Healthcare (Commonwealth Union) – The liver is a key organ of the body as it plays a vital role in detoxification, digestion, energy metabolism regulation among the many key functions it has.
When the liver malfunctions, toxic substances such as ammonia, which are normally removed from the blood, build up and reach the brain. This can cause hepatic encephalopathy (HE), a serious neurological complication of liver disease that causes anxiety, confusion, memory loss, and, in extreme cases, coma. It often develops in patients with liver cirrhosis, leading to frequent hospitalisations and imposing a major burden on patients and health systems worldwide.
Current treatments offer only limited relief. Lactulose and the antibiotic rifaximin are the main treatments, and their main action is to reduce the production of ammonia in the gut, but they do not address the complete range of metabolic disturbances that lead to the condition. Patients are still at risk of relapse and rifaximin could further disrupt the gut’s natural microbiome. What is desperately needed is a new, more comprehensive approach that can simultaneously target multiple disease mechanisms.
A team of researchers at the National University of Singapore (NUS) led by Professor Matthew Chang from the NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI) has recently made a major breakthrough in this area.
Collaborating with colleagues from the NUS Yong Loo Lin School of Medicine, the team engineered strains of a naturally occurring beneficial gut bacterium to act as programmable therapeutics, designed to restore metabolic balance across the gut, liver, and brain. Their findings were published in the journal Cell on 24 April this year.
Engineering Bacteria to Tackle Disease from Multiple Angles has the potential presenting new opportunities to tackle disease. Researchers have transformed Lactobacillus plantarum WCFS1 — a well-studied gut-friendly bacterium — into two therapeutic strains that work together. The first strain captures excess ammonia in the intestines and converts it into branched-chain amino acids (BCAAs), vital nutrients often lacking in patients with hepatic encephalopathy (HE). The second strain prevents conversion of L-glutamine in the gut to more ammonia, the main source of this dangerous toxin. When both strains were used together in animals with, HE, blood ammonia levels were reduced by as much as ten times, and brain ammonia was reduced to levels similar to healthy animals. The treatment also corrected key metabolic imbalances, including restoring BCAAs and reducing high levels of L-glutamine, with benefits in cognitive function and anxiety-related symptoms. Professor Chang said that by engineering gut bacteria, they could remove toxic ammonia, replenish essential nutrients and boost brain function all at once. He said this approach overcomes a key limitation of current therapies that typically only target one cause rather than all the different metabolic problems.
In the lab, treating HE with a combination of both strains reduced blood ammonia levels by as much as tenfold, and lowered ammonia in the brain to levels seen in healthy people. The treatment also improved key metabolic imbalances including restoring BCAAs and lowering high L-glutamine as well as improving cognitive performance and anxiety-related symptoms.
Professor Chang stated that they can take out toxic ammonia, replenish essential nutrients and enhance brain function all in one go by engineering gut bacteria.
He also noted that this approach overcomes a major limitation of current therapies that typically address only one cause rather than the entire spectrum of metabolic dysfunction.
Scientists involved in the study pointed out that it had a clear benefit compared to a frontline antibiotic. In comparison with rifaximin, the specially designed bacterial mix produced greater improvements in anxiety levels and short-term memory. Furthermore, it restored normal neuronal signaling and reduced neuroinflammation, indicating that correcting gut metabolism can have positive effects on brain function. As antimicrobial resistance becomes a serious concern these treatments can become a major solution.
Unlike rifaximin, which significantly diminishes microbial diversity, the engineered strains maintained the natural richness of the gut microbiome—a notable advantage. Long-term safety assessments showed the bacteria were well tolerated, caused no systemic toxicity, and were fully eliminated within 72 hours after the final dose.
“Our study demonstrates the development of a multi-functional, programmable microbial therapy that can coordinate several therapeutic actions simultaneously inside the body,” explained Professor Chang. “Unlike standard treatments such as rifaximin, which broadly suppress gut bacteria, our approach uses live biotherapeutics to precisely reprogramme metabolism while preserving the natural gut ecosystem.”
