Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration

Abstract

Background & Aims The pathways regulating liver regeneration have been extensively studied within the liver. However, the signaling contribution derived from the gut microbiota to liver regeneration is poorly understood. Methods Microbiota and expression of hepatic genes in regenerating livers obtained from mice 0 hour to 9 days post 2/3 partial hepatectomy (PHx) were temporally profiled to establish their interactive relationships. Results PHx led to rapid changes in gut microbiota that was reflected in increased abundance of Bacteroidetes S24-7 and Rikenellaceae and decreased abundance of Firmicutes Clostridiales, Lachnospiraceae, and Ruminococcaceae. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to infer biological functional changes of the shifted microbiota. RNA-sequencing data revealed 6,125 genes with more than 2 folds difference in their expression levels during regeneration. By analyzing their expression pattern, six uniquely expressed patterns were observed. In addition, there were significant correlations between hepatic gene expression profiles and shifted bacterial populations during regeneration. Moreover, hepatic metabolism and immune function were closely associated with the abundance of Ruminococcacea, Lachnospiraceae, and S24-7. Bile acid (BA) profile was analyzed because bacterial enzymes produce BAs that significantly impact hepatocyte proliferation. The data revealed that specific bacteria were closely associated with the concentration of certain BAs and expression of hepatic genes. Conclusions The presented data established, for the first time, an intimate relationship between intestinal microbiota and the expression of hepatic genes in regenerating livers.

Alteration of gut microbial community after N,N-Dimethylformamide exposure

“…The present study shows that DMF can also influce the gut microbiota composition. The gut and the liver are the key organs in nutrient absorption and metabolism, and the gut microbiota plays a critical role in liver diseases, such as alcoholic fatty liver disease, non-alcoholic fatty liver disease, liver cirrhosis and liver regeneration (Liu et al, 2016). However, whether DMF, a industrial chemical used in leather production, changed gut microbiota composition or not is uncertain.…”

“…Although highly stable over time, gut microbiota may be influenced by a number of factors, including environmental stimulus, disease, diet, and age (Goel et al, 2014). A recent study demonstrates that intestinal microbiota is apparently altered during liver regeneration, and bile acid, which plays a significant role in liver regeneration, interacted with microbes (Liu et al, 2016). Evidence also suggests that different pathological condition of liver diseases, including viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease, may alter gut microbiota differently (Brenner et al, 2015).…”

The role of bile salts in liver regeneration

“…TGR5 protects the liver during the transient bile salt overload after PHx, likely by preventing an excessive inflammatory response to toxic bile salts. A contribution of the gut microbiota in modulation of liver regeneration is emerging, and this may involve effects via bile salt signaling [56,57]. Certain microbial species can convert the host's primary bile salts to secondary bile salt species, and accordingly influence the affinity for bile salt binding to FXR or TGR5.…”

“…Certain microbial species in the colon are equipped with enzymes that convert the host's primary bile salt species into secondary bile salts, thus, altering their affinity for TGR5 and FXR. During liver regeneration following PHx, the composition of the gut microbiome changes [57]. A direct correlation was found between the concentration of the different bile salts, expression of genes involved in bile salt homeostasis Shp and Cyp7a1, and the gut microbiota composition [57].…”

“…During liver regeneration following PHx, the composition of the gut microbiome changes [57]. A direct correlation was found between the concentration of the different bile salts, expression of genes involved in bile salt homeostasis Shp and Cyp7a1, and the gut microbiota composition [57]. It will be interesting to gain further insights how the microbiota-bile salt interaction influences liver regeneration, and whether a probiotic approach can precondition the liver prior to liver surgery.…”