Episode 008 Professor Debbie Shawcross – the gut-liver-brain axis, the microbiome in liver disease, treating cirrhosis through the microbiome

Inside Matters

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Debbie Shawcross is a clinician scientist and Professor of Hepatology and Chronic Liver Failure at Kings College London. She is a global key opinion leader in hepatic encephalopathy (HE) and has a specific research interest in why patients with advanced chronic liver disease are susceptible to developing an infection. Professor Shawcross also leads the gut microbial manipulation and chronic liver failure laboratory (Shawcross Laboratory) in the James Black Centre, Kings College London. She is the Chief Investigator of the National Institute for Health Research (NIHR) EME-funded PROMISE Trial investigating faecal microbiota transplantation as a treatment for patients with alcohol and metabolic-related cirrhosis and Principal Investigator of the EU Horizon 20:20-funded MICROB-PREDICT Trial.

Liver disease is a growing problem globally, with 40% of adults alive today having excess fat accumulating in their livers. This condition, called fatty liver disease, is a starting point for a range of liver diseases including cirrhosis (scarring of the liver) and liver cancer.

There is a known link between the gut, liver and brain. These connections and interrelationships are called the ‘gut-liver-brain axis’. The liver and the blood are connected anatomically through the hepatic portal vein. The gut and the brain are connected anatomically through a nerve called the vagus nerve. More generally, the organs are connected through metabolites and signalling molecules produced by the gut microbiome that can travel in the blood.

Multiple studies that have been conducted in humans and animals have shown that the microbiome plays a fundamental role in the development of liver disease and is therefore a promising potential target for prevention/treatment. In the episode, Professor Shawcross provides an excellent overview of what changes to the microbiome occur and why these are important. Briefly, in patients with liver disease, there is lower bacterial microbiome diversity (fewer species) and within the species that are residing, there are relatively higher proportions of bacteria that cause inflammation, as well as bacteria that are resistant to antibiotics (multi-drug resistant organisms ‘MDROs’). Additionally, in liver disease, a barrier that prevents bacteria from seeping out of the intestine into the blood/body becomes damaged and ‘leaky’. This process constellation results in something called ‘leaky gut’.

As patients get sicker with the liver disease they progress to cirrhosis, and patients with cirrhosis can suffer from life-threatening complications, such as hepatic encephalopathy (HE). HE is a devastating condition that has parallels to dementia and severely impacts the quality of life in patients suffering from the disease. The current standard of care (best available treatment) for HE is the combination of a laxative and an antibiotic, both modulating the gut microbiome. The treatments are inadequate through and there is still a high unmet need. Professor Shawcross believes that intestinal microbiota transfer (IMT) could be an effective solution that decolonises MDROs, improves the gut-intestinal barrier and improves the composition of the microbiome.

Professor Shawcross completed an IMT study in patients suffering from cirrhosis (the PROFIT study) https://kclpure.kcl.ac.uk/portal/en/publications/profit-a-prospective-randomised-placebo-controlled-feasibility-trial-of-faecal-microbiota-transplantation-in-cirrhosis(4c186477-ea55-48eb-b7b9-a4b8b11d5099)/export.html. The results were promising, with IMT being safe, well tolerated and having favourable impacts on the microbiome. The success of this trial enabled Professor Shawcross to raise money from the NIHR to undertake a larger study (the PROMISE trial). Professor Shawcross is also involved in several other studies – the details of which can be found here: https://www.fmt-trials.org. Professor Shawcross’s vision is to develop new treatments for patients with liver disease that modulate the microbiome.

Dr James McIlroy and Professor Shawcross also discussed a number of other topics such as the microbiome in depression, the potential importance of coffee for liver health and much more.

00:39 Faecal microbiota transplantation (FMT) and the PROFIT trial

11:38 The microbiome in liver disease

13:58 The history of FMT in liver disease

18:35 Microbiome diversity

20:03 The impact of the pandemic on the microbiome

22:14 Types of liver disease

25:32 Treating cirrhosis

26:44 Hepatitis C and Hepatitis B

29:40 Fatty liver and the microbiome

32:27 Animal models and liver disease

33:15 Ammonia and liver disease

35:07 Hepatic Encephalopathy

39:15 The gut barrier

41:52 Hepatic Encephalopathy

46:40 The PROMISE trial

54:24 The liver and mental health

58:37 The threat of antimicrobial resistance

1:02:22 The FERARO trial

1:03:30 Coffee and the liver

1:05:33 Probiotics in liver disease

1:09:15 Veganism

1:10:40 What makes a good FMT donor

1:12:30 Antibiotics before FMT

1:14:16 Diet and FMT