Biology subjects

Bakke, I.

Publications and source records attributed to Bakke, I..

4 recordsLinked to original sources

bioRxiv2026

JAK and TYK2 inhibitors differentially modulate interferon/TNF-driven inflammation, stemness and proliferation in the colonic epithelium of ulcerative colitis

BackgroundJanus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathway is a key regulator of inflammatory signaling in ulcerative colitis (UC). While most studies have focused on JAK/tyrosine kinase 2 (TYK2) inhibitors effects on immune cell-mediated responses, their direct epithelial impact remains less known. We investigated epithelial-specific transcriptional responses to JAK/TYK2 inhibitors using patient-derived intestinal epithelial organoids (IEOs) under UC-relevant conditions. MethodsColonic IEOs from UC patients were pretreated with various concentrations of tofacitinib, upadacitinib, filgotinib, brepocitinib, and deucravacitinib for 1 hour prior to stimulation with IFN{beta}, IFN{gamma}, or IFN{lambda}1 for Western blot analysis of STAT1/3 and TYK2 phosphorylation. For transcriptomic profiling, IEOs were pretreated with upadacitinib or deucravacitinib for 16 hours, followed by 8-hour stimulation with IFN{gamma}, IFN{lambda}1, TNF, or IFN{gamma} + TNF. Bulk RNA sequencing assessed differential gene expression, and multiplex assays quantified chemokine secretion. Ki67 immunohistochemistry on colonic biopsies from healthy controls, and UC patients with and without JAK inhibitors-treatment were assessed for epithelial proliferation. ResultsIFNs induced distinct STAT1/3 and TYK2 activation, with IFN{beta}/{gamma} eliciting stronger phosphorylation than IFN{lambda}1. All JAK/TYK2 inhibitors regulated pSTAT1/3 and pTYK2, with upadacitinib most strongly inhibiting pSTAT1/3 and deucravacitinib selectively targeting pTYK2. Transcriptomic analysis revealed extensive cytokine-driven gene regulation, with IFN{gamma} + TNF eliciting the strongest response. Enrichment analysis highlighted upregulation of IFN signaling, antigen presentation, and innate immune pathways, alongside downregulation of cell-cycle processes. Drug-response profiling showed minimal transcriptional changes with upadacitinib and deucravacitinib alone. Upadacitinib broadly modulated IFNs and IFN{gamma} + TNF-regulated genes, attenuating JAK-STAT, NF{kappa}B, antiviral, and cell death pathways, while restoring genes linked to mucosal healing. Upadacitinib also reduced IFNs and IFN{gamma} + TNF-driven chemokine genes and protein secretion. In contrast, deucravacitinib showed selective, potent inhibition of inflammatory genes under IFN{lambda}1-stimulation. Both inhibitors minimally impacted TNF-driven pathways. Ki67 immunohistochemistry confirmed enhanced epithelial proliferation in JAK inhibitor-treated UC patients regardless of mucosal inflammation status. ConclusionsOur findings provide novel evidence that JAK/TYK2 inhibitors influence epithelial transcriptional programs associated with inflammation and mucosal healing. Upadacitinib demonstrated broader modulation of cytokine-driven gene networks compared to TYK2-selective inhibition. These findings provide insight into epithelial-specific drug actions and support precision approaches for UC therapy.

molecular biology↗

bioRxiv2025

Aquaculture facility-specific microbiota shape the zebrafish gut microbiome

BackgroundEnvironmental microbiomes, such as those in recirculating aquaculture systems (RAS), can play a key role in shaping host-associated microbial communities. In zebrafish (Danio rerio) research, these interactions can introduce uncontrolled sources of variation, potentially confounding experimental outcomes across multiple facilities. Despite widespread zebrafish use in microbiome studies, few have characterized the microbial composition of both tank water and fish across multiple independent facilities to evaluate the consequences of environmental microbiome variation on the host microbiome. ResultsWe compared water and zebrafish gut microbiomes across five aquaculture facilities--two in the United States and three in Norway--using a nested sampling design and 16S rRNA gene sequencing. Alpha diversity was consistently higher in tank water than in fish guts, and beta diversity metrics revealed distinct clustering by sample type, facility, and location. Differences in microbial community composition were significant across facilities, with both water and fish samples exhibiting facility-specific profiles. Similarity Percentage analysis identified taxonomic groups driving these differences, while Fast Expectation-Maximization for Microbial Source Tracking detected measurable contributions of tank water microbiota to zebrafish gut communities. Bray-Curtis dissimilarity values were lowest between fish and water from the same tank and increased with geographic and facility distance, indicating local microbial overlap. Relative abundance patterns and ordination plots further supported distinct and structured microbial assemblages across systems. ConclusionsThis study demonstrates that zebrafish aquaculture systems harbor unique microbial communities shaped by both environmental and geographic factors, with tank water acting as a potential source of gut-associated microbes. These findings underscore the importance of incorporating environmental microbiome assessments into zebrafish experimental design, particularly for studies focused on host-microbe interactions. Without such consideration, unaccounted variation in environmental microbiota may affect microbiome composition and reduce cross-study reproducibility. Moving forward, standardized reporting of environmental conditions and microbial composition across facilities will be critical for strengthening reproducibility and interpretation in zebrafish microbiome research.

microbiology↗

bioRxiv2023

Phage therapy minimally affects the water microbiota in an Atlantic salmon (Salmo salar) rearing system while still preventing infection

Excessive usage of antibiotics threatens the bacterial diversity in the microbiota of animals. An alternative to antibiotics that has been suggested to not disturb the microbiota is (bacterio)phage therapy. In this study, we challenged germ-free and microbially colonized yolk sac fry of Atlantic salmon with Flavobacterium columnare and observed that the mere presence of a microbiota protected the fish against lethal infection. We then investigated the effect of phage-or oxytetracycline treatment on fish survival and rearing water bacterial community characteristics using 16S rRNA gene amplicon sequencing. Phage treatment led to an increased survival of F. columnare-challenged fish and reduced the relative amounts of the pathogen in the water microbiota. In the absence of F. columnare, phage treatment did not affect the composition or the -diversity of the rearing water microbiota. In the presence of the phages host, phage treatment induced minor changes to the bacterial community composition, without affecting the -diversity. Surprisingly, oxytetracycline treatment had no observable effect on the water microbiota and did not reduce the relative abundance of F. columnare in the water. In conclusion, we showed that phage treatment prevents mortality while not negatively affecting the rearing water microbiota, thus suggesting that phage treatment may be a suitable alternative to antibiotics. We also demonstrated a protective effect of the microbiota in Atlantic salmon yolk sac fry.

microbiology↗

bioRxiv2021

The effect of periodic disturbances and carrying capacity on the significance of selection and drift in complex bacterial communities

Understanding how periodical disturbances affect the community assembly processes is vital for predicting temporal dynamics in microbial communities. The effect of dilutions as disturbances are poorly understood. We used a marine bacterial community to investigate the effect of disturbance (+/-) and carrying capacity (high/low) over 50 days in a dispersal-limited 2x2 factorial crossover study in triplicates. The communitys disturbance regime was crossed halfway. We modelled the rate of change in community composition between replicates and used this rate to quantify selection and ecological drift. The disturbed communities increased in Bray-Curtis similarity with 0.011{+/-}0.0045 (Period 1) and 0.0092{+/-}0.0080 day-1 (Period 2), indicating that selection dominated community assembly. The undisturbed communities decreased in similarity at a rate of -0.015{+/-}0.0038 day-1 in Period 1 and were stable in Period 2 at 0.00050{+/-}0.0040 day-1, suggesting drift structured community assembly. Interestingly, carrying capacity had minor effects on community dynamics. This study is the first to show that stochastic effects are suppressed by periodical disturbances resulting in exponential growth periods due to density-independent biomass loss and resource input. The increased contribution of selection as a response to disturbances implies that ecosystem prediction is achievable.

ecology↗