Biology subjects

Zarek, C.

Publications and source records attributed to Zarek, C..

5 recordsLinked to original sources

bioRxiv2026

A Urinary Metabolomic Signature Associated with Small Intestinal Bacterial Overgrowth in Children with Short Bowel Syndrome

Direct sampling of the small intestinal microbiome is challenging. Urinary metabolites may offer a noninvasive approach to studying microbial functional activity. We used clinically available gas chromatography/mass spectrometry to profile urinary organic acids in 94 children with short bowel syndrome, comparing those with clinically defined small intestinal bacterial overgrowth (SIBO; n=21) with those without SIBO (n=73). SIBO-associated metabolites included microbial fermentation products, dietary derivatives, and host metabolic intermediates. Metabolites enriched in SIBO mapped to aromatic amino acid metabolism, including tryptophan and tyrosine pathways, consistent with altered microbial fermentation. Many associations persisted after adjustment for intestinal anatomy, age, antibiotic exposure, and nutritional composition. These findings identified a urinary metabolic profile associated with clinically defined SIBO in children with short bowel syndrome and support further evaluation of urinary metabolomics as a noninvasive approach to studying small intestinal microbial function.

microbiology↗

bioRxiv2026

A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8+ T cell antitumor immunity

Gut microbiota are critical determinants of effective immune checkpoint therapy (ICT), yet the microbial mediators and host mechanisms that enhance antitumor immunity remain poorly understood. Here, we identify the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as a metabolite associated with immune checkpoint therapy (ICT) response. TDCA administration alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness across multiple murine tumor models. Mechanistically, TDCA directly enhances CD8 T cell-mediated antitumor immunity, increasing cytotoxicity. These effects required signaling through the bile acid receptor TGR5. Together, these findings reveal TDCA as a gut microbial metabolite that restores ICT efficacy after antibiotic disruption by directly augmenting CD8 T cell anti-tumor activity. This work supports metabolite replacement as a therapeutic strategy to mitigate antibiotic-associated loss of cancer immunotherapy response. SignificanceTDCA is a microbiota-derived metabolite that restores immune checkpoint therapy efficacy after antibiotic disruption by directly enhancing CD8 T-cell-mediated anti-tumor immunity through bile acid receptor TGR5 signaling. Our findings suggest that supplementation with defined microbial metabolites can mitigate antibiotic-associated loss of immunotherapy response without requiring broader microbiome reconstitution.

cancer biology↗

bioRxiv2025

Timing of immune checkpoint blockade shapes anti-tumor immunity via a clock-dependent chemokine axis

Circadian clocks regulate immunity, yet how they shape the tumor immune microenvironment and influence cancer immunotherapy remains unclear. Here, we show that tumor immune infiltration and immune checkpoint inhibitor efficacy vary by time of day in mice, driven by intrinsic clocks in dendritic cells and CD8+ T cells. Time-of-day modulates the abundance, spatial organization, and cytokine-chemokine production of tumor-infiltrating immune cells. Mechanistically, dendritic cell clocks control expression of Cx3cl1, driving recruitment of CX3CR1+CD8+ T cells and thereby reshaping the tumor immune microenvironment to enhance immunotherapy efficacy. Disruption of this axis abolishes time-of-day-dependent differences in treatment response. These findings identify a circadian mechanism of immune cell recruitment to tumors and provide mechanistic insight into clinical observations linking treatment timing to immunotherapy outcomes. One sentence summaryTime of day determines cancer immunotherapy efficacy through a circadian clock-dependent chemokine axis.

immunology↗

bioRxiv2022

Coinfection with Intestinal Parasite Expands Resident Macrophages and Impairs Control of Chronic Herpesvirus Infection

In addition to a range of homeostatic functions, resident macrophages are essential for immune surveillance in tissues. Therefore, anything that alters the phenotype or function of these cells potentially impacts their response to infectious challenges. Parasite infections cause proliferation of large peritoneal macrophages (LPMs), which are the resident macrophages of the peritoneal cavity. However, the functional consequences of LPM expansion on the control of secondary infectious challenge is unknown. Using a coinfection model with the intestinal parasite Heligmosomoides polygyrus (HP) and the virus, murine gammaherpesvirus-68 (MHV68), we investigated the impact of LPM expansion on viral infection. We determined that LPM expansion induced by HP required retinoic acid signaling. When we challenged HP-infected mice with MHV68, we observed increased herpesvirus infection and latency. Coinfection of mice with macrophage-specific deletion of GATA6, the retinoic acid-responsive transcription factor that drives LPM transcriptional programming, eradicated the increase in viral infection. In addition to increased MHV68 infection, parasite coinfected mice displayed increased herpesvirus reactivation from latency, indicating impaired control of chronic herpesvirus infection. Elimination of dietary vitamin A, which depletes retinoic acid and LPMs, abolished the increased MHV68 reactivation in parasite coinfected mice. These results indicate that parasite- and retinoic acid-mediated resident macrophage expansion drives increased herpesvirus infection, latency, and reactivation.

immunology↗

bioRxiv2020

Th2 Cytokine Modulates Herpesvirus Reactivation in a Cell Type Specific Manner

Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposis sarcoma associated virus (KSHV), and murine {gamma}-herpesvirus 68 (MHV68), establish latent infection in B cells, macrophages, and non-lymphoid cells, and can induce both lymphoid and non-lymphoid cancers. Research on these viruses has relied heavily on immortalized B cell and endothelial cell lines. Therefore, we know very little about the cell type specific regulation of virus infection. We have previously shown that treatment of MHV68-infected macrophages with the cytokine interleukin-4 (IL-4) or challenge of MHV68-infected mice with an IL-4-inducing parasite leads to virus reactivation. However, we do not know if all latent reservoirs of the virus, including B cells, reactivate the virus in response to IL-4. Here we used an in vivo approach to address the question of whether all latently infected cell types reactivate MHV68 in response to a particular stimulus. We found that IL-4 receptor expression on macrophages was required for IL-4 to induce virus reactivation, but that it was dispensable on B cells. We further demonstrated that the transcription factor, STAT6, which is downstream of the IL-4 receptor and binds a viral promoter in macrophages, did not bind to the viral promoter in B cells. These data suggest that stimuli that promote herpesvirus reactivation may only affect latent virus in particular cell types, but not in others. ImportanceHerpesviruses establish life-long quiescent infections in specific cells in the body, and only reactivate to produce infectious virus when precise signals induce them to do so. The signals that induce herpesvirus reactivation are often studied only in one particular cell type infected with the virus. However, herpesviruses establish latency in multiple cell types in their hosts. Using murine gammaherpesvirus-68 (MHV68) and conditional knockout mice, we examined the cell type specificity of a particular reactivation signal, interleukin-4 (IL-4). We found that IL-4 only induced herpesvirus reactivation from macrophages, but not from B cells. This work indicates that regulation of virus latency and reactivation is cell type specific. This has important implications for therapies aimed at either promoting or inhibiting reactivation for the control or elimination of chronic viral infections.

microbiology↗