Biology subjects

Reardon, C.

Publications and source records attributed to Reardon, C..

13 recordsLinked to original sources

bioRxiv2026

Oral exposure to Perfluorooctanoic acid disrupts the microbiota-gut-liver axis and enhances the severity of chemically induced colitis in mice.

Inflammatory bowel diseases (IBD) affect millions of patients worldwide and impair quality of life. Although genetic and environmental factors are known to disrupt the gastrointestinal (GI) epithelial barrier and increase susceptibility to IBD, the precise contribution of specific environmental exposures remains unclear. Per- and polyfluoroalkyl substances (PFAS), or "forever chemicals," are widely used in consumer products and contaminate food and water sources, resulting in chronic oral exposure worldwide. Perfluorooctanoic acid (PFOA), a common PFAS, has been epidemiologically associated with the development of IBD, particularly in older adults. Here, we assessed the effects of oral PFOA exposure on the GI tract, liver, and susceptibility to colitis. C57BL/6 mice were exposed to PFOA (0.1 mg/kg or 1.0 mg/kg) beginning at weaning (post-natal day [P]21) for a time course of 4 or 8 weeks. GI physiology/pathology (Ussing chambers; histology), expression of pro-inflammatory cytokines (qPCR), microbiota composition (16S sequencing), bile acids production (qPCR; LC/MS), and liver pathology (histology) were assessed. Colitis susceptibility was evaluated in genetically predisposed (IL10 knockout) mice, and in induced (dextran sodium sulfate [DSS]) mouse models following PFOA exposure (8 weeks at 1.0 mg/kg). Oral PFOA exposure increased intestinal permeability, mildly increased cytokine expression, altered gut microbiota composition, disrupted liver and serum bile acids, and caused hepatic hypertrophy at higher doses and longer exposure. Although PFOA did not increase disease susceptibility in genetically predisposed Il10 KO mice, it significantly worsened DSS-induced colitis, but only in male mice. Together, these findings demonstrate that early-life PFOA exposure disrupts the gut-liver axis and may contribute to colitis development in a sex dependent manner.

pharmacology and toxicology↗

bioRxiv2026

Vagus nerve stimulation limits colonic inflammation through distinct neuroimmune circuitry shaped by inflammatory history

Bidirectional communication between the nervous and immune systems has been demonstrated to limit or enhance immune cell function across organ systems and conditions. Although these neuroimmune circuits can become activated as an anti-inflammatory reflex, vagus nerve stimulation (VNS) reduces inflammation in models of endotoxemia, rheumatoid arthritis, and intestinal inflammation. In the spleen during endotoxemia, VNS activates a "cholinergic anti-inflammatory pathway" (CAIP), whereby choline acetyltransferase (ChAT)-expressing T cells release acetylcholine to reduce macrophage activation. VNS can also drive CAIP-independent pathways to reduce inflammation in the spleen and intestinal tract, although the circuitry modulating colonic inflammation remains underexplored. Here, we demonstrate that left cervical VNS reduces acute LPS-induced inflammation, evidenced by reduced Tnfa expression in colon and spleen and decreased circulating TNF. In the colon, these protective effects required efferent but not afferent VNS and were independent of ChAT+ T cells, IL10, {beta}-adrenergic signaling, and colonic sympathetic innervation. Critically, the ability of VNS to modulate colonic inflammation depended on prior tissue-specific inflammation. Mice recovering from DSS colitis, despite near-complete histological recovery, were refractory to the protective effects of VNS in the colon. This lack of efficacy in the colon was not reflected in measures of inflammation in the spleen or serum, highlighting the need for target-organ-specific monitoring. This loss of efficacy after colonic inflammation was transient, with restoration occurring upon complete recovery. These findings demonstrate that VNS efficacy in colonic inflammation depends on circuitry distinct from canonical systemic anti-inflammatory pathways, and that tissue responsiveness is shaped by anatomical site and inflammatory history. Key PointsO_LIElectrical stimulation of the left cervical vagus nerve reduces LPS-induced inflammation in the mouse colon. C_LIO_LIThis colonic anti-inflammatory effect requires vagal efferents but not afferent signaling. C_LIO_LIUnlike canonical splenic anti-inflammatory pathways, the colonic response does not require ChAT+ T cells, IL-10, {beta}-adrenergic signaling, or local sympathetic innervation. C_LIO_LIRecent DSS colitis abolishes colonic responsiveness to VNS despite preserved splenic and systemic anti-inflammatory effects. C_LIO_LIRecovery of VNS anti-inflammatory efficacy after colitis shows that neuroimmune responsiveness in the colon is dynamically shaped by inflammatory history. C_LI

immunology↗

bioRxiv2026

Neonatal Enteric Infection Disrupts the Microbiota-Gut-Brain Axis Through Pattern Recognition Receptors and Altered Neuroimmune Signaling

Early-life enteric infection can have long-lasting effects on the microbiota-gut-brain (MGB) axis. Using a neonatal Enteropathogenic Escherichia coli (EPEC) model, we show that intestinal epithelial cell (IEC) NOD1 signaling coordinates mucosal immunity, barrier repair, and neuroimmune outcomes throughout early development and into adulthood. Neonates infected at postnatal day (P) 7 exhibited ileal inflammation, as demonstrated by increased expression of inflammatory cytokines (Il1{beta}, Il6, Il12, Il22), chemokines/chemokine receptors (Ccl2, Cxcl1, Ccr2), and barrier-repair genes (Muc2, Slc26a3), with increased monocyte/macrophage infiltration and reduced epithelial proliferation in WT mice that was blunted in Nod1{Delta}IEC mice. Neonatal infection of WT mice induced persistent defects into adulthood (P56), including increased intestinal permeability, sustained inflammatory/repair signatures, hippocampal inflammation, altered neurogenesis, and impaired recognition memory, which were largely absent in Nod1{Delta}IEC mice, establishing a crucial role for IEC NOD1 as a determinant of long-term MGB remodeling. Microbially derived ligands of NOD2, muropeptides, isolated from probiotic Lactobacillus species attenuated EPEC-induced mucosal inflammation and chemokine induction without altering bacterial burden, demonstrating NOD2 host-directed immunomodulation. Together, these findings identify an important role for NOD-dependent signaling axis in the gastrointestinal tract that links early-life infection to enduring gut-brain dysfunction and reveals probiotic-derived muropeptides as candidate microbial therapeutics.

physiology↗

bioRxiv2025

Tac1 Deficiency Reduces the Severity of Enteric Bacterial Infection

BackgroundInfection with enteric bacterial pathogens continues to cause significant morbidity and mortality throughout the world. These pathogens include enterohemorrhagic and enteropathogenic Escherichia coli, which transit the intestinal tract, efface microvilli, and attach firmly to intestinal epithelial cells predominantly in the colon. Investigation of these human-adapted pathogens has been greatly aided by mouse models of infection. The mouse-adapted attaching and effacing pathogen Citrobacter rodentium utilizes many similar mechanisms of pathogenesis, including the use of a type III secretion system, and virulence factors encoded in a locus of enterocyte effacement. Although this model has allowed for assessing the complexity of the host response, the complex interplay between the nervous and immune systems in response to infection remains incomplete. MethodsWe assessed the role of sensory neurotransmitters encoded by the Tac1 gene in the host response to C. rodentium. ResultsTac1-deficient mice had significantly reduced pathogen shedding and colonic bacterial burden, accompanied by decreased expression of inflammatory cytokines and chemokines. In accordance with reduced chemokine production, we observed reduced colonic recruitment of specific immune cell populations in Tac1-/- compared to WT mice. ConclusionsSensory neuropeptides regulate key aspects of enteric bacterial infection and may serve as unique targets in the treatment of enteric disease.

immunology↗

bioRxiv2025

The sympathetic nervous system enhances host immune responses to enteric bacterial pathogens.

Mucosal immune responses to enteric bacterial infections are highly coordinated processes that orchestrate host protection while minimizing the potential for immune-triggered pathology. In the intestinal tract, bidirectional communication occurs between the nervous and immune systems to affect local immune responses by modulating the activity of resident and recruited immune cells, and indirectly on the supporting stromal cells. These neuroimmune signaling pathways that alter host defense have focused on specialized sensory innervation and the unique neurotransmitters released from them. Although the sympathetic nervous system has been established to induce a tissue-protective phenotype in subpopulations of neuron-associated macrophages in the small intestine, the role of these neurons during enteric bacterial infection was unknown. Using genetic labeling of activated neurons with ArcTRAP, we demonstrate that colonic infection induces activation of the rostral ventrolateral medulla, a major sympathetic center in the brainstem. The importance of peripheral sympathetic neurons was further demonstrated using chemical sympathectomy that significantly increased bacterial burden during Citrobacter rodentium (C. rodentium) infection. Increased bacterial burden was matched by a deficit in host protection due to reduced IFN{gamma} production by colonic CD4+ T-cells. Sympathectomy, however, did not diminish the capacity to differentiate into IFN{gamma}- or IL-17A- producing T-cells in vitro, suggesting that the lack of sympathetic innervation during infection may alter this process in vivo without causing sustained T-cell intrinsic defects. In assessing which receptors could mediate these effects, pharmacological antagonists selective for - adrenergic receptors (AR), but not {beta}-adrenergic receptors, increased bacterial burden and reduced colonic IFN{gamma} production. Using isolated cell types from the colon of uninfected and infected mice, we identified the AR subtypes expressed on immune and stromal cells, with significant upregulation of these receptors on T-cells during C. rodentium infection. Together these data demonstrate the unique role of the sympathetic nervous system and AR in mucosal immune responses against enteric bacterial pathogens.

immunology↗

bioRxiv2025

Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation.

Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons has been previously demonstrated to reduce maladaptive host responses during endotoxemia, only selective stimulation of vagal afferent neurons was able to inhibit TLR7-induced macrophage activation and neutrophil recruitment in the lung. These anti-inflammatory actions are facilitated by systemic increases in epinephrine, as VNS significantly increased epinephrine in the serum and bronchoalveolar lavage fluid, and inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the {beta}2-adrenergic receptor ({beta}2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in {beta}2AR-knock out mice, and with pharmacological inhibition of the {beta}2AR. Analysis of the immune cells responding to R848 critically identified that plasmacytoid dendritic cells were refractive to inhibition by VNS, and this corresponded to lack of {beta}2AR expression. These findings demonstrate a novel neuro-immune circuit elicited by VNS that can control acute lung inflammation. SummaryWe have identified a novel neuro-immune circuit activated by afferent vagus nerve stimulation to reduce acute lung inflammation. This effect was dependent on vagal-induced adrenal gland-derived epinephrine release that initiates anti-inflammatory {beta}2-adrenergic receptor signaling in innate immune cells within the lung.

immunology↗

bioRxiv2025

Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation

Microbial pathogens generate extracellular vesicles (EVs) for intercellular communication and quorum sensing. Microbial EVs also induce inflammatory pathways within host innate immune cells. We previously demonstrated that EVs secreted by Candida albicans trigger type I interferon signaling in host cells specifically via the cGAS-STING innate immune signaling pathway. Here, we show that despite sharing similar properties of morphology and internal DNA content, the interactions between EVs and the innate immune system differ according to the parental fungal species. EVs secreted by C. albicans, Saccharomyces cerevisiae, Cryptococcus neoformans, and Aspergillus fumigatus are endocytosed at different rates by murine macrophages triggering varied cytokine responses, innate immune signaling, and subsequent immune cell recruitment. Notably, cell wall constituents that decorate C. neoformans and A. fumigatus EVs inhibit efficient internalization by macrophages and dampen innate immune activation. Our data uncover the transcriptional and functional consequences of the internalization of diverse fungal EVs by immune cells and reveal novel insights into the early innate immune response to distinct clinically significant fungal pathogens.

microbiology↗

bioRxiv2024

Substance P receptor signaling contributes to host maladaptive responses during enteric bacterial infection.

Immune responses in the intestine are intricately balanced to prevent pathogen entry without inducing immunopathology. The nervous system is well-established to interface with the immune system to fine-tune immunity in various organ systems including the gastrointestinal tract. Specialized sensory neurons can detect bacteria, bacterial products, and the resulting inflammation, to coordinate the immune response in the gastrointestinal tract. These sensory neurons release peptide neurotransmitters such as Substance P (SP), to induce both neuronal signaling and localized responses in non-neuronal cells. With this in mind, we assessed the immunoregulatory roles of SP receptor signaling during enteric bacterial infection with the non-invasive pathogen Citrobacter rodentium. Pharmacological antagonism of the SP receptor significantly reduced bacterial burden and prevented colonic crypt hyperplasia. Mice with SP receptor signaling blockade had significantly reduced inflammation and recruitment of T-cells in the colon. Reduced colonic T-cell recruitment is due to reduced expression of adhesion molecules on colonic endothelial cells in SP receptor antagonist-treated mice. Using SP receptor T-cell conditional knockout mice, we further confirmed SP receptor signaling enhanced select aspects of T-cell responses. Our data demonstrates that SP receptor signaling can significantly reduce inflammation and prevent host-maladaptive responses without impinging upon host protection.

immunology↗

bioRxiv2024

A novel functional gene delivery platform based on a commensal human anellovirus demonstrates transduction in multiple tissue types

Anelloviridae is a family of non-enveloped viruses with negative-sense, circular, single-stranded deoxyribonucleic acid (ssDNA) genomes that infect vertebrates and are a ubiquitous component of the human virome. Human anelloviruses evade induction of humoral immune responses and appear to be non-pathogenic. These properties, in conjunction with their enormous genomic diversity and wide tissue distribution, make anelloviruses compelling candidates as vectors for next-generation genetic medicines. Here we report the first gene delivery vector system based on a human commensal virus. This Anellovector is based on a virus of the Betatorquevirus genus. Production is enabled by the development of the Self-Amplifying Trans-complementation of a Universal Recombinant aNellovector (SATURN) system, which relies on a self-replicating plasmid to provide viral proteins in trans that drive replication and capsid-dependent packaging of vector genomes. The SATURN system also utilizes a Cre-lox-based recombination mechanism to generate single unit-sized circular genomes inside the MOLT-4 production cell line. We demonstrate that the SATURN system can package a vector genome from a single betatorquevirus with capsids from multiple betatorquevirus species, supporting the feasibility of establishing a novel vector platform that takes advantage of the remarkable diversity of anelloviruses. The Anellovector demonstrated function in vitro in retinal pigment epithelial (RPE) cells. The Anellovector also demonstrated durable in vivo function in the mouse eye for 9 months after subretinal administration, and achieved comparable gene expression to dose-matched adeno-associated virus 9 (AAV9) when transduced by the intracerebroventricular (ICV) route of administration. To our knowledge, this is the first report of a functional anellovirus-based gene therapy vector. Anellovectors have great potential to deliver safe, redosable, and potent therapeutics, helping to expand the reach of programmable medicines.

bioengineering↗

bioRxiv2023

TRPV1 controls innate immunity during Citrobacter rodentium enteric infection

Mucosal immunity is critical to host protection from enteric pathogens and must be carefully controlled to prevent immunopathology. Regulation of immune responses can occur through a diverse range of mechanisms including bi-directional communication with the neurons. Among which include specialized sensory neurons that detect noxious stimuli due to the expression of transient receptor potential vanilloid receptor 1 (TRPV1) ion channel and have a significant role in the coordination of host-protective responses to enteric bacterial pathogens. Here we have used the mouse-adapted attaching and effacing pathogen Citrobacter rodentium to assess the specific role of the TRPV1 channel in coordinating the host response. TRPV1 knockout (TRPV1-/-) mice had a significantly higher C. rodentium burden in the distal colon and fecal pellets compared to wild-type (WT) mice. Increased bacterial burden was correlated with significantly increased colonic crypt hyperplasia and proliferating intestinal epithelial cells in TRPV1-/- mice compared to WT. Despite the increased C. rodentium burden and histopathology, the recruitment of colonic T cells producing IFN{gamma}, IL-17, or IL-22 was similar between TRPV1-/- and WT mice. In evaluating the innate immune response, we identified that colonic neutrophil recruitment in C. rodentium infected TRPV1-/- mice was significantly reduced compared to WT mice; however, this was independent of neutrophil development and maturation within the bone marrow compartment. TRPV1-/- mice were found to have significantly decreased expression of the neutrophil-specific chemokine Cxcl6 and the adhesion molecules Icam1 in the distal colon compared to WT mice. Corroborating these findings, a significant reduction in ICAM-1 and VCAM-1, but not MAdCAM-1 protein on the surface of colonic blood endothelial cells from C. rodentium infected TRPV1-/- mice compared to WT was observed. These findings demonstrate the critical role of TRPV1 in regulating the host protective responses to enteric bacterial pathogens, and mucosal immune responses. Author SummaryNeuroimmune communications are vital in regulating the immune response to invading pathogens. Here, we show that during a gastrointestinal infection, pain-sensing neuronal fibers can modulate the immune response to recruit phagocytic neutrophils via upregulation of cell adhesion molecules on local blood endothelial cells. This research elucidates a novel impact of the pain-sensing ion channel, TRPV1, on host-pathogen interactions in the gastrointestinal tract as well as a potential methodology for modulating the immune response during enteric infections.

immunology↗

bioRxiv2020

Neonatal enteropathogenic Escherichia coli infection disrupts microbiota-gut-brain axis signaling

BackgroundDiarrheal diseases are a leading cause of death in children under age five worldwide. Repeated early life exposures to diarrheal pathogens can result in co-morbidities including stunted growth and cognitive deficits suggesting an impairment in the microbiota-gut-brain (MGB) axis. MethodsNeonatal C57BL/6 mice were infected with EPEC (strain e2348/69; {Delta}escV [T3SS mutant]), or vehicle (LB broth) via orogastric gavage (105 CFU) at post-natal day (P7). Behavior (novel object recognition [NOR] task, light/dark [L/D] box, and open field test [OFT]), intestinal physiology (Ussing chambers), and the microbiota (16S Illumina sequencing) were assessed in adulthood (6-8 weeks). ResultsNeonatal infection of mice with EPEC impaired recognition memory (NOR task), coupled with increased neurogenesis (Ki67 and doublecortin immunostaining) and neuroinflammation (increased microglia activation [Iba1]) in adulthood. Intestinal pathophysiology was characterized by increased secretory state (short circuit current; Isc) and permeability (conductance; FITC-dextran flux) in the ileum and colon of neonatally EPEC-infected mice, along with increased expression of pro-inflammatory cytokines (Tnf, Il12, Il6) and pattern recognition receptors (Nlr, Tlr). Finally, neonatal EPEC infection caused significant dysbiosis of the gut microbiota, including decreased Firmicutes, in adulthood. ConclusionsTogether these findings demonstrate that infection in early life can significantly impair the MGB axis in adulthood.

microbiology↗

bioRxiv2019

Nod-like receptors are critical for gut-brain axis signaling

Gut-brain axis signaling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signaling, leading to altered mood, cognition and intestinal dysfunction. Here we identify nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signaling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, important in the regulation of gastrointestinal (GI) physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal neurogenesis, and reduced neural activation. In addition, NodDKO mice had increased GI permeability and altered serotonin signaling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioral impairments and restored serotonin signaling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+Nod1f/f), but not Nod2, increased susceptibility to stress-induced anxiety-like behavior and cognitive impairment following exposure to stress. Together these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.

physiology↗

bioRxiv2018

Multiple large-scale gene and genome duplications during the evolution of hexapods

Polyploidy or whole genome duplication (WGD) is a major contributor to genome evolution and diversity. Although polyploidy is recognized as an important component of plant evolution, it is generally considered to play a relatively minor role in animal evolution. Ancient polyploidy is found in the ancestry of some animals, especially fishes, but there is little evidence for ancient WGDs in other metazoan lineages. Here we use recently published transcriptomes and genomes from more than 150 species across the insect phylogeny to investigate whether ancient WGDs occurred during the evolution of Hexapoda, the most diverse clade of animals. Using gene age distributions and phylogenomics, we found evidence for 18 ancient WGDs and six other large-scale bursts of gene duplication during insect evolution. These bursts of gene duplication occurred in the history of lineages such as the Lepidoptera, Trichoptera, and Odonata. To further corroborate the nature of these duplications, we evaluated the pattern of gene retention from putative WGDs observed in the gene age distributions. We found a relatively strong signal of convergent gene retention across many of the putative insect WGDs. Considering the phylogenetic breadth and depth of the insect phylogeny, this observation is consistent with polyploidy as we expect dosage-balance to drive the parallel retention of genes. Together with recent research on plant evolution, our hexapod results suggest that genome duplications contributed to the evolution of two of the most diverse lineages of eukaryotes on Earth.

evolutionary biology↗