P61 Systemic albumin administration improves the gut microbiome and intestinal permeability in animal models of cirrhosis and ACLF

<h3>Background and Aims</h3> Gut dysbiosis impacts negatively on gut permeability, bacterial translocation and endotoxemia, which is a target of therapy in patients with decompensated cirrhosis. Long term albumin administration in cirrhosis patients reduces endotoxemia, modulates inflammatory response and improves survival. This study was designed to test the hypothesis that albumin modulates the composition of the gut microbiome and permeability. We also tested whether the administered albumin could cross into the gut lumen. <h3>Methods</h3> Cirrhosis induced in 70 rats by 4-week bile duct ligation (BDL) and acute-on-chronic liver failure (ACLF) model induced by lipopolysaccharide (LPS) 0.025 mg/kg intraperitoneal injection (ip) to BDL model. Human albumin 20% administered (1.5 g/kg ip; 2-week) to cirrhosis and ACLF models in analbuminaemic (NAR) and wild-type (WT) rats. Caecal stool 16s PCR analysis of microbiome and mass spectrometry analysis for gut proteome of ileal, caecal and left colon stool. Plasma biochemistry and cytokines were measured. Plasma D-lactate was used as a measure of gut permeability. <h3>Results</h3> The absence of endogenous albumin in NAR rats was associated with significant differences of 3 operational taxonomic unit (OTUs) in healthy rats. Albumin infusion in NAR rats restored these OTUs to that observed in wild-type (WT) rats. In both WT and NAR cirrhotic rats, 20 and 25 OTUs were different compared with their sham controls. Treatment of both WT and NAR rats with albumin ameliorated the differential abundance seen in cirrhosis. Proteomic analysis of stool detected human albumin in the gut of albumin-treated animals, with the highest levels in the left colon. Otherwise, albumin treatment did not change the proteome. The highest number of significant changes in proteins following albumin treatment was seen in ACLF models of WT rats, where proteomic differences were associated with pathways of precursor metabolites, energy generation, and protein digestion and absorption. These microbiome changes in human albumin-replete rats were associated with preserved gut permeability, reduced systemic inflammation, severity of liver injury and survival in the ACLF animals. <h3>Conclusions</h3> The results of this study show for the first time the importance of albumin in maintaining the health of the gut microbiome. The detection of administered human albumin in the rat colonic lumen suggests that this effect of albumin may at least partially be mediated by the action of administered albumin directly in the colonic lumen. These novel data allow development of potential new therapeutic uses of albumin.