Project Details
Description
PROJECT SUMMARY/ABSTRACT
Irritable bowel syndrome is a globally prevalent disorder (~11%) characterized by an alteration in stool
form/frequency and abdominal pain one or more days per week. Abdominal pain in IBS, like other forms of
visceral pain, is often diffuse and poorly localized, making it difficult to delineate the site of pathology, and as a
result there are few therapeutic options. Gut microbial products have been shown to be important luminal signals
for abdominal pain, but these studies have largely focused on the colon. We recently found that small intestinal
microbial composition is associated with gastrointestinal (GI) symptoms like abdominal pain, but the mechanisms
underlying the role of small intestinal microbiota/microbial products in the pathophysiology of abdominal pain
remains a critical knowledge gap. To address this gap, we will elucidate the sensory innervation of the proximal
small intestine and identify the cellular and molecular pathways by which the small intestine detects and
transduces luminal microbial signals that contribute to visceral hypersensitivity. In our extensive preliminary
studies, we established a dedicated model to study the physiologic effects of human small intestinal microbiome
in germ free (GF) mice, metabolite effects on isolated DRGs and epithelial cells, and a novel ex vivo spinal cord-
small intestine preparation to study the transmission of luminal signals to the spinal cord via luminal metabolite
signaling through (1) EC cells, that are epithelial cells which signal to neurons via serotonin, a neurotransmitter
in the gut that modulates visceral pain, and (2) sensory neurons in dorsal root ganglia (DRG), the first-order
afferent neurons of pain pathways. Using these models, we identified distinct bacteria and bacterial metabolites
that activate EC cells and thoracic DRG neurons. Based on our preliminary findings, we hypothesize that small
intestinal bacterial products contribute to visceral hypersensitivity by activating small intestine sensory afferents
directly and through neuro-epithelial connections by activating EC cells. We will address the hypothesis in two
Specific Aims using cutting-edge stimulation/acquisition approaches, including combination of Ca2+ imaging in
organoids, electrophysiology of EC cells and DRG neurons, ex vivo preparations from novel transgenic mice,
and adeno-associated viruses (AAVs) characterizing the sensory input from the small intestine, and optogenetics
to study neuro-epithelial signaling. In Specific Aim 1, we will determine mechanisms underlying activation of EC
cells and DRG neurons, and in Specific Aim 2, we will determine the sensory transduction pathways involved
in responding to distinct microbial products. These studies will be the first to provide a functional and molecular
characterization of sensory neurons in the DRG that innervate the small intestine, determine which
subpopulations are activated and/or sensitized by microbial products in the lumen, and test whether EC cells are
involved in the sensory transduction pathway. Our findings will allow the development of novel microbial
therapies for abdominal pain that target distinct microbial pathways in the small intestine.
Status | Active |
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Effective start/end date | 9/19/23 → 7/31/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $795,071.00
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