GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis.

Background & Aims: Cellular senescence is characterized by the loss of proliferative capacity, cell cycle arrest, and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP). Senescence is frequently present in advanced chronic liver diseases; however, the impact of hepatocellular senescence in alcohol-associated liver disease (ALD) progression and alcohol-associated hepatitis (AH) is poorly understood.

Methods: Senescence was evaluated in transcriptomic data from patients at different ALD stages: advanced fibrosis (n = 10), cirrhosis (n = 10), and AH (n = 29).

Single-cell multiomics identifies both shared and unique features of immune dysfunction in Parkinson's disease and inflammatory bowel disease colon, plasma and stool.

Parkinson's disease (PD) is the fastest growing neurodegenerative disease in the world. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD. We investigated peripheral relationships that may underlie mechanisms along the gut-blood axis that contribute to PD pathogenesis.

Differential effects of tofacitinib on macrophage activation contribute to lack of response in ulcerative colitis patients.

Background And Aims: Tofacitinib, a Janus kinase inhibitor, is approved for the treatment of moderate-to-severe ulcerative colitis. Nonetheless, 40-60% of patients will not respond adequately. The mechanisms underlying responses to tofacitinib remain unknown.

Expert recommendations to standardize transcriptomic analysis in inflammatory bowel disease clinical trials.

Background And Aims: Substantial methodological and reporting heterogeneity confounds the interpretation and generalizability of transcriptomic data for inflammatory bowel disease (IBD) studies. We aimed to develop recommendations to standardize transcriptomic research in clinical trials.

Methods: A 2-part study was undertaken.

Mitochondrial Dysfunction: Unraveling the Elusive Biology Behind Anti-TNF Response During Ulcerative Colitis.

Background: Recent studies hint at mitochondrial genes influencing UC patient response to anti-TNF treatment. We evaluated this hypothesis by following a targeted strategy to identify gene expression that captures the relationship between mitochondrial dysregulation and response to treatment. Our objective was to initially examine this relationship in colon samples and subsequently assess whether the resulting signal persists in the bloodstream.

Single-cell omics in inflammatory bowel disease: recent insights and future clinical applications.

Inflammatory bowel diseases (IBDs), which include ulcerative colitis (UC) and Crohn's disease (CD), are chronic conditions characterised by inflammation of the intestinal tract. Alterations in virtually all intestinal cell types, including immune, epithelial and stromal cells, have been described in these diseases. The study of IBD has historically relied on bulk transcriptomics, but this method averages signals across diverse cell types, limiting insights.

Single-cell integration reveals metaplasia in inflammatory gut diseases.

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood.

Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease.

Ulcerative colitis and Crohn's disease are chronic inflammatory intestinal diseases with perplexing heterogeneity in disease manifestation and response to treatment. While the molecular basis for this heterogeneity remains uncharacterized, single-cell technologies allow us to explore the transcriptional states within tissues at an unprecedented resolution which could further understanding of these complex diseases. Here, we apply single-cell RNA-sequencing to human inflamed intestine and show that the largest differences among patients are present within the myeloid compartment including macrophages and neutrophils.

Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress.

Introduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease.

Methods: We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli.

Diet prevents the expansion of segmented filamentous bacteria and ileo-colonic inflammation in a model of Crohn's disease.

Background: Crohn's disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of Tnf mice, a mouse model of CD-like ileitis pointed towards segmented filamentous bacteria (SFB), a commensal mucosal adherent bacterium involved in ileal inflammation.

Results: We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in two mouse models of ileal inflammation, including Tnf and SAMP/Yit mice.

Unraveling the impact of a germline heterozygous frameshift variant in serrated polyposis syndrome.

Serrated polyposis syndrome (SPS) is one of the most frequent polyposis syndromes characterized by an increased risk for developing colorectal cancer (CRC). Although SPS etiology has been mainly associated with environmental factors, germline predisposition to SPS could also be relevant for cases with familial aggregation or a family history of SPS/CRC. After whole-exome sequencing of 39 SPS patients from 16 families, we identified a heterozygous germline frameshift variant in the gene (c.

Generation of human colon organoids from healthy and inflammatory bowel disease mucosa.

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases (IBD) of unknown cause characterized by a relapsing-remitting behavior. Growing evidence supports the idea that the epithelial barrier plays a central role in the pathogenesis of IBD as well as in its evolution over time, thus representing a potential target for novel therapeutic options. In the last decade, the introduction of 3D epithelial cultures from ex vivo-expanded intestinal adult stem cells (ASCs) has impacted our ability to study the function of the epithelium in several gastrointestinal disorders, including IBD.

Experimental and genetic evidence for the impact of and expression and variation in inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. and are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While and expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear.

Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation.

Ulcerative colitis (UC) is characterized by a chronic overproduction of proinflammatory cytokines. During an acute phase, the endoplasmic reticulum (ER) is overloaded and the protein folding process is impaired, a condition named ER stress. This state induces a response (unfolded protein response (UPR)), initiated by the activation of IRE1/Xbp-1, PERK/eIF2, and ATF6 pathways, which has previously been linked to intestinal inflammation in experimental models.

Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease.

Immune cell trafficking is a critical element of the intestinal immune response, both in homeostasis and in pathological conditions associated with inflammatory bowel disease (IBD). This process involves adhesion molecules, chemoattractants and receptors expressed on immune cell surfaces, blood vessels and stromal intestinal tissue as well as signalling pathways, including those modulated by sphingosine 1-phosphate (S1P). The complex biological processes of leukocyte recruitment, activation, adhesion and migration have been targeted by various monoclonal antibodies (vedolizumab, etrolizumab, ontamalimab).

Intestinal Microbiome in Hematopoietic Stem Cell Transplantation For Autoimmune Diseases: Considerations and Perspectives on Behalf of Autoimmune Diseases Working Party (ADWP) of the EBMT.

Over the past decades, hematopoietic stem cell transplantation (HSCT) has been evolving as specific treatment for patients with severe and refractory autoimmune diseases (ADs), where mechanistic studies have provided evidence for a profound immune renewal facilitating the observed beneficial responses. The intestinal microbiome plays an important role in host physiology including shaping the immune repertoire. The relationships between intestinal microbiota composition and outcomes after HSCT for hematologic diseases have been identified, particularly for predicting the mortality from infectious and non-infectious causes.

Meta-analysis of gene expression disease signatures in colonic biopsy tissue from patients with ulcerative colitis.

Publicly available ulcerative colitis (UC) gene expression datasets from observational studies and clinical trials include inherently heterogeneous disease characteristics and methodology. We used meta-analysis to identify a robust UC gene signature from inflamed biopsies. Eight gene expression datasets derived from biopsy tissue samples from noninflammatory bowel disease (IBD) controls and areas of active inflammation from patients with UC were publicly available.