Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function

Abstract

Background & aims: The gut-liver axis plays a key role in the pathogenesis of alcohol-associated liver disease (ALD). We demonstrated that Opn^-/- develop worse ALD than wild-type (WT) mice; however, the role of intestinal osteopontin (OPN) in ALD remains unknown. We hypothesized that overexpression of OPN in intestinal epithelial cells (IECs) could ameliorate ALD by preserving the gut microbiome and the intestinal barrier function.

Methods: Opn^{KI IEC}, Opn^ΔIEC, and WT mice were fed control or ethanol Lieber-DeCarli diet for 6 weeks.

Results: Opn^{KI IEC} but not Opn^ΔIEC mice showed improved intestinal barrier function and protection from ALD. There were less pathogenic and more beneficial bacteria in ethanol-fed Opn^{KI IEC} than in WT mice. Fecal microbiome transplant (FMT) from Opn^{KI IEC} to WT mice protected from ALD. FMT from ethanol-fed WT to Opn^{KI IEC} mice failed to induce ALD. Antimicrobial peptides, Il33, pSTAT3, aryl hydrocarbon receptor (Ahr), and tight-junction protein expression were higher in IECs from jejunum of ethanol-fed Opn^{KI IEC} than of WT mice. Ethanol-fed Opn^{KI IEC} showed more tryptophan metabolites and short-chain fatty acids in portal serum than WT mice. FMT from Opn^{KI IEC} to WT mice enhanced IECs Ahr and tight-junction protein expression. Oral administration of milk OPN replicated the protective effect of Opn^{KI IEC} mice in ALD.

Conclusion: Overexpression of OPN in IECs or administration of milk OPN maintain the intestinal microbiome by intestinal antimicrobial peptides. The increase in tryptophan metabolites and short-chain fatty acids signaling through the Ahr in IECs, preserve the intestinal barrier function and protect from ALD.

Keywords: Antimicrobial Peptides; Aryl Hydrocarbon Receptor; Gut-liver Axis; Short-chain Fatty Acids; Tryptophan.