Polymyositis (PM) and dermatomyositis (DM) are autoimmune muscle diseases characterized by an infiltration of inflammatory cells in the muscle tissue (Ricroch and Hénard-Damave, 2016), and both belong to the category of idiopathic inflammatory myopathies (IIM) (Findlay et al., 2015). The incidence rates for these diseases range from 4.27 and 7.89 per 100,000 person-years, with prevalence rates ranging from 9.54 to 32.74 cases per 100,000 individuals (Bernatsky et al., 2009; Furst et al., 2012; Smoyer-Tomic et al., 2012). PM is more common in women and African Americans, while DM primarily affects children and adults (Amato and Barohn, 2009). Recent studies have implicated the potential role of the gut microbiota in the development of various autoimmune diseases, including PM and DM (Findlay et al., 2015). Understanding the underlying mechanisms is critical for future treatment and prevention of PM/DM (Li et al., 2021).

The gut microflora has always been a more popular topic (De Luca and Shoenfeld, 2019). Compared to other parts of the body, the intestinal flora has the largest number and variety of bacteria (Zhufeng et al., 2022), with about 35,000 species. Human gut microbes are determined by a combination of genetic, epigenetic, and dietary factors. Interestingly, several studies have shown that gut microbiota plays a key role in autoimmune diseases by altering the abundance of microbial metabolites for immunomodulatory functions (Findlay et al., 2015). In particular, the Firmicutes (FC) and Bacteroidetes (BT) phyla play important roles in nutrient metabolism, antimicrobial protection, and immunomodulation (Geuking et al., 2011; Chung et al., 2012; Jandhyala et al., 2015). Previous studies have shown that the human gut microbiota is determined by a combination of genetic, epigenetic, and dietary factors. Recent studies have revealed the potential role of gut microbiota dysbiosis in the pathogenesis of various autoimmune diseases, including PM and DM (Findlay et al., 2015). Moreover, the dysregulation of gut microbiota has been associated with several human diseases, such as inflammatory bowel disease (IBD), metabolic disorders like diabetes and obesity, allergic diseases, and neurodevelopmental disorders (Bisgaard et al., 2011; Karlsson et al., 2013; Ferreira et al., 2014). However, the specific causal relationship between different gut microorganisms and the development of PM/DM remains uncertain and requires further research (Liu et al., 2023).

To address the need for causal inference and identify the primary influencing factors within the gut microbiome, we conducted a Mendelian randomization (MR) analysis. MR analysis was employed as a driving force for further research to meet the need for causal inference and to identify key factors influencing the gut microbiome. By utilizing genetic instruments to minimize confounding factors, MR analysis enables the assessment of causal effects and aims to uncover the potential relationship between gut microbiota and polymyositis (PM) and dermatomyositis (DM). This analysis furthers understanding of the role of gut flora in PM/DM by identifying relevant gut microbes to facilitate early disease screening, implementation of interventions, and personalized healthcare (Bowden and Holmes, 2019).

Previous observational studies have emphasized the link between reduced microbial diversity and DM, but a causal relationship has not been established (Zhufeng et al., 2022). In addition, there is a dearth of research on the key gut microbiota that may impact the development of PM. This study aims to elucidate the specific gut microflora that potentially contribute to the onset of PM/DM and assess their potential as novel targets for treatment. Notably, as muscle biopsy is invasive and required for definitive PM/DM diagnosis (Findlay et al., 2015), the non-invasive, convenient, and rapid fecal testing for gut flora offers promising opportunities. It is anticipated that the use of fecal testing of intestinal flora will enable early identification of patients with PM/DM and provide personalized therapeutic interventions.

This study represents the first attempt to investigate the causal relationship between gut microbiota and PM/DM using a two-sample MR analysis. Our findings reveal five different bacterial genera (Alloprevotella, Ruminococcaceae, Anaerotruncus, Sutterella, and Dialister) that are associated with PM and DM. Notably, the genus Ruminococcaceae was found to be causally involved in both conditions, which may allow us to early prevention strategies rather than just treating the disease after it has progressed (Xi et al., 2023). It is also worth noting that muscle biopsy is invasive and requires a definitive diagnosis of PM/DM (Findlay et al., 2015), and that non-invasive, convenient, and rapid fecal testing for intestinal flora offers excellent opportunities.

Gut microbes associated with PM and DM play an important role in prevention and treatment. One particular bacterium we studied, Ruminococcaceae (De Weirdt and Van de Wiele, 2015), belonging to the Clostridium sp. Blautia genus in the Lachnospiraceae family (Azzouz et al., 2019). It is a strictly anaerobic bacterium known for its ability to promote intestinal health by producing butyrate and other short-chain fatty acids (SCFA) (Gu et al., 2022). Ruminococcaceae is naturally present in the colonic mucosa of healthy individuals and has been found to play an important role in the development of various autoimmune diseases such as ankylosing spondylitis, lupus, and inflammatory bowel disease (Azzouz et al., 2019; Zhang et al., 2021). Recent reports have shown that Ruminococcaceae is present in high abundance in patients with these conditions.

Through our research, we discovered that the relative abundance of Ruminococcaceae may be related to disease activity in PM as well as DM. Although Ruminococcaceae are commonly found in low levels in the feces of healthy populations (Liu et al., 2008), even patients with mild disease activity showed higher-than-normal levels of Ruminococcaceae. We observed that patients with high disease activity had even higher levels of Ruminococcaceae, leading us to hypothesize that increased activity of this bacterium could raise the risk of developing PM/DM. Considering this association, monitoring the abundance of Rumenococcaceae flora at an early stage can provide targeted recommendations for preventive and therapeutic approaches.

Several studies have indicated that butyrate-producing bacteria promote the development of regulatory T cells (Tregs) in the gut-associated lymphatic system, which helps restore immune homeostasis and reduce the risk of autoimmune disease pathogenesis (Chen et al., 2020; Zhufeng et al., 2022). Additionally, butyrate production by Ruminococcaceae is known to enhance gut health, support epithelial cell function and morphology, and regulate the balance of intestinal flora (Zhufeng et al., 2022).

However, it is important to note that butyrate production by Ruminococcaceae inhibits histone deacetylase (HDAC), which can affect the accumulation of immune-related molecules and CD8+ T cells. The increase in CD8+ T cells has been associated with muscle fiber destruction observed in PM, suggesting a potential mechanism linking Ruminococcaceae and an increased risk of PM. Furthermore, evidence from observational studies, MR analyses, and clinical trials suggests that the effects of Ruminococcaceae may vary depending on the specific species and strain. Genomic analysis has revealed that certain Ruminococcaceae strains associated with autoimmune diseases are distinct from those found in healthy individuals (Azzouz et al., 2019). However, further investigation at a specialized genomic level is necessary to fully understand this new finding.

Overall, the interactions between Ruminococcaceae and autoimmune diseases like PM involve butyrate production, modulation of Tregs, influence on immune-related molecules and CD8+ T cells, and strain-specific determinants that require in-depth genomic analysis for better insights.

The strength of this study lies in the early monitoring of risk factors and the availability of effective treatment strategies that can minimize the burden of healthcare costs and disease suffering. Our study utilized MR to use genetic letters as IVs, thereby predicting the relationship between gut flora and PM/DM at the genetic level (Xi et al., 2023). The strengths of our study compared with previous studies are threefold: first, it is the first attempt of its kind, giving us more possibilities to study this type of disease; second, it lies in our rigorous selection of IVs and thorough sensitivity analyses to ensure the validity of our causal estimates. During the IV selection process, we employed stringent quality control measures, including the use of independent GW AS SNPs and the assessment of horizontal pleiotropy; finally, the large sample size of this study and the European origin of the participants further enhanced the reliability of our results. These advantages help to deepen our understanding of the relationship between gut flora and PM/DM and facilitate the development of therapeutic strategies for PM/DM.

Indeed, certain limitations in our study should be acknowledged. Firstly, our analysis of the intestinal flora was conducted at the genus level, and a more detailed analysis at the species or strain level could provide deeper insights and improve the accuracy of the findings. By examining specific bacterial species or strains, we could potentially identify more precise associations with PM and DM. Additionally, it is important to consider the age differences in the occurrence of PM and DM. DM shows a bimodal pattern of incidence, with peaks in childhood and later between the ages of 50 and 70 years. On the other hand, PM is rare in childhood and typically occurs after the second decade of life. Furthermore, both conditions are more common in females (Dalakas and Hohlfeld, 2003; Khan and Christopher-Stine, 2011). Gender differences are known to exist in autoimmune disorders, but our study did not explore the gender-specific effects of the gut microbiota on PM and DM. Future research should aim to investigate these potential differences and explore the specific associations between gut microbiota, gender, and PM/DM. Another aspect to be considered is the threshold used for statistical significance. In our study, we employed a p-value threshold of p < 1 × 10⁻⁵, which may have resulted in some significant associations being missed. Future studies aiming to establish a causal relationship between gut bacteria and PM/DM should consider using a more stringent threshold to ensure robust findings.

Moving forward, it is important for future studies to address these limitations. More detailed analysis at the species or strain level, consideration of age and gender differences, and the use of appropriate statistical thresholds will enable a more comprehensive understanding of the relationship between gut microbiota and PM/DM and provide more reliable strategies for early monitoring and treatment.

In Summary, our study reveals the causal impact of specific gut microbiota on PM/DM. This finding opens up new avenues for future studies of these diseases. In particular, our finding of a consistent association between Ruminococcaceae and PM and DM could provide a promising direction for early prevention of the disease. These findings contribute to a better understanding of the intricate relationship between the gut microbiota and PM/DM. In addition, more in-depth investigations at a finer taxonomic level and consideration of the influence of gender will enhance our knowledge and potentially lead to the study of therapeutic interventions targeting the gut microbiota for the effective management of these diseases. It is important to note that these findings are based on the current scientific evidence and the interpretation of the study results. For these individuals with abnormal intestinal flora, it is important to consider early and aggressive correction of intestinal dysbiosis, which can be done through dietary changes, probiotic supplementation, and increased physical activity. Especially for patients with dysbiosis of the Ruminococcaceae, direct oral administration of probiotics may be considered. Precise personalized treatments, such as individually testing the individual gut microbiota, designing probiotic strains that are relevant to a particular individual person, dietary changes, and administration of specific probiotic preparations may help to improve muscle inflammatory responses and symptoms and improve the quality of life of patients with PM/DM in the early stages of the disease, leading to secondary prevention of the disease. As research progresses, new findings and insights may further shape our understanding of these diseases and their relationship with gut microbiota. Consulting with medical professionals and experts in the field can provide personalized guidance and recommendations for individuals experiencing or at risk of developing polymyositis and dermatomyositis.