Changes in the Gut Microbiome following treatment with Dupilumab. Gut microbiome following Dupilumab

Purpose: Dupilumab is a humanised Ig4 monoclonal antibody directed against IL-4Rα which is used fortreatment of severe atopic dermatitis (AD). Conjunctivitis has been reported as a side effect of treatment,although the mechanism for this is unknown. Immunosuppressive therapy influences the gut microbiome, andgut microbiota modulates medication efficacy and toxicity. Understanding of the immunotherapy-microbiomenetwork in patients with AD is lacking. We wished to delineate the impact of Dupilumab therapy on the gutmicrobiota in patients with AD, and correlate this with ocular findings.Methods: Pre- and post-Dupilumab ocular assessment was completed on 6 patients. Faecal samples wereobtained from 4 patients. Each patient provided 2 samples collected at different time points: 3 patients beforeand after treatment, and 1 patient not yet treated with Dupilumab as disease control. Samples were placed in80% ethanol prior to DNA extraction and 16Sv4 rRNA sequencing.Results: 5/6 patients had undiagnosed conjunctivitis at baseline assessment, with deterioration in all patientsfollowing commencement of Dupilumab. Post-treatment clinical phenotype was variable, ranging from mildnon-specific conjunctivitis to a severe psuedomembranous conjunctivitis.There were no significant changes in the α-diversity during treatment. β-diversity analysis through principalcoordinate profile using Bray-Curtis distance revealed alterations in the gut microbiome in response toDupilumab. Linear Discriminant Analysis Effect Size detected significant increase in the relative abundance ofCollinsella, and decrease in Bacteroidales, Anaerotruncus, Oscillospira genera (LDA score> 2.0, a=0.01)following treatment with Dupilumab.Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis showed thatdifferent metabolic pathways were enriched post-Dupilumab, in particular, functional categories associated with transporters, ABC transporters, DNA repair and recombination proteins, ribosome, purine metabolism,peptidases, pyrimidine metabolism and transcription factors pathways (False Detection Rate <0.001).Conclusions: There is a high prevalence of undiagnosed conjunctivitis in patients with AD, with deteriorationfollowing Dupilumab treatment. We have shown a previously unreported modulation of the taxonomy andpredicted functional profile of the gut microbiome through Dupilumab therapy.