Biology subjects

Scharl, M.

Publications and source records attributed to Scharl, M..

9 recordsLinked to original sources

bioRxiv2026

Shifting Perspectives on Biotherapeutic Treatment in Ulcerative Colitis using Lipid Mesophases: Formulation Design and Preclinical Validation

Biotherapeutics are required to achieve high remission rates in patients with severe ulcerative colitis (UC); however, adverse effects, complex dosing regimens, administration routes, and low patient compliance may limit their widespread clinical use. Given the localized nature of UC, this study aimed to develop and evaluate a localized delivery strategy for infliximab (IFX), an anti-tumor necrosis factor- (TNF-) monoclonal antibody (mAb) recommended by the European Crohns and Colitis Organization (ECCO) and the American Crohns & Colitis Foundation for moderately-to-severely active UC. Exploiting the intrinsic biocompatibility, mucoadhesivity, and protein-entrapment capacity of lipid mesophases (LMPs), IFX was encapsulated within the gel matrix, providing protection against enzymatic and environmental degradation. IFX-loaded LMPs were designed for targeted delivery to inflamed colonic tissues via rectal or oral administration, with patient-centric oral dosage forms manufactured using a 3D printing approach. A comprehensive physicochemical characterization was performed to elucidate mesophase self-assembly and its relationship with IFX release profiles in biorelevant fluids. Therapeutic efficacy was evaluated in vivo using a dextran sulfate sodium (DSS)-induced colitis rat model, which demonstrated rectal gel retention for at least 8 h and colonic targeting of the oral formulation within 6 h. Under severe inflammatory conditions, LMP-based formulations reduced disease activity, inflammatory biomarkers (TNF- and fecal lactoferrin), and colon shortening to values comparable to those of healthy controls, outperforming the therapeutic efficacy of subcutaneous IFX. Overall, this study establishes a biocompatible delivery platform that enables targeted colonic IFX release and suppresses systemic absorption, representing a promising advancement in the biotherapeutic treatment of UC.

pathology↗

bioRxiv2026

Altered Crosstalk of Bacterial Lipopolysaccharide with Immune Cells in Colorectal Cancer Compared to Paired Adjacent Intestinal Tissue

Commensal bacteria play a crucial role in modulating human immune responses in the intestine. Under homeostatic conditions, gut microbiota are tightly regulated by interactions with the mucosal immune system. However, colorectal cancer (CRC) is characterized by an imbalance in bacterial composition and bacterial translocation across the intestinal barrier. The spatial distribution of bacteria and their interactions with immune cells in CRC tumors are poorly understood. By applying 3D light-sheet imaging, spatial transcriptomics, and imaging mass cytometry to patient-derived CRC and adjacent tissue, bacterial lipopolysaccharide (LPS) is visualized alongside immune cells and vessels. The results show regional bacterial LPS accumulation and colocalization with distinct immune cell subsets. In CRC-adjacent tissue, bacterial LPS is mainly associated with CD11c+ dendritic cells, CD15+ neutrophils, and CD163+ macrophages. In matched CRC tissue, the number and LPS colocalization of CD163+ macrophages and CD11c+ dendritic cells decreased, while CD15+ neutrophils and their colocalization with LPS increased. Notably, immune cell composition and immune cell-bacteria interactions differ between tumor and adjacent tissue, offering insights into host-microbiota dynamics and mechanistic interactions.

cancer biology↗

bioRxiv2024

Blood-borne immune cells carry low biomass DNA remnants of microbes in patients with colorectal cancer or inflammatory bowel disease

The involvement of the human intestinal microbiome in the regulation of immune cell homeostasis, as well as in the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC), are well-established1-4. Bacteria interact with immune cells at the sites of intestinal inflammation, but also in the CRC tumor microenvironment1-6. Indeed, bacterial remnants have recently been detected in human intestinal tissue in patients with IBD, at primary tumor sites and in the metastases of patients with CRC, and in whole blood3,7,8. A defective intestinal epithelial barrier is thought to promote bacterial remnant translocation and disease progression6. However, it is unknown, how bacterial remnants translocate from the intestine to sites of metastasis or into the circulation. We hypothesized that bacterial remnants translocate within peripheral blood immune cells into the circulation. Here, we thus explored the composition of the detectable microbiome in peripheral blood mononuclear cells (PBMCs) of patients with CRC or IBD compared to healthy controls. The PBMC microbiome profiles partially align with the tumor- and metastasis-derived or intestinal tissue-derived microbiome signatures obtained from the same patients with CRC or IBD, respectively. Our metagenomics data, supported by 16S-rRNA-FISH-Flow, imaging flow cytometry and species-specific qPCR, reveal the presence of translocated bacterial genetic sequences in the patients with CRC and IBD, likely due to an intestinal barrier defect. Pathway and serum metabolomics analysis connected to the metabolic potential of the PBMC-derived microbiome sequences support the onset of microbial translocation in such patients. Thus, our data suggest that in patients with intestinal barrier leakage, such as those with CRC or IBD, there is the potential for the translocation of bacterial remnants into the circulation via peripheral immune cells.

cancer biology↗

bioRxiv2024

Eosinophils restrict CRC metastasis by inhibiting pro-tumorigenic SPP1+ macrophage differentiation

Eosinophils, traditionally associated with allergic responses, have emerged as critical immune modulators in colorectal cancer (CRC). Here, we reveal that eosinophils actively shape the tumor microenvironment and influence metastatic progression. Using comprehensive transcriptomics analysis of human CRC and a murine orthotopic tumor model, we identify a conserved tumor-specific eosinophil signature and activation profile. Despite their declining presence in advanced CRC, eosinophils suppress metastatic dissemination by counteracting the pro-tumorigenic functions of SPP1+ macrophages - a subset linked to immune exclusion and tumor metastasis. Mechanistically, eosinophils respond to tumor-derived signals and inhibit macrophage differentiation into SPP1+ cells. Eosinophil depletion exacerbates peritoneal tumor spread. These findings highlight the pivotal role of eosinophils in restraining late-stage CRC progression and unveil a novel eosinophil-macrophage axis as potential therapeutic targets.

cancer biology↗

bioRxiv2024

An oncoembryology approach uncovers SoxC-driven regulation of colon development and cancer

Reactivated embryonic programs are associated with cancer progression, yet their role and regulatory mechanisms remain poorly understood. In this study, we introduce oncoembryology, an approach that systematically compares embryonic and cancerous tissues to identify shared molecular programs and assess their functional relevance in disease. Applying this strategy to colorectal cancer, we identified SoxC transcription factors (Sox4, Sox11, Sox12) as critical regulators of both embryonic development and tumorigenesis. SoxC transcription factors regulate diverse downstream targets, including Tead2, Mdk, and Klf4, thereby regulating crucial steps of colon development. Abrogating SoxC function in murine models reduced tumor growth and prevented liver metastasis. Concordantly, a SoxC-driven oncoembryonic gene signature correlated with poor survival in colorectal cancer patients, underscoring the therapeutic potential of targeting SoxC-regulated pathways in cancer treatment.

cancer biology↗

bioRxiv2020

Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

Coronavirus disease (COVID-19), caused by SARS-CoV-2, has affected over 65 million individuals and killed over 1.5 million persons (December 8, 2020; www.who.int)1. While fatality rates are higher among the elderly and those with underlying comorbidities2, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.3-7 We report that the autoimmune PTPN2 risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry mediated by SARS-CoV-2 spike protein. Elevated ACE2 expression and viral entry were mediated by increased JAK-STAT signalling, and were reversed by the JAK inhibitor, tofacitinib. Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

microbiology↗

bioRxiv2018

Microbiota stability in healthy individuals after single-dose lactulose challenge - a randomized controlled study

Background and aimsLactulose is a common food ingredient and widely used as a treatment for constipation or hepatic encephalopathy and a substrate for hydrogen breath tests. Lactulose is fermented by the colon microbiota resulting in the production of hydrogen (H2). H2 is a substrate for enteropathogens including Salmonella Typhimurium (S. Typhimurium) and increased H2 production upon lactulose ingestion might favor the growth of H2-consuming enteropathogens. We aimed to analyze effects of single-dose lactulose ingestion on the growth of intrinsic Escherichia coli (E. coli), which can be efficiently quantified by plating and which share most metabolic requirements with S. Typhimurium.\n\nMethods32 healthy volunteers (18 females, 14 males) were recruited. Participants were randomized for single-dose ingestion of 50 g lactulose or 50 g sucrose (controls). After ingestion, H2 in expiratory air and symptoms were recorded. Stool samples were acquired at days -1, 1 and 14. We analyzed 16S microbiota composition and abundance and characteristics of E. coli isolates.\n\nResultsLactulose ingestion resulted in diarrhea in 14/17 individuals. In 14/17 individuals, H2-levels in expiratory air increased by [≥]20 ppm within 3 hours after lactulose challenge. H2-levels correlated with the number of defecations within 6 hours. E. coli was detectable in feces of all subjects (2 x 102 - 109 CFU/g). However, the number of E. coli colony forming units (CFU) on selective media did not differ between any time point before or after challenge with sucrose or lactulose. The microbiota composition also remained stable upon lactulose exposure.\n\nConclusionIngestion of a single dose of 50 g lactulose does not significantly alter E. coli density in stool samples of healthy volunteers. 50 g lactulose therefore seems unlikely to sufficiently alter growth conditions in the intestine for a significant predisposition to infection with H2-consuming enteropathogens such as S. Typhimurium (www.clinicaltrials.gov NCT02397512).

microbiology↗

bioRxiv2018

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis

The gene encoding for Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied.\n\nWe found increased mRNA expression of EBI2 and oxysterol synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated extraintestinal levels of 25-hydroxylated oxysterols, including 7,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2-/- mice in the IL-10 colitis model.\n\nThe colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2-/- mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures.\n\nIn summary, we report induction of the EBI2-7,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7,25-dihydroxycholesterol axis in IBD pathogenesis.

immunology↗

bioRxiv2018

The oxysterol synthesizing enzyme CH25H contributes to the development of intestinal fibrosis

Intestinal fibrosis and stenosis are common complications of Crohns disease (CD), frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidized cholesterol derivatives, with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase (CH25H) converts cholesterol to 25-hydroxycholesterol (25-HC), which modulates immune responses and oxidative stress. In human intestinal samples from CD patients we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme using the sodium dextran sulfate (DSS)-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

immunology↗