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Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome

Abstract

Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6Chi monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C+) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.

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Acknowledgements

We gratefully thank the Teagasc sequencing facility, Dr. Fiona Crispie, Laura Finnegan and Dr. Paul Cotter; the APC Flow cytometry platform, Dr. Panagiota Stamou and Dr. Ken Nally; as well as MS-Omics (Copenhagen, Denmark) for faecal metabolites analysis. We also thank Pat Fitzgerald, Colette Manley, Dr. Kieran Rea, Veronica Peterson, Marta Neto, and Dr. Emanuela Morelli for their invaluable help.

Funding

APC Microbiome Ireland is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan (grant no. 12/RC/2273). In addition, this study was supported through the Joint Programming Initiative - a healthy diet for a healthy life (JPI-HDHL) – investigating Nutrition and Cognitive Function (NutriCog) by a Science Foundation Ireland (SFI) grant ‘AMBROSIAC – A Menu for Brain Responses Opposing Stress-Induced Alterations in Cognition’ (15/JP-HDHL/3270).

Author information

MB, GC, CS, TGD, HS and JFC have contributed to the conception and design of the work. Acquisition, analysis and interpretation of data were performed by MB, MvDW, TFSB, LO-R, KL, FF, AVG, GMM, CM, KVS and KAS. MB and JFC wrote the manuscript. MB, MvDW, TFSB, FF, AVG, GMM, KVS, KAS, GC, CS, TGD, HS and JFC critically revised the manuscript. All authors approve the final version of the manuscript and agree to be accountable for all aspects of the work.

Conflict of interest

JFC, TGD & CS have research funding from Dupont Nutrition Biosciences APS, Cremo SA, Alkermes Inc, 4D Pharma PLC, Mead Johnson Nutrition, Nutricia Danone, Suntory Wellness. JFC, TGD, CS & GC have spoken at meetings sponsored by food and pharmaceutical companies. All other authors report no financial interests or potential conflicts of interest

Correspondence to John F. Cryan.

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