Role of gut microbiota in total parenteral nutrition associated injury

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PROJECT SUMMARY / ABSTRACT Total Parenteral nutrition (TPN) is the method of intravenous nutrition delivery bypassing the gut in patients unable to receive regular enteral nutrition (EN). It is a crucial lifesaving therapy for over 30,000 individuals in the US permanently dependent on TPN. Several fold higher number of patients require TPN for a prolonged duration. Unfortunately, side effects of this critical therapy used world-wide include potentially fatal liver and gut injury from a likely multifactorial etiology. Emerging data, including results from our K08 funding suggests that a disruption of gut-derived signals in response to a lack of luminal nutrient delivery, as occurring with TPN therapy drives such injury. Our lab has been investigating the role of such signaling. Using a novel ambulatory TPN piglet model, developed at our lab which recapitulates human TPN delivery; we have published significant alterations in the gut microbiota of animals on TPN. Specifically we have shown a significant increase in the pro-inflammatory Bacteroidetes phylum and a decrease in the Firmicutes phylum in TPN animals. We have also noted significant alterations in key hepatobiliary receptors and transporters that drive gut-systemic signaling and contribute to TPN associated injury. Recent data also suggests that alteration in inflammatory cytokines secondary to microbial shifts can lead to such injury. Therefore we believe that the altered gut microbiota, during TPN, may have a prominent role in TPN associated injury. We thus hypothesize that a restoration of the altered gut microbiota in TPN animals by a transfer of fecal microbiota from control EN animals will mitigate TPN-associated injury. As detailed in the research plan; with Aim 1 we will test the impact of rigorously monitored fecal transplantation from control EN animals to those on TPN and evaluate gut injury. As part of this aim, we shall objectively identify and quantify stool microbiota using culture independent 16S ribosomal sequencing and assess serological gut injury markers, gut permeability, histology and perform gut morphometric analysis. Aim 2 relates to exploring the impact of fecal transplantation on hepatic injury and critically testing the gut-systemic cross talk. This aim is rationalized by an alteration of hepatobiliary receptors and transporters as well as cytokine mediated injury secondary to microbial shifts with TPN therapy. Liver injury serological markers, histology and key hepatobiliary receptors, transporters and signaling molecules driving the gut- systemic cross talk will be assessed to gain mechanistic insights. This proposal complements our K08 work and could provide important insights into the role of gut microbiota in TPN associated injury and help develop strategies to mitigate complication of this life saving therapy.