PROJECT SUMMARY / ABSTRACT
Bowel resection leads to the devastating condition of Short Bowel Syndrome (SBS). SBS patients cannot
maintain nutrition through regular enteral nutrition (EN) due to insufficient intestines. Such patients, in the
absence of EN, require intravenous nutrition via a process called Total Parenteral nutrition (TPN) for survival.
Worldwide, tens of thousands of patients require TPN. Despite the lifesaving TPN, side effects in SBS include
potentially fatal liver and gut injury. Although, many researchers have focused on the detrimental effects of the
constituents of TPN, results from our published studies highlight our novel hypothesis that the state of luminal
content deprivation in SBS, disrupts the normal gut derived signals and drives injury mechanisms in SBS.
Our published data shows that during EN, as part of normal enterohepatic circulation of bile acids (BA),
activation of gut Farnesoid X Receptor (FXR) by BA results in release of Fibroblast Growth Factor 19 (FGF19).
FGF19 regulates hepatic BA, cholestasis, lipid, and glucose homeostasis. Due to a lack of gut FXR activation
in SBS we hypothesize that the FXR-FGF19 signaling axis is impaired. We have also published that BA
prevent gut atrophy by enhancing Glucagon Like Peptides (GLPs). GLPs are regulated via BA activated gut
receptor TGR5. While GLP-2 is a gut trophic factor; GLP-1 modulates hepatic steatosis, insulin, and glucose.
We hypothesize that inadequate gut TGR5 activation in SBS additionally drives liver and gut injury.
Novel Model: We have established a novel untethered ambulatory SBS piglet model using miniature pumps,
jugular and duodenal catheters, and surgical bowel resection (SLU#2346,43-R-011) to closely recapitulate
human SBS. Proof of Concept: We have published that in animals on TPN without bowel resection (and not
receiving EN), treatment with gut FXR agonist, Chenodeoxycholic acid (CDCA) or gut TGR5 agonist Oleanolic
Acid (OA), as well as intravenous FGF19 and GLP-1/GLP-2 can prevent liver and gut injury. Importantly, we
have shown inadequate gut FXR and gut TGR5 activation and decreased FGF19, GLP-1/GLP-2 in SBS
animals. In pilot studies we have noted hepatic and gut protection with CDCA and OA treatment in SBS.
Thus, our central premise is to critically understand alteration in gut FXR and gut TGR5 driven signaling in
SBS and to test if its restoration in SBS animals mitigates injury. As detailed in the research plan, we will test
our hypothesis under the following aims. With Aim 1 we will critically test the roles of intravenous FGF19 and
the gut FXR agonist, CDCA on liver injury in SBS. We will analyze serum, histology, key receptors, and
transporters along the FXR-FGF19 axis to understand mechanistic links. With Aim 2 we will deliver the gut
TGR5 agonist, OA as well as GLP-1/GLP-2 in SBS animals and explore TGR5-GLP axis driven protective
mechanisms in SBS, assessing serology, histology, gut trophic factors, morphometrics and gene expression.
This project, using a highly translatable SBS model will help advance strategies to mitigate serious
complications and provide key insights into drivers of injury in SBS.
