Gut microbes control liver genes by flipping DNA switches

A local research study led by scientists from the A*STAR Genome Institute of Singapore (A*STAR GIS) has uncovered how the gut microbiome can influence gene activity in the liver by acting on short stretches of regulatory DNA that function like molecular "switches". By testing the activity of more than 100,000 human DNA switches linked to liver biology and comparing results from both in vitro and in vivo approaches, the team identified which switches operate under real physiological conditions and how microbial signals can modify their activity. This provides a clearer biological basis for how gut microbes shape liver function, offering new avenues for precision diagnostics and targeted therapies for liver disease. The findings were published in Molecular Cell.

The liver plays a central role in metabolism and immune regulation, and growing evidence links gut microbial imbalance to liver diseases. While gut microbial imbalance has been linked to liver diseases, the pathway connecting gut signals to liver gene control has remained unclear.

A key challenge is that genes are not controlled only by their own sequences. They are heavily influenced by nearby regulatory elements, often described as DNA switches, that determine when a gene is used and how strongly it is expressed. Identifying which of these switches are truly active in living tissue is critical for pinpointing actionable drug targets.

To identify this, the researchers conducted a high-throughput evaluation of over 100,000 human regulatory DNA elements associated with liver biology. These DNA elements were sourced from a publicly available international research dataset.

The study found that only a minority of the tested DNA switches were active in living liver tissue, and these active switches were mainly linked to genes involved in metabolism and immune responses-key pathways implicated in liver disease and therapeutic intervention.

Importantly, a substantial portion of these in vivo-active switches were responsive to changes in the gut microbiome. When the microbial community shifted, the activity of specific DNA switches shifted as well, along with the expression of the genes those switches control.

The researchers also demonstrated that certain microbe-derived molecules can directly influence how some switches behave, strengthening evidence that gut microbes can affect liver gene regulation through chemical signalling.

In addition, the team identified a rare genetic variation, predominantly found in East Asian populations, that makes at least one regulatory switch more sensitive to microbial inputs, highlighting how genetic differences can shape individual responses to the microbiome, an important consideration for precision health approaches.

By showing that microbial signals can act through specific DNA "switches" in living liver tissue, this study strengthens the evidence behind the gut-liver link in disease. The findings could also drive practical implications for precision medicine and therapeutic development through:

• Improved target selection: identifying the DNA switches that function in living liver tissue can improve how drug targets are chosen, helping research move faster toward treatments that are more likely to succeed in patients.
• Patient stratification: Genetic differences that alter sensitivity to microbial signals can help explain why people with similar risk factors can experience different disease trajectories or respond differently to treatment.
• New therapeutic opportunities: The findings could help inform future strategies for liver disease management that incorporate gut-focused approaches, expanding treatment options beyond conventional therapies.

We are excited to see how these findings can support the development of microbiome‑informed biomarkers and treatment strategies, and guide gut-targeted or gene‑regulatory interventions to prevent or improve liver disease cases."

Dr. Benson Chen, Principal Scientist at A*STAR GIS

"This work strengthens the scientific base for understanding liver health in the context of the whole body," said Dr Wan Yue, Executive Director at A*STAR GIS. "By identifying functional regulatory switches in living tissue, it equips the research community with a more reliable framework for discovering targets and developing precision interventions."

The research team is now working with clinical partners to translate these findings into patient-relevant insights, focusing on identifying microbial and genetic markers that can support more personalised approaches to liver disease.