Abstract
BackgroundCirrhosis and hepatic encephalopathy (HE) are linked with an altered gut-liver-brain axis, however, the relative contribution of hepatic vagal innervation is unclear. We aimed to determine the impact of hepatic vagotomy on the gut microbiome, brain, and liver in murine cirrhosis.Methods10–15-week-old male C57BL/6 mice with and without hepatic vagotomy underwent carbon tetrachloride (CCl4) gavage for 8 weeks. Frontal cortex [inflammation, glial/microglial activation, BDNF (brain-derived neurotrophic factor)], liver [histology including inflammation and steatosis, fatty acid synthesis (sterol-responsive binding protein-1) SREBP-1, insulin-induced gene-2 (Insig2) and BDNF], and colonic mucosal microbiota (16srRNA microbial sequencing) were evaluated on sacrifice. Conventional mice with and without cirrhosis were compared to vagotomized counterparts.ResultsConventional control vs. cirrhosis: Cirrhosis resulted in dysbiosis, hepatic/neuro-inflammation with glial/microglial activation, and low brain BDNF vs. controls. Conventional control vs. vagotomy controls: Vagotomized control mice had a lower colonic dysbiosis than conventional mice but the rest of the hepatic/brain parameters were similar. Conventional cirrhosis vs. vagotomized cirrhosis: After vagotomy + cirrhosis, we found lower dysbiosis but continuing neuroinflammation in the absence of glial/microglial activation vs. conventional cirrhosis. Vagotomy + Cirrhosis groups showed higher hepatic steatosis due to higher SREBP1 and low Insig2 protein and altered activation of key genes involved in hepatic lipid metabolism and inflammation. BDNF levels in the brain were higher but low in the liver in vagotomy + cirrhosis, likely a protective mechanism.ConclusionsHepatic vagal innervation affects the gut microbial composition, hepatic inflammation and steatosis, and cortical inflammation and BDNF expression and could be a critical modulator of the gut-liver-brain axis with consequences for HE development.
Highlights
The gut-liver-brain axis mediates the development and progression of complications of cirrhosis, such as hepatic encephalopathy (HE) (Kang et al, 2016a; Ochoa-Sanchez and Rose, 2018)
There was a significant increase in IL-1β and monocyte chemoattractant protein-1 (MCP-1) mRNA expression in mice with vagotomy compared to the controls, which marginally changed after the development of cirrhosis
Glial (GFAP) and microglial (IBA) markers were higher in cirrhotic mice without vagotomy
Summary
The gut-liver-brain axis mediates the development and progression of complications of cirrhosis, such as hepatic encephalopathy (HE) (Kang et al, 2016a; Ochoa-Sanchez and Rose, 2018). In addition to the microbial metabolite and barrier impairment, gut-brain axis alterations could be modulated through vagal innervation (Cryan et al, 2019). The additional impact of hepatic failure and inflammation adds to the overall inflammatory milieu that can affect brain function (Shawcross et al, 2004, 2011). Cirrhosis and hepatic encephalopathy (HE) are linked with an altered gutliver-brain axis, the relative contribution of hepatic vagal innervation is unclear. We aimed to determine the impact of hepatic vagotomy on the gut microbiome, brain, and liver in murine cirrhosis
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