Gut Microbes Shape Microglia and Cognitive Function During Malnutrition

Overview

Journal Glia

Specialty Neurology

Date 2022 Jan 12

PMID 35019164

Authors

Kylynda C Bauer

Elisa M York

Mihai S Cirstea

Nina Radisavljevic

Charisse Petersen

Kelsey E Huus

Eric M Brown

Tahereh Bozorgmehr

Rebeca Berdun

Louis-Philippe Bernier

Amy H Y Lee

Sarah E Woodward

Zakhar Krekhno

Jun Han

Robert E W Hancock

Victoria Ayala

Brian A MacVicar

Barton Brett Finlay

Affiliations

Soon will be listed here.

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.

Citing Articles

Microglial Mechanisms and Therapeutic Potential in Brain Injury Post-Intracerebral Hemorrhage.

Gong Y, Li H, Cui H, Gong Y J Inflamm Res. 2025; 18:2955-2973.

PMID: 40026311 PMC: 11872102. DOI: 10.2147/JIR.S498809.

Compound Probiotics Improve Neuropathic Pain Prognosis in a Murine Model of Chronic Constriction Injury.

Wang X, Chen Y, Qian S, Kong J, Su Z, Wang Q J Pain Res. 2024; 17:4213-4221.

PMID: 39679428 PMC: 11646395. DOI: 10.2147/JPR.S486259.

Gut microbiota regulates blood-cerebrospinal fluid barrier function and Aβ pathology.

Xie J, Bruggeman A, De Nolf C, Vandendriessche C, Van Imschoot G, Van Wonterghem E EMBO J. 2023; 42(17):e111515.

PMID: 37427561 PMC: 10476279. DOI: 10.15252/embj.2022111515.

The Effects of Extrinsic and Intrinsic Factors on Neurogenesis.

Jiang M, Jang S, Zeng L Cells. 2023; 12(9).

PMID: 37174685 PMC: 10177620. DOI: 10.3390/cells12091285.

Different gender-derived gut microbiota influence stroke outcomes by mitigating inflammation.

Wang J, Zhong Y, Zhu H, Mahgoub O, Jian Z, Gu L J Neuroinflammation. 2022; 19(1):245.

PMID: 36195899 PMC: 9531521. DOI: 10.1186/s12974-022-02606-8.

References

Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P . Object recognition test in mice. Nat Protoc. 2013; 8(12):2531-7. DOI: 10.1038/nprot.2013.155. View

Bourin M, Hascoet M . The mouse light/dark box test. Eur J Pharmacol. 2003; 463(1-3):55-65. DOI: 10.1016/s0014-2999(03)01274-3. View

McNamara R, Almeida D . Omega-3 Polyunsaturated Fatty Acid Deficiency and Progressive Neuropathology in Psychiatric Disorders: A Review of Translational Evidence and Candidate Mechanisms. Harv Rev Psychiatry. 2019; 27(2):94-107. PMC: 6411441. DOI: 10.1097/HRP.0000000000000199. View

. Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: findings from the MAL-ED birth cohort study. BMJ Glob Health. 2018; 3(4):e000752. PMC: 6058175. DOI: 10.1136/bmjgh-2018-000752. View

Akseer N, Kandru G, Keats E, Bhutta Z . COVID-19 pandemic and mitigation strategies: implications for maternal and child health and nutrition. Am J Clin Nutr. 2020; 112(2):251-256. PMC: 7337702. DOI: 10.1093/ajcn/nqaa171. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Kozich J, Westcott S, Baxter N, Highlander S, Schloss P . Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol. 2013; 79(17):5112-20. PMC: 3753973. DOI: 10.1128/AEM.01043-13. View

Mehta S, Huey S, McDonald D, Knight R, Finkelstein J . Nutritional Interventions and the Gut Microbiome in Children. Annu Rev Nutr. 2021; 41:479-510. DOI: 10.1146/annurev-nutr-021020-025755. View

Ishii C, Nakanishi Y, Murakami S, Nozu R, Ueno M, Hioki K . A Metabologenomic Approach Reveals Changes in the Intestinal Environment of Mice Fed on American Diet. Int J Mol Sci. 2018; 19(12). PMC: 6321133. DOI: 10.3390/ijms19124079. View

10.

Pamplona R, Dalfo E, Ayala V, Bellmunt M, Prat J, Ferrer I . Proteins in human brain cortex are modified by oxidation, glycoxidation, and lipoxidation. Effects of Alzheimer disease and identification of lipoxidation targets. J Biol Chem. 2005; 280(22):21522-30. DOI: 10.1074/jbc.M502255200. View

11.

Caspi R, Altman T, Billington R, Dreher K, Foerster H, Fulcher C . The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases. Nucleic Acids Res. 2013; 42(Database issue):D459-71. PMC: 3964957. DOI: 10.1093/nar/gkt1103. View

12.

Wu Y, Dissing-Olesen L, MacVicar B, Stevens B . Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol. 2015; 36(10):605-613. PMC: 4841266. DOI: 10.1016/j.it.2015.08.008. View

13.

Bazinet R, Laye S . Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014; 15(12):771-85. DOI: 10.1038/nrn3820. View

14.

Cani P, Bibiloni R, Knauf C, Waget A, Neyrinck A, Delzenne N . Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008; 57(6):1470-81. DOI: 10.2337/db07-1403. View

15.

Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M . The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014; 6(263):263ra158. PMC: 4396848. DOI: 10.1126/scitranslmed.3009759. View

16.

Hinwood M, Morandini J, Day T, Walker F . Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex. 2011; 22(6):1442-54. DOI: 10.1093/cercor/bhr229. View

17.

Schloss P, Westcott S, Ryabin T, Hall J, Hartmann M, Hollister E . Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol. 2009; 75(23):7537-41. PMC: 2786419. DOI: 10.1128/AEM.01541-09. View

18.

Manary M, Leeuwenburgh C, Heinecke J . Increased oxidative stress in kwashiorkor. J Pediatr. 2000; 137(3):421-4. DOI: 10.1067/mpd.2000.107512. View

19.

Munz C . Antigen processing via autophagy--not only for MHC class II presentation anymore?. Curr Opin Immunol. 2010; 22(1):89-93. PMC: 3082731. DOI: 10.1016/j.coi.2010.01.016. View

20.

Pickering A, Null C, Winch P, Mangwadu G, Arnold B, Prendergast A . The WASH Benefits and SHINE trials: interpretation of WASH intervention effects on linear growth and diarrhoea. Lancet Glob Health. 2019; 7(8):e1139-e1146. DOI: 10.1016/S2214-109X(19)30268-2. View