— The intestinal microbiota may act as a trigger in pediatric enthesitis-related arthritis.
by Nancy Walsh, Senior Staff Writer, MedPage Today December 3, 2014

Alterations in the intestinal microbiota have been identified in children with enthesitis-related arthritis (ERA), suggesting the possibility that the microbiome may play a triggering role in the disease, researchers reported.

Among children with ERA, which is a subtype of juvenile idiopathic arthritis considered to be the pediatric equivalent to axial spondyloarthritis in adults, there were lower levels of organisms of the Faecalibacterium genus compared with controls (5.2% versus 11%, P=0.005), according to Matthew L. Stoll, MDopens in a new tab or window, and colleagues from the University of Alabama at Birmingham.

Specifically, F. prausnitzii constituted 10% of the microbiota of healthy controls compared with only 3.8% in children with ERA (P=0.008).

This decrease has previously been reported among patients with inflammatory bowel disease, and may be relevant because of the potential for this organism to exert anti-inflammatory effects through production of butyrate, the researchers explained online in Arthritis Research & Therapy.opens in a new tab or window

“The human intestine is colonized with an estimated 100 trillion bacteria, a process that begins shortly after birth. It is becoming increasingly clear that these bacteria play important roles in immune function as well as in a variety of autoimmune and inflammatory disorders,” they wrote.

Next-generation sequencing has permitted the full assessment of intestinal microbiota, with distinct alterations identified in a number of inflammatory diseasesopens in a new tab or window such as rheumatoid arthritis and celiac disease. This has sparked interest in the microbiome as an environmental trigger for the diseases.

Furthermore, “intestinal bacteria need not be present in abnormal quantities to trigger arthritis; it is also possible that a pathologic immune response to normal resident microbes may result in disease,” Stoll and colleagues wrote.

For instance, many patients with Crohn’s disease develop antibodies against intestinal microbial flagellinsopens in a new tab or window, and the presence of those antibodies is associated with stricturing disease.

To explore the possibility of abnormalities in commensal quantities and immune responses in children with ERA, the researchers recruited 25 patients and 13 controls.

They performed sequencing of 16S ribosomal DNA on fecal samples of all participants, and ELISAs to measure bacterial IgG and IgA in order to evaluate antigenic reactivity.

Participants’ mean age was 13, and median disease duration was 2.4 years. Among the 25 ERA patients, 11 were female and two had concomitant inflammatory bowel disease. Immunosuppressive therapies were being used by 21.

Sequencing analysis of fecal samples of all 38 children showed that there were notable differences in three taxa other than Faecalibacterium.

As with Faecalibacterium, the ERA patients had lower levels of Lachnospiraceae (7% versus 12%, P=0.020).

However, levels of Bifidobacterium (primarily B. adolescentis) were higher in the ERA group (1.8% versus 0%, P=0.032), as were Bacteroides (21% versus 11%).

“Thus, at the genus and species levels, our data demonstrate some statistically significant differences between patients and controls,” Stoll and colleagues wrote.

Further analysis divided the ERA patients into two clusters. The eight patients in cluster 1 had higher levels of Bacteroides than those in cluster 2 (32% versus 13%, P<0.001), but similar levels of F. prausnitzii (4.7 versus 3.2%, P=0.897).

None of the patients in cluster 1 had high levels of Akkermansia, but 41% of those in cluster 2 had levels of 2% or greater.

“A novel finding of this study is that both Bacteroides species and Akkermansia muciniphila were found to be associated with disease states in largely non-overlapping subsets of ERA patients,” the researchers noted.

Then, to examine the possible influence of immunoreactivity, the researchers conducted ELISA tests against B. fragilis and F. prausnitzii in 31 of the participants, and found that patients in cluster 1, who had higher levels of Bacteroides, also exhibited greater IgA and IgG reactivity against B. fragilis.

Abnormal immune responses to Bacteroides also have been observed in adult patients with ankylosing spondylitis, they pointed out.

The presence of increased levels of A. muciniphila also was of interest. This is a recently identified bacterium that thrives on mucin in the intestine, “suggesting that high quantities could potentially lead to a defect in the intestinal wall barrier function,” they noted.

In addition, the IgA responses to B. fragilis may result in invasion of the intestinal wall and a subsequent systemic immune response.

The study findings represent “the first comprehensive evaluation of the microbiota in pediatric or adult [spondyloarthritis], confirming a potential role for insufficient protective F. prausnitzii in the pathogenesis of ERA and introducing potential novel bacteria as associative agents,” Stoll and colleagues observed.

“These findings suggest that altering the gut microbiota may be beneficial in children with ERA,” they concluded.

Limitations of the study included its small sample size and a lack of information about diet.