Biology subjects

Pizarro, T. T.

Publications and source records attributed to Pizarro, T. T..

3 recordsLinked to original sources

bioRxiv2025

A missense mutation in Muc2 promotes gut microbiome- and metabolome-dependent colitis-associated tumorigenesis.

Colitis-associated cancer (CAC) arises from a complex interplay between host and environmental factors, including the gut microbiome. Since ulcerative colitis (UC), a significant risk factor for CAC, is rising in prevalence worldwide, an integrative approach is essential to identify potential triggers linking inflammation to cancer. In the present study, we investigated the role of the gut microbiome using Winnie mice, a UC-like model with a relevant missense mutation in the Muc2 gene. Upon transfer from a conventional (CONV) to a specific-pathogen-free (SPF) facility, Winnie mice exhibited a more severe colitis phenotype, and notably, spontaneous CAC as early as four weeks of age, which progressively worsened over time. In contrast, CONV Winnie developed only mild colitis but with no overt signs of tumorigenesis. Notably, when rederived into germ-free (GF) conditions, SPF Winnie mice were protected from colitis or colon tumor development, indicating an essential role for the gut microbiome in the initiation and progression of CAC in these mice. Using shotgun metagenomics, metabolomics, and lipidomics, we identified a distinct pro-inflammatory microbial and metabolic signature that potentially drives the transition from colitis to CAC. Fecal microbiota transplantation (FMT), using either SPF Winnie or WT (Bl/6) donors into GF Winnie recipients, demonstrated that while colitis developed regardless of donor, only FMT from SPF Winnie donors resulted in CAC, revealing a microbiota-driven, host-specific susceptibility to tumorigenesis in Winnie mice. Our studies present a novel and relevant model of CAC, providing further evidence that the microbiome plays a key role in the pathogenesis of CAC, thereby challenging the concept of colon cancer as a strictly non-transmissible disease. Lay summaryThis study reveals a distinct metagenomic, metabolomic, and lipidomic profile associated with tumorigenesis in a murine model of ulcerative colitis, highlighting the risks of specific intestinal dysbiosis in genetically predisposed subjects. What you need to knowO_ST_ABSBackground and contextC_ST_ABSColitis-associated colorectal cancer arises from complex host-environment interactions, including gut microbiome influences, driving chronic inflammation, with the intestinal lumen environment remaining a largely unexplored potential risk factor in cancer development. New findingsWinnie mice in specific pathogen-free conditions developed severe colitis, and a novel juvenile colon dysplasia and cancer, with gut microbiome changes driving colitis-associated cancer initiation and progression. LimitationsWe identified a pro-inflammatory microbial/metabolic signature promoting colitis-to-CAC transition in Winnie mice, with FMT confirming microbiota-driven tumor susceptibility. However, further research is needed to pinpoint the key bacteria-metabolite-lipid combination driving CAC. Clinical research relevanceThis newly characterized microbiota-metabolome-based model of CAC, challenges the dogma of cancer as a non-transmittable disease, providing a foundation for developing microbiota-based strategies for CAC prevention and treatment. Basic research relevanceUnlike genetic or chemically induced models, the Winnie mouse model uniquely serves as a dual model for spontaneous colitis and juvenile CAC, offering a fast, 100% penetrant phenotype that enhances reliability, accelerates research, and provides valuable insights into IBD and CAC.

cancer biology↗

bioRxiv2024

TL1A/DR3 signaling regulates the generation of pathogenic Th9 cells in experimental inflammatory bowel disease

ObjectiveDeath receptor 3 (DR3) and its ligand tumor necrosis factor like ligand 1A (TL1A), are involved in the regulation of the balance between effector and regulatory T cells in IBD. New evidence suggests a role of IL-9-secreting Th9 cells in the pathogenesis of ulcerative colitis (UC), although the molecular pathways through which IL-9 and Th9 cells may mediate intestinal inflammation in Crohns disease (CD) are still unclear. DesignWe investigated the role of DR3 signaling in the differentiation of Th9 cells in mouse models of CD-like ileitis and colitis, including SAMP1/YitFc (SAMP) mice. ResultsPolarized-Th9 cells with functional DR3 from SAMP WT (Th9WT) harbor a pro-inflammatory signature compared to DR3-deficient Th9 cells that were obtained from DR3-/-xSAMP mice (Th9KO). Conversely, ablation of DR3 signaling generated anti-inflammatory responses, as reflected by higher numbers of IL-10 producing cells in DR3-/-xSAMP mice. Additionally, RNA-seq and phosphoproteomic analyses showed that inflammatory pathways are significantly more activated in Th9WT than in Th9KO cells. Finally, in the T-cell adoptive transfer model, Th9KO cells were less colitogenic than Th9WT, while IL-9 blockade diminished the severity of intestinal inflammation, indicating a crucial role of functional DR3 receptor in Th9 cells pathogenicity. ConclusionWe describe herein that a functional DR3 receptor is required for the pathogenicity of Th9 cells, thus, constituting a novel mechanism by which TL1A/DR3 signaling mediates experimental CD-like ileitis. The TL1A/DR3/Th9 pro-inflammatory pathway may offer a novel therapeutic target for patients with CD. What is already known on this topic - TL1A/DR3 system plays a pivotal role in the pathogenesis of Crohns disease like ileitis. - Th9 cells are a novel subset of T lymphocytes mainly producing the pro-inflammatory cytokine IL-9 which contributes to intestinal inflammation. - Those finding provided us with a strong rationale to investigate IL-9-producing cells in our SAMP1/YitFc mouse model of CD-like ileitis. What this study adds - DR3 receptor is involved in the regulation and progression of intestinal inflammation by promoting Th9 cell differentiation and pathogenicity. - Using RNA-seq and phosphoproteomic comparative analyses we were able to characterize Th9 cells with and without functional DR3 receptor showing that presence of DR3 confers a pro-inflammatory signature to Th9 cells. - We describe a novel role of DR3 in Th9 cells development that appears to regulate their pro-inflammatory phenotype in models of CD-like ileitis and colitis. How this study might affect research, practice or policy - TLA1/DR3 axis and Th9 cells may be useful as therapeutic targets in CD.

immunology↗

bioRxiv2023

Dysregulation of γδ intraepithelial lymphocytes precedes Crohn's disease-like ileitis

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IELs) provide immunosurveillance of the intestinal barrier. Interestingly, {gamma}{delta} IEL number is reduced in patients with active Crohns disease (CD). Here, we report an underappreciated role for {gamma}{delta} IELs in maintaining mucosal tolerance during the onset and progression of CD-like ileitis using the TNF{Delta}ARE/+ mouse model. Decreased epithelial HNF4G/BTNL expression is followed by a loss of ileal {gamma}{delta} IELs and impaired barrier surveillance prior to the histological onset of disease. A reduction of immunoregulatory CD39+ {gamma}{delta} IELs coincides with the influx of immature, peripheral CD39- {gamma}{delta} T cells into the epithelium leading to an expansion of induced IELs, while an earlier depletion of {gamma}{delta} IELs correlates with accelerated onset of ileal inflammation. Our findings identify multiple layers of {gamma}{delta} IEL dysregulation prior to ileitis development indicating that the loss of tissue-resident immunoregulatory {gamma}{delta} IELs may contribute to the initiation of ileal CD.

immunology↗