Role of the bile acid activated receptors FXR and TGR5 in Total Parenteral Nutrition associated hepatic and gut disease

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PROJECT SUMMARY / ABSTRACT Total Parenteral nutrition (TPN) provides nutrition by bypassing the gut. It is a crucial lifesaving therapy for over 30,000 individuals in the US permanently dependent on TPN. Several fold higher numbers of patients require TPN for a prolonged duration. It is also used worldwide. Unfortunately, its use causes potentially fatal liver and gut injury from a likely multifactorial, yet unknown etiology. No established ameliorative strategies exist. Dr. Jain’s long-term career goal is to become an independent NIH-funded physician scientist in the niche field to develop strategies to ameliorate TPN associated pathology. His focus is on understanding the interplay of bile acid regulated pathways that modulate the Gut-Liver axis during TPN infusion. The objective of the K08 proposal was to obtain training in designing hypothesis driven proposals, acquiring research techniques, performing experiments, critically analyzing data and developing skills to overcome pitfalls. He has obtained very encouraging data resulting in many manuscripts and several national awards, helping advance his academic pursuits. Indeed, with this award he has also been generating a critical mass of data and publications to apply for an NIH R01 grant, however, his trajectory was interrupted due a halt in studies for almost 12 months, per University policies and guidelines, in response to COVID-19 during most of 2020 and the beginning of 2021. The university has now, in 2021 allowed the studies to continue. As detailed in his research plan; with Aim 1 he evaluated gut and hepatic outcomes in TPN infused animals given Farnesoid X Receptor (FXR) agonists and will further assess impact from FXR regulated downstream protein FGF19 to determine additional mechanistic links. Aim 2 relates to exploring the mechanisms by which the TGR5-GLP axis additionally regulates TPN pathology. He has tested responses to intravenously infused Glucagon Like Peptide-2 (GLP-2) and enterally administered TGR5 agonist and will further assess GLP-1 in animals receiving TPN. Aim 3 addresses alteration in gut microbiota, specifically a clonal Bacteroidetes proliferation leading to impaired gut integrity and thus endotoxin and cytokine mediated injury in animals on TPN. Each of his aims have used several highly novel strategies. These aims have supported Dr. Jain’s career development by providing training in mechanistic aspects of TPN pathobiology as related to the roles of bile acid regulated pathways. Finally, Dr. Jain continues to have a research environment in a preeminent academic research institution (Saint Louis University) with leaders in the field at the SLU Liver center, a designated center of excellence. Most importantly, Dr. Jain is a candidate who has shown extreme determination to advance his research and has full institutional commitment to enable him to succeed.