Biology subjects

Gareau, M. G.

Publications and source records attributed to Gareau, M. G..

5 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

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

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↗

bioRxiv2022

Unique features of the gut microbiome characterized in animal models of Angelman Syndrome

A large subset of patients with Angelman syndrome (AS) suffer from concurrent gastrointestinal (GI) issues, including constipation, poor feeding, and reflux. AS is caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. Clinical features of AS, which include developmental delays, intellectual disability, microcephaly, and seizures, are primarily due to the deficient expression or function of the maternally inherited UBE3A allele. The association between neurodevelopmental delay and GI disorders is part of the increasing evidence suggesting a link between the brain and the gut microbiome via the microbiota-gut-brain (MGB) axis. To investigate the associations between colonization of the gut microbiota in AS, we characterized the fecal microbiome in three animal models of AS containing maternal deletions of Ube3A, including mouse, rat, and pig, using 16S ribosomal RNA amplicon sequencing. Overall changes in the microbial composition of all three animal models of AS in both the phylum and genus levels of bacterial abundance were identified. Specific bacterial groups were significantly increased across all animal models, including: Lachnospiraceae Incertae sedis, Desulfovibrios sp., and Odoribacter, which have been correlated with neuropsychiatric disorders. Taken together, these findings suggest that specific changes to the local environment in the gut are driven by a Ube3a maternal deletion, unaffected by varying housing conditions and are prominent and detectable across multiple small and large model species. These findings may begin to uncover the underlying mechanistic causes of GI disorders in AS patients and provide future therapeutic options for AS patients. IMPORTANCEAngelman syndrome (AS) associated gastrointestinal (GI) symptoms significantly impact quality of life in patients. Using AS models in mouse, rat, and pig, AS animals showed impaired colonization of the gut microbiota compared to wild type (healthy) control animals. Unique changes in AS microbiomes across all three animal models may be important in causing GI symptoms and may help to identify ways to treat these comorbidities in patients in the future.

microbiology↗