Biology subjects

Florsheim, E. B.

Publications and source records attributed to Florsheim, E. B..

8 recordsLinked to original sources

bioRxiv2026

Cholera toxin remodels intestinal immunity and suppresses systemic metabolism

Cholera toxin (CTx) is a potent enterotoxin and widely used mucosal adjuvant, yet the acute host response to CTx itself, in the absence of a co-administered antigen, remains vague. In this study, we integrated physiological and metabolic phenotyping with intestinal transcriptomics, epithelial imaging, immune profiling, hepatic gene-expression analysis, and paired microbiome profiling to characterize the response to a single oral CTx exposure in mice. Within 24 h, CTx remodeled immune-cell composition in both epithelial and lamina propria compartments, with responses shaped by sex and genetic background. Recurrent changes included increased epithelial group 3 innate lymphoid cells, reduced lamina propria ROR{gamma}t+ regulatory T cells, and decreased epithelial ILC1/NK cells in males of both strains. CTx also increased villus DCLK1+ tuft cells and reduced MUC2 immunoreactivity. Jejunal transcriptomics revealed induction of inflammatory defense, glycolytic, autophagy, and lipid-utilization programs together with suppression of proliferative and mitochondrial programs, consistent with coordinated stress adaptation. These local changes were accompanied by rapid restructuring of the fecal microbial community and by systemic hypometabolism, despite markedly different hypothermic responses across strains. CTx also elicited a selective hepatic stress and metabolic program, including conserved suppression of Cyp7a1 across sexes and strains. Together, these findings show that CTx alone rapidly reorganizes the intestinal immune, epithelial, metabolic, and microbial environment while suppressing whole-body metabolism. This work provides an integrated framework for understanding the acute host response to CTx and for interpreting its widespread use as a mucosal adjuvant.

immunology↗

bioRxiv2026

Sennoside A differentially regulates mast cell activation and attenuates gut allergic inflammation

Introduction: Mast cells are central effectors of IgE-mediated allergic responses and reside in barrier tissues, where they encounter diverse environmental compounds. How naturally occurring bioactive compounds influence mast cell function under resting versus allergic conditions remains poorly defined. Methods: We compared the effects of cholera toxin, aconitine, and sennoside A on viability, degranulation, and cytokine production in murine bone marrow-derived mast cells. We then examined the acute physiological effects of oral sennoside A in an ovalbumin-induced mouse model of food allergy. Results: None of the compounds reduced mast cell viability at the concentrations tested. Sennoside A, but not cholera toxin or aconitine, induced modest degranulation in resting mast cells without increasing TNF- or IL-6 secretion. In contrast, sennoside A markedly suppressed IgE-dependent antigen-induced degranulation, TNF- and IL-6 secretion, and Il1b expression. Acute oral sennoside A induced dose-dependent diarrhea and hypothermia and increased colonic Tnfa, Il1b, Il33, and Hdc expression. In allergic mice, sennoside A attenuated allergen-induced hypothermia, reduced duodenal Tpsab1 expression, and decreased circulating total IgE, OVA-specific IgE, and OVA-specific IgG1, while increasing Il5 expression. Conclusion: Sennoside A differentially regulates mast cell responses according to activation state and attenuates features of experimental food allergy. These findings identify a previously unrecognized immunomodulatory effect of sennoside A on IgE-driven mast cell activation. However, the mechanisms and the contribution of mast cells to the in vivo phenotype remain to be defined.

immunology↗

bioRxiv2026

Repeated shrimp allergen exposure drives 5-lipoxygenase-dependent avoidance and selective gut-brain activation

Peripheral immune processes can shape animal behavior, yet how noninfectious inflammatory reactions affect neural activity and behavioral outputs remains poorly understood. We developed an optimized murine model of shrimp allergy using whole shrimp extract to examine how a complex dietary allergen elicits integrated immune, neural, and behavioral responses. Sensitized mice received repeated oral shrimp challenges and were assessed for allergic pathology, food preference, affective-like behaviors, and neuronal activation in the brain. Repeated exposure increased total IgE and shrimp-specific IgG1, induced mast cell activation, accelerated gastrointestinal transit, caused mild hypothermia consistent with oral anaphylaxis, and increased intestinal length. Shrimp-sensitized mice did not avoid shrimp solution after sensitization alone. Instead, avoidance emerged only after repeated oral challenges and strengthened over time. This delayed aversion occurred without detectable changes in locomotor activity or measures of anxiety-like or depressive-like behavior at the time points tested. Repeated shrimp exposure increased cFOS expression in the area postrema, nucleus of the tractus solitarius, central amygdala, and paraventricular nucleus of the thalamus, implicating brainstem and limbic-thalamic pathways involved in visceral sensing and aversion. Pharmacological inhibition of 5-lipoxygenase partially reversed avoidance and reduced circulating mast cell protease-1 in allergic mice. These findings establish a robust whole-shrimp allergy model and show that a complex food allergen engages gut-brain pathways to promote 5-lipoxygenase-dependent avoidance. The delayed, selective nature of this response supports immune-mediated food aversion as a shared output of food allergy, while suggesting that its kinetics and neural recruitment vary with allergen identity and inflammatory context.

immunology↗

bioRxiv2026

Systemic endotoxemia induces integrated sickness physiology in female BALB/c mice

Sickness is an organismal response to inflammation, yet its immune, metabolic, neural, and behavioral components are often studied separately and predominantly in male C57BL/6 mice. In this study, we characterized these responses to systemic lipopolysaccharide (LPS) in female BALB/c mice. Mice received intraperitoneal LPS at moderate concentrations and outcomes were assessed during the acute and resolving phases of endotoxemia. LPS caused rapid disappearance of resident peritoneal macrophages, followed by neutrophil accumulation and increased circulating TNF- and IL-6. In the liver, LPS induced inflammatory, acute-phase, and anti-inflammatory transcripts while suppressing genes involved in lipid, cholesterol, and xenobiotic metabolism. Hepatic glutathione was reduced, whereas total superoxide dismutase activity was unchanged. These peripheral responses were followed by transient hypothermia, reduced food intake, and body weight loss. Regional brain mapping showed increased c-Fos labeling in the area postrema, nucleus of the solitary tract, external lateral parabrachial nucleus, paraventricular nucleus of the hypothalamus, and arcuate nucleus. In parallel, LPS selectively promoted IBA1-positive area in the median eminence and arcuate nucleus, whereas several other regions showed no changes, indicating that neuronal and microglial responses are regionally distinct. Behaviorally, LPS reduced locomotion and exploration, increased freezing, and increased forced-swim immobility. Changes in spatial exploration were most pronounced during the acute phase, whereas locomotor suppression and passive stress-coping persisted longer and varied in magnitude with the timing of inflammatory challenge. Together, these findings show that systemic LPS produces a coordinated sickness state in female BALB/c mice that links peripheral inflammation and hepatic metabolic and redox changes with region-specific neuronal and microglial responses, altered thermoregulation and feeding, and behavioral suppression.

immunology↗

bioRxiv2026

Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis

Maternal obesity is associated with increased risk of sporadic colorectal cancer (CRC) in offspring, suggesting that early-life environmental exposures durably shape disease susceptibility. Intestinal stem cells (ISCs), long-lived drivers of epithelial renewal and tumor initiation, are well poised to mediate this effect; however, how maternal obesity influences ISC programming during development remains poorly understood. Using mouse models of diet-induced obesity, we show that exposure to a maternal high-fat Western diet (mHFD) during pre- and postnatal development stably programs colonic ISCs. Offspring exhibit increased ISC proliferation, enhanced self-renewal, a hypermetabolic state, and altered epithelial lineage composition that persists into adulthood despite dietary normalization. These changes are accompanied by increased tumor burden following loss of Apc heterozygosity. Mechanistically, we identify the pro-inflammatory cytokine IL-17A as a key extrinsic driver and PPARd/a nuclear receptors as intrinsic mediators of the mHFD phenotype, revealing an immune-epithelial axis that programs ISC function during early life. Together, our findings demonstrate that maternal metabolic environments durably enhance stem cell fitness, providing a mechanistic link between developmental exposure and adult disease risk.

cell biology↗

bioRxiv2024

Systemic Dosing of Virus-derived Serpin Improves Survival and Immunothrombotic Damage in Murine Colitis

Inflammatory bowel disease (IBD) is potentially life-threatening, with risk of bleeding, clotting, infection, sepsis, cancer and toxic megacolon. Systemic and local immune and coagulation dysfunction increase IBD severity. Current treatments are partially effective, but there is no definitive cure. Serine protease cascades activate thrombotic, thrombolytic and complement pathways and are regulated by inhibitors, serpins. Viruses encode proteins evolved from endogenous central regulatory pathways. A purified secreted Myxomavirus-derived serpin, Serp-1, dosed as a systemic anti-inflammatory drug, has proven efficacy in vascular and inflammatory disorders. PEGylated Serp-1 protein (PEGSerp-1) has improved efficacy in lupus and SARS-CoV-2 models. We examined PEGSerp-1 treatment in a mouse Dextran Sodium Sulfate (DSS) colitis model. Prophylactic PEGSerp-1 significantly improved survival in acute severe 4-5% DSS colitis, reducing inflammation and crypt damage in acute 4-5% DSS induced colitis and when dosed as a chronic delayed treatment for recurrent 2% DSS colitis. PEGSerp-1 reduced iNOS+ M1 macrophage invasion, damage to crypt architecture and vascular inflammation with decreased uPAR, fXa, fibrinogen and complement activation. This work supports PEGSerp-1 as a tissue targeting serpin therapeutic.

molecular biology↗

bioRxiv2023

Immune sensing of food allergens promotes aversive behaviour

In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations1-3. The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Using a mouse food allergy model, here we show that allergic sensitization drives antigen-specific behavioural aversion. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus, and central amygdala. Food aversion requires IgE antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote aversion requires leukotrienes and growth and differentiation factor 15 (GDF15). In addition to allergen-induced aversion, we find that lipopolysaccharide-induced inflammation also resulted in IgE-dependent aversive behaviour. These findings thus point to antigen-specific behavioural modifications that likely evolved to promote niche selection to avoid unfavourable environments.

immunology↗

bioRxiv2022

Treatment with anti-inflammatory viral serpin modulates immuno-thrombotic responses and improves outcomes in SARS-CoV-2 infected mice

1.Severe acute respiratory distress syndrome (ARDS) during SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection, manifests as uncontrolled lung inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies can reduce COVID-19 severity if administered in the early viremic phase, but treatments for later stage immuno-thrombotic syndrome and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases during thrombotic, thrombolytic and immune responses. The myxoma poxvirus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated coagulation and complement protease pathways as part of a self-defense strategy to combat viral clearance by the innate immune system. When purified and utilized as an anti-immune therapeutic, Serp-1 is effective as an anti-inflammatory drug in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 (PEGSerp-1) as a therapy for immuno-thrombotic complications during ARDS. Treatment with PEGSerp-1 in two distinct mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved clinical outcomes. PEGSerp-1 significantly reduced M1 macrophage invasion in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR) and complement membrane attack complex (MAC). Sequential changes in urokinase-type plasminogen activator receptor (uPAR) and serpin gene expression were observed in lung and heart with PEGSerp-1 treatment. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for treatment of severe viral ARDS with additional potential to reduce late SARS-CoV-2 complications related to immune-thrombotic events that persist during long COVID. SignificanceSevere acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection manifests as uncontrolled tissue inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies reduce COVID-19 severity if administered early, but treatments for later stage immuno-thrombosis are limited. Serine protease inhibitors (SERPINS) regulate thrombotic, thrombolytic and complement pathways. We investigate here systemic treatment with purified poxvirus-derived PEGSerp-1 as a therapeutic for immuno-thrombotic complications in viral ARDS. PEGSerp-1 treatment in two mouse-adapted SARS-CoV-2 models (C57Bl/6 and BALB/c) significantly reduced lung and heart inflammation and improved clinical outcomes, with sequential changes in thrombolytic (uPAR) and complement expression. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for immune-thrombotic complications in severe viral ARDS and has potential benefit for long COVID.

microbiology↗