#Singapore #liver dysfunction #NUS scientists #engineered bacteria

Tackling Hepatic Encephalopathy with Engineered Bacteria

Scientists at the National University of Singapore (NUS) have made a significant leap in the treatment of hepatic encephalopathy (HE), a debilitating brain condition that arises from liver failure. This innovative research, spearheaded by Professor Matthew Chang and his team at NUS's Synthetic Biology for Clinical and Technological Innovation and the Yong Loo Lin School of Medicine, unveils a new method of employing engineered bacteria as therapeutic agents.

The Problem of Hepatic Encephalopathy

When the liver fails, toxins that should be cleared from the blood can accumulate, reaching the brain and causing neurological problems. Hepatic encephalopathy can range from mild confusion to severe complications, including coma, impacting the quality of life significantly for patients suffering from liver disease. Traditional treatments like lactulose and rifaximin provide only moderate relief, focusing primarily on reducing ammonia production in the gut but failing to tackle the comprehensive metabolic dysregulation this condition causes.

This necessitates a fresh approach that can address multiple factors contributing to HE simultaneously.

Breakthrough Engineering of Bacteria

The research team has engineered strains of a beneficial gut bacterium, specifically Lactobacillus plantarum WCFS1, into two complementary forms that work synergistically. The first strain has been modified to absorb excess ammonia from the gut, converting it into branched-chain amino acids (BCAAs) — crucial nutrients typically deficient in HE patients. Meanwhile, the second strain preemptively breaks down L-glutamine, reducing its conversion into ammonia before it can accumulate.

Laboratory experiments demonstrated that this engineered bacterial combination could significantly lower ammonia levels in the blood, even achieving reductions up to tenfold. Moreover, the key metabolic imbalances associated with hepatic encephalopathy were effectively addressed, leading to noticeable improvements in cognitive functions and anxiety-like behaviors observed in tests.

Advantages Over Traditional Treatments

The findings reveal that these engineered bacteria outperform traditional treatments like rifaximin. The bacterial cocktail not only showed better results in improving both cognitive abilities and anxiety but also maintained the gut microbiome's natural composition, something rifaximin disrupts. Furthermore, long-term safety assessments indicated no toxicity in the subjects as the engineered bacteria were cleared from the body within 72 hours following treatment.

A New Class of Precision Therapeutics

This groundbreaking research establishes a versatile platform for what Professor Chang describes as a new class of precision therapeutics. The modular nature of the bacterial strains means they can be adapted for other diseases linked to the gut-liver-brain axis, such as certain metabolic disorders beyond hepatic encephalopathy.

In conclusion, this study not only signals a pivotal stride in the fight against hepatic encephalopathy but also paves the way for future microbiome-directed therapies.

With a patent application filed to advance this program into clinical practice, the team’s next steps will focus on extended evaluations and adaptations aimed at numerous metabolic conditions.

"Our ultimate aim is to bring these innovative treatments to the clinic, creating a new generation of programmable, microbe-based therapies," stated Professor Chang.

For more details on their findings, visit NUS's Website.