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

Yuan Zhang; Jason D Kang; Derrick Zhao; Siddartha S Ghosh; Yanyan Wang; Yunling Tai; Javier Gonzalez-Maeso; Masoumeh Sikaroodi; Patrick M Gillevet; H Robert Lippman; Phillip B Hylemon; Huiping Zhou; Jasmohan S Bajaj

doi:10.3389/fphys.2021.702646

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

Front Physiol. 2021 Jun 25:12:702646. doi: 10.3389/fphys.2021.702646. eCollection 2021.

Affiliations

¹ Division of Microbiology and Immunology, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States.
² Division of Nephrology, Virginia Commonwealth University, Richmond, VA, United States.
³ Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, United States.
⁴ Microbiome Analysis Center, George Mason University, Manassas, VA, United States.
⁵ Department of Pathology, Central Virginia Veterans Health Care System, Richmond, VA, United States.
⁶ Division of Gastroenterology, Hepatology, and Nutrition, Central Virginia Veterans Health Care System, Virginia Commonwealth University, Richmond, VA, United States.

Abstract

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.

Keywords: BDNF; hepatic encephalopathy; inflammation; microbiota (16S); pathobiont; vagotomy.