Maternal dietary omega-3 deficiency worsens the deleterious effects of prenatal inflammation on the gut-brain axis in the offspring across lifetime

Abstract

Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD.

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Fig. 1: Effect of n-3 PUFA deficiency on MIA-induced behavioral deficits in neonates and in adult offspring.
Fig. 2: Dietary n-3 PUFA deficiency exacerbates MIA-induced alterations of the hippocampal lipid and transcriptional profiles in adulthood.
Fig. 3: Effect of n-3 PUFA deficiency and MIA on microglia-neuron crosstalk pathways, spine density, oligodendrocyte and myelin protein expression.
Fig. 4: Effect of n-3 PUFA deficiency and MIA on gut microbiota composition at PND14 and PND21.
Fig. 5: Correlations between microbial modifications, gut inflammation, and neurobiological parameters.

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Acknowledgements

We thank Atika Zouine and Vincent Pitard for technical assistance at the Flow cytometry facility, CNRS UMS 3427, INSERM US 005, Univ. Bordeaux, F-33000 Bordeaux, France. We also thank Christel Poujol, Sébastien Marais, Fabrice Cordelières, Jérémie Teillon, Magali Mondin, Monica Fernandez-Monreal who help for all the experiment of microscopy as well as Franck Letourneur and Sébastien Jacques, from the Genom’ic platform (Institut Cochin, Paris, France) who performed microarray experiments. We finally thank the animal facility for taking care of and providing the animals that were necessary to perform the experiments.

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QL, FD, ARAAQ, IV, CL, ANB, JB, AA, AS, FC, LS, BM, TB, SG, JMC performed all animal experimentations. SG, CJ, and LB performed and analyzed lipid experiments on whole hippocampus. BM and TB performed physiological and behavioral measurements on neonates. GB performed and UR and PT oversaw bioinformatic analyses of transcriptomic data. CA performed correlation analyses. FG performed microbiota analyses. JMC and FC performed gut measurements. SL and AN equally supervised the entire project and wrote the manuscript. All authors proof-read the manuscript.

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Correspondence to S. Layé or A. Nadjar.

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Leyrolle, Q., Decoeur, F., Briere, G. et al. Maternal dietary omega-3 deficiency worsens the deleterious effects of prenatal inflammation on the gut-brain axis in the offspring across lifetime. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00793-7

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