Sex differences in neurocognitive deficits induced by ceftriaxone-driven disruptions to the gut microbiome

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Introduction: The gut-brain axis is a bidirectional communication pathway in which gut microbiota can influence neuroimmune signaling and subsequent behavioral responses. Our recent study has illuminated that some antibiotics, while essential for combating bacterial infections, exert profound off-target effects on host physiology through the disruption of the gut microbiome. Thus, the objective of this study was to observe the neurobehavioral and neuroinflammatory effects of ceftriaxone (CTX) in mice, and the extent of sex effects associated with this disruption. We hypothesize that CTX-induced perturbations to the gut microbiome will result in measurable cognitive impairment in both male and female mice. Methodology: Male and Female C57BL/6 mice were administered CTX (n = 20) via oral gavage at a dose of 200 mg/kg once per day for 4 consecutive days, while controls (n = 20) were administered sterile water. Fecal samples were collected on days 1 and 5 for gut microbiome analysis utilizing 16S rRNA sequencing methods. Mice were subject to behavioral testing after 4 days of CTX treatment. After sacrificing the mice, striatum, hippocampus, frontal cortex, and colon were dissected and used for immunoblotting and proteomic analysis. Plasma was also collected for cytokine evaluations. Half-brains were dissected for immunohistochemical staining. Results: Microbiome analysis revealed a significant decrease in richness, evenness, and heterogeneity in CTX-treated male (CTX-M) and CTX-treated female (CTX-F) mice, as well as a significant disruption in microbial structure. CTX induced significant cognitive impairments, decreased sensitivity to pain, and anxiety-like behaviors, which were more pronounced in CTX-M, while CTX-F exhibited less anxiety-like behaviors compared to controls. Inflammatory markers Calprotectin and IL-1β were elevated in colon samples with CTX in all mice. In brain, expression of receptors for anaerobic bacteria fermentation products (GPR109 and MCT-1) were decreased in frontal cortex, and Synaptophysin levels in hippocampus were decreased in CTX-M. Fractalkine was shown to be decreased in the plasma of all mice. Conclusion: Short-term CTX treatment disrupts gut microbial composition and diversity, resulting in measurable changes in behavior and inflammatory signaling and neuroplasticity among both male and female mice. CTX-induced impairments in memory, pain sensitivity, and anxiety-like behaviors were more pronounced in CTX-M, indicating greater susceptibility to antibiotic-induced cognitive impairments in males. Increased inflammatory markers in the colon, along with reduced metabolic and plasticity markers in the brain, suggest a disruption in gut–brain signaling and altered neuroimmune pathways in both male and female mice, with males showing a stronger neuroinflammatory response. This study highlights the modulatory role of the gut microbiome in maintaining neural function and suggests that even brief antibiotic exposure may influence behavior, inflammation, and neuroplasticity through microbiome-mediated pathways. Funding Source: This work was supported by the Department of Veterans Affairs (1I21BX005850 and 1I01BX004757-01A1 to M.A.-P.) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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