Understanding how microbial imbalances may influence Juvenile Dermatomyositis, a rare immune-mediated disease

“Juvenile Dermatomyositis (JDM) is a rare immune-mediated disease that affects children, leading to muscle weakness and skin rashes,” explains Sean Koester, a current medical student at the University of Kansas who is conducting his honors thesis research in Dr. Neel Dey’s lab at Fred Hutch. The cause for this condition, which is characterized by chronic muscle inflammation, is poorly understood, but it is thought “to involve an interplay of genetic predisposition and environmental triggers, leading to an abnormal immune response that targets the body's own tissues, particularly muscles and skin,” states Koester. There is growing evidence that our microbiome, which includes bacteria, viruses and fungi, plays an important role in regulating our immune responses. In many cases, our microbiomes are beneficial and working for us rather than against us. However, when things get out of whack—for example, when pathogenic bacteria taking over and push out beneficial strains—this imbalance or “dysbiosis” in our microbiome can lead to inflammation and increase susceptibility to various diseases and cancers. Since the microbiome’s composition has been shown to influence the development and progression of immune-mediated diseases, “studying the microbiome of JDM patients could identify specific microbial patterns or imbalances that may be associated with the disease and potentially provide insights into how environmental factors, such as infections or diet, contribute to the onset or severity of JDM. If certain microbes are found to be protective or harmful in JDM, it could lead to novel therapeutic strategies,” describes Koester.

While JDM primarily affects the muscles and skin, it “can carry significant morbidity and mortality due to calcinosis and cardiac, respiratory, and gastrointestinal system involvement—most children will have active disease into adulthood,” Koester explains. With the growing knowledge of the role of the microbiome in inflammatory and immune-mediated conditions, “there is a strong interest by patients and families, as well as industry, to use probiotics (beneficial bacteria) or prebiotics (compounds that promote growth of beneficial bacteria) as adjunct treatment,” he adds. Despite this, no study had investigated the microbiome of JDM patients which would be necessary to know what beneficial strains of bacteria might mitigate disease symptoms and could therefore help formulate JDM-tailored probiotics. The goal of this work was to profile the microbiome of JDM patients “and their healthy family members to identify differences that may be used to leverage therapeutic interventions,” Koester shares. This study, led by Koester, was recently published in Scientific Reports.

Any study involving human subjects is a challenge to conduct, especially when it comes to obtaining meaningful control subjects that are necessary to accurately assess any data collected. Since microbiomes are unique to each individual, it’s even more challenging to identify which microbiome differences are associated with diseases and which are due to person-to-person variability. However, for this work, Dr. Dey shares that “an exciting aspect of this study was the study design [itself]. Our collaborators at Seattle Children’s Hospital and the NIH recruited not just children afflicted with JDM but their entire family units. They selected for patients with an unaffected sibling to enable downstream paired statistical comparisons, thereby allowing us to adjust for (to the greatest extent possible) factors that would affect entire family units such as shared diet and culture, as well as co-habitation, to home in on differences specific to JDM.” Critical to this were Drs. Anne Stevens and Susan Shenoi at Seattle Children’s and Dr. Lisa Rider at the NIH, who were responsible for leading the study design and recruitment processes. In their multi-center cohort study, the researchers asked if JDM is associated with specific oral or gut microbiome signatures. To do so, authors generated 16S rRNA sequencing data to identify specific microbial strains from fecal and oral samples from individuals afflicted with JDM and their healthy family members. While a strength of this study was having familial cohorts recruited which allowed for control of family attributes, a challenge of this work was the lack of a true healthy cohort. “To overcome this challenge, we used previously published data from healthy adults and children to see if there are observable differences between JDM and non-JDM families – which surprisingly there were considerable differences,” explains Koester.

After adjusting for microbiome differences attributed to family, Koester notes, “we found differences in several potentially immunomodulatory bacteria in patients with JDM,” which include differences in Faecalibacterium in the gut and Streptococcus in the oral cavity. However, “future studies will be needed to understand the role of these bacteria in JDM pathogenesis and whether interventions targeting them has therapeutic value,” Koester adds. This work emphasizes the importance of focusing on “family units in characterizing the microbiomes of patients,” the authors describe. More broadly, these findings “raise the question of whether microbiome-based therapies can ultimately succeed in treating individuals in isolation, or whether familial and social network units need to be addressed as a whole.”

“When it comes to JDM, I think the answer to what role the microbiome plays in the disease pathogenesis is a complicated one. There is still so much left to be learned about the microbiome and the role it plays in immune system regulation and how genetic factors influence this relationship. It is also unlikely to be the end all be all. Rather, the microbiome is one piece of the puzzle that when put together with other pieces can pave the way for JDM to develop. Importantly, this study offers a framework to guide future projects and research inquiries into JDM,” acknowledges Koester. Dr. Dey adds, “The microbiome is one piece of the puzzle, and observing dysbiosis is not much different from arriving at the scene of the crime and needing to conduct a forensic investigation to figure out what happened before you got there: it’s tough.”

This work was supported by the National Institutes of Health, the CARRA-Arthritis Foundation, and the Cure JM Foundation.

Fred Hutch/UW/Seattle Children’s Cancer Consortium members Drs. Neel Dey and Anne Stevens contributed to this work.

Koester ST, Chow A, Pepper-Tunick E, Lee P, Eckert M, Brenchley L, Gardner P, Song HJ, Li N, Schiffenbauer A, Volochayev R, Bayat N, McLean JS, Rider LG, Shenoi S, Stevens AM, Dey N. Familial clustering of dysbiotic oral and fecal microbiomes in juvenile dermatomyositis. 2024. Scientific Reports.