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Gut microbiota drive the development of neuroinflammatory response in cirrhosis in mice
Author(s) -
Kang Dae Joong,
Betrapally Naga S.,
Ghosh Siddhartha A.,
Sartor R. Balfour,
Hylemon Phillip B.,
Gillevet Patrick M.,
Sanyal Arun J.,
Heuman Douglas M.,
Carl Daniel,
Zhou Huiping,
Liu Runping,
Wang Xiang,
Yang Jing,
Jiao Chunhua,
Herzog Jeremy,
Lippman H. Robert,
Sikaroodi Masoumeh,
Brown Robert R.,
Bajaj Jasmohan S.
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28696
Subject(s) - neuroinflammation , systemic inflammation , hyperammonemia , dysbiosis , cirrhosis , inflammation , glutamine , medicine , immunology , gut flora , endocrinology , biology , biochemistry , amino acid
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 CCl 4 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 CCl 4 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. (H epatology 2016;64:1232‐1248)