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5 recordsLinked to original sources
PubMed2026

Defined human Clostridia consortia reverse colitis via dual effects of tryptophan metabolites on microbiota and immunity.

Microbial dysbiosis and disrupted mucosal immune homeostasis are integrally involved in the pathogenesis of inflammatory bowel diseases (IBDs). Live biotherapeutic products (LBPs) offer a potential therapeutic strategy to restore beneficial microbes and mitigate disease. We investigated the therapeutic efficacy of 2 LBPs, human Clostridia consortia 17-mix and 11-mix, by treating established colitis in murine models. Both LBPs exhibited therapeutic effects in T cell-mediated chronic colitis models induced by human microbiota and in pathobiont-driven gnotobiotic colitis models established with combinations of IBD-relevant human-derived strains. Metagenomic and metabolomic analyses elucidated mechanisms that go beyond established functions driven by short-chain fatty acids (SCFAs) and interleukin (IL)-10-producing regulatory T cells. Notably, LBPs exerted therapeutic effects by directly inhibiting resident pathobionts and through IL-10-independent activation of host anti-inflammatory aryl hydrocarbon receptor (AhR) pathways by bacterial tryptophan metabolites. These results elucidate SCFA- and IL-10-independent protective mechanisms exerted by defined resident bacterial strains that are depleted in IBD dysbiosis.

Animals↗
PubMed2026

Bridging the airway microbiome and targeted therapy in bronchiectasis: multi-omics insights, endotypes and emerging therapies.

Bronchiectasis is a heterogeneous chronic airway disease primarily driven by persistent infection, microbial dysbiosis and dysregulated host immunity. While culture-based microbiology has historically informed clinical management, advances in high-throughput sequencing and multi-omic technologies have transformed our understanding of the airway ecosystem, revealing that disease activity is shaped not only by individual pathogens, but by complex and dynamic host-microbe interactions. Despite the breadth of descriptive microbiome data, translation into clinically actionable diagnostics or therapies has been limited. Importantly, cross-sectional correlations between microbiota and inflammation do not establish cause and effect, underscoring the need to embed host-microbiome profiling within both longitudinal and interventional therapeutic trials. In this review, we critically appraise current microbial and host multi-omics research in bronchiectasis, integrating microbiome studies with host inflammatory, proteomic and immunophenotyping data. We highlight themes emerging across cohorts, including low microbial diversity, pathogen dominance, loss of commensal networks and neutrophil-driven inflammation, and discuss how these features align with biological endotypes associated with exacerbations and treatment response. Drawing on lessons from host-directed therapeutic successes, we examine translational roadblocks limiting microbiome-guided care. We further review emerging microbiome-modulating strategies such as pathogen-specific biologics, bacteriophage therapy, live biotherapeutic products, biofilm-targeting adjuncts and precision antibiotic stewardship. Finally, we propose a roadmap toward microbiome-informed precision medicine through harmonised methodologies, integration of host and microbial biomarkers into clinical trials, and embedding multi-omics pipelines within large international registries. Collectively, these advances have the potential to shift bronchiectasis research and clinical management towards rationally designed, precision medicine-driven therapeutic strategies.

Humans↗
PubMed2026

A stable and potent buffalo EF1α1 promoter for robust gene expression in mammalian systems.

This study reports the first isolation and characterization of the buffalo EF1α1 promoter, demonstrating its strong gene expression activity both in vitro across diverse cultured cell types and in vivo across multiple mouse organs. Although viral promoters, such as cytomegalovirus (CMV) and simian virus (SV40), are widely used for their strong expression in various cell lines in mammalian expression systems and in animal tissues, they are prone to methylation-induced transcriptional silencing and subsequent loss of exogenous gene expression. The most effective alternative to viral promoters is the synthetic hybrid CAG promoter (cytomegalovirus major immediate-early enhancer combined with the chicken beta-actin promoter) or mammalian cellular promoter such as human elongation factor 1 alpha (hEF1α), which drives strong gene expression but lacks consistency and is limited in their in vivo expression potential due to their vulnerability to epigenetic silencing. To overcome these challenges, the bbEF1α1 promoter was cloned and evaluated both in vitro and in vivo. It consistently drives higher levels of exogenous gene expression than CMV in diverse cell lines. Importantly, transgene expression was achieved in various organs of transgenic mice and in muscle tissue following in vivo electroporation. These findings establish the bbEF1α1 promoter as a powerful ubiquitous driver of gene expression, offering high stability with broad applications in gene therapy, biopharmaceutical production, and functional genomics.

Animals↗
PubMed2026

Proteomic analysis of ammonia-induced stress in Chinese hamster ovary (CHO) cell cultures.

Ammonia (NH₃) and its ionic form ammonium (NH₄+) are both metabolic waste products and essential nitrogen sources within Chinese hamster ovary (CHO) cell cultures. Although necessary for amino acid synthesis, excessive accumulation in the extracellular environment can exert stress, reducing cell proliferation and impairing the efficiency of recombinant protein production. Proper endoplasmic reticulum (ER) function is critical for CHO cells as biotherapeutic producers. Previous work has linked elevated ammonia concentrations to reduced productivity via altered N-glycosylation pathways, but its broader effects on ER biology remain unclear. In this study, we applied high-resolution mass spectrometry to perform a comprehensive analysis of changes in the ER proteome in CHO cells exposed to two ammonia concentrations, 10 mM and 30 mM, 48 and 120 h after supplementation. Both conditions suppressed cell growth and reduced product titre; however, the 10 mM supplementation resulted in a minor increase in specific cell productivity. Gene Ontology analysis revealed that ammonia strongly affected the tricarboxylic acid cycle, as well as key metabolic, catabolic and biogenetic processes. Several ER membrane proteins, including HMGCR and PREB, were consistently downregulated. In extended cultures, transmembrane proteins linked to Golgi-transport were upregulated, while vesicle transport associated proteins were downregulated, indicating altered intracellular trafficking. SIGNIFICANCE: This study provides a novel perspective on CHO cell biology under environmental stress by investigating the impact of ammonia accumulation in culture. Despite its presence in CHO culture, ammonia has been relatively under-investigated, compared to other culture conditions. Using high-throughput mass spectrometry for comprehensive proteomic profiling, we characterise the cellular response to ammonia build-up with a level of depth not previously applied to the study of this biological stressor. By specifically analysing proteins localised to the ER, we identify candidate pathways and molecular mechanisms that contribute to reduced CHO cell growth and productivity, offering insights directly relevant to industrial bioprocessing conditions. The link between ammonia concentration and a decrease in productivity has previously been linked to genes involved in N-glycosylation of the recombinant biotherapeutic, but the full extent of ammonia stress on ER function has not yet been investigated. These methods were applied to two IgG producing CHO cell lines to allow for comparison of cell line specific stress adaptations, as well as comparing the short- and long-term effects of excess ammonia.

Proteomics↗
PubMed2026

Mitigating pH-induced instability in deruxtecan-based ADCs: an onboard-mixing icIEF approach for robust charge heterogeneity characterization.

Accurate charge variant analysis of antibody-drug conjugates (ADCs) is essential for understanding product heterogeneity and ensuring quality control. However, Deruxtecan (DXd)-based ADCs present a unique analytical challenge due to the intrinsic instability of the payload, where the lactone ring readily undergoes hydrolysis under alkaline conditions, resulting in time-dependent shifts in charge distribution during imaged capillary isoelectric focusing (icIEF). In this study, we describe the development of an onboard-mixing icIEF method designed to minimize pH-induced degradation during sample preparation. By separating ADC samples from carrier ampholytes (CAs) prior to injection and enabling real-time mixing within the instrument, this approach effectively suppresses premature lactone ring opening and stabilizes charge variant profiles. Comparative studies between conventional premixing and onboard-mixing approach demonstrated that the latter significantly enhances reproducibility, particularly for acidic variants that are highly sensitive to structural conversion. Comprehensive method validation confirmed excellent precision, linearity, and sensitivity, with consistent performance across run-to-run and intra-day analyses. The results underscore the importance of controlling microenvironmental pH exposure in the analysis of chemically instable ADCs. The proposed onboard-mixing strategy provides a robust and efficient solution for icIEF-based characterization, reducing analytical artifacts while simplifying method development. This approach is broadly applicable to ADCs and other biotherapeutics containing pH-sensitive functional groups.

Hydrogen-Ion Concentration↗