The gut-brain axis is a relatively new focus of research that has rapidly expanded after the development of culture-independent analytic techniques. Of interest to hepatologists is the microbiome-gut-liver- brain axis and its role in the pathogenesis of hepatic encephalopathy (HE). HE is defined as brain dysfunction secondary to liver insufficiency and/or portosystemic shunts, which is epidemic in cirrhosis and is the leading cause of readmissions in North American cirrhotic patients. It has two major subtypes, covert (CHE), which is subclinical, and overt (OHE), the clinically apparent form. Fundamental to the pathogenesis in both subtypes is gut microbial dysbiosis, which is a deleterious shift in microbial community composition. This means a higher relative abundance of potentially pathogenic taxa that are predominantly gramnegative bacteria that produce endotoxins and generate a pro-inflammatory milieu which engages the host immune system.
Each cirrhosis etiology, such as alcohol or nonalcoholic fatty liver disease, has a specific gut microbial fingerprint i.e dysbiotic features. Regardless of etiology, decompensation of cirrhosis and HE development is associated with a worsening of dysbiosis compared to the compensated and non-cirrhotic stage. Microbiota can potentiate HE through several potential pathways related to endotoxemia and upregulated inflammatory cytokine production. The microbiota is a major source of ammonia and indole byproducts toxic to neurons/astrocytes. Ammonia can also be produced by the breakdown of dietary glutamine by intestinal glutaminase. Both ammoniagenesis and inflammation are relevant as systemic inflammatory cytokines can influence the development of neuro-inflammation and potentiate the effects of ammonia in the brain. In a study on germ-free mice in whom cirrhosis was induced in a similar method to conventional mice using CCL4, with cirrhosis, despite hyperammonemia, there was little neuro-inflammation, which was not the case in conventional cirrhotic mice. This indicates that both are necessary for HE development. Lastly, the microbiome lends to an altered bile acid (BA) physiology. An altered BA profile with a reduction in secondary BAs indicates a relative lack of abundance of autochthonous taxa that may be responsible for this conversion. Some of these taxa are also able to generate beneficial short-chain fatty acids and support intestinal barrier integrity. Eventually, HE is likely related to multiple alterations in gut microbial composition and function, which is propagated in the setting of liver disease and impaired local and systemic immune response.
Ultimately, an altered microbiome-gut-liver-brain axis is critical in the development and propagation of hepatic encephalopathy and there remains a need for targeted therapies to modulate this connection between the gut and the brain.
Given this association, the case has been made to focus therapies on modulation of this microbiome-gut-liver-brain axis to modify clinical outcomes. There are several potential targets in this pathway such as the intestinal microbial milieu, targeting ammonia production and ammonia scavenging from extra-intestinal sources, modulation of the immune response and reducing neuro-inflammation. Modulation of neuro-inflammation is limited in therapeutic options (benzodiazepine antagonists, neurosteroids approaches), and suppressing the immune- inflammatory response i.e interleukins/cytokines (using nonsteroidal anti-inflammatory drugs in animal models) are not currently ready for prime time in humans. Ammonia-scavenging therapies do not solve the issue of ammonia generation and are more reactionary. Therefore, studies have focused on reversing gut dysbiosis and ammonia production. This approach aims to reduce inflammation, ameliorate production of ammonia/indoles and potentially improve BA physiology. There are currently several modalities to affect the intestinal microbial milieu i.e. antibiotics (absorbable/non-absorbable), prebiotics, probiotics and synbiotics. Our current first-line therapeutic option for HE, lactulose, likely acts as a laxative rather than a prebiotic given its negligible impact on microbiota composition. On the other hand, rifaximin improves endotoxemia. BA profile and cognition despite a modest effect on microbiota composition. The other options, probiotics and synbiotics, have been studied for CHE (treatment) and OHE (secondary prevention), with successful modulation of the microbiome but without a clear evidence basis currently. Extra-intestinal ammonia modulation can occur in the form of specialized amino acid formulations that scavenge ammonia in the systemic circulation or promote its uptake into the skeletal muscle. Therefore, the production of ammonia and inflammation, primarily at the gut level, is the mainstay of therapy. However, there remains a significant proportion of patients who breakthrough with these therapies.
The future of HE treatment lies in targeted therapies; more specifically gut targeted specific therapies. In a small randomized clinical trial, fecal microbial transplantation (FMT) via lower-intestinal delivery was useful but larger randomized studies are required. FMT changes the gut microbiota composition and can improve microbial function to potentially improve brain function. Genetically engineered bacteria that can consume ammonia are also in the process of being studied. Newer therapies will also need to be studied as additives to current treatments for HE given the limited success of the drugs currently recommended. In addition, there is no consensus or multi-center randomized trials for CHE therapy. Ultimately, an altered microbiome-gut-liver-brain axis is critical in the development and propagation of HE and there remains a need for targeted therapies to modulate this connection between the gut and the brain.
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Dr. Acharya has no conflicts to disclose.
Dr. Bajaj has acted as a consultant for Norgine, Alfa-Wasserman, Ocera, Synlogic and Valeant Pharmaceuticals. Dr. Bajaj is a member of the AGA Center for Gut Microbiome Research and Education Scientific Advisory Board.