Hepatic Branch Vagotomy Modulates the Gut-Liver-Brain Axis in Murine Cirrhosis

肝硬化 迷走神经切断术 内科学 内分泌学 医学 炎症 脂肪变性 肝性脑病
作者
Yuan Zhang,Jason D. Kang,Derrick Zhao,Siddartha Ghosh,Yanyan Wang,Yunling Tai,Javier González‐Maeso,Masoumeh Sikaroodi,Patrick M. Gillevet,H Lippman,Phillip B. Hylemon,Huiping Zhou,Jasmohan S. Bajaj
出处
期刊:Frontiers in Physiology [Frontiers Media]
卷期号:12 被引量:12
标识
DOI:10.3389/fphys.2021.702646
摘要

Background Cirrhosis 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. Methods 10–15-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. Results Conventional 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. Conclusions Hepatic 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.
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