Role of intestinal microbiota in driving injury mechanisms in short bowel syndrome

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PROJECT SUMMARY / ABSTRACT Patients with Short Bowel Syndrome (SBS) require intravenous nutrition via a process called Total Parenteral Nutrition (TPN) as they cannot sustain nutritional needs through regular enteral nutrition (EN) due to insufficient intestines. Worldwide, tens of thousands of patients require TPN. Unfortunately, side effects in SBS include potentially fatal liver and gut injury from a likely multifactorial etiology. While many prior studies have focused on the possible detrimental effects induced by TPN constituents, we instead postulate the novel hypothesis that the state of luminal content deprivation as occurring in SBS alters gut-systemic signals driving injury mechanisms. Further analyzing these pathways, using a novel ambulatory SBS piglet model developed by us, which recapitulates human SBS (SLU#2346,43-R-011), we have shown gut microbial shifts in SBS with a significant increase in the Bacteroidetes phylum and decrease in the Firmicutes phylum as well as significant sub phylum changes. Pertinently, in SBS we have also published decreased synthesis of hepato-protective Fibroblast Growth Factor 19 (FGF19) secondary to inadequate gut Farnesoid X Receptor (FXR) activation and a decrease in the gut growth hormone, glucagon like peptide – 2 (GLP-2) due to a lack of gut receptor TGR5 activation. Indeed, during normal enterohepatic circulation, primary bile acids (FXR ligands), synthesized by the liver undergo transformation to secondary bile acids (TGR5 ligands) by the gut microbiota and thus we highlight a novel mechanism by which gut microbes modulate bile acid signaling properties and thus alter the course of injury in SBS. Thus, we note that an altered gut microbiota, has a prominent role in driving injury in SBS and hypothesize that its restoration in SBS animals by intestinal microbiota transplant (IMT), obtained from EN animals, will mitigate injury. Using our model, as proof of concept, we have noted mitigation of hepatic and gut injury in SBS upon IMT, attesting to its therapeutic role. As detailed in the research plan; with Aim 1 we will test the impact of rigorously monitored IMT to SBS and evaluate gut injury. We shall objectively classify and quantify stool microbiota using culture-independent targeted amplicon sequencing and shotgun metagenomics, assess serological gut injury markers, histology and perform gut morphometric analysis to gain mechanistic insights. Aim 2 relates to assessing the impact of IMT in SBS on hepatic injury. We will thus assess liver injury serological markers, hepato-toxic cytokine profiles and liver histology to assess impact of IMT. Aim 3 will focus on understanding mechanisms along the gut-systemic signaling axis driving injury in SBS. We will evaluate key hepatobiliary receptors, transporters and signaling molecules along the FXR-FGF19 and TGR5-GLP-2 gut-systemic axis to gain insights into microbial modulators and their mechanisms driving SBS injury. This project, using a highly translatable SBS model will help advance strategies to mitigate serious complications and provide critical insights into microbiota driven modulation of injury in SBS.