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Liver disease. Liver infection. Viral infection
October 29, 2019

What’s new with the liver and the microbiome

Dr. Jasmohan Bajaj highlights three key articles advancing our understanding of the interplay between liver disorders and the gut microbiome.
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By Jasmohan Bajaj, MD, AGAF, Virginia Commonwealth University
Member, AGA Center for Gut Microbiome Research and Education Scientific Advisory Board

There is a growing interest in the gut-brain-liver axis as well as the relationship between the gut microbiome and prevalent liver diseases such as nonalcoholic fatty liver disease (NAFLD). I want to highlight three recent articles with clinical implications for those with an interest in the potential connection between the gut and the liver.

This first paper generated a lot of media coverage recently. It is a fascinating story that started with a single patient who presented with severe nonalcoholic steatohepatitis (NASH) and autobrewery syndrome — which caused the patient to have extremely high blood alcohol concentrations despite an alcohol-free (but high-carbohydrate) diet. The authors went on to study the broader implications of the gut microbiota on patients with NAFLD.

  • Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae
    Yuan et al. Cell Metab. 2019 Oct 1;30(4):675-688.e7.

  • Key takeaway: This translational study found that the gut microbiomes of Chinese patients with NAFLD, when compared to healthy patients, had significantly higher levels of high-alcohol-producing strains of Klebsiella pneumoniae (Kpn).

  • More details: When Kpn were isolated from human subjects and transplanted to mice, the mice developed NAFLD. Mice who received Kpn transplants also had higher blood alcohol levels when given a glucose infusion. These results suggest that endogenous alcohol produced by the gut microbiota could help drive NAFLD and that assessing blood alcohol concentration after a glucose infusion should be studied further as a potential biomarker for the clinical diagnosis and treatment of NAFLD. 

  • Important caveats: Only 60% of patients in the study had elevated Kpn in their gut microbiomes and that only Chinese patients were studied, so these results must be tested in more diverse racial, ethnic and geographic populations for broader applicability. (Note that Zhu et al. have shown this phenomenon from other taxa belonging to Enterobacteriaceae in pediatric NASH.)

The next two publications focus on hepatic encephalopathy (HE), a very prevalent neuro-cognitive disorder that is epidemic in patients with chronic liver disease and can also occur as part of acute liver failure. HE can have an overt acute form (OHE), characterized by altered mental status that is prone to recurrence even after the patient returns to their baseline and a more common minimal or subclinical form (MHE). MHE is associated with poor clinical and psycho-social outcomes, is treatable but is difficult to diagnose due to logistic concerns regarding testing strategies. The first paper compares the gut microbiomes of patients with cirrhosis but with or without OHE during hospitalizations, including associations with mortality and recurrences after one year. The second paper, from my own group, looks at the gut and salivary microbiomes as potential signatures for diagnosing cognitive function in patients with HE.

  • Predicting Clinical Outcomes of Cirrhosis Patients with Hepatic Encephalopathy from the Fecal Microbiome
    Sung et al. Cell Mol Gastroenterol Hepatol. 2019;8(2):301-318.e2

  • Key takeaway: This study tracked the gut microbiomes of patients with acute episode of overt hepatic encephalopathy (AHE) throughout the treatment and recovery process as well as the outcomes of these patients one year after they were treated at the emergency unit. Importantly, increased Lactobacillus during the AHE stage was significantly associated with patient mortality one year later.

  • More details: The investigators compared the gut microbiomes of emergency room patients with cirrhosis and AHE versus outpatients with compensated cirrhosis without HE, advanced stages of cirrhosis without HE, and healthy individuals. They found that several genera were significantly more abundant in patients with AHE: VeillonellaClostridium XIPrevotella and EnterococcusVeillonella parvula was the most prevalent species in patients with AHE. The authors concluded that specific microbiota are associated with the disease progression of HE and that certain microbiota could be further explored as probiotic treatments to suppress HE in susceptible patients.

  • Important caveats: We know that strains of microbiota within the same species can have dramatically different effects, and this study does not explore the gut microbiota to the strain-specific level. The authors also acknowledged that their results conflict with other recent studies that showed no difference in the gut microbiota between cirrhosis patients with and without HE. Clearly, there are more studies that need to be done before we can develop meaningful clinical diagnostics or interventions based on this study and other related studies.

  • Specific Gut and Salivary Microbiota Patterns are Linked with Different Cognitive Testing Strategies in Minimal Hepatic Encephalopathy
    Bajaj et al. Am J Gastroenterol. 2019 Jul; 114(7):1080-1090.

  • Key takeaway: This study of nearly 250 patients found unique signatures of gut and salivary microbiota in cirrhotic patients with minimal hepatic encephalopathy (MHE) and found specific taxa that were associated with normal cognition regardless of modality of testing used to diagnose MHE.  

  • More details: The investigators found that Lactobacillaceae was higher in both the gut and salivary microbiomes of cirrhosis patients with MHE, even in patients not on lactulose therapy. In contrast, patients without MHE had higher levels of Lachnospiraceae. Independent of clinical variables, Lachnospiraceae genera (including Ruminococcus and Clostridium XIVb) were associated with good cognitive function. These results could inform future cognitive testing strategies for MHE. MHE testing was performed using three separate strategies (app-based, computer-based, paper-pencil based) and specific microbiota were associated with normal cognition regardless of which testing strategy was used.

  • Important caveats: These studies were limited to a regional population of patients in the United States and should be repeated in more diverse patient populations before the results are generally applied to all patients with MHE. 

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AGA Center for Gut Microbiome Research & Education

Brought to you by the
AGA Center for Gut Microbiome Research & Education
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