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

Abstract

The mechanisms behind the development of hepatic encephalopathy (HE) are unclear although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. Aim Define the individual contribution of hyperammonemia and systemic inflammation on neuro-inflammation in cirrhosis using germ-free (GF) and conventional mice. Methods GF and conventional C57BL/6 mice were made cirrhotic using CCl4 gavage. These were compared to their non-cirrhotic counterparts. Intestinal microbiota, systemic and neuro-inflammation (including microglial and glial activation), serum ammonia, intestinal glutaminase activity and cecal glutamine content were compared between groups. Results GF-cirrhotic mice developed similar cirrhotic changes to the conventional mice after four extra weeks (16 vs. 12 weeks) of CCL4 gavage. GF-cirrhotic mice exhibited higher ammonia compared to the GF controls but this was not associated with systemic or neuro-inflammation. 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 neuro-inflammation and glial/microglial activation. Correlation network analysis in conventional mice showed significant linkages between systemic/neuro-inflammation, 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 Conclusions Gut microbiota changes drive the development of neuro- and systemic inflammatory responses in cirrhotic animals.

Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation

“…They include Ruminoccoccaceae that has been associated with fibrosis, neuroinflammation and memory [76]. The present study also reports genus specific effects of bacteria in GW-T group that is associated in both small intestine and neuroinflammation[77]. Allobaculum sp .…”

Gut microbiome and liver diseases

“…Direct evidence for the important role of the gut microbiota in the development of brain changes and cognitive dysfunction in HE comes from recent clinical and preclinical studies 91 92. In a comprehensive study in 147 cirrhotics and 40 healthy controls, Ahluwalia et al performed systemic inflammatory assessment, cognitive testing, assessment of regional brain astrocyte and metabolite changes by MR spectroscopy (MRS) and assessment of neuronal integrity and oedema by diffusion tensor imaging, 16S RNA sequencing of microbial composition and inference of the metagenomic content of samples from 16S data 83.…”

“…These findings for the first time demonstrate correlations between altered gut microbial taxa and specific neuronal and astrocytic changes in the brain of cirrhotics with HE. Kang et al 92 further characterised the relative role of the gut microbiota and ammonia levels in the development of neuroinflammation in a CCl 4 -induced model of cirrhosis in GF and in conventional mice. When compared with non-cirrhotic GF animals, cirrhotic GF mice showed higher ammonia levels, but no evidence of systemic or brain-related inflammatory changes.…”

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

“…The gut microbiota, which plays an important role in the pathogenesis of ALD 87–89 , has been examined in mouse models of chronic ALD but not in the chronic-plus-binge ethanol feeding model. One recent study examined the role of immunoglobulin A (IgA) in chronic-plus-binge ethanol-induced liver injury 90 .…”