Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?

Abstract

The development of overt hepatic encephalopathy (HE) in a patient with cirrhosis confers a damning prognosis with a 1-year mortality approaching 64%. This complex neuropsychiatric syndrome arises as a consequence of a dysfunctional gut–liver–brain axis. HE has been largely neglected over the past 30 years, with the reliance on therapies aimed at lowering ammonia production or increasing metabolism following the seminal observation that the hepatic urea cycle is the major mammalian ammonia detoxification pathway and is key in the pathogenesis of HE. The relationship with ammonia is more clear-cut in acute liver failure; but in cirrhosis, it has become apparent that inflammation is a key driver and that a disrupted microbiome resulting in gut dysbiosis, bacterial overgrowth and translocation, systemic endotoxemia and immune dysfunction may be more important drivers. Therefore, it is important to re-focus our efforts into developing therapies that modulate the disrupted microbiome or alleviating its downstream consequences.

Keywords:

• ammonia
• cirrhosis
• gut dysbiosis
• hepatic encephalopathy
• immune dysfunction
• inflammation
• microbiota

Financial & competing interests disclosure

DL Shawcross has received honoraria from Norgine for consultancy, advisory board membership and chairing/lecturing in Industry Sponsored Symposia. The author has no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.