota influences many aspects of host physiology, spanning metabolism, gastrointestinal function,
neuroactivity, and immune homeostasis. However, the molecular mechanisms that govern the symbiotic
relationship between the host and gut microbiome remains unclear. Current evidence suggests that
immunological tolerance in the intestine is essential for maintaining healthy host-microbe interactions by
dampening immune responses to beneficial gut microbes and thus, promote commensalism. Interestingly, recent
studies suggest that specific microbes that preferentially reside in the colon can promote immune tolerance by
enhancing the development and function of regulatory T cells (Treg), a T helper (Th) subset important for
tolerance. For example, polysaccharide A from Bacteroides fragilis can increase the suppressive capacity of
Tregs, mediate the conversion of CD4+ Th cells to Tregs, and enhance microbe colonization onto host mucosa
in the colon. Furthermore, Clostridial species (Clostridial spp), an abundant member of the proximal colon,
produce short-chain fatty acids (SCFAs) that can also promote colonic Treg development and function. In the
absence of SCFAs, Clostridial spp maintain some capacity to induce Treg development, suggesting an
undescribed alternative mechanism. Interestingly, Clostridial spp are also potent inducers of host serotonin
synthesis by colonic enteroendocrine cells. While commonly associated with neurotransmission in the brain
regulating mood and behavior, serotonin in the periphery can also regulate diverse processes including gut
motility and platelet activity. Furthermore, serotonin has immunomodulatory properties and can signal through
the variety of serotonin receptors expressed by immune subsets. In the gut, serotonin receptor 7 (5-HT7) is
highly expressed by innate immune cells, such as dendritic cells (DCs) and macrophages, that are important for
Treg induction and maintenance. Since DCs are essential for T cell activation, we hypothesize that serotonin
signaling through 5-HT7+ colonic DCs contribute to immunological tolerance that support the symbiotic
relationship with gut microbes. To test this hypothesis, I will leverage novel transgenic mice and intersectional
genetic approaches to determine i) the spatiotemporal regulation of 5-HT7 expression on colonic DCs, ii) the
cellular consequences of 5-HT7-mediated signaling on colonic DCs, iii) the functional effects of DC-specific 5-
HT7-mediated signaling on immune tolerance to the gut microbiota. Moreover, immunological tolerance is
essential for dampening inflammatory responses during immune resolution to prevent chronic activation of
proinflammatory pathways. In the gastrointestinal tract, chronic inflammatory disorders, such as irritable bowel
disease (IBD), is associated with dysbiosis and dysregulated serotonergic signaling, suggesting a relationship
between IBD, gut microbiota, and the enteric serotonergic system. Thus, results from our studies will advance
our understanding of the crosstalk between the host and microbiota through serotonin-immune interactions and
raise the potential for identifying novel targets that promote immune tolerance and intestinal homeostasis.