Plant toxins linked to biliary atresia in newborn animals
Studies in cell and animal models have led to the discovery of a plant toxin that causes changes that resemble the important pediatric liver disease called biliary atresia. Biliary atresia is a disease of the bile ducts that affects newborns and invariably leads to liver failure. The disease is fatal if not treated with surgery in the newborn period or liver transplantation thereafter. In biliary atresia, the bile ducts that drain the liver and deliver bile acids to the intestine become inflamed and scarred, which causes a back-up of bile into the liver, resulting in jaundice and liver failure. Although a rare disease, biliary atresia is still the most common form of severe liver disease in children and is the leading cause for pediatric liver transplantation. Its causes are not known, but both inherited and environmental factors seem to play a role. Clustering of biliary atresia cases within some geographic areas and time periods suggests that an environmental component, such as an infectious agent or toxin, may contribute to the disease.
An insight into a possible environmental factor came when Australian scientists identified a disease of newborn sheep that resembled biliary atresia. Strikingly, outbreaks of this condition occurred in Australian lambs during the immediate period following severe droughts. They subsequently found that pregnant sheep in searching for food would consume plant species that were growing on land that was usually under water. Analysis of the plants eaten by the Australian sheep herds during a recent drought pointed to a species of the genus Dysphania. Scientists in the United States imported samples of these plants from Australia and analyzed their components, isolating and examining 95 distinct fractions. Each of these components was then tested for its effects on the larvae of a small translucent fish called the zebrafish, a “model system” that can be used to identify substances and genes that cause injury or disease states. In one of the plant extracts, they identified a toxin that caused a similar damage to the bile ducts of zebrafish larvae as was described in the newborn sheep. They named this toxin “biliatresone” and showed that in high doses it caused defects in the formation of both the gallbladder and bile ducts of zebrafish larvae. They also found that larvae with a certain genetic mutation were more sensitive to gallbladder and bile duct injury from biliatresone. The region of the zebrafish genome that contained this mutation was sequenced and was found to be similar to regions in the human genome that have been associated with increased susceptibility to biliary atresia in humans. Moving to a mammal model closer to humans, the researchers analyzed cells in culture taken from newborn mouse bile ducts that had been exposed to biliatresone. The exposure reduced the number of hair-like projections called cilia on the cell surface, which perform essential functions, including sensing fluid flow and detecting molecules such as bile acids. In a final experiment, the group used a mouse bile duct cell culture system in which the duct cells form spherical-shaped structures with hollow centers, similar to true bile ducts. Exposure to biliatresone disrupted their hollow centers and proper orientation of the cells, which could obstruct bile ducts in the whole animal and contribute to diseases such as biliary atresia.
These findings of a newly identified plant-derived chemical that is toxic specifically for bile duct cells, particularly in genetically susceptible animals, suggests that this or other similar chemicals in the environment might serve as a trigger for biliary atresia in young humans. Even normal bacteria in the human gastrointestinal tract may produce compounds similar to biliasterone by metabolizing nutrients found in the human diet, such as soy, beets, and chard. This research has also identified pathways that are critically altered in the course of biliary atresia and focused attention on regions of the human genome containing genes that appear to play a central role in this disease. These insights bring new light to our understanding of biliary atresia and point to directions for future research into means of prevention and treatment of this most important and fatal newborn liver disease.