Researchers investigated an animal model for metabolic dysfunction–associated steatohepatitis (MASH) specifically for children and adolescents. The researchers say that using guinea pigs as a model can help scientists to study disease progression and explore potential treatments for children and adolescents.
About 38% of adults globally have metabolic dysfunction–associated steatotic liver disease (MASLD), which can progress to a more severe disease, MASH, in which fat accumulates in the liver, inflammation progresses and scar tissue forms.
MASH is closely linked to obesity and unhealthy lifestyles. An estimated 5–10% of children and adolescents globally have MASLD, placing them at risk of developing MASH.
Although MASH is somewhat similar for both children and adults, there are notable differences. Studies suggest that MASH progresses more aggressively among children, with liver damage and scar tissue developing more rapidly. Researchers and doctors still lack sufficient knowledge about MASH among children and adolescents and the best treatment approaches.
One challenge is the ethical implications of using children in clinical studies, leaving researchers to rely on animal models to understand diseases among children.
Researchers have now developed a MASH animal model specifically for children. By using guinea pigs, this model may provide valuable insight into how MASH develops among children and adolescents, potentially helping to improve prevention and treatment.
“Since studies are very rarely conducted on children, a reliable animal model that closely reflects children with MASH is essential. Children and adults differ considerably, partly since children are still growing and undergoing hormonal and metabolic changes. We aim to understand how having MASH in childhood affects adult life. For example, does it make people more predisposed to MASH and other diseases in adulthood, even after periods of healthier living?” says a researcher behind the study, Kamilla Pedersen, PhD Fellow, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark.
The research, which was carried out by Kamilla Pedersen and colleagues, including Pernille Tveden-Nyborg, has been published in Nutrients.
Studying children and adolescents with MASH is difficult
Kamilla Pedersen and Pernille Tveden-Nyborg explain that diagnosing MASH with certainty requires a liver biopsy, which is an invasive and risky procedure and therefore seldom performed on children and adolescents. Researchers and doctors therefore have limited knowledge about children and adolescents with MASH.
To address this gap, the researchers developed a guinea pig model for MASH. They highlight that guinea pigs are very effective for modelling human MASH, since it develops similarly in both species.
Researchers have confirmed this similarity multiple times by examining the livers of guinea pigs under a microscope and comparing the findings with human data.
“The close resemblance is quite remarkable," notes Pernille Tveden-Nyborg. “In contrast, other laboratory animals such as mouse and rat models show a MASH progression that is not as similar to the human disease,” she says.
She further explains that guinea pigs are very suitable for studying diseases associated with unhealthy diet among children and adolescents because guinea pigs begin eating solid food immediately after birth and researchers can control their diet almost from the very beginning.
Insight into disease trajectory
The researchers developed a MASH model for children and adolescents by feeding the guinea pigs a diet high in fat, sugar and cholesterol starting just a few weeks after birth.
When the guinea pigs reached an age equivalent to about 20 years for people, the researchers removed their livers and examined them under a microscope, obtaining insight into the characteristics of MASH in young versus adult guinea pigs, mirroring the comparison between MASH among children and adolescents versus adult humans.
This approach enabled the researchers to investigate differences in gene expression and other manifestations of MASH.
“Overall, the guinea pigs develop MASH similarly to children. This model enables us to study MASH more effectively and in depth than if we only had access to blood samples and ultrasound from children,” explains Kamilla Pedersen.
Promising MASH model for children and adolescents
The study primarily validates the MASH model for children and adolescents. Although the young guinea pigs with MASH had less fat in their livers than their adult counterparts, they still exhibited the same level of scar tissue and even more inflammation.
According to the researchers, this indicates that MASH is more aggressive in young versus adult guinea pigs, similar to children and adolescents versus adult humans.
The researchers also compared the livers of the young guinea pigs with reported findings from children and adolescents with MASH and confirmed that the disease characteristics were similar.
Vitamin C may affect MASH
Like humans, guinea pigs are among the few animals that cannot produce vitamin C on their own. This similarity enabled researchers to explore how vitamin C affects MASH in guinea pigs and thereby how it may affect humans.
The researchers divided the guinea pigs into two groups: one received vitamin C supplements, and the other group was vitamin C deficient. Vitamin C deficiency was associated with increased liver inflammation and changes in the epigenetics of liver cells.
According to Pernille Tveden-Nyborg, these findings provide deeper understanding of MASH among humans.
“This suggests that vitamin C deficiency among children and adolescents with MASH may impair the liver cells’ ability to protect themselves against stress from the fat accumulation, influencing the expression of MASH. In addition, vitamin C deficiency can affect genes that promote inflammation, leading to liver damage and scar tissue formation. Notably, increased scar tissue in the liver is an indication of severe liver damage. Our model offers insight into the factors contributing to scar tissue formation and the potential role of vitamin C,” she says.
Testing the effect of a high-fat diet during pregnancy
Using the MASH model, the researchers can conduct new experiments to better understand how children and adults differ in liver disease and how to improve treatment for children and adolescents.
Their ongoing studies include finalising a project investigating how the diet of the mother guinea pigs during pregnancy affects the risk of their offspring developing MASH. They hypothesise that an unhealthy maternal diet during fetal development may predispose children to more rapid disease progression.
In addition, the researchers aim to study how exposure to an unhealthy diet during fetal development or early childhood, followed by a period of healthy diet, might affect the risk profile in adulthood.
“This knowledge can show whether certain people may require special attention because of an increased risk of MASH. Similarly, we can explore the role of vitamin C, in which supplementation might help mitigate disease severity, preventing it from progressing as aggressively. We can investigate these kinds of questions with our model,” concludes Kamilla Pedersen.
