Gut microbiota drive the development of neuroinflammatory... : Hepatology (original) (raw)

Liver Failure/Cirrhosis/Portal Hypertension

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

Kang, Dae Joong1; Betrapally, Naga S.5; Ghosh, Siddhartha A.2; Sartor, R. Balfour6; Hylemon, Phillip B.3; Gillevet, Patrick M.5; Sanyal, Arun J.1; Heuman, Douglas M.1; Carl, Daniel2; Zhou, Huiping3; Liu, Runping3; Wang, Xiang3; Yang, Jing3; Jiao, Chunhua3; Herzog, Jeremy6; Lippman, H. Robert4; Sikaroodi, Masoumeh5; Brown, Robert R.5; Bajaj, Jasmohan S.*,1

1Division of GastroenterologyHepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical CenterRichmondVA

2Division of NephrologyVirginia Commonwealth University and McGuire VA Medical CenterRichmondVA

3Division of Microbiology and Immunologyand, Virginia Commonwealth University and McGuire VA Medical CenterRichmondVA

4Division of PathologyVirginia Commonwealth University and McGuire VA Medical CenterRichmondVA

5Microbiome Analysis CenterGeorge Mason UniversityManassasVA

6National Gnotobiotic Rodent Resource CenterDepartment of Medicine, University of North CarolinaChapel HillNC

* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Jasmohan S. Bajaj, M.D.
Division of Gastroenterology, Hepatology and Nutrition
Virginia Commonwealth University and McGuire VA Medical Center
1201 Broad Rock Boulevard
Richmond, VA 23249
Tel: + 1‐804‐675‐5802
E‐mail: [email protected]

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)