Source: Vigrinia Commonwealth University.

Jasmohan Bajaj, M.D., associate professor at Virginia Commonwealth University, had findings from his research on gut bacteria in cirrhosis published recently in the journals Hepatology and Scientific Reports.

The findings conclude that gut bacteria, found in the intestinal tract and stool, are associated with brain inflammation in cirrhotic patients and animals known as hepatic encephalopathy (HE). HE can lead to fatigue, the inability to concentrate, mental confusion and death.

“HE is an epidemic in patients with liver disease and cirrhosis,” said Bajaj, associate professor in the Department of Gastroenterology, Hepatology and Nutrition in the VCU School of Medicine. “Bacteria can result in inflammation in the systemic circulation, which in turn could inflame the brain.”

His research published in Hepatology involved the study of germ-free and conventionally raised mice with cirrhosis. The researched shows that gut microbes are essential for brain inflammation in cirrhotic mice. The human study published in Scientific Reports shows that specific bacteria were associated with nerve cell or neuron damage, while others were associated with damage to supporting cells or astrocytes.

Further investigation must include HE treatment that targets particular gut bacterial populations and specific affected brain region that might be affected as a result, said Bajaj, who practices at both VCU Health and the McGuire VA Medical Center.

Despite treatment for HE using the current standard of care, patients still experience the progression to overt HE and residual brain damage, Bajaj said. Consequently, further treatment options must be researched and made available to patients, Bajaj said.

To that end, Bajaj and the McGuire VAMC are performing fecal microbial transplants in HE patients. This process is the transfer of stool from a healthy donor into the gastrointestinal tract of someone with HE, for the purpose of treatment.

Patients who were part of Bajaj’s study were examined within the last two years. Mice were also used as study subjects during the last year of research.

Funding: The study was supported by the National Institutes of Health.

Source: Michelle Uher – Vigrinia Commonwealth University
Image Source: This NeuroscienceNews.com image is credited to BruceBlaus and is licensed CC BY SA 4.0.
Original Research: Abstract for “Gut microbiota drive the development of neuro-inflammatory response in cirrhosis” by Dae Joong Kang, Naga S Betrapally, Siddhartha A Ghosh, R Balfour Sartor, Phillip B Hylemon, Patrick M Gillevet, Arun J Sanyal, Douglas M Heuman, Daniel Carl, Huiping Zhou, Runping Liu, Xiang Wang, Jing Yang, Chunhua Jiao, Jeremy Herzog, H Robert Lippmann, Masoumeh Sikaroodi, Robert R Brown, and Jasmohan S Bajaj in Hepatology. Published online June 23 2016 doi:10.1002/hep.28696

Full open access research for “Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis” by Vishwadeep Ahluwalia, Naga S Betrapally, Phillip B Hylemon, Melanie B White, Patrick M Gillevet, Ariel B Unser, Andrew Fagan, Kalyani Daita, Douglas M Heuman, Huiping Zhou, Masoumeh Sikaroodi and Jasmohan S Bajaj in Hepatology. Published online May 26 2016 doi:10.1038/srep26800

Abstract

Gut microbiota drive the development of neuro-inflammatory response in cirrhosis

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.

“Gut microbiota drive the development of neuro-inflammatory response in cirrhosis” by Dae Joong Kang, Naga S Betrapally, Siddhartha A Ghosh, R Balfour Sartor, Phillip B Hylemon, Patrick M Gillevet, Arun J Sanyal, Douglas M Heuman, Daniel Carl, Huiping Zhou, Runping Liu, Xiang Wang, Jing Yang, Chunhua Jiao, Jeremy Herzog, H Robert Lippmann, Masoumeh Sikaroodi, Robert R Brown, and Jasmohan S Bajaj in Hepatology. Published online June 23 2016 doi:10.1002/hep.28696

Abstract

Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis

Cirrhosis is associated with brain dysfunction known as hepatic encephalopathy (HE). The mechanisms behind HE are unclear although hyperammonemia and systemic inflammation through gut dysbiosis have been proposed. We aimed to define the individual contribution of specific gut bacterial taxa towards astrocytic and neuronal changes in brain function using multi-modal MRI in patients with cirrhosis. 187 subjects (40 controls, 147 cirrhotic; 87 with HE) underwent systemic inflammatory assessment, cognitive testing, stool microbiota analysis and brain MRI analysis. MR spectroscopy (MRS) changes of increased Glutamate/glutamine, reduced myo-inositol and choline are hyperammonemia-associated astrocytic changes, while diffusion tensor imaging (DTI) demonstrates changes in neuronal integrity and edema. Linkages between cognition, MRI parameters and gut microbiota were compared between groups. We found that HE patients had a significantly worse cognitive performance, systemic inflammation, dysbiosis and hyperammonemia compared to controls and cirrhotics without HE. Specific microbial families (autochthonous taxa negatively and Enterobacteriaceae positively) correlated with MR spectroscopy and hyperammonemia-associated astrocytic changes. On the other hand Porphyromonadaceae, were only correlated with neuronal changes on DTI without linkages with ammonia. We conclude that specific gut microbial taxa are related to neuronal and astrocytic consequences of cirrhosis-associated brain dysfunction.

“Impaired Gut-Liver-Brain Axis in Patients with Cirrhosis” by Vishwadeep Ahluwalia, Naga S Betrapally, Phillip B Hylemon, Melanie B White, Patrick M Gillevet, Ariel B Unser, Andrew Fagan, Kalyani Daita, Douglas M Heuman, Huiping Zhou, Masoumeh Sikaroodi and Jasmohan S Bajaj in Hepatology. Published online May 26 2016 doi:10.1038/srep26800