Abstract
All-trans Retinoic acid (RA) regulates hepatic lipid and bile acid homeostasis. Similar to bile acid (BA), RA accelerates partial hepatectomy (PHx)-induced liver regeneration. Because there is a bidirectional regulatory relationship between gut microbiota and BA synthesis, we examined the effect of RA in altering the gut microbial population and BA composition and established their relationship with hepatic biological processes during the active phases of liver regeneration. C57BL/6 mice were treated with RA orally followed by 2/3 PHx. The roles of RA in shifting gut microbiota and BA profiles as well as hepatocyte metabolism and proliferation were studied. RA-primed mice exhibited accelerated hepatocyte proliferation revealed by higher numbers of Ki67-positive cells compared to untreated mice. Firmicutes and Bacteroidetes phyla dominated the gut microbial community (>85%) in both control and RA-primed mice after PHx. RA reduced the ratio of Firmicutes to Bacteroidetes, which was associated with a lean phenotype. Consistently, RA-primed mice lacked transient lipid accumulation normally found in regenerating livers. In addition, RA altered BA homeostasis and shifted BA profiles by increasing the ratio of hydrophilic to hydrophobic BAs in regenerating livers. Accordingly, metabolic regulators fibroblast growth factor 21, Sirtuin1, and their downstream targets AMPK and ERK1/2 were more robustly activated in RA-primed than unprimed regenerating livers. Priming mice with RA resulted in a lean microbiota composition and hydrophilic BA profiles, which were associated with facilitated metabolism and enhanced cell proliferation.
Highlights
The gut microbiota plays a crucial role in promoting cell proliferation
Retinoic acid (RA) reduced the ratio of Firmicutes to Bacteroidetes, which was associated with a lean phenotype
Metabolic regulators fibroblast growth factor 21, Sirtuin1, and their downstream targets AMPK and extracellular-signal-regulated kinase 1 and 2 (ERK1/2) were more robustly activated in RA-primed than unprimed regenerating livers
Summary
The gut microbiota plays a crucial role in promoting cell proliferation. For examples, germ-free mice have reduced intestinal epithelial cell turnover due to decreased proliferation, apoptosis, and crypt-to-tip cellular migration [1]. One mechanism by which bacteria promote cell proliferation is through the stimulatory effect of gram negative bacteria-generated lipopolysaccharide (LPS) on DNA synthesis [5]. It has been shown in mice that hepatic DNA synthesis is impaired when gut-derived LPS is blocked from reaching the liver [6]. Both germ-free and LPS-resistant mice exhibit delayed liver regeneration after liver resection, which can be rescued by LPS administration [7]. Because there is a bidirectional regulatory relationship between gut microbiota and BA synthesis, we examined the effect of RA in altering the gut microbial population and BA composition and established their relationship with hepatic biological processes during the active phases of liver regeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
