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Cox Timothy O, Devason Ashwarya S, de Araujo Alan, Mason Sydney, Subramanian Madhav, Salvador Andrea F M, Descamps Hélène C, Kim Junwon, Zhu Yixuan, Litichevskiy Lev, Jung Sunhee, Song Won-Suk, Cortés-Martín Adrián, Henderson Nathan T, Huang Kuei-Pin, Nguyen Thao, Sae-Lee Wisath, Umana Iboro C, Sacta Maria, Rahman Ryan J, Wisser Stephen, Nelson J Andrew D, Golynker Ilona, McSween Alana M, Hohmann Eric F, Patel Shaan, Bub Anna L, Soekler Clara, Blank Niklas, Hoxha Kevt'her, Boccia Lavinia, Wong Andrea C, Bahnsen Klaas, Kim Jihee, Biderman Natalie, Abbasian Dina, Shoffler Clarissa, Petucci Christopher, McAllister Fiona E, Alhadeff Amber L, Fuccillo Marc V, Hill Colin, Jang Cholsoon, Betley J Nicholas, de Lartigue Guillaume, Lee Virginia Y-M, Levy Maayan, Thaiss Christoph A
Аннотация
Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population1. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as attractive targets for peripheral interventions2-6, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome ageing and its functional consequences throughout the lifespan of mice, we identify a mechanism by which inhibition of gut-brain signalling during ageing results in impaired neuronal activation in the hippocampus and loss of memory encoding. Specifically, accumulation of gut bacteria that produce medium-chain fatty acids, such as Parabacteroides goldsteinii, can drive peripheral myeloid cell inflammation through GPR84 signalling. As a result, the function of vagal afferent neurons is impaired, the interoceptive signal received by the brain is weakened and hippocampal function declines. We leverage this pathway to define interventions that enhance memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition and restoration of vagal activity. These findings indicate a key role for interoceptive dysfunction in brain ageing and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.