Jan Söderman

Psoriasis is a chronic immune-mediated disease driven by genetic susceptibility and environmental factors, including microbial exposure. While HLA-C-linked variants represent the strongest genetic risk factors, their relationship with the cutaneous microbiome remains incompletely understood. This study aimed to investigate host–microbiome interactions in psoriasis through integrative multi-omics analysis. Skin microbiome profiling using 16S rRNA sequencing and targeted genotyping of psoriasis-associated single-nucleotide polymorphisms (SNPs) was performed in lesional and non-lesional skin from patients with plaque psoriasis and in healthy controls. Integrated analysis was conducted using supervised multivariate modeling (DIABLO) to identify coordinated genetic and microbial features associated with disease status. Combined genetic and microbial signatures differentiated lesional, non-lesional, and healthy skin. Variants within the HLA-C susceptibility region, including rs12191877, rs10484554, and rs4406273, showed contributions to group separation and demonstrated positive associations with Peptostreptococcus anaerobius. Associations involving ERAP1 variants linked antigen-processing pathways with inflammation-associated microbial taxa in lesional skin. Importantly, genotype–microbiome correlations were also detected in clinically non-lesional skin, where an increased psoriasis risk allele dosage co-varied with a higher relative abundance of P. anaerobius and Aerococcus urinae. In contrast, commensal-associated taxa were enriched in healthy controls and formed genotype-linked clusters only in non-lesional skin. These findings suggest that psoriasis is characterized by coordinated host genetic and microbial interaction patterns centered on antigen presentation pathways. The presence of a genotype–microbiome coupling in non-lesional skin may indicate that genetically determined immune configurations could shape microbial community structure prior to visible lesion development. Rather than reflecting uniform dysbiosis, psoriasis may represent a dynamic host–microbe ecosystem in which genetic susceptibility influences microbial persistence and inflammatory readiness.

Celiac disease (CD) diagnosis in children with sub‐threshold tissue transglutaminase autoantibody (anti‐TG2) levels requires a small intestinal biopsy. Through RNA sequencing and real‐time PCR of small intestinal biopsies, gene expression in such children was compared with the expression in children with active CD and anti‐TG2 levels above the threshold, and with non‐CD children. The study also included CD children with a non‐diagnostic first biopsy to explore early gene expression changes in CD. The aim of the study was to explore gene expression in relation to anti‐TG2 levels, investigate gene expression in Potential CD, and provide a gene expression profile to aid in CD diagnostics. The results showed that in active CD, expression changes involved genes associated with e.g., immune response, transport, angiogenesis, and epithelial barrier function, with even more pronounced changes of genes associated with cell cycle progression, absorption, lipid and lipoprotein processes, and retinoid metabolism in the active CD group with higher anti‐TG2 levels. Gene expression changes in CD children with a non‐diagnostic first biopsy showed large inter‐individual variations, but in general, gene expressions were associated with many of the same biological contexts as in active CD, including epithelial barrier function. Overall, the results show that gene expression profiling has great potential as a complement to the histopathologic assessment in CD diagnostics, even early in the disease course, but probably cannot be used for prognostic purposes.

Background and Objectives: Lichen sclerosus (LSc) is a chronic inflammatory and sclerosing condition that primarily affects the genital region. In women, vulvar lichen sclerosus presents with a wide range of clinical features, including pruritus, erythema, burning, pain, dysuria, architectural distortion, scarring, and the formation of ivory-white atrophic plaques. While the precise etiology of LSc remains unclear, increasing evidence indicates that prolonged exposure to urine and occlusion may play a central role in its pathogenesis. Additionally, the role of the genital microbiome has garnered increasing attention, with dysbiosis—an imbalance in microbial communities—emerging as a potential contributing factor. Prior investigations have reported an increased abundance of Gardnerella in women with LSc, but findings regarding Streptococcus and Lactobacillus have been inconsistent. This study aimed to investigate the relationship between the vulvar microbiome and LSc. Materials and Methods: Forty-seven women with LSc and seven healthy controls were recruited from the Division of Dermatology, Ryhov Hospital, Jönköping. Vulvar swabs were obtained from affected skin areas. The 16S rRNA regions were amplified and sequenced using the Illumina MiSeq system. Differential abundance analyses were conducted using four regression methods, and genera were considered significant only if identified by at least two methods. Results: Compared to controls, LSc patients showed reduced abundance of Lactobacillus, Finegoldia, Lawsonella, Stapylococcus, Cutibacterium, and an unidentified genus belonging to the Actinomycetaceae family. In contrast, Porphyromonas and Ezekiella, were significantly increased. Beta diversity analysis revealed significant differences in microbiome composition between groups (p = 0.022). Conclusions: The vulvar microbiome of women with LSc differs significantly from that of healthy controls. These findings support a possible role of microbial dysbiosis in LSc pathogenesis, highlighting the need for further research into microbiome-targeted interventions.

The pathogenesis of psoriasis is complex and many specific immunopathogenic mechanisms still remain unclear. Our goal was to identify novel pathways involved in the pathogenesis of psoriasis by analyzing differentially expressed genes, and to conduct pathway and cluster analysis by comparing lesional and non-lesional skin with healthy controls. Accordingly, 2 mm punch biopsies were taken from lesional elbow skin and non-affected adjacent skin of 23 patients with plaque-type psoriasis and from the elbow skin of 25 healthy controls. Differentially expressed genes were analyzed through RNA sequencing, and gene set enrichment analysis was used to analyze biological pathways. Our results showed downregulation of the pathway clusters “Mitophagy” and “Respiratory Electron Transport” when comparing both lesional and non-lesional skin to control skin. The pathway “Signaling by ROBO receptors” was downregulated in all three comparisons. Conversely, pathways relating to SUMOylation were upregulated when comparing lesional skin to both non-lesional and control skin, and those relating to the synthesis of PIPs at the early endosome membrane were found to be upregulated in lesional skin compared to control skin. The dysregulation of pathways relating to mitophagy (involved in the removal of damaged mitochondria), complex I biogenesis (a component of the mitochondrial respiratory chain), signaling by ROBO receptors (important for cell migration), and the synthesis of PIPs at the early endosome membrane (with a pivotal role in endocytic pathways and autophagy) suggests their potential role in psoriasis. Further research into the mechanisms of these dysregulated pathways, along with confirmation of protein expression levels, is necessary to validate their roles in psoriasis pathogenesis.

Vedolizumab is efficacious in the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). However, a significant proportion of patients present with a non-response. To investigate whether differences in the clinical response to vedolizumab is reflected in changes in gene expression levels in whole blood, samples were collected at baseline before treatment, and at follow-up after 10–12 weeks. Whole genome transcriptional profiles were established by RNA sequencing. Before treatment, no differentially expressed genes were noted between responders (n = 9, UC 4, CD 5) and non-responders (n = 11, UC 3, CD 8). At follow-up, compared with baseline, responders displayed 201 differentially expressed genes, and 51 upregulated (e.g., translation initiation, mitochondrial translation, and peroxisomal membrane protein import) and 221 downregulated (e.g., Toll-like receptor activating cascades, and phagocytosis related) pathways. Twenty-two of the upregulated pathways in responders were instead downregulated in non-responders. The results correspond with a dampening of inflammatory activity in responders. Although considered a gut-specific drug, our study shows a considerable gene regulation in the blood of patients responding to vedolizumab. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes. However, treatment outcomes may depend on several interacting genes, and our results indicate a possible potential of pathway analysis in predicting response to treatment, which merits further investigation.

Ulcerative colitis (UC) arises from a complex interplay between host and environmental factors, but with a largely unsolved pathophysiology. The pathophysiology was outlined by RNA-sequencing of mucosal biopsies from non-inflamed and inflamed colon of UC patients (14 and 17, respectively), and from 27 patients without intestinal inflammation. Genes differentially expressed (DE), or present in enriched gene sets, were investigated using statistical text analysis of functional protein information. Compared with controls, inflamed and non-inflamed UC mucosa displayed 9360 and 52 DE genes, respectively. Seventy-three non-pseudogenes were DE relative to both gender and inflammation. Mitochondrial processes were downregulated in inflamed and upregulated in non-inflamed UC mucosa, whereas angiogenesis and endoplasmic reticulum (ER) stress were upregulated in both tissue states. Immune responses were upregulated in inflamed mucosa, whereas the non-inflamed UC mucosa presented both up- and downregulated gene sets. DE and enriched genes overlapped with genes present in inflammatory bowel disease genome-wide associated loci (p = 1.43 × 10⁻¹⁸), especially regarding immune responses, respiratory chain, angiogenesis, ER stress, and steroid hormone metabolism. Apart from confirming established pathophysiological mechanisms of immune cells, our study provides evidence for involvement of less described pathways (e.g., respiratory chain, ER stress, fatty-acid oxidation, steroid hormone metabolism and angiogenesis).

Establishing a celiac disease (CD) diagnosis can be difficult, such as when CD-specific antibody levels are just above cutoff or when small intestinal biopsies show low-grade injuries. To investigate the biological pathways involved in CD and select potential biomarkers to aid in CD diagnosis, RNA sequencing of duodenal biopsies from subjects with either confirmed Active CD (n = 20) or without any signs of CD (n = 20) was performed. Gene enrichment and pathway analysis highlighted contexts, such as immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. Twenty-nine potential CD biomarkers were selected based on differential expression and biological context. The biomarkers were validated by real-time polymerase chain reaction of eight RNA sequencing study subjects, and further investigated using an independent study group (n = 43) consisting of subjects not affected by CD, with a clear diagnosis of CD on either a gluten-containing or a gluten-free diet, or with low-grade intestinal injury. Selected biomarkers were able to classify subjects with clear CD/non-CD status, and a subset of the biomarkers (CXCL10, GBP5, IFI27, IFNG, and UBD) showed differential expression in biopsies from subjects with no or low-grade intestinal injury that received a CD diagnosis based on biopsies taken at a later time point. A large number of pathways are involved in CD pathogenesis, and gene expression is affected in CD mucosa already in low-grade intestinal injuries. RNA sequencing of low-grade intestinal injuries might discover pathways and biomarkers involved in early stages of CD pathogenesis.

Microscopic colitis (MC) has been associated with increased paracellular permeability. Therefore, we aimed to investigate potential associations between MC and several genes encoding tight junction (TJ) proteins reported to interact with each other.

Inflammatory bowel disease (IBD) is associated with increased intestinal permeability, which involves paracellular passage regulated through tight junctions (TJ). The aim of the study was to investigate single nucleotide polymorphisms (SNP) located in genes encoding interacting TJ proteins and corresponding expressions, in relation to IBD. Allelic associations between TJ-related genes (F11R, MAGI1, MAGI2, MAGI3, PARD3, PTEN, and TJP1) and IBD, Crohn’s disease (CD), or ulcerative colitis (UC) were investigated. PTPN22 was included since it’s located in the same genetic region as MAGI3. Gene expression levels were investigated in relation to genotype, inflammatory status, phenotype, and medical treatment. The two strongest allelic associations were observed between IBD and SNPs in MAGI2 (rs6962966) and MAGI3 (rs1343126). Another MAGI3 SNP marker (rs6689879) contributed to increased ileal MAGI3 expression level in non-IBD controls. Furthermore, association between inflammation and decreased expression levels of MAGI3, PTEN, and TJP1 in colonic IBD as well as UC mucosa, and between inflammation and increased expression of PTPN22 in colonic IBD mucosa, was observed. Our findings lend support to a genetic basis for modulation of intestinal epithelial barrier in IBD, and we have identified MAGI3 as a new candidate gene for IBD.