Just a gut feeling

BGI study finds gut and oral microbiomes relevant to early diagnosis and treatment of rheumatoid arthritis

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SHENZEN, China—With an eye toward the future of personalized medicine and caring for a growing population of elderly citizens, researchers from BGI and the hospital of Peking Union Medical College have discovered a more effective way to treat rheumatoid arthritis (RA), a debilitating autoimmune disorder that often strikes older people, thus opening the door to microbiome-assisted personalized treatments. BGI’s recent discovery was published online July 27 in Nature Medicine.
More than 50 million people worldwide suffer from painful bouts of RA, while patient mortality increases due to cardiovascular and other systemic complications, said Zhang Dongya, a lead researcher in the BGI study. Bacterial infection has also long been suggested to relate to RA. However, the identity and functional capacity of the RA-associated bacterial agents have been largely unclear. That fact alone presents a major hurdle for healthcare professionals.
“Microbial infection has long been suspected to trigger RA,” Dongya tells DDNews. “However, the identity and pathogenicity of specific microbes have remained unclear ... we decide to carry out a MGWAS (metagenome-wide association study) to decode the relationships between oral and gut microbial communities and the pathogenicity and protection of RA.”
BGI “plays one of the leading roles globally in association studies between gut microbiomes and complex diseases,” Dongya says. “This RA study and other MGWASs we published before established the connection between RA and bacteria in our mouths and guts for the first time in a large-scale population, and with astonishing discoveries in functional details of those RA-characterized bugs.”
These discoveries have “provided us a new picture of this worldwide disease and will definitely facilitate our understanding and future treatment of RA,” he adds.
“Our understanding of the pathogenicity of RA is still very limited,” Dongya says. “Our study looked into the disease at a novel aspect and discovered that specific microorganisms such as Lactobacillus salivarius are enriched in the dental plaque, saliva and stool of RA patients, and aberration in citrulline may directly lead to the disease.”
Dongya reports that he and his colleagues have also developed a novel method for early diagnosis of RA based on gut microbiome, adding: “However, as to the complexity of RA, we are still far away from the full understanding of this disease.”
The Nature Medicine study offers the opportunity to look into the potential disease markers for the development of diagnostic technologies, but Dongya stresses that while it would facilitate the early diagnosis of RA, it cannot replace the current clinic practice for RA identification.
Recently, “DMARDs (disease-modifying antirheumatic drugs) are first- line medications used for RA treatment, and glucocorticoid, NSAIDs (nonsteroidal anti-inflammatory drugs) and biologic agents are frequently employed as well, and the use of these drugs depends on the symptoms and severity of RA patients,” he says. “But we think that gut and oral microbial will be most useful for RA treatment in the future.”
The BGI study gave researchers more insight than expected, and with the new RA insights, the next logical leap was to consider that many immune system diseases are likely influenced by disorder in oral and gut microbial communities. As Dongya recalls, “I thought, then why don’t we take a look at other immune diseases such as ankylosing spondylitis, systemic lupus erythematosus, etc.? As I mentioned, we are also working on the development of diagnostic strategies based on gut and oral microorganisms as our answer to personal precision medicine in the future. Personalized treatment is one of our goals. However, much more information is still needed to understand the relationship between RA and human microorganisms.”
The researchers will also be looking at proteomic features and metabolites in future association studies.
DMARDs alleviate but do not cure RA, and present possible severe side effects. A comprehensive understanding of the RA-associated microbiome holds promise for new advancement in RA pathophysiology, as well as early diagnosis and precision treatment, BGI researchers observe.
MGWASs have proved to be a powerful approach to study gut microbiomes for type 2 diabetes, colorectal cancer and other diseases, but this is the first study to also address dental and saliva microbiomes, according to BGI. The researchers found that Haemophilus influenza is depleted in RA patients at all three gut and oral sites and negatively correlates with RA auto-antibodies, while Lactobacillus salivarius is over-represented in RA patients at all three sites, especially in the very active cases.
Functional convergence was also observed as the RA gut and oral microbiomes show abnormalities in the redox environment, iron, sulfur, zinc and arginine transport and metabolism, and possible molecular mimicry to RA-related human antigens.
In addition, the study indicates that fecal, dental and salivary microbial markers could all be useful for the diagnosis and management of RA, while the oral microbiome might be more sensitive to DMARD treatment than the gut microbiome.
Microbiome-based classifiers that distinguish between RA patients from healthy controls were constructed for all three body sites, and the use of all three body sites further improved accuracy to nearly 100 percent, BGI stated. The same classifiers were applied to samples after DMARD treatment, and dental samples with low disease activity were often classified as healthy, consistent with clinical relief of periodontitis in RA patients after treatment.
Furthermore, gut and oral microbial markers were identified that possibly distinguish between patients of different disease duration, improvement after DMARDs and types of DMARDs, although validations in additional cohorts would be necessary.
Clinical validation would further deepen researchers’ understanding of RA. BGI expects the metagenome-wide association study will actively promote patient stratification, drug improvement and novel therapeutic targets of RA, and lead to the precise diagnosis and treatment.
In a story published in Financial Times April 6, it appears China has come into its own with genetic testing and medical lab testing. In fact, BGI is poised to become the world’s largest at gene sequencing, and considering the volume genetic data it generates, it is expected to give this company the world’s largest database of genetic information. BGI has 230 of the largest, high-throughput gene-sequencing machines and wants to become the world’s largest genome-mapping company, according to Financial Times.
Ironically, at the same time, it seems China has a shortage of well-trained pathologists, which is why some American lab organizations are establishing medical lab testing ventures in China.
Such developments could mean that, “in just a few years, pathologists and molecular scientists in the United States will be accessing this trove of genetic data as they conduct research to identify new biomarkers or work with clinical specimens,” the news agency said.
Launched in 1999 as the Beijing Genomics Institute, BGI’s first success was a small role in the International Human Genome Project, the only developing nation to do so. That initial foray onto the world stage was followed by a string of achievements, including sequencing the rice genome, which landed BGI on the cover of the journal Science.
BGI has also carried out research on the SARS virus and E. coli, contributed to the International Human HapMap Project and mapped the genomes of species ranging from the giant panda to 40 types of silkworms, according to The New Yorker. Identifying the genes associated with extremely high IQ is among the company’s latest goals.

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