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Metagenomic Study Finds Differences in Oral, Gut Microbiomes of Rheumatoid Arthritis Patients

NEW YORK (GenomeWeb) – The oral and gut microbiomes of people with rheumatoid arthritis differ from those of healthy people, according to researchers from BGI and elsewhere. They further reported that this dysbiosis was partially resolved following treatment.

Rheumatoid arthritis is an autoimmune disorder that affects some 1.5 million people in the US and is marked by joint inflammation and fatigue. While BGI's Jun Wang and his colleagues noted that the etiology of the disease remains elusive, they added that both genetic and environmental — including microbial — factors appear to influence disease development.

Wang and his colleagues performed both metagenomic shotgun sequencing and metagenome-wide association studies of fecal, dental, and salivary samples from people with RA and controls, as they reported in Nature Medicine today. The oral and gut microbiomes of people with RA differed from controls in both the composition and functions of the microbes present, but patients treated with disease-modifying antirheumatic drugs (DMARDS) had microbiomes that began to resemble those of controls, they said.

"Our [study] supports the notion that RA represents a state of chronic inflammation that might be provoked or aggravated by the overgrowth of pathogenic bacteria or a lack of immune-modulating commensal bacteria," Wang and his colleagues said in their paper. "These findings are a first step toward microbiome-based therapeutics and patient stratification in preclinical and clinical phases of RA."

To examine the gut and oral microbiomes of RA patients, the researchers collected 212 fecal samples from 77 treatment-naïve patients, 21 patients treated with DMARDs, and 97 controls. They also obtained dental samples from 54 treatment-naïve RA patients and 51 controls, and saliva samples from 51 patients and 47 controls. They noted that 69 participants gave a complete set of all three sample types.

They carried out metagenomic shotgun sequencing on all of these samples. After assembling these sequences, the researchers uncovered gene markers that were enriched in patients as compared to controls and clustered these into metagenomic linkage groups (MLGs).

For instance, they reported that RA-enriched MLGs included Clostridium asparagiforme, Gordonibacter pamelaeae, Eggerthella lenta, and Lachnospiraceae bacterium, and noted that a few control MLGs were negatively correlated with RA MLGs — like Klebsiella pneumoniae and Bacteroides species — which they said suggests an antagonistic or mutually exclusive relationship.

Similarly, the oral microbiomes of RA patients differed from controls, as the researchers found that, among other differences, Rothia aeria was enriched in control saliva, while Rothia mucilaginosa–like MLGs were enriched in RA saliva and dental plaques and Rothia dentocariosa was enriched in RA dental plaques.

In addition, the researchers noted that all three sites shared some microbial alterations. Haemophilus species, they noted, were depleted in RA patients while, Lactobacillus salivarious was enriched at all three sites in RA patients.

Based on the gut MLGs, Wang and his colleagues developed random forest disease classifiers. Their final model included eight gut MLGs and had a specificity of 0.922 and a sensitivity of 0.838, a performance that they said rivaled that of existing classifiers based on serum markers.

They similarly devised classifiers based on dental and salivary MLGs.

Wang and his team also examined how treatment affects the RA microbiome by comparing the relative abundance of control and RA MLGs before and after treatment. They noted greater changes in the oral MLGs than the gut ones, though all did vary after treatment.

In particular, they noted that the amount of the MLG RA-24803 fell after DMARD therapy, especially in patients who experienced moderate or good improvement on the therapeutic.

In addition, their random forest models based on gut salivary MLGs could distinguish patients who experienced improvement on the treatment versus those who did not improve while on the drug.

"Our MGWAS identified compositional and functional alterations in RA-associated gut and oral microbiomes that were partly relieved by DMARD treatment," Wang and his colleagues said.

This, they added, highlights a potential role for the microbiome in diagnosing, determining prognosis, and treating autoimmune disorders like RA.