Of Microbes and Minds: A Narrative Review on the Second Brain Aging

Abstract

In recent years, an extensive body of literature focused on the gut-brain axis and the possible role played by the gut microbiota in modulating brain morphology and function from birth to old age. Gut microbiota has been proposed as a relevant player during the early phases of neurodevelopment, with possible long-standing effects in later life. The reduction in gut microbiota diversity has also become one of the hallmarks of aging, and disturbances in its composition are associated with several (age-related) neurological conditions, including depression, Alzheimer's disease, and Parkinson's disease. Several pathways have been evoked for gut microbiota-brain communication, including neural connections (vagus nerve), circulating mediators derived by host-bacteria cometabolism, as well as the influence exerted by gut microbiota on host gut function, metabolism, and immune system. Although the most provoking data emerged from animal studies and despite the huge debate around the possible epiphenomenal nature of those findings, the gut microbiota-brain axis still remains a fascinating target to be exploited to attenuate some of the most burdensome consequences of aging.

Keywords: Alzheimer; Parkinson; brain development; gut metabolism; gut microbiota; gut–brain crosstalk; inflamm-aging; neurological disorders.

Figure 1

A gut–brain axis supports the interactions between gut microbiota and the CNS through direct and indirect pathways involving vagal nerve activation, cytokine production, and release of neuropeptide/neurotransmitters and SCFAs. These mediators can pass the BBB and control the maturation and activation of brain immune cells (microglia). Following its activation, microglia modulates immune surveillance, synaptic pruning, and clearance of debris. On the other side, the HPA axis can suppress microglia activation, as well as influence cytokine release and trafficking of monocytes from the periphery to the brain. Abbreviations: BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; GABA, gamma-aminobutyric acid; HPA axis, hypothalamic–pituitary–adrenal axis; LPS, lipopolysaccharide; MAMPs, microbe-associated molecular patterns; SCFAs, short-chain fatty acids; CNS, central nervous system.

Figure 2

Age-related changes in gut–brain axis possibly involved in neurodegeneration. Abbreviations: AD, Alzheimer’s disease; PD, Parkinson’s disease.

Figure 3

Gut microbial richness and diversity across life stages impact neurodevelopment and the central nervous homeostasis (yellow: low richness/diversity; red: high richness/diversity). Abbreviation: BBB, blood–brain barrier.