MASH is a serious form of fatty liver disease that affects about 7% of people worldwide. It can progress to cirrhosis, liver cancer, and liver failure, yet effective treatment options remain limited.

The investigational compound, known as DT-109, is a glycine-based tripeptide. Researchers found that it reversed MASH in animal models by interrupting a harmful biological process linking the gut and liver.

“We see clear evidence that DT-109 protects the gut epithelial barrier, reducing the systemic influx of harmful microbial products that are thought to contribute to MASH development and progression,” said Eugene Chen, M.D., Ph.D., senior author of the study and Frederick G. L. Huetwell Professor of Cardiovascular Medicine at the University of Michigan Medical School.

“This compound shows benefits to the gastrointestinal system and has great potential as a treatment for MASH.”

How Gut Bacteria Can Drive Liver Disease

Earlier studies from Chen’s laboratory had already shown that DT-109 could improve MASH in animals. The new research explains how the compound produces those benefits.

The team first identified a major contributor to the disease: an overgrowth of the bacterium Clostridium perfringens, which generates ammonia inside the gut.

High ammonia levels damage the lining of the digestive tract, weakening the intestinal barrier. Once that protective barrier is compromised, harmful microbial products can enter the bloodstream, reach the liver, and trigger inflammatory immune responses, including excessive activation of CD8+ T cells.

Through a series of experiments, the researchers found that DT-109 disrupted this chain of events, helping restore the health of both the gut and the liver.

DT-109 Restores the Gut Barrier

In both mice and nonhuman primates, DT-109 reduced Clostridium perfringens levels and lowered ammonia production in the intestines. As a result, the intestinal barrier became stronger, limiting the movement of harmful substances from the gut into the body.

The results were especially encouraging in nonhuman primates, whose liver biology and gut microbiota more closely resemble those of humans. In these animals, DT-109 reduced liver inflammation and significantly improved the severity of MASH.

“DT-109 connects microbiota modulation with liver protection by restoring gut barrier integrity and limiting the systemic translocation of ammonia and other pro-inflammatory microbial products within the gut-liver axis,” said Jifeng Zhang, Ph.D., co-author and research professor of cardiovascular medicine at U-M Medical School.

“We also found that DT-109 primarily acts in the gastrointestinal tract, but its reach stretches much further.”

Potential Benefits Beyond MASH

The researchers believe DT-109 may have uses beyond treating fatty liver disease.

Previous studies have shown that the compound can reduce the formation of atherosclerosis plaques and prevent vascular calcification in nonhuman primates, suggesting it could also become a treatment for cardiovascular disease.

Because breakdown of the intestinal barrier has also been linked to several digestive disorders, the team believes DT-109 could eventually be explored as a treatment for conditions such as inflammatory bowel disease (IBD).

Future research will focus on additional testing needed to move DT-109 into clinical trials and evaluate its safety and effectiveness in people.

“This study presents novel evidence about the pathogenesis of MASH and provides excitement about a therapeutic avenue to explore for a condition that remains difficult to treat,” said Elliot Tapper, M.D., Academic Director of Hepatology at Michigan Medicine.

“What patients with MASH need is a safe and effective therapy capable of improving their liver and heart health — of course we are excited about these developments.”

Additional authors include Yang Zhao, Ph.D., Ying Zhao M.S., and Yanhong Guo, MD., Ph.D., all of the University of Michigan. Additional co-authors are listed in the published study.

Funding and Disclosures

Ying Zhao, Oren Rom, Jifeng Zhang, and Y. Eugene Chen are inventors on the patent application (Tripeptides and treatment of metabolic, cardiovascular, and inflammatory disorders).

Chen is also an inventor of DT-109. The University of Michigan has patented the compound and licensed it to Diapin Therapeutics. Chen and the university hold an ownership interest in the company. Diapin Therapeutics supplied DT-109 for the study and is continuing to develop the compound.

The study protocol involving humans, all amendments and the informed consent form were reviewed and approved by the Institutional Review Boards at each site, including the First Affiliated Hospital of Xi’an Jiaotong University (approval number: XJTU1AF2023LSK330), and the Institutional Review Board of Jinan University (approval number: 2016-017) and the University of Hong Kong/Hospital Authority Hong Kong West Cluster (approval number: UW 20-700). All experimental protocols involving non-human primates were approved by the Laboratory Animal Care Committee of Xi’an Jiaotong University (approval number: 20191278) and the Institutional Animal Care and Use Committee of Spring Biological Technology Development Co., Ltd. (approval number: 201901). The study was performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

In an earlier study, Elseline Hoekzema and colleagues became the first to demonstrate that pregnancy changes the structure of the human brain. They also showed that pregnancy affects how the brain functions. For this latest research, the team followed 110 women over time. Some were expecting their first child, some were pregnant with their second, and others remained childless. By performing repeated brain scans, the researchers tracked how the brain changed throughout the study.

“With this, we have shown for the first time that the brain not only changes during the first pregnancy, but also during a second,” says Hoekzema, head of the Pregnancy Brain Lab at Amsterdam UMC. “During a first and second pregnancy, the brain changes in both similar and unique ways. Each pregnancy leaves a unique mark on the female brain.”

Brain Networks Shift in Different Ways

The researchers found that a first pregnancy produced the largest changes in the structure and activity of the brain’s Default Mode Network, a system involved in self reflection, social thinking, and other important mental functions.

During a second pregnancy, this same network changed again, although to a lesser degree. Instead, the most noticeable changes occurred in brain networks responsible for directing attention and responding to sensory information.

“It appears that during a second pregnancy, the brain is more strongly altered in networks involved in reacting to sensory cues and in controlling your attention,” explains researcher Milou Straathof, who analyzed the data. “These processes may be beneficial when caring for multiple children.”

Brain Changes Linked to Maternal Bonding and Mental Health

The study also uncovered a relationship between pregnancy related brain changes and the emotional bond between mother and child. This connection was stronger after a first pregnancy than after a second.

Researchers also identified links between structural changes in the brain and peripartum depression during both first and second pregnancies. According to the team, this is the first evidence that changes occurring in the brain’s cortex during pregnancy are associated with maternal depression.

The timing of these associations differed depending on pregnancy history. Among first time mothers, they were most apparent after childbirth. For women expecting a second child, they were more noticeable during pregnancy.

“This knowledge can help to better understand and recognize mental health problems in mothers. It is important that we understand how the brain adapts to motherhood.”

Understanding the Maternal Brain

The findings offer new insight into the remarkable adaptability of the maternal brain. Although most women experience one or more pregnancies during their lifetime, scientists are only beginning to understand how pregnancy influences the brain over the long term.

The researchers say these discoveries help fill an important gap in knowledge about women’s biology and could eventually improve care for mothers, including efforts to prevent and treat postpartum depression. The study also highlights the brain’s remarkable ability to continually adapt to major life experiences such as pregnancy and motherhood.

The breakthrough was led by Associate Professor Kezilbeiek Shawulienu in collaboration with Aalto University researchers, including Professor Peter Liljeroth and Professor Jose Lado. The team fabricated the material by growing an atomically thin film consisting of just two layers of tin telluride (SnTe) on top of a niobium diselenide (NbSe₂) substrate.

Atomically Thin Crystal Reveals Unique Quantum States

To examine the material’s properties, the researchers used molecular beam epitaxy together with low temperature scanning tunneling microscopy, allowing them to probe its electronic behavior with atomic level precision.

Their measurements revealed pairs of conducting edge states, a defining feature of topological crystalline insulators. These special pathways allow electrons to travel along the edges of the material and are protected by the symmetry of the crystal lattice.

Strain Controls the Material’s Quantum Properties

The conducting edge states appear within a large electronic band gap of more than 0.2 electron volts (eV). The team found that the tin telluride film is compressed by the underlying substrate, creating strain that is essential for stabilizing the material’s topological state.

Even more importantly, the researchers demonstrated that these edge states can be adjusted by changing the strain, offering a practical way to tune the material’s electronic behavior for future technologies.

Potential for Future Quantum Electronics

First principles quantum mechanical calculations confirmed that the observed edge states have a topological origin. The team also examined how neighboring edge states interact, finding that their energy levels shift because of a combination of electrostatic interactions and quantum tunneling.

Because the material has a relatively large band gap, its topological properties are expected to remain stable even at room temperature. That makes it a promising platform for exploring strain tunable two dimensional topological states and could support future advances in spin based electronics and nanoscale devices.

The findings were published in the journal Nature Communications.