Spotlight on Impactful Research: Impact of Liver Transplantation on Gut Microbiota and Cognitive Function

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Abbreviations

HRQoL

health‐related quality of life

LT

liver transplantation

PHES

Psychometric Hepatic Encephalopathy Score

Key Points

How does this study change day‐to‐day clinical practice, if at all?

• This study advances the understanding of the impact of LT on gut microbial dysbiosis and its relationship to cognitive function in recipients but, at this point, does not change our current clinical practice.

What new clinical research questions are raised by this study that can be addressed by future research?

• This study offers specific gut organisms as therapeutic targets to directly alter gut microbial dysbiosis. Specifically, could reducing pathogenic taxa such as Proteobacteria and cultivating autochthonous taxa such as Firmicutes improve posttransplant cognitive dysfunction and quality of life of liver transplant recipients?

The role of gut microbiota in cirrhosis has received increased attention in recent years because of increased understanding of the impact that microbial composition and bacterial translocation may have on clinical outcomes and complications. Prior studies have demonstrated significant gut microbial dysbiosis in patients with cirrhosis that is distinct from healthy volunteers1 and can influence complications and progression of liver disease.2 Bajaj et al.3 have demonstrated that dysbiosis, indicated by a relative decrease of beneficial autochthonous taxa such as Lachnospiraceae and a relative overgrowth of pathogenic taxa such as Enterococcaceae, is associated with worsening liver function and decompensation. In addition, dysbiosis was found to be associated with worsening intestinal permeability and endotoxemia. The gut‐liver‐brain axis is significantly altered in patients with cirrhosis, and specific bacterial taxa have been shown to be associated with astrocytic and neuronal changes in the brains with cirrhosis and hepatic encephalopathy,4 one of the most important causes of decreased quality of life. Patients with cirrhosis with hepatic encephalopathy have been shown to have different microbiota1 and colonic mucosal microbiome5 compared with patients with cirrhosis who do not have hepatic encephalopathy. A preliminary study suggests that fecal microbiota transplantation may improve dysbiosis and cognition in patients with cirrhosis with recurrent encephalopathy.6 The impact of liver transplantation (LT) on microbial composition and its relationship to quality of life had not previously been studied.

In a significant article of 2017 published in Liver Transplantation, Bajaj and his team7 evaluated the effect of LT on gut microbiota, including transplant recipients with posttransplant cognitive dysfunction, as assessed by the Psychometric Hepatic Encephalopathy Score (PHES) and health‐related quality of life (HRQoL) score. Forty‐five patients with cirrhosis underwent testing with PHES, HRQoL, and stool microbiota tests for multitagged sequencing; all tests were performed while the patients were listed for transplant and again approximately 7 months after successful LT. The majority of recipients experienced significant improvement in HRQoL testing after transplantation. Stool microbiome testing after transplant revealed significantly increased diversity with reduction in potentially pathogenic genera belonging to Enterobacteriaceae with significant increases in potentially beneficial native taxa, including Clostridial families. Although the gut microbiome may be reconstituted after successful LT, some degree of dysbiosis persisted after transplantation compared with healthy control subjects.

Although there was a significant reduction in minimal hepatic encephalopathy on PHES testing after transplant, almost one‐third of transplant recipients did not have improvement and had similar posttransplant Sickness Impact Profile scores despite well‐functioning allografts. Whereas patients with improved cognitive function after transplant demonstrated reduction of pathogenic taxa Proteobacteria, including Enterococcaceae, and an increase in autochthonous Firmicutes taxa, such as Lachnospiraceae, recipients without cognitive improvement showed relative Enterococcaceae abundance. Delta Proteobacteria, rather than pre‐LT Proteobacteria, was an independent predictor of post‐LT cognitive function, and the authors suggest that this may be affected by a patient’s posttransplant course. Causality can be challenging to evaluate because events in the posttransplant course, such as antibiotics and infections, treatment for rejection, hospitalizations, and immunosuppression, all can affect both gut microbial composition and cognitive function.

Overall this study is a major step forward in understanding the effect of LT on the gut microbiome and cognitive function. Perhaps the most exciting aspects of this study are not the questions that it answers but rather the questions that it raises by identifying potential therapeutic targets. By modulating the gut microbiota and targeting Proteobacteria and cultivation of Firmicutes, could we alter the incidence of posttransplant complications and improve our patients’ quality of life?