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Hepatology. 2016 Oct;64(4):1232-48. doi: 10.1002/hep.28696. Epub 2016 Jul 29.

Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice.

Author information

1
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA.
2
Microbiome Analysis Center, George Mason University, Manassas, VA.
3
Division of Nephrology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA.
4
National Gnotobiotic Rodent Resource Center, Department of Medicine, University of North Carolina, Chapel Hill, NC.
5
Division of Microbiology and Immunology, and, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA.
6
Division of Pathology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA.
7
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA. jsbajaj@vcu.edu.

Abstract

The mechanisms behind the development of hepatic encephalopathy (HE) are unclear, although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. The aim of this work was to define the individual contribution of hyperammonemia and systemic inflammation on neuroinflammation in cirrhosis using germ-free (GF) and conventional mice. GF and conventional C57BL/6 mice were made cirrhotic using CCl4 gavage. These were compared to their noncirrhotic counterparts. Intestinal microbiota, systemic and neuroinflammation (including microglial and glial activation), serum ammonia, intestinal glutaminase activity, and cecal glutamine content were compared between groups. GF cirrhotic mice developed similar cirrhotic changes to conventional mice after 4 extra weeks (16 vs. 12 weeks) of CCl4 gavage. GF cirrhotic mice exhibited higher ammonia, compared to GF controls, but this was not associated with systemic or neuroinflammation. Ammonia was generated through increased small intestinal glutaminase activity with concomitantly reduced intestinal glutamine levels. However, conventional cirrhotic mice had intestinal dysbiosis as well as systemic inflammation, associated with increased serum ammonia, compared to conventional controls. This was associated with neuroinflammation and glial/microglial activation. Correlation network analysis in conventional mice showed significant linkages between systemic/neuroinflammation, intestinal microbiota, and ammonia. Specifically beneficial, autochthonous taxa were negatively linked with brain and systemic inflammation, ammonia, and with Staphylococcaceae, Lactobacillaceae, and Streptococcaceae. Enterobacteriaceae were positively linked with serum inflammatory cytokines.

CONCLUSION:

Gut microbiota changes drive development of neuroinflammatory and systemic inflammatory responses in cirrhotic animals. (Hepatology 2016;64:1232-1248).

PMID:
27339732
PMCID:
PMC5033692
DOI:
10.1002/hep.28696
[Indexed for MEDLINE]
Free PMC Article

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