Background/Purpose: The microbiome serves a number of important functions, including modulation of the immune system and protection from pathogenic microorganisms¹. Many autoimmune diseases have been associated with intestinal microbial dysbiosis¹. Recent studies have also demonstrated that microbiota can affect the lifetime, bioavailability and efficacy of drugs². Conversely, even drugs designed to specifically target human cells have been associated with changes in microbial composition³. To date, most research has focused on bacterial microorganisms and little is known about the role that fungal microorganisms (the mycobiome) play, including their interactions with bacteria. In this study, we characterized the ecological effects of biologic therapies on the intestinal mycobiome.

Methods: Fecal samples were collected from SpA patients pre- and post-treatment with either tumor necrosis factor inhibitors (TNFi; n=15) or secukinumab (n=14), an anti-IL-17A monoclonal antibody (IL-17i). Subjects treated with TNFi were naïve to biologic therapy, whereas those treated with secukinumab previously failed or had incomplete response to TNFi. Samples underwent DNA extraction, amplification, and gene sequencing of the ITS1 region conserved in fungi. In parallel, gene sequencing of the 16S rRNA gene region conserved in bacteria was also performed. Sequences were analyzed with R and Quantitative Insights into Microbial Ecology (QIIME).

Results: ITS fungal data reveled that, on average, subjects treated with TNFi and IL-17i did not have major differences in overall microbial alpha or beta diversity pre- and post-treatment. However, there were dramatic shifts in the relative abundance of specific taxa, such as Candida albicans, which were more prominent in the IL-17i cohort compared to the TNFi cohort (p=0.04). The IL-17i cohort also demonstrated similar changes in certain 16S bacterial taxa, including Clostridia (p=0.02) and Clostridiales (p=0.02).

Conclusion: We characterized, for the first time, the effects of two biologic therapies on human intestinal fungal and bacterial microbiota composition. Treatment with biologics, particularly IL-17i, leads to a gut microbial dysbiosis characterized by significant changes in abundance of C. albicans and Clostridia in a subgroup of SpA patients. This is in line with the known increased risk of candidiasis seen with IL-17i, and may at least partially explain the potential link between IL-17 blockade, intestinal dysbiosis, and the subclinical and clinical gut inflammation observed in some patients treated with these molecules. Further studies to understand the downstream effects of these perturbations may allow for the development of precision medicine approaches in PsA and SpA.

References:

1. Clemente JC, Manasson J, Scher JU. The role of the gut microbiome in systemic inflammatory disease. BMJ. 2018;360:j5145.

2. Koppel N, Maini Rekdal V, Balskus EP. Chemical transformation of xenobiotics by the human gut microbiota. Science. 2017;356(6344).

3. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555(7698):623-8.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/perturbations-of-the-gut-fungal-and-bacterial-microbiome-with-biologic-therapy-in-spondyloarthritis/