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Updated: Oct 7, 2025

Intracerebroventricular Delivery of Gut-Derived Microbial Metabolites in Freely Moving Mice
Published on: June 2, 2022
Gut microbes shape microglia and cognitive function during malnutrition
Kylynda C Bauer1,2, Elisa M York3, Mihai S Cirstea1,2
1Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
Abstract:
Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target.
Insights
Early life malnutrition and gut microbe exposure impair cognitive function. Supplementing with omega-3 polyunsaturated fatty acids (PUFAs) and antioxidants can improve brain health and cognitive deficits.
Area of Science:
- Neuroscience
- Microbiology
- Nutritional Science
Background:
- Early life malnutrition has lasting cognitive consequences, but the mechanisms involving gut microbes are unclear.
- Gut-brain axis disruptions are implicated in malnutrition-associated neurodevelopmental issues.
- Microglia play key roles in neuroimmune responses and brain plasticity.
Purpose of the Study:
- To investigate the impact of malnutrition combined with fecal-oral contamination on cognitive function and brain pathology in a murine model.
- To explore the role of gut microbiota and associated changes in microglia.
- To identify potential therapeutic targets for cognitive impairment in malnutrition.
Main Methods:
- Utilized a murine model (MAL-BG) with malnutrition and iterative fecal commensal exposure, compared to malnourished (MAL) and healthy (CON) controls.
- Assessed spatial memory, learning plasticity, microglial morphology, and transcriptional profiles.
- Performed metabolomic profiling of the cortex and analyzed cytokine and blood-brain barrier (BBB) integrity.
- Investigated the effects of omega-3 polyunsaturated fatty acid (PUFA)/antioxidant (PAO) diet supplementation.
Main Results:
- Malnourished mice (MAL-BG) exhibited impaired spatial memory and learning plasticity.
- Chronic fecal-oral exposures altered microglial morphology and transcriptional profiles, promoting phagocytic features.
- These microglial changes occurred independently of significant inflammation or BBB disruption.
- Cortical metabolomics revealed altered PUFA profiles and systemic lipoxidative stress in MAL-BG mice.
- PAO diet supplementation mitigated cognitive deficits in the MAL-BG model.
Conclusions:
- Early life malnutrition combined with gut microbial exposure negatively impacts cognitive function via altered microglial responses and PUFA metabolism.
- Gut microbiota-brain axis dysregulation in malnutrition involves lipoxidative stress and altered PUFA profiles.
- Targeting PUFA metabolism, potentially through dietary interventions like PAO supplementation, offers a promising therapeutic strategy for malnutrition-induced cognitive impairment.
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