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Bacterial ADP-Heptose triggers stem cell regeneration in the intestinal epithelium following injury [scRNA-seq]

ABSTRACT: ADP-Heptose (ADP-Hep), a metabolite produced by Gram-negative bacteria as an intermediate of lipopolysaccharide biosynthesis, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the functional role of the ALPK1-TIFA pathway in the intestinal epithelium remains poorly understood. Here, we use bulk RNA sequencing of murine derived ileal organoids to study the role of ADP-Hep in initiating stem cell regeneration in the intestinal epithelium.

ORGANISM(S): Mus musculus

PROVIDER: GSE297524 | GEO | 2025/08/18

REPOSITORIES: GEO

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Bacterial ADP-Heptose triggers stem cell regeneration in the intestinal epithelium following injury [RNA-seq]

Project description:ADP-Heptose (ADP-Hep), a metabolite produced by Gram-negative bacteria as an intermediate of lipopolysaccharide biosynthesis, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the functional role of the ALPK1-TIFA pathway in the intestinal epithelium remains poorly understood. Here, we use bulk RNA sequencing of murine derived ileal organoids to study the role of ADP-Hep in initiating stem cell regeneration in the intestinal epithelium.

2025-08-18 | GSE297523 | GEO

Identification of proteins that interact with TRAF6 in ADP-heptose- or IL-1β-stimulated HEK293 cells

Project description:The bacterial metabolite ADP-heptose activates the mammalian protein kinase ALPK1 (alpha protein kinase 1), which then phosphorylates TIFA (TRAF interacting protein with FHA domain). This leads to the oligomerisation of TIFA and the recruitment and oligomerisation of TRAF6 (TNF receptor-associated factor 6), activating a signalling network that culminates in the production of inflammatory mediators that mount responses to combat microbial infection. To identify other protein(s) that associate with TRAF6 in ADP-heptose-stimulated cells, we re-expressed FLAG-TRAF6 in TRAF6 KO cells, stimulated the cells with ADP-heptose and immunoprecipitated TRAF6 from the cell extracts using a FLAG antibody. Proteins associated with TRAF6 were identified by mass spectrometry and included the components of LUBAC (the linear ubiquitin assembly complex), the components of the TAK1 and IB kinase (IKK) complexes, TRAF2 and c-IAP1, providing insight into the molecular details and mode of operation of the ADP-heptose signalling pathway. In parallel experiments the cells were stimulated with IL-1b, a cytokine that also signals via TRAF6, which served as a control.

2022-09-14 | PXD034964 | Pride

Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1 [RNA-seq]

Project description:Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during aging remain rudimentary. Here we report that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes leukemic cell expansion. Specifically, we show that ADP-D-glycero-b-D-manno-heptose (ADP-heptose), a biosynthetic bi-product specific to gram-negative bacteria, is uniquely found in the circulation of older individuals and favors the expansion of pre-leukemic hematopoietic stem cells. Mechanistically, ADP-heptose binds its receptor, ALPK1, triggering transcriptional reprogramming that endows pre-leukemic cells with a competitive advantage. Thus, the accumulation of ADP-heptose represents a direct link between aging and expansion of rare pre-leukemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukemia and immune-related conditions.

2025-02-10 | GSE232794 | GEO

Tifa-/- vs Tifa+/+ small intestinal organoids stimulated with water, IL-22, IL-22+ADP-Heptose

Project description:Tifa-/- vs Tifa+/+ small intestinal organoids stimulated with water, IL-22, IL-22+ADP-Heptose

| PRJEB85839 | ENA

Fusobacterium nucleatum upregulates the immune inhibitory receptor PD-L1 in intestinal epithelial cells via the activation of ALPK1

Project description:Fusobacterium nucleatum is a Gram-negative oncobacterium that is associated with colorectal cancer. The molecular mechanisms utilized by F. nucleatum to promote colorectal tumor development have largely focused on adhesin-mediated binding to the tumor tissue and on the pro-inflammatory capacity of F. nucleatum. However, the exact manner in which F. nucleatum promotes inflammation in the tumor microenvironment and subsequent tumor promotion remains underexplored. Here, we show that both live F. nucleatum and sterile F. nucleatum-conditioned medium promote CXCL8 release from the intestinal adenocarcinoma HT-29 cell line. We determined that the pro-inflammatory response was ALPK1-dependent in both HEK293 and HT-29 cells and that the released F. nucleatum molecule had characteristics that match those of the pro-inflammatory ALPK1 ligand ADP-heptose or related heptose phosphates. In addition, not only F. nucleatum but also other Fusobacterium species such as F. varium, F. necrophorum and F. gonidiaformans promoted an ALPK1-dependent pro-inflammatory environment, indicating that ADP-heptose or related heptose phosphates secretion is a conserved feature of the Fusobacterium genus. By performing transcriptional analysis of ADP-heptose stimulated HT-29 cells, we found several inflammatory and cancer-related pathways to be differentially regulated, including DNA mismatch repair genes and the immune inhibitory receptor PD-L1. Finally, we show that stimulation of HT-29 cells with F. nucleatum resulted in an ALPK1-dependent upregulation of PD-L1. These results aid in our understanding of the mechanisms by which F. nucleatum can affect tumor development and therapy and pave the way for future therapeutic approaches.

2024-05-13 | GSE267317 | GEO

LB001: The ALPK1 pathway drives the inflammatory response to Campylobacter jejuni in human intestinal epithelial cells

Project description:The Gram-negative bacterium Campylobacter jejuni is a major cause of foodborne disease in humans. After infection, C. jejuni rapidly colonizes the mucus layer of the small and large intestine and induces a potent pro-inflammatory response characterized by the production of a large repertoire of cytokines, chemokines, and innate effector molecules, resulting in (bloody) diarrhea. The virulence mechanisms by which C. jejuni causes this intestinal response are still largely unknown. Here we show that C. jejuni releases a potent pro-inflammatory compound into its environment, which activates an NF-B-mediated pro-inflammatory response including the induction of CXCL8, CXCL2, TNFAIP2 and PTGS2. This response was dependent on a functional ALPK1 receptor and independent of Toll-like Receptor and Nod-like Receptor signaling. Chemical characterization, inactivation of the heptose-biosynthesis pathway by the deletion of the hldE gene and in vitro engineering identified the released factor as the LOS-intermediate ADP-heptose and/or related heptose phosphates. During C. jejuni infection of intestinal cells, the ALPK1-NF-kB axis was potently activated by released heptose metabolites without the need for a type III or type IV injection machinery. Our results classify ADP-heptose and/or related heptose phosphates as a major virulence factor of C. jejuni that may play an important role during Campylobacter infection in humans.

2021-07-15 | GSE70610 | GEO

Single-cell level gene expression profiles of immune cells within B16F10-OVA tumours treated with PBS or UDSP-Hep

Project description:Activation of the Alpha kinase 1 (ALPK1) is a promising strategy to be developed as a next-generation cancer immunotherapy. We used single cell RNA sequencing (scRNA-seq) to analyze the ALPK1 activation-triggered antitumour immune responses within the tumour microenvironment of B16F10-OVA tumours treated with PBS or UDSP-Hep.

2024-08-28 | GSE275540 | GEO

ADP

Project description:ADP array data, comprised of 2217 samples of Asian ancestry (excluding the Japanese population from ADP). Samples were genotyped on different Illumina or Affy platform.

| EGAD00010001491 | EGA

Fibrosis associated changes detected in the proteome of surface epithelium overlying Crohn’s Disease Strictures

Project description:Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD). It is characterised by an excessive accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods: A total of 113 CD and control subjects were studied. We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser capture microdissection in normal and fibrotic zones of resected ileal CD strictures (n=5). Selected proteins were validated by immunohistochemistry (IHC) in colonic and ileal samples of stricturing CD patients (n=44), pure inflammatory CD (n=29) and control subjects (n=40). Functional assays with cell lines cultures and a fibroblast to myofibroblast differentiation model were used to assess the role of the highlighted epithelial proteins in CD fibrosis. Results: Proteomic study revealed an endoplasmic reticulum (ER) stress and unfolded protein response (UPR) markers increase in the epithelium overlying ileal fibrotic strictures, involving Anterior gradient protein 2 homolog (AGR2) and Binding immunoglobulin protein (BiP). This was confirmed by IHC. The ER stress induction in intestinal epithelial cells increased AGR2 as well as BiP expression and led to an extracellular secreted AGR2. A fibroblast to myofibroblast differentiation was obtained with the supernatant of intestinal epithelial cells pre-conditioned by ER stress and with recombinant AGR2. Conclusions: AGR2 and other ER stress markers are increased within the intestinal epithelium overlying fibrotic strictures and might contribute to profibrotic signals involved in CD fibrosis.

2022-04-04 | PXD022214 | Pride

ADP-heptose attenuates H. pylori-induced type I IFN signaling in DCs and impairs subsequent T cell responses

Project description:Helicobacter pylori (H. pylori) colonizes the gastric mucosa of approximately 50% of the world’s population. While it is well established that H. pylori is a major cause of gastric cancer, it has only recently been reported that H. pylori can also have adverse effects on immunological processes, including autoimmune diseases and immunotherapies. Understanding the paradoxical interplay between H. pylori and the human immune system will therefore be beneficial to improve a variety of therapeutic approaches. Here we show that ADP-heptose, a metabolite originally reported to act as a bona fide PAMP, attenuates full-fledged activation of primary human dendritic cells in the context of H. pylori infection by impairing type I IFN signaling, which in turn results in reduced DC maturation and T cell activation. Thus, this study provides novel mechanistic insights into how H. pylori utilizes ADP-heptose to mitigate host immunity.

2024-09-13 | PXD046603 | Pride

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