Interleukin‐17 Inhibition in Spondyloarthritis Is Associated With Subclinical Gut Microbiome Perturbations and a Distinctive Interleukin‐25–Driven Intestinal Inflammation

Abstract

Objective To characterize the ecological effects of biologic therapies on the gut bacterial and fungal microbiome in psoriatic arthritis (PsA)/spondyloarthritis (SpA) patients. Methods Fecal samples from PsA/SpA patients pre‐ and posttreatment with tumor necrosis factor inhibitors (TNFi; n = 15) or an anti–interleukin‐17A monoclonal antibody inhibitor (IL‐17i; n = 14) underwent sequencing (16S ribosomal RNA, internal transcribed spacer and shotgun metagenomics) and computational microbiome analysis. Fecal levels of fatty acid metabolites and cytokines/proteins implicated in PsA/SpA pathogenesis or intestinal inflammation were correlated with sequence data. Additionally, ileal biopsies obtained from SpA patients who developed clinically overt Crohn's disease (CD) after treatment with IL‐17i (n = 5) were analyzed for expression of IL‐23/Th17–related cytokines, IL‐25/IL‐17E–producing cells, and type 2 innate lymphoid cells (ILC2s). Results There were significant shifts in abundance of specific taxa after treatment with IL‐17i compared to TNFi, particularly Clostridiales (P = 0.016) and Candida albicans (P = 0.041). These subclinical alterations correlated with changes in bacterial community co‐occurrence, metabolic pathways, IL‐23/Th17–related cytokines, and various fatty acids. Ileal biopsies showed that clinically overt CD was associated with expansion of IL‐25/IL‐17E–producing tuft cells and ILC2s (P < 0.05), compared to pre–IL‐17i treatment levels. Conclusion In a subgroup of SpA patients, the initiation of IL‐17A blockade correlated with features of subclinical gut inflammation and intestinal dysbiosis of certain bacterial and fungal taxa, most notably C albicans. Further, IL‐17i–related CD was associated with overexpression of IL‐25/IL‐17E–producing tuft cells and ILC2s. These results may help to explain the potential link between inhibition of a specific IL‐17 pathway and the (sub)clinical gut inflammation observed in SpA.

Bugs, Drugs, and Shrugs

“…These enigmas are not each directly addressed by Manasson and a large talented group of international colleagues in their study on the effect of biologics, specifically tumor necrosis inhibitors (TNFi) or anti–IL‐17, on the gut microbiome, in this issue of Arthritis & Rheumatology . Nonetheless, their findings support the hypothesis that unintentional effects on the microbiome could be the solution to many puzzling therapeutic observations.…”

“…As discussed in their report , Manasson and colleagues are not the first to examine how biologic therapies influence the microbiome . A dysbiosis or alteration in the gut microbiome is characteristic of the majority of immune‐mediated diseases .…”

The microbiome in rheumatology: Where are we and where should we go?

“…62 In animal experiments, cage effects 63 and facilities 64 have a significant influence on the data and should be treated as separate variables of interest. Due to potential fluctuations in the microbiome, possibly related to disease flare/activity 65 66 and/or treatment, 67 characterising the microbiome in a longitudinal fashion is of utmost importance (instead of assessing a single cross-sectional time point). Most importantly, many microbiome experiments are performed on small cohorts, leading to conclusions that are based on statistically invalid methodology.…”

“…113 This appears to also hold true for methotrexate, which is known to be metabolised by the gut microbiome in mice 114 115 and humans, 116 and may have off-target, antibiotic effects. 117 In axial SpA, patients who respond to anti-TNF inhibitors exhibit a more resilient pretreatment gut microbiome, 118 while IL-17A inhibitors are associated with expansion of intestinal C. albicans in a subgroup of paients with SpA/PsA, 67 as well as an increased risk for the development of candidiasis. 119 120 Further progress in pharmacomicrobiomics will lead towards personalised therapeutic approaches that are based on patient microbiome features, allowing for improved selection of medications with the highest efficacy and lowest risk for toxicity.…”

<p>Therapeutic Potential of Ixekizumab in the Treatment of Ankylosing Spondylitis: A Review on the Emerging Clinical Data</p>

“…15 Secukinumab safety profile was satisfactory, with a slight increased risk for infections, 31 no increased risk of latent tuberculosis (TB) reactivation. 34 Due to the physiological protective role exerted by IL-17 on mucosae, 35 and on gut microbiome, 36 a special attention was reserved to the risk of opportunistic infections and increased occurrence of inflammatory bowel diseases induced by IL-17 inhibition. As expected, an increased occurrence of candidiasis was observed in secukinumab-exposed, but not requiring the drug withdrawal, 37 while the risk of IBD development was low or absent.…”