Background: Psoriatic Arthritis (PsA) is a chronic inflammatory disease that affects the peripheral joints and/or axial skeleton. Its articular manifestations can progress rapidly, potentially leading to joint damage and functional impairment. In recent years, studies have shown that gut microbiota play a significant role in the onset and progression of PsA. However, many intricate connections remain to be uncovered, warranting further exploration. With the rapid advancement of metagenomics technology, we are now able to analyze the interactions between gut microbiota and disease more comprehensively and in greater depth. In this study, shotgun metagenomic sequencing was employed to systematically investigate the host–gut microbiota interactions in PsA, in both cross-sectional (PsA vs. healthy controls) and longitudinal (during PsA treatment) contexts.

Objectives: To explore the characteristics of gut microbiota in patients with PsA (Psoriatic Arthritis) and their potential links to Interleukin-17 (IL-17)-dependent immune regulation; to evaluate the effects of IL-17 monoclonal antibody therapy on gut microbiota composition and metabolic function; and to elucidate the mechanisms underlying IL-17-mediated host-microbiota interactions.

Methods: A combined cross-sectional and longitudinal study design was employed.Cross-sectional study: Treatment-naïve PsA patients and healthy controls (HC) were recruited. Gut microbiota profiles were analyzed using shotgun metagenomic sequencing, and serum Interleukin-17A (IL-17A) levels were measured to identify microbial taxa significantly associated with IL-17A.Longitudinal study: PsA patients were monitored at three time points (baseline, week 4, and week 12) during IL-17A monoclonal antibody therapy. Fecal samples were collected for metagenomic sequencing, untargeted metabolomics, and targeted quantification of short-and medium-chain fatty acid to evaluate changes in microbiota composition and metabolic function following treatment.

Results: Cross-sectional study : Thirty PsA patients and 16 HC were included. Gut microbiota composition and functional profiles differed between PsA and HC groups. The α-diversity of gut microbiota was significantly lower in PsA patients compared to HC. Differential species were predominantly derived from Bacillota , Actinobacteriota , and Bacteroidota . Carbohydrate-active enzyme functions were downregulated in PsA patients. Species significantly associated with serum IL-17A levels were mainly from Bacteroidota , including Phocaeicola , Bacteroides , and Parabacteroides , all showing a negative correlation with IL-17A levels. IL-17A-related functions included polysaccharide lyase, which showed a significant negative correlation. IL-17A-associated species were positively correlated with polysaccharide lyase functions.

Longitudinal study: A longitudinal study included 20 PsA patients treated with IL-17 monoclonal antibody, showing a significant decrease in PsA disease activity post-treatment. Analysis of a total of 60 fecal samples collected before and after treatment revealed the following findings: (1) Diversity Changes: The α-diversity of gut microbiota increased significantly after treatment. (2) Species Changes: Post-treatment, there was an expansion trend in the phylum Bacteroidota , with a significant increase in the genus Phocaeicola . (3) Functional Changes: Most carbohydrate-active enzyme functions were upregulated after treatment, with polysaccharide lyases, carbohydrate esterases, and auxiliary oxidoreductases functions showing significant increases. (4) Metabolite Changes: Twenty-eight differential metabolites were enriched in three metabolic pathways, with short-chain and medium-chain fatty acids showing an increasing trend. (5) Key Role of Phocaeicola : The genus Phocaeicola was identified as a central node in the correlation network. Its abundance significantly increased after IL-17 monoclonal antibody treatment and showed significant positive correlations with gut microbial α-diversity, polysaccharide lyases function, and butyrate levels.

Conclusions: PsA patients exhibit reduced gut microbiota stability, which can be improved by IL-17 monoclonal antibody therapy, indicating a “cross-organ effect” of IL-17-mediated inflammation control. The “Host–IL-17 Immune Regulation– Phocaeicola –Polysaccharide Lyase Function” interaction axis provides new insights into the pathogenesis of PsA and potential strategies for microbiota-based interventions. Within this axis, Phocaeicola may shape the inflammatory microenvironment by modulating polysaccharide lyase function and metabolite production. Future studies should incorporate animal models and metabolic research to further elucidate its mechanisms and translational potential.

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Acknowledgments: NIL.

Disclosure of Interests: None declared.