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.

The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed agingassociated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.Aging triggers metabolic and immune alterations that lead to perturbation of brain function and behavior, including impairments in hippocampal-associated cognitive behavior 1 . Notably, the gut microbiota, encompassing the population of trillions of microorganisms, undergoes a parallel community shift, which has been correlated to changes in host frailty and cognition 2,3 .Animal models have shown specific roles for the microbiota in shaping hallmarks of aging in the gut 4,5 . Moreover, the consequences of an elderly-associated microbiota on a young host involve alterations in host immunity, neurogenesis and cognition [6][7][8][9] . Notably, transferring microbiota from young fish (African turquoise killifish) into middle-aged fish improves lifespan and motor behavior 10 . However, it is completely unknown whether microbiota from young donors can restore aging-associated impairments in mammals.To determine whether fecal microbiota transplantation (FMT) from young mice can ameliorate aging-induced neurocognitive and immune impairments, we collected fecal microbiota from naive young mice (3-4 months) and transplanted this into aged mice ('aged yFMT' , 19-20 months). A separate group of aged mice received fecal microbiota from naive old mice to control for handling during FMT administration ('aged oFMT' ,(19)(20). To allow aging-associated comparisons, naive young mice received the same yFMT mixture ('young yFMT'). We found aging-associated differences in microbiota (Fig. 1 and Supplementary Tables 1 and 2), immunity (Fig. 2 and Extended Data Figs. 2 and 3), hippocampal neurogenesis (Extended Data Fig. 2), hippocampal metabolomics (Fig. 3, Extended Data Fig. 7 and Supplementary Table 3) and transcriptomics (Fig. 2 and Extended Data Fig. 7), and behavior (Fig. 4 and Extended Data Fig. 5); some, but not all, of which were attenuated by microbiota transplantation from a young mouse into an aged host. Our research offers the possibility that a microbiota from a young individual may have beneficial effects when given to an aged host.

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Neural communication is facilitated by intricate networks of white matter (WM) comprised of both long and short range connections. The maturation of long range WM connections has been extensively characterized, with projection, commissural, and association tracts showing unique trajectories with age. There, however, remains a limited understanding of age-related changes occurring within short range WM connections, or U-fibers. These connections are important for local connectivity within lobes and facilitate regional cortical function and greater network economy. Recent studies have explored the maturation of U-fibers primarily using cross-sectional study designs. Here, we analyzed diffusion tensor imaging (DTI) data for healthy children and adolescents in both a cross-sectional (n 5 78; mean age 5 13.04 6 3.27 years) and a primarily longitudinal (n 5 26; mean age 5 10.78 6 2.69 years) cohort. We found significant age-related differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) across the frontal, parietal, and temporal lobes of participants within the cross-sectional cohort. By contrast, we report significant age-related differences in only FA for participants within the longitudinal cohort. Specifically, larger FA values were observed with age in frontal, parietal, and temporal lobes of the left hemisphere. Our results extend previous findings restricted to long range WM to demonstrate regional changes in the microstructure of short range WM during childhood and adolescence. These changes possibly reflect continued myelination and axonal organization of short range WM with increasing age in more anterior regions of the left hemisphere. Hum Brain Mapp 39:204-217, 2018. Key words: short-range WM; DTI; white matter maturation; linear mixed effects model r rAdditional Supporting Information may be found in the online version of this article.

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Recent investigations in neuroscience implicate the role of microbial-derived metabolites, such as short-chain fatty acids (SCFAs) in brain health and disease. The SCFAs acetate, propionate and butyrate have pleiotropic effects within the nervous system. They are crucial for the maturation of the brain's innate immune cells, the microglia, and modulate other glial cells through the aryl-hydrocarbon receptor. Investigations in preclinical and clinical models find that SCFAs exert neuroprotective and antidepressant affects, while also modulating the stress response and satiety . However, many investigations thus far have not assessed the impact of sex on SCFA activity. Our novel investigation tested the impact of physiologically relevant doses of SCFAs on male and female primary cortical astrocytes. We find that butyrate (0–25 ​μM) correlates with increased Bdnf and Pgc1-α expression, implicating histone-deacetylase inhibitor pathways. Intriguingly, this effect is only seen in females. We also find that acetate (0–1500 ​μM) correlates with increased Ahr and Gfap expression in males only, suggesting immune modulatory pathways. In males, propionate (0–35 ​μM) correlates with increased Il-22 expression, further suggesting immunomodulatory actions. These findings show a novel sex-dependent impact of acetate and butyrate, but not propionate on astrocyte gene expression.