Disorders of gut-brain interactions (DGBIs), the most common GI problems world-wide, are characterized by
recurring, chronic gastrointestinal (GI) symptoms including dysmotility (constipation/diarrhea), GI pain and
abnormal gut-brain communication. Treatment options for DGBIs are extremely limited due to a poor
understanding of their pathophysiology. What is known about DGBIs is that the majority of affected patients
have a co-morbid mood disorder, mainly anxiety (AD) but also depression (DD). Like DGBIs, AD and DD are
common and with limited treatment options. Further, studies show an increased risk of DGBI development
with a pre-existent mood disorder and vice versa. Identifying links between DBGIs and mood disorders is
thus highly likely to elucidate mechanisms that instigate development of novel therapies for both conditions.
The transmitter, serotonin (5-HT) modulates symptoms of DGBIs, AD and DD, leading many treatments to be
targeted towards 5-HT regulation. In particular, selective serotonin reuptake inhibitors (SSRIs) are highly
prescribed. Yet, SSRIs have severe limitations: low remission (<50%) and resolution (<1/3) rates and;
adverse effects (e.g., GI pain, dysmotility, and [paradoxical] anxiety). SSRIs function by inhibiting the
serotonin reuptake transporter (SERT), thus increasing 5-HT transmission. SERT is located in the CNS, ENS
and the GI epithelium and SSRIs are systemically absorbed, leading to SSRI action/SERT antagonism in the
CNS, ENS and GI epithelium. Yet, it is not known where SSRIs precisely act to induce their beneficial versus
adverse effects. Our data show that: (1) beneficial SSRI effects (anxiolytic, anti-depressive, anti-nociceptive)
result from SERT antagonism in the GI epithelium and may involve vagal- and 5-HT3-mediated signaling and;
(2) detrimental SSRI effects result from ENS or CNS SERT antagonism (AD, dysmotility, pain). Thus,
selective pharmacologic blockade of GI epithelial SERT could be beneficial for treating DGBIs, AD and DD
without producing negative effects linked to systemic SSRI exposure. We have created a state-of-the-art
SSRI delivery system that maximally disperses and retains SSRI locally on the intestinal epithelium while
minimizing systemic absorption. We now propose to: (1) elucidate the roles of vagal signaling in linking gut
epithelial 5-HT to beneficial effects on GI pain and mood; (2) examine how ENS SERT ablation affects DGBI
symptoms and mood, to determine if avoidance of ENS SERT antagonism is necessary to prevent negative
and efficacy-reducing effects of systemic SSRIs; (3) determine whether our novel SSRI delivery platform
provides the beneficial mood effects of SSRIs while avoiding deleterious effects on GI pain, GI motility and
mood. If successful, the platform is known to be safe so can be efficiently translated to clinical studies.
