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.

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

ObjectivesTo investigate the cutaneous microbiome spanning the entire psoriatic disease spectrum, and to evaluate distinguishing features of psoriasis (PsO) and psoriatic arthritis (PsA).MethodsSkin swabs were collected from upper and lower extremities of healthy individuals and patients with PsO and PsA. Psoriatic patients contributed both lesional (L) and contralateral non-lesional (NL) samples. Microbiota were analysed using 16S rRNA sequencing.ResultsCompared with healthy skin, alpha diversity in psoriatic NL and L skin was significantly reduced (p<0.05) and samples clustered separately in plots of beta diversity (p<0.05).KocuriaandCutibacteriumwere enriched in healthy subjects, whileStaphylococcuswas enriched in psoriatic disease. Microbe–microbe association networks revealed a higher degree of similarity between psoriatic NL and L skin compared with healthy skin despite the absence of clinically evident inflammation. Moreover, the relative abundance ofCorynebacteriumwas higher in NL PsA samples compared with NL PsO samples (p<0.05), potentially serving as a biomarker for disease progression.ConclusionsThese findings show differences in diversity, bacterial composition and microbe–microbe interactions between healthy and psoriatic skin, both L and NL. We further identified bacterial biomarkers that differentiate disease phenotypes, which could potentially aid in predicting the transition from PsO to PsA.

Objective: Diabetes is a group of disorders characterized by high blood glucose levels. Disturbances in serum electrolytes like sodium (Na+) and potassium (K+) are found in diabetes. The purpose of the study was to investigate the disturbances in concentrations of serum electrolytes in hyperglycemic crisis and the effect of syzygium cumini and momordica charantia standardized aqueous extracts on serum electrolytes (Na+and K+) in normal and diabetic rats.Methods: Diabetes is induced by intraperitoneal injection of alloxan at a dose of 120 mg/kg b. w in rats. Rats were divided into 5 groups (normal control, disease control, metformin, test 1 and test 2). In test groups 1 and 2, SASESC (standardized aqueous seed extract of syzygium cumini) and SAFEMC (standardized aqueous fruit extract of momordica charantia) were respectively administered orally to alloxan induced diabetic rats, and their serum electrolyte levels were observed at 1st, 4th, 7th and 14th days.Results: By the 14thday, the Na+ and K+ levels in groups 4 and 5 were almost normal. However, in group 3 (standard), Na+levels were relatively lower and K+ levels were relatively higher than groups 4 and 5 (test). In group 2 (disease control) as compared to group 1 (normal control), a decrease in Na+ and increase in K+ levels was observed even on day 14.Conclusion: Treatment with anti diabetic drugs like metformin, syzygium cumini (test-1), momordica charantia (test-2) restored the electrolyte levels almost back to normal over a period of study (14 d). There was significant (**P<0.01, *P<0.05) normalization of electrolyte levels in diabetic rats. It was concluded that syzygium cumini and momordica charantia showed better efficiency in restoring the electrolyte imbalance as compared to metformin during our study.

Background:Intestinal microbiota plays a prominent role in shaping the T cell immune response. Increasing evidence suggests that the gut microbiota is perturbed in patients with RA, and a variety of animal models demonstrated involvement of (mouse) microbiota in arthritis development. This underlines the necessity of understanding whether and how indigenous human NORA-associated microbiota may trigger RA.Objectives:To comprehensively investigate the intestinal mucosa cytokine production and DC, T and B cell responses to human gut microbiota associated with new-onset RA.Methods:We utilizedin vitrocultures of mucosal-like DCs (differentiated from bone marrow cells) and primary splenic DCs, as well asex vivocultures of healthy human intestinal biopsies, cultured in the presence of heat-killed fecal microbiota from either NORA or control donors. Furthermore, we performed studies in humanized mice carrying intestinal NORA microbiota, to study the effect on immune response during homeostasis and upon joint inflammation during collagen-induced arthritis (CIA).Results:In 24h DC cultures, NORA fecal microbiota more potently induced the expression of co-stimulatory molecules CD40 and CD80, and this enhanced DC maturation was partially mediated through TLR4 as demonstrated using the TLR4 antagonist TAK242. Interestingly, HC and NORA fecal microbiota differentially induced IL-12 and IL-6 production, with significantly enhanced IL-6 and reduced IL-12 secretion by the NORA microbiome. Furthermore, inex vivocultures of human ileum biopsies, the production of IL-1 and IL-33, as well as IL-23/Th17 cytokines IL-23, IL-22, and GM-CSF, were significantly increased by NORA-derived microbiome. Interestingly, in the small intestine lamina propria (SILP) of NORA-colonized mice, we observed enhanced Th17 polarization, increased innate GM-CSF expression and higher B cell CD40 and IgA levels during homeostasis. To study whether colonization with HC and NORA microbiota alters arthritis development, humanized mice and controls (mock, autologous, HC and NORA microbiota) were used in a CIA experiment. Macroscopic scoring of the arthritis severity at weekly intervals demonstrated that arthritis severity was significantly enhanced in NORA-colonized mice compared to HC-colonization and mock controls.Conclusion:Our data reveal that NORA microbiota, in addition to the previously described Th17 differentiation, induce higher levels of GM-CSF and B cell IgA in LP and have increased potential to aggravate arthritis through the activation of TLR4.References:[1]Scher et al., eLife 2013; Maeda Y et al., Arthritis & rheumatology 2016; Zhang X et al., Nature medicine 2015; Chen J et al., Genome Med 2016Disclosure of Interests:Marije Koenders: None declared, Heather Evans-Marin: None declared, Joyce Aarts: None declared, Parvathy Girija: None declared, Rebecca Rogier: None declared, Sergei Koralov: None declared, Julia Manasson: None declared, Peter van der Kraan: None declared, Shahla Abdollahi-Roodsaz: None declared, Jose Scher Consultant of: Novartis, Janssen, UCB, Sanofi.