Aging and the microbiota-gut-brain axis: Increased gut permeability, altered gut microbiota composition and increased peripheral inflammation are associated with neurobehavioural effects in aged mice

Abstract

Aging is associated with a number of adverse symptoms related to physical and mental decline, including altered immune function, cognitive impairment and altered mood. The mechanisms underlying these effects are unknown, but stress and inflammation likely play a role in their development. Recently, the gut microbiota has been shown to be a key regulator of stress, neuroinflammation and aging. Moreover, interest has arisen in the role of gut permeability on the development of pathological effects of aging. Better understanding of these processes may enable us to prevent or ameliorate some of the adverse aspects of aging. To this end we characterised the physiological and behavioural differences between young and aged male mice, with particular attention to the microbiota- gut-brain axis.

Young (2 month old) and aged (18 month old) C57Bl/6 mice (n= 10–12) underwent a battery of behavioural tests to assess their anxiety, cognitive and social performance over a 4 week period. In addition we assessed neuroendocrine responses to stress and markers of peripheral inflammation. At the end of the experiment caecal contents were collected for microbiota sequencing.

Aged mice demonstrated an increase in anxiety-like behaviour as assessed by open field test (OFT) and elevated plus maze (EPM), with fewer entries into the centre arena during the OFT and fewer entries into the open arms of the EPM. No differences in depressive-like behaviours were observed during the forced swim test. Aged mice also exhibited impaired social recognition as assessed by the 3-chamber test, failing to demonstrate a preference for a novel over a familiar conspecific, as normally observed.

At a physiological level a different pattern of corticosterone (CORT) release was observed following swim stress, suggesting an altered neuroendocrine response to stress. Notably, aged animals have a delayed or blunted CORT response. Fluorescein isothiocyanate–labeled dextran (FITC) was used to assess gut permeability of mice. Aged males demonstrated increased permeability, which correlated with elevated plasma IL-6, TNF-α and IL-1β. The caecal microbiota was also significantly altered in aged mice and may also contribute to the observed effects of aging. Our results suggest that changes in gut microbiota composition, gut permeability and elevated circulating pro-inflammatory cytokines together may contribute to the development of some of the negative neurobehavioural symptoms associated with aging.

Support or Funding Information

The APC Microbiome Institute is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. TG Dinan and JF Cryan are supported in part by SFI in the form of a Centre Grant (grant nos. 02/CE/B124, 07/CE/B1368 and SFI/12/RC/2273). Additional financial support was provided by Suntory Wellness Limited.