Gut microbiome may influence sulfasalazine reaction in IBD-SpA

Findings could 'shape precision medicine' to improve treatment

Lindsey Shapiro avatar

by Lindsey Shapiro |

Share this article:

Share article via email
An illustration shows a close-up view of the human digestive system.

The gut microbiome, the collection of microbes that populate the intestinal tract, could influence the way people with inflammatory bowel disease (IBD) and associated peripheral spondyloarthritis (SpA) respond to sulfasalazine — a medication commonly used to treat IBD that’s also been shown to be effective for SpA.

That’s according to a new study that found that patients achieving clinically meaningful reductions in joint symptoms with sulfasalazine treatment had a greater predominance of the Faecalibacterium prausnitzii bacteria and a higher production of butyrate, a chemical byproduct of microbial chemical reactions.

The study, “The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis,” was published in Cell Reports Medicine.

Mouse studies also indicated that F. prausnitzii and butyrate contribute to the therapeutic effects of sulfasalazine.

“These findings reveal a mechanistic link between the efficacy of sulfasalazine therapy and the gut microbiome, with the potential to guide diagnostic and therapeutic approaches,” the researchers wrote.

Recommended Reading
Assorted bacteria are seen in this illustration.

Changing abudance of gut bacteria may lead to axSpA in IBD patients

Investigating the link between IBD and Spa

Ulcerative colitis (UC) and Crohn’s disease, two inflammatory diseases affecting the gastrointestinal tract, are collectively known as IBD.

Outside of intestinal symptoms, forms of SpA are the most commonly seen manifestations of IBD. Further, IBD patients are found to be at an elevated risk of developing various types of SpA.

SpA is a group of inflammatory diseases affecting the joints. Axial types such as ankylosing spondylitis mostly affect the spine, while peripheral types largely involve joints other than the spine.

The underpinnings of the relationship between the two groups of inflammatory disorders is not entirely clear. Alterations in the gut microbiome “are thought to be a contributor to SpA,” the researchers wrote.

Sulfasalazine, sold under the brand name Azulfidine, with available generics, have proven to be effective for easing peripheral SpA manifestations.

Although the exact mechanisms by which sulfasalazine is therapeutic are not known, it is broken down by bacteria in the intestinal tract, where it has anti-bacterial and anti-inflammatory effects.

That indicates the gut microbiome could play an important role in determining sulfasalazine’s efficacy for IBD-associated SpA, according to the researchers.

Recommended Reading
ankylosing spondylitis diet | Ankylosing Spondylitis News | Banner for Janneke Phung's column,

How my life has changed since my ankylosing spondylitis diagnosis

Common gut microbe dynamics seen in those responding to sulfasalazine

Here, the team — from NewYork-Presbyterian Hospital/Weill Cornell Medical Center, in New York — set out to discover whether features of the microbiome were associated with clinical responses to sulfasalazine efficacy among patients with active IBD-associated peripheral SpA.

A total of 33 patients were enrolled in the study, 25 with Crohn’s and eight with UC. In all, 22 were treated with sulfasalazine, and 11 who did not tolerate or refused the treatment served as a control group.

Consistent with sulfasalazine’s known efficacy profile in SpA patients, a significantly higher proportion of sulfasalazine-treated patients achieved clinically meaningful responses in joint symptoms compared with the control group (45.4% versus 9.1%) after 12 weeks. This was measured by a reduction of more than two points on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

In a series of experiments, the researchers identified certain gut microbial dynamics that might influence these treatment responses in terms of joint symptoms.

Among a handful of bacteria found to differ between treatment responders and non-responders, Fprausnitzii was found to most strongly distinguish the groups, with higher levels found in responders.

Butyrate, a metabolic molecule produced from certain bacteria, including Fprausnitzii, also was found at higher levels in the feces of treatment responders.

Additional experiments found sulfasalazine treatment increased the activity of genes related to butyrate production within Fprausnitzii to increase the bacteria’s production of the metabolite. This was accompanied by a depletion of molecules that would normally regulate butyrate production.

These findings have the potential to shape precision medicine to enhance therapeutic strategies.

In a mouse model of colitis, sulfasalazine had therapeutic benefits, including reduced mortality. These benefits were not observed in mice genetically engineered to lack the butyrate receptor on which butyrate exerts its biological effects.

Mice were then transplanted with the microbiome from IBD patient treatment responders or non-responders. Sulfasalazine treatment in mice with colitis only enhanced butyrate production and limited intestinal symptoms in animals colonized with responder microbiomes.

Supplementing the non-responder microbiome with Fprausnitzii was enough to restore sulfasalazine’s protective effects.

The findings suggest that sulfasalazine acts on Fprausnitzii bacteria to boost butyrate production, which in turn helps facilitate a therapeutic effect, the researchers said.

“Our results highlight the potential role for microbial biomarkers in stratifying therapeutic responses to [sulfasalazine], as well as the potential for microbial-based therapies in optimizing and enhancing medication efficacy,” they wrote.

“Management of IBD-pSpA remains an unmet need, and these findings have the potential to shape precision medicine to enhance therapeutic strategies,” the researchers said.