Biology subjects

Coughlin, L.

Publications and source records attributed to Coughlin, L..

5 recordsLinked to original sources

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↗

bioRxiv2023

Susceptible bacteria survive antibiotic treatment in the mammalian gastrointestinal tract without evolving resistance

In vitro systems have provided great insight into the mechanisms of antibiotic resistance. Yet, in vitro approaches cannot reflect the full complexity of what transpires within a host. As the mammalian gut is host to trillions of resident bacteria and thus a potential breeding ground for antibiotic resistance, we sought to better understand how gut bacteria respond to antibiotic treatment in vivo. Here, we colonized germ-free mice with a genetically barcoded antibiotic pan-susceptible Escherichia coli clinical isolate and then administered the antibiotic cefepime via programmable subcutaneous pumps which allowed for closer emulation of human parenteral antibiotic pharmacokinetics/dynamics. After seven days of antibiotics, we were unable to culture E. coli from feces. We were, however, able to recover barcoded E. coli from harvested gastrointestinal (GI) tissue, despite high GI tract and plasma cefepime concentrations. Strikingly, these E. coli isolates were not resistant to cefepime but had acquired mutations - most notably in the wbaP gene, which encodes an enzyme required for the initiation of the synthesis of the polysaccharide capsule and lipopolysaccharide O antigen - that increased their ability to invade and survive within intestinal cells, including cultured human colonocytes. Further, these E. coli mutants exhibited a persister phenotype when exposed to cefepime, allowing for greater survival to pulses of cefepime treatment when compared to the wildtype strain. Our findings highlight a mechanism by which bacteria in the gastrointestinal tract can adapt to antibiotic treatment by increasing their ability to persist during antibiotic treatment and invade intestinal epithelial cells where antibiotic concentrations are substantially reduced.

microbiology↗

bioRxiv2022

Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal anti-tumor immunity

Gut microbiota are critical for effective immune checkpoint blockade therapy (ICT) for cancer. The mechanisms by which gut microbiota augment extraintestinal anti-cancer immune responses, however, are largely unknown. Here, we find that ICT induces translocation of specific endogenous gut microbiota into secondary lymphoid organs and subcutaneous melanoma tumors. Mechanistically, gut microbiota activated dendritic cells (DCs) traffic a selective subset of gut bacteria to mesenteric lymph nodes (MLN) and promote optimal anti-tumor T-cell responses in both the tumor draining lymph nodes (TDLN) and the primary tumor. Antibiotic treatment resulted in decreased gut microbiota translocation into MLN and TDLN, diminished polyfunctional effector CD8+ T cell responses, and attenuated response to ICT. Our findings illuminate a key mechanism by which gut microbiota promote extraintestinal anti-cancer immunity. One sentence summaryFollowing immune checkpoint blockade therapy, dendritic cells traffic gut microbiota into secondary lymphoid organs, promoting optimal extraintestinal anti-cancer immunity.

immunology↗

bioRxiv2020

MCT2 Overexpression Rescues Metabolic Vulnerability and Protects Retinal Ganglion Cells in Two Models of Glaucoma

Improving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2fl/+ mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration. HighlightsO_LILoss of MCT2 in retina compromises visual function and ATP production in optic nerve C_LIO_LIMCT2 overexpression preserves RGC soma and axon number in two glaucoma models C_LIO_LIMCT2 overexpression improves energy homeostasis in optic nerve C_LI

neuroscience↗