Age-associated deficits in social behaviour are microbiota-dependent.

Aging is associated with remodelling of immune and central nervous system responses resulting in behavioural impairments including social deficits. Growing evidence suggests that the gut microbiome is also impacted by aging, and we propose that strategies to reshape the aged gut microbiome may ameliorate some age-related effects on host physiology. Thus, we assessed the impact of gut microbiota depletion, using an antibiotic cocktail, on aging and its impact on social behavior and the immune system. Indeed, microbiota depletion in aged mice eliminated the age-dependent deficits in social recognition. We further demonstrate that although age and gut microbiota depletion differently shape the peripheral immune response, aging induces an accumulation of T cells in the choroid plexus, that is partially blunted following microbiota depletion. Moreover, an untargeted metabolomic analysis revealed age-dependent alterations of cecal metabolites that are reshaped by gut microbiota depletion. Together, our results suggest that the aged gut microbiota can be specifically targeted to affect social deficits. These studies propel the need for future investigations of other non-antibiotic microbiota targeted interventions on age-related social deficits both in animal models and humans.

Microbiota-immune-brain interactions: A lifespan perspective.

There is growing appreciation of key roles of the gut microbiota in maintaining homeostasis and influencing brain and behaviour at critical windows across the lifespan. Mounting evidence suggests that communication between the gut and the brain could be the key to understanding multiple neuropsychiatric disorders, with the immune system coming to the forefront as an important mechanistic mediator. Throughout the lifespan, the immune system exchanges continuous reciprocal signals with the central nervous system. Intestinal microbial cues alter immune mediators with consequences for host neurophysiology and behaviour. Several factors challenge the gut microbiota composition, which in response release molecules with neuro- and immuno-active potential that are crucial for adequate neuro-immune interactions. In this review, multiple factors contributing to the upkeep of the fine balance between health and disease of these systems are discussed, and we elucidate the potential mechanistic implications for the gut microbiota inputs on host brain and behaviour across the lifespan.

Prebiotic supplementation modulates selective effects of stress on behavior and brain metabolome in aged mice.

Aging has a significant impact on physiology with implications for central nervous system function coincident with increased vulnerability to stress exposures. A number of stress-sensitive molecular mechanisms are hypothesized to underpin age-related changes in brain function. Recent cumulative evidence also suggests that aging impacts gut microbiota composition. However, the impact of such effects on the ability of mammals to respond to stress in aging is still relatively unexplored. Therefore, in this study we assessed the ability of a microbiota-targeted intervention (the prebiotic FOS-Inulin) to alleviate age-related responses to stress. Exposure of aged C57BL/6 mice to social defeat led to an altered social interaction phenotype in the social interaction test, which was reversed by FOS-Inulin supplementation. Interestingly, this occured independent of affecting social defeat-induced elevations in the stress hormone corticosterone. Additionally, the behavioral modifications following FOS-Inulin supplementation were also not coincident with improvement of pro-inflammatory markers. Metabolomics analysis was performed and intriguingly, age associated metabolites were shown to be reduced in the prefrontal cortex of stressed aged mice and this deficit was recovered by FOS-Inulin supplementation. Taken together these results suggest that prebiotic dietary intervention rescued the behavioral response to stress in aged mice, not through amelioration of the inflammatory response, but by restoring the levels of key metabolites in the prefrontal cortex of aged animals. Therefore, dietary interventions could be a compelling avenue to improve the molecular and behavioral manifestations of chronic stress exposures in aging via targeting the microbiota-gut brain axis.

Depression's Unholy Trinity: Dysregulated Stress, Immunity, and the Microbiome.

Depression remains one of the most prevalent psychiatric disorders, with many patients not responding adequately to available treatments. Chronic or early-life stress is one of the key risk factors for depression. In addition, a growing body of data implicates chronic inflammation as a major player in depression pathogenesis. More recently, the gut microbiota has emerged as an important regulator of brain and behavior and also has been linked to depression. However, how this holy trinity of risk factors interact to maintain physiological homeostasis in the brain and body is not fully understood. In this review, we integrate the available data from animal and human studies on these three factors in the etiology and progression of depression. We also focus on the processes by which this microbiota-immune-stress matrix may influence centrally mediated events and on possible therapeutic interventions to correct imbalances in this triune.

The Microbiota-Gut-Brain Axis.

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.