Microbiota from young mice counteracts selective age-associated behavioral deficits

Abstract

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.

Organoids: An Emerging Tool to Study Aging Signature across Human Tissues. Modeling Aging with Patient-Derived Organoids

“…Recently, the role of human papillomavirus (HPV) in carcinogenesis was studied in ecto-and endocervicalderived organoids [65]. Besides, organoids can be co-cultured with microbiota [66], which is relevant due to its role in cancer and other aging-related processes [67].…”

The Impact of IgA and the Microbiota on CNS Disease

“…Recent work demonstrated that FMT from aged donor mice into young recipients impairs spatial learning and memory in young recipients (4). Conversely, FMT from young donor mice into aged recipients can rejuvenate age-associated CNS metabolic, transcriptomic, and behavioral changes (5). Aged into young FMT induced an altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus, an area of the CNS known to be affected by the ageing process.…”

Is the Gut Microbiome a Target for Adjuvant Treatment of COVID-19?

“…The main symptoms of this chronic COVID-19 syndrome (CCS) (1) were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnoea (24%); however, joint pain, sleeping problems, depression, and diarrhoea were reported as well. Fatigue, headache, attention disorders, joint pain, headaches, sleeping problems, depression, and diarrhoea have been linked to dysbiosis in the gut microbiome [92][93][94][95][96][97][98][99][100]. There seems to be an intriguing overlap between these symptoms and more research in this area might reveal new treatment options for CCS.…”