“Living medicines”: Scientists engineer gut bacteria to treat mental health issues in liver disease

Scientists at the National University of Singapore (NUS) have announced a major breakthrough in the treatment of a common endpoint of liver disease — hepatic encephalopathy. The neurological condition is characterized by anxiety, confusion, memory loss, and, in severe cases, coma. The researchers discovered it can be tackled by mediating the gut microbiome. 

The study engineered strains of a naturally occurring beneficial gut bacterium to function as “programmable therapeutics” capable of restoring metabolic balance across the gut, liver, and brain.

According to the authors, the new method offers “distinct advantages” over a front-line antibiotic.

“We found that engineered gut bacteria can simultaneously remove toxic ammonia, restore essential nutrients, and improve brain-related outcomes,” explains study lead professor Matthew Chang from the NUS Synthetic Biology for Clinical and Technological Innovation.

“This directly addresses a major limitation of current treatments, which typically target only a single root cause rather than the full spectrum of metabolic drivers.”

The NUS research team has filed a patent application to support translation of the technology toward clinical use. The team’s next steps include evaluating the long-term performance of the engineered strains and expanding their portfolio of microbes to target other diseases linked to metabolic imbalance.

“Our long-term goal is to translate this work into the clinic and develop a new class of programmable, microbe-based therapies,” adds Chang. “These findings establish a strong foundation toward realizing that vision.”

Full-spectrum alternative therapy

Hepatic encephalopathy occurs when the liver fails and toxins that should be filtered from the blood, such as ammonia, build up and reach the brain. The condition is a common endpoint of liver cirrhosis, driving frequent hospitalizations and placing a heavy burden on global health care systems.

Current treatments offer only partial relief, stress the researchers. The two most common therapies for treating hepatic encephalopathy — lactulose and the antibiotic rifaximin — work by reducing ammonia production in the gut.

However, neither corrects the full spectrum of metabolic disruptions that drive the disease. Patients on these treatments remain vulnerable to recurrence, and rifaximin carries the extra risk of disrupting the gut’s natural microbiome.

The scientists stress that a fundamentally different approach is needed — one that can tackle several disease drivers at the same time. Addressing this, they redesigned a well-characterized commensal bacterium, Lactobacillus plantarum WCFS1, into two complementary therapeutic strains.

Hepatic encephalopathy occurs when the liver fails and toxins that should be filtered from the blood, such as ammonia, build up and reach the brain.The first strain absorbs excess ammonia from the gut and converts it into branched-chain amino acids (BCAAs), essential nutrients that are depleted in hepatic encephalopathy patients. The second strain breaks down L-glutamine in the gut before it can be converted into more ammonia, cutting off a key source of the toxin.

Laboratory studies involved a mouse model of hyperammonemia. After 13 days of daily administration of the treatments, blood samples were collected from mice, and serum levels of ammonia, BCAA, and L-glutamine were measured.

The cocktail of both strains for hepatic encephalopathy demonstrated that the combination reduced circulating ammonia by up to 10-fold and lowered brain ammonia to levels “comparable to those in healthy conditions.”

Additionally, key metabolic imbalances — including depleted BCAAs and elevated L-glutamine — were restored, alongside noticeable improvements in anxiety-like symptoms and cognitive function.

Neuronal signaling was also normalized while neuroinflammation was reduced, suggesting gut metabolic correction can drive benefits in the central nervous system, the authors highlight.

Reprogramming bacteria

The study on these “living medicines” published in Cell illustrates that the engineered bacterial cocktail achieved greater improvements in anxiety and short-term memory, compared to rifaximin.

The engineered strains also preserved the natural diversity of the gut microbiome, which the scientists note is a major advantage over rifaximin. Conversely, the pharmaceutical significantly reduces microbial richness.

In long-term safety studies, the bacteria were well tolerated, showed no signs of systemic toxicity, and were cleared within 72 hours of the final dose.

Engineered bacterial cocktail achieved greater improvements in anxiety and short-term memory, compared to rifaximin. The team’s findings point to a versatile platform for what Chang refers to as “a new class of precision therapeutics.”

Since the bacterial strains are modular — engineered to each perform a specific metabolic task — they could potentially be adapted to target other disorders involving the gut-liver-brain axis, including urea-cycle defects and other hyperammonemic conditions.

“Our study demonstrates the development of a multifunctional, programmable microbial therapy that can coordinate several therapeutic actions simultaneously inside the body,” says Chang. 

“Unlike standard treatments such as rifaximin, which broadly suppress gut bacteria, our approach uses live biotherapeutics to precisely reprogram metabolism while preserving the natural gut ecosystem.”

In other explorations into gut-mediated approaches, an ongoing study by Chinese researchers is investigating how interactions between the brain and gut microbiome contribute to psychiatric disorders. Scientists from the Guangzhou Medical University and the South China University of Technology are leading this clinical research as part of the Brain-Gut Health Initiative.