Alterations in liver metabolism experienced by individuals with Down syndrome

Researchers at the University of Colorado Anschutz Linda Crnic Institute for Down Syndrome (Crnic Institute) have uncovered compelling evidence that individuals with Down syndrome experience significant alterations in liver metabolism, including elevated levels of bile acids in the bloodstream and other biomarkers of liver dysfunction. The study, published in Cell Reports, suggests that these changes may be modifiable through diet, providing hope for improved health outcomes.

Results identify unique liver dysfunction in Down syndrome

The liver is a dynamic and vital organ that removes toxins from blood, produces bile for fat digestion, metabolizes nutrients, and makes proteins for blood clotting, making it essential for detoxification, metabolism and immunity. Using multiomic analysis of plasma samples from more than 400 research participants in the Human Trisome Project, a large cohort study of the population with Down syndrome run by the Crnic Institute, the team identified consistent elevations in bile acids across the lifespan, independent of body mass index (BMI) or co-occurring conditions. Bile acids are molecules made from cholesterol in the liver that are crucial for digesting fats and fat-soluble vitamins in the small intestine, while also acting as signaling molecules that can regulate metabolism and inflammation.

The study also demonstrated that hepatocytes, the most abundant cells in the liver, derived from induced pluripotent stem cells donated by individuals with Down syndrome exhibit intrinsic metabolic dysfunction, including altered bile acid production and abnormally high fat storage. These cellular findings reinforce the systemic observations in research participants and point to a genetic basis for liver abnormalities in Down syndrome.

To better understand the mechanisms underlying liver dysfunction in Down syndrome, Crnic Institute researchers turned to the Dp16 mouse model, which mirrors many genetic features of Down syndrome. These mice exhibited striking abnormalities in the liver, including inflammation, fibrosis, and a ductular reaction, a phenomenon involving bile duct proliferation and remodeling of blood vessels. Metabolomic analysis revealed elevated bile acids like those observed in people with Down syndrome, and gene expression profiling uncovered widespread disruptions in metabolic and inflammatory signaling pathways. Notably, dietary fat intake profoundly influenced these outcomes: mice fed a high-fat diet developed steatosis, a form of liver disease, and exacerbated liver injury, while a low-fat diet mitigated these effects.

Our data show that Down syndrome profoundly impacts hepatic metabolism. Importantly, we found that dietary fat intake can exacerbate or ameliorate these effects in the mouse models, suggesting that nutrition could play a key role in managing liver health in this population."

Kelly Sullivan, PhD, Senior Author and Associate Professor of Pediatrics, University of Colorado Anschutz

"The study demonstrates the importance of combining human research studies with cellular and animal models to drive scientific discovery," says Lauren Dunn, PhD, lead author of the study. "These findings open the door to practical interventions, where something as simple as dietary modification could significantly improve liver and overall health."

A healthy liver is vital to living longer with Down syndrome

Liver disease affects up to 100 million adults in the U.S., yet its prevalence in Down syndrome has been poorly understood. This research provides comprehensive evidence of liver dysfunction in Down syndrome and underscores the importance of early monitoring and dietary strategies to reduce risk.

"The liver is an incredibly important organ for many biological functions across the lifespan, even mild liver dysfunction can have broad impacts on human health," says Joaquín Espinosa, PhD, executive director of the Crnic Institute and professor of Pharmacology. "The fact that liver dysfunction had not been well documented in this population until now highlights the value of transformative research funding through the National Institutes of Health INCLUDE Project and the Global Down Syndrome Foundation."

"GLOBAL is so grateful to our donors and research participants who make this kind of breakthrough research possible," says Michelle Sie Whitten, president & CEO of the Global Down Syndrome Foundation (GLOBAL). "Our dedicated scientists understand the importance of a healthy liver and related functions. With additional research in this area, we hope that more detailed information on diet and other treatments will help my 22-year-old daughter and millions of others with Down syndrome to live longer, healthier lives."

The research team plans to explore clinical interventions, including low-fat diets and lifestyle modifications, to determine their impact on liver health in individuals with Down syndrome.