Biology subjects

Hillary, T.

Publications and source records attributed to Hillary, T..

3 recordsLinked to original sources

bioRxiv2026

UNRAVELLING A HIDDEN SUBTYPE: MULTIOMICS REVEAL PSORIASIS-LIKE SIGNATURE WITH SURGICAL RELEVANCE IN A SUBSET OF PERIANAL FISTULIZING CROHN'S DISEASE

Background and aimsPerianal fistulizing Crohns disease (pCD) affects 20% of patients with Crohns disease (CD) and severely impacts quality of life. Current therapies fail to provide sustained relief, and the molecular underpinnings of pCD remain poorly understood. This study aimed to elucidate the molecular landscape of perianal fistulas through multiomic profiling. MethodsPaired fistula-tract and adjacent rectal mucosal biopsies were collected from 63 patients (48 with pCD, 15 with cryptoglandular fistula [CPTGL]). Longitudinal sampling generated 101 unique molecular profiles, comprising of both RNA sequencing (RNA-seq) and 16S rRNA sequencing from both tissue sites, followed by integrative multiomics and gene network analyses. ResultsUnsupervised clustering revealed three patient clusters primarily defined by host gene expression, with minimal contribution from microbial profiles. Fistulae in clusters 1 and 2 showed strong immune activation and epithelial-mesenchymal transition (EMT). In contrast, cluster 3 fistulae displayed keratinization and metabolic reprogramming resembling psoriatic skin, together with reduced JAK-STAT signalling. Cluster 3 was enriched for patients classified as TOpClass:2a, who are more suitable for surgical repair (p = 0.02). Conversely, cluster 2, characterized by rectal keratinization and EMT in both fistula and rectum, showed the highest MRI inflammatory-mass score (p = 0.02) and a greater risk of subsequent ileostomy (Kaplan-Meier; p = 0.008). An independent RNAseq dataset validated the keratinization signature in a subset of pCD fistulae. ConclusionIntegrated multiomic analysis identified distinct molecular subtypes of pCD with surgical and therapeutic relevance. These findings refine the molecular understanding of pCD and support a precision medicine approach. What You Need to Know?O_ST_ABSBACKGROUND AND CONTEXTC_ST_ABSO_LIPerianal fistulas affect 1 in 5 Crohns disease patients and have a severe negative impact on the quality of life of the patients. C_LIO_LIMost advanced IBD therapies are not efficacious for perianal Crohns disease. C_LIO_LISurgical repair is not suitable for all patients. C_LI NEW FINDINGSO_LIThis study is the first to delineate molecularly defined patient subtypes in perianal fistulizing Crohns disease. It further characterizes a psoriasis-like keratinization program in a subset of fistulas. Finally, it identifies molecular features and histological indicators that may explain-and potentially help predict-favorable surgical outcomes in selected patients C_LI LIMITATIONSO_LIFunctional and mechanistic studies will be required to further dissect the drivers and dynamics of the epithelial remodeling identified. C_LI CLINICAL RESEARCH RELEVANCEO_LIRaises the possibility of refining of existing clinical stratification using molecular markers for improved therapeutic management and outcome. C_LI BASIC RESEARCH RELEVANCEO_LIProposes keratinization as an opposing molecular process to EMT within the perianal fistula tract. C_LIO_LIIdentifies robust gene signatures associated with EMT and keratinization in the fistula for further experimental and clinical studies. C_LI

immunology↗

bioRxiv2023

Understanding the bacterial imbalance in Hidradenitis Suppurativa patients: Insights into microbial community shifts and colonization by opportunistic pathogens

Patients suffering from hidradenitis suppurativa (HS) develop painful skin lesions, significantly decreasing their quality of life. This chronic disease is triggered by plugged hair follicles resulting in an aberrant immune response, skin microbiome imbalance and secondary bacterial colonization. As a result, a diversity of treatment options are currently applied, including antibiotics, biologicals like adalimumab and surgery, which often provide only short-term relief. Alternative strategies, like phage therapy, have been proposed but identification of the target bacterium is key. Therefore, a spatial and longitudinal analysis was performed on skin swabs of lesions from 39 HS patients and 18 healthy controls, leading to a total collection of 108 lesional samples and 35 control samples at different time points and locations throughout the body. Samples were subjected to 16S rRNA community analysis, as well as bacterial isolation using aerobic and anaerobic culturing in combination with MALDI-TOF. Our data demonstrate that the bacterial community present in lesions of patients with HS is out of balance compared to healthy individuals, in which the niche of Staphylococcus and Corynebacterium is taken over by Escherichia-Shigella. Overall, three bacterial community profiles of HS lesions and one of healthy individuals could be distinguished. Although the overall bacterial composition was not associated with the disease severity defined by the Hurley classification system, lesions often become colonized with opportunistic pathogens including Staphylococcus aureus and Pseudomonas aeruginosa at increasing disease severities. Furthermore, patients with a concurrent IBD diagnosis did not reveal a significantly different bacterial skin community.

microbiology↗

bioRxiv2023

Hidradenitis suppurativa patients exhibit a distinctive and highly individualized skin virome

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by recurring painful skin lesions. Despite ongoing research, the exact cause underlying the initiation and progression of disease remains unknown. While prior research has linked the skin microbiota to HS pathology, the role of viruses has remained unexplored. To investigate the skin virota, metagenomic sequencing of viral particles was performed on 144 skin samples from 57 individuals (39 HS patients and 18 controls). It was found that the virome is not only linked to BMI, but also to the presence and severity of HS, marking a diverging viral profile in the progression of disease. Despite no differences in alpha-diversity, HS patients exhibited a significantly higher beta-diversity compared to healthy controls, indicating a more personalized virome with reduced viral sharing among patients. We identified distinct groups of commonly shared phages, referred to as the core phageome, associated with either healthy controls or patients. Healthy controls displayed a higher abundance of two core Caudoviricetes phages predicted to infect Corynebacterium and Staphylococcus, comprising normal skin commensals. In contrast, HS patients carried previously uncharacterized phages that were more prevalent in advanced stages of the disease, which likely infect Peptoniphilus and Finegoldia, known HS-associated pathogens. Interestingly, genes involved in superinfection exclusion and antibiotic resistance could be found in phage genomes of healthy controls and HS patients, respectively. In conclusion, we report the existence of distinct core phages that may have clinical relevance in HS pathology by influencing skin bacteria through mechanisms such as superinfection exclusion and antibiotic resistance.

microbiology↗