Nancy A. Melville

September 20, 2016

GHENT, Belgium — The gut microbiome in carriers of HLA-B27, a signature gene associated with ankylosing spondylitis, is different than that in noncarriers, new research shows.

"In healthy control stool specimens, we found a consistent effect of HLA-B27 on the microbiome," said investigator Matt Brown, MD, director of genomics at the Queensland University of Technology in Brisbane, Australia.

This supports "models in which genes influence the microbiome — presumably through effects on mucosal immunity — and, in turn, cause AS, rather than the effect of AS or its treatment on the microbiome," he said here at the International Congress on Spondyloarthritides 2016.

Dr Brown was involved in a previous study (Arthritis Rheumatol. 2014;67:686-691) that revealed a microbial profile in the ileum of people with confirmed ankylosing spondylitis that is highly consistent with findings from the current study.

That was a "seminal paper," and "the first demonstration in humans that the gut microbiome of AS patients is different from healthy controls (P < .001)," he explained. It raised the critical question of whether ankylosing spondylitis causes microbiome differences, or whether the opposite is true.

For the current study, Dr Brown and his colleagues looked at two large cohorts of healthy people who had not been diagnosed with ankylosing spondylitis.

The first cohort involved 135 stool samples from people undergoing routine colorectal screening. The samples, from six different sites in the colon, were genotyped for HLA-B27, and 16S rRNA sequencing was used to produce a microbial profile.

The investigators found that carriers of HLA-B27 had significantly less Veillonellaceae (P < .001) and Clostridiales (P < .05) than noncarriers, and significantly more Bacteroidaceae (P < .05) and Ruminococcaceae (P < .05).

These findings support the theory that microbiome differences cause ankylosing spondylitis, said Dr Brown.

The Microbiome and Ankylosing Spondylitis

"We do see a very clear distinction between HLA-B27-positive and -negative subjects, with significant P values," he reported. "The pattern was found across all of the different mucosal sites — including the cecum, the left colon, right colon, and rectum — and all were statistically significant."

To further test the findings, Dr Brown and his colleagues evaluated 107 HLA-B27-positive and 1285 HLA-B27-negative stool samples from the TwinsUK cohort of dizygotic twins. Again, the results were consistent, showing that HLA-B27 status is associated with the microbial signature identified in the previous study.

If gut disruptions are a causal factor in ankylosing spondylitis, the intestinal microbiome likely triggers immunologic processes, particularly interleukin-23 production, that lead to ankylosing spondylitis.

These findings have implications for the treatment of ankylosing spondylitis, Dr Brown told Medscape Medical News. "It is known that the treatment of AS is associated with improvement in gut disease, and that the severity of gut disease is linked to the severity of AS," he explained.

Approximately half of all patients with spondyloarthritis show signs of gut inflammation similar to that seen in early Crohn's disease.

"The real implication is that treatments targeting the gut microbiome may be effective in AS and, potentially, in its prevention," Dr Brown added.

But the evidence is far from conclusive, and he cautioned against the use of treatments targeting the microbiome just yet.

The real implication is that treatments targeting the gut microbiome may be effective in AS and, potentially, in its prevention.

"At the moment, there are many people using unproven therapies — such as probiotics and fecal transplantation — with the goal of treating their AS by influencing the microbiome. But we have no idea if they are effective or safe," he said.

"Given that the microbiome is involved in causing a wide range of diseases, it is completely inappropriate at this point to deliberately change its composition without knowing whether this is safe," he explained. "This is equivalent to taking a new drug with no safety data. No one would or should do it."

These findings are intriguing but preliminary, said Dirk Elewaut, MD, PhD, professor of rheumatology and immunology and chair of the Department of Rheumatology at Ghent University Hospital.

It is too early to determine "the true interpretation," he told Medscape Medical News.

"One of the difficult things regarding microbiome changes in spondyloarthritis is how to interpret this," he said. "Is it driven primarily by the genetic background and, if so, what is the reason for this? Or is it, rather, driven by inflammation, or is the microbiome the main driver itself?"

"The study on HLA-B27 is an important first step to understand this further," Dr Elewaut pointed out.

But evidence of other microbial distinctions in spondyloarthritis is emerging, he added.

"We have recently discovered a microbial signature driven by genus Dialister abundance and its link with disease activity," he reported.

"This is not dependent on HLA-B27, but it may well be that there are multiple changes in intestinal microbiota — some that are modulated by host genetic background and others that are not."

Dr Brown reports relationships with AbbVie, Janssen Pharmaceuticals, Pfizer, and UCB. Dr Elewaut has disclosed no relevant financial relationships.

International Congress on Spondyloarthritides (SPA) 2016: Abstract 10. Presented September 17, 2016


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