Biology subjects

Glickman, J. N.

Publications and source records attributed to Glickman, J. N..

4 recordsLinked to original sources

bioRxiv2026

Microbial-associated acylated putrescines as immunomodulatory molecules in inflammatory bowel diseases

The gut microbiota regulates intestinal immunity through metabolite production, yet most disease-associated metabolites remain functionally uncharacterized. In inflammatory bowel diseases (IBD), where the microbial metabolome is profoundly altered, we identify N-acyl putrescines as microbiome-associated metabolites enriched across two independent cohorts. N-oleoylputrescine (NOP) emerges as the primary immunomodulatory candidate, inducing robust transcriptional responses in dendritic cells and colonic organoids. Enterocloster species harboring nonribosomal peptide synthetase gene clusters synthesize NOP, confirmed by isotope-tracing in vitro and germ-free mouse colonization in vivo. NOP suppresses core IBD inflammatory pathways in mouse dendritic cells and human monocytes, reducing signatures of histologic inflammation and therapy non-response. NOP dampens inflammation in four colitis models, decreases myeloid cell NF-{kappa}B activation, and suppresses type 1 immune responses through a T cell-intrinsic mechanism. That NOP accumulates in IBD despite its anti-inflammatory properties reveals a holobiont defense strategy: the gut microbiota deploys immunomodulatory metabolites as a compensatory response to restore homeostasis.

immunology↗

bioRxiv2025

GPR15 and CD38 define a subset of peripheral blood pathogenic effector Th2 cells associated with active eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergic disease driven by exposure to culprit antigens. Due to the local nature of the inflammation, diagnosis and assessment are limited to invasive procedures. Based on prior single-cell RNA sequencing (scRNA-seq) data linking peripheral GPR15+ pathogenic effector Th2 (peTh2) cells to esophageal tissue peTh2s, we hypothesized the direct involvement of GPR15+ peTh2 cells in EoE pathogenesis and aimed to further evaluate their association with EoE disease status. We subjected samples from subjects with or without EoE to flow cytometry (n = 74 peripheral blood, 17 biopsy) and scRNA-seq (n = 27 peripheral blood, 10 biopsy). Expression of GPR15 by peripheral peTh2 cells was increased in EoE, and these cells expressed increased CD38 in active EoE--findings recapitulated in esophageal biopsies. We also identified a peTh2-associated, CD38-containing gene expression program that peripheral GPR15+ peTh2 cells upregulated in active EoE. The level of upregulation was distinct from other circulating peTh2 cells and was more similar to that seen in esophageal peTh2 cells. An association between expression of GPR15 by peripheral peTh2 cells, the aryl hydrocarbon receptor was strongest in subjects with EoE, suggesting an environmental exposure or susceptibility. The magnitude of GPR15 expression by peripheral peTh2 cells could effectively in discriminate active EoE from no EoE in our study population (AUC 0.93). Our data suggest that EoE-related peTh2 cells are identifiable and accessible in the peripheral blood, and could be exploited in both clinical practice as a non-invasive biomarker and continued investigation into mechanisms driving EoE. One sentence summaryGPR15 marks a subset of peripheral blood pathogenic effector Th2 cells associated with eosinophilic esophagitis (EoE) that upregulate CD38 during active disease - an observation that has potential to be used for non-invasive diagnosis and monitoring of EoE and that has suggests new mechanisms driving this increasingly prevalent allergic disease.

immunology↗

bioRxiv2025

Acetoacetate suppresses colon cancer via an MR1-MAIT axis

Colorectal cancer (CRC) is a leading cause of cancer mortality and additional preventative, and therapeutic strategies are urgently needed. Ketogenic diets have mixed effects on tumorigenesis and compliance is challenging. Exogenous ketones, {beta}-hydroxybutyrate ({beta}HB) or acetoacetate (AcAc), offer an alternative approach. While {beta}HB has been investigated, the anti-cancer effects of AcAc are poorly defined. Here, we show that orally administering ethyl AcAc (EAA) suppresses tumor growth in several pre-clinical CRC models. Single-cell RNA sequencing, flow cytometry, and genetic and antibody-mediated depletion studies reveal that EAA selectively expands and activates cytotoxic mucosal-associated invariant T (MAIT) cells in an MHC class I-related protein 1 (MR1)-dependent manner. EAA increases MR1 expression by tumor monocytes, which is recapitulated in human cell cultures, where AcAc and 5-amino-6-D-ribitylaminouracil (5-A-RU) induce MAIT cell expansion and tumor killing. Mechanistically, AcAc converts to methylglyoxal, combining with microbially-derived 5-A-RU to generate 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a potent MR1 ligand. These findings identify an AcAc-MR1-MAIT cell axis as a potential immunotherapy approach for CRC therapy.

immunology↗

bioRxiv2020

Diet Post-translationally Modifies The Gut Microbial Proteome To Modulate Renal Function

We identify a novel mechanism linking diet, gut microbial metabolism, and renal function. We found that a sulfur amino acid-based dietary intervention post-translationally modifies a microbial enzyme, blunting its uremic toxin-producing activity and alleviating chronic kidney disease (CKD) in a preclinical model. We also define a heretofore unknown role for the post-translational modification S-sulfhydration within the gut microbiome. This study provides a framework for understanding how diet can tune microbiota function via protein post-translational modification without altering microbial community composition to support healthy host physiology beyond the gut and specifically how a dietary modification can inhibit tryptophanase activity to ameliorate CKD progression. One Sentence SummaryWe found that diet post-translationally modifies the gut microbiota proteome to modulate kidney function.

microbiology↗