Reintroduction of gut microbiota improves liver regeneration in germ-free mice

Abstract

. The gut microbiota has been implicated in liver regeneration, evident by delayed liver regeneration in mice with sterile gut (germ-free mice) and mice subjected to antibiotic treatment. Here we investigated the involvement of gut microbiota in liver regeneration by observing liver regeneration process in germ-free mice which have been reconstituted with normal gut microbiota (ex-germ-free mice). Ex-germ-free (XGF), germ-free (GF) and normal wild-type (WT), C57BL/6 mice underwent two-thirds partial hepatectomy (PHx). Early regenerative response of the liver was assessed by cytokine and growth factor tissue concentration and gene expression at 3-hours post PHx, while liver mass restoration was assessed by liver/body weight ratio (LW/BW) ratio at 72-hour post PHx. At 3-hours post PHx, GF mice demonstrated significantly lower concentrations of IL6R and lower expressions cytokine receptors Il6ra and Tnfrsf1a, and growth factor Hgf genes compared to control mice. Signifying reduced early regenerative response in the remnant liver of GF mice. Similarly, LW/BW ratio and normalised liver growth percentage of GF mice were significantly lower compared to control mice at 72- hours post PHx, signifying reduced liver mass restoration. Conversely, early regenerative response and liver mass restoration indices in XGF mice were similar to that of controls, with no significant differences observed. Therefore, signifying normal liver regeneration in XGF mice. The study demonstrated that reconstitution of normal gut microbiota in GF mice ameliorates liver regeneration following partial hepatectomy in GF mice, evident by normal liver mass restoration and early cytokine and growth factor response in XGF mice. Taken together, our findings indicate that gut microbiota is involved in the early regenerative response of the liver and that reconstitution of gut microbiota may improve liver regeneration.