Hepatic encephalopathy arises when a failing liver allows toxins, ammonia chief among them, to reach the brain. Existing management relies largely on antibiotics that suppress ammonia-producing gut flora, with the collateral cost of disturbing the microbiome. Researchers at the NUS Synthetic Biology for Clinical and Technological Innovation centre, with colleagues from the Yong Loo Lin School of Medicine, have taken a more targeted route by engineering the gut bacteria themselves.
Two strains were derived from Lactobacillus plantarum WCFS1, a common gut resident. The first absorbs ammonia from the gut and converts it into branched-chain amino acids, which patients with liver failure often lack, turning a toxin into something nutritionally useful. The second degrades L-glutamine before it can be metabolised into further ammonia, cutting off a precursor rather than mopping up the product. Administered together, the two act at different points in the same pathway.
In laboratory studies the combination reduced circulating ammonia by up to tenfold and brought brain ammonia close to healthy levels. Compared with rifaximin, a widely prescribed antibiotic, it produced greater improvements in measures of anxiety and short-term memory, reduced brain inflammation and preserved gut microbial diversity. The engineered bacteria were well tolerated and cleared within three days of the final dose. The work was published in Cell and a patent application has been filed.
The modularity is what makes this more than a single therapy. Because the chassis organism and the delivery route stay fixed while the metabolic function is swapped, the same platform could in principle be retargeted at related metabolic disorders such as urea-cycle defects. Living therapeutics that clear quickly after dosing also sidestep some of the containment concerns that have slowed engineered-microbe medicine.