Some argue that we are more microbial than human. Microbial cells outnumber our own cells by a ratio of ten to one and harbor as many as 20 million genes versus 20 thousand in the human genome. Subsequently, it is no surprise that the human gut microbiota continues to be an emerging research topic as majority of the bacteria found in the body is in the gut. A global challenge that the aging population faces is the ability to maintain healthy brain function. Aging triggers changes in the immune system that lead to cognitive impairment. Advancements in metagenomic sequencing have provided a bidirectional relationship between the gut microbiota and host cognition as it is an important regulator of homeostasis in the immune system. Researchers noticed rapid gut dysbiosis, or the depletion in microbial diversity, that occurs from infancy to adulthood. As a result, they tested whether or not microbiota from young donors can be transplanted into an old recipient to restore host immunity and neurocognitive impairment.
Fecal Microbiota Transplantation (FMT) Experimental Design
In the paper published in the journal Nature Aging, researchers collected and transplanted fecal microbiota from naive young mice (3 to 4 months old) into 19 to 20 month old aged mice (‘aged yFMT’). Fecal microbiota from naive old mice (‘aged oFMT’) that were 19 to 20 months old were also transplanted into a separate group of aged mice, which served as a control. In addition, naive young mice received the same yFMT mixture (‘young yFMT’) that the aged yFMT mice received as a second control. The main objective was to observe and compare changes in microbiota, immunity, brain metabolomes, gene expression, and behavior pre and post-FMT to assess possible attenuations in cognitive impairments.
Were there any changes in microbiota composition post-FMT?
The abundance of Enterococcus genera in the aged yFMT mice was one of the first aged-associated shifts that was discussed. In Fig. 1, it is evident that the Enterococcus abundance shifted towards levels similar to that of the pre young yFMT mice. The consistent results presented in the controls imply that the shift of Enterococcus abundance in pre aged yFMT to post aged yFMT is exclusively due to do FMT.
Did any of the changes affect brain health and immunity?
Researchers then proceeded to test whether changes in the immune system caused by aging can be improved by yFMT. Since the gut microbiota regulates the immune system, which subsequently influences hippocampal-associated cognitive behavior, it was a critical test. In order to observe the impact of the FMT from a young donor on the aged recipient’s immunity, they looked at gut associated mesenteric lymph nodes (MLNs) and in the circulation. Early activated CD8+ T cells were increased due to aging; however, it was reversed by yFMT in MLNs. In addition, the CD103+ dendritic cells, which are tightly linked to CD8+ T cell activation, were reduced in aged mice that received fecal microbiota from a young donor, further emphasizing the positive effects of FMT on host immunity. Furthermore, researchers focused on the microglia of the hippocampus, which is a key factor for regulating cognitive functions. Enlarged microglia cell size and elevated levels of activated microglia are the hallmarks for neurodegenerative conditions. Aged oFMT mice had larger microglia cell soma size, whereas aged yFMT mice showed a decrease in cell size. In addition, target RNA sequencing was utilized to see if yFMT can alter the genes that allow microglial sensing function (sensome). Trem2 and Dap12, immunoregulatory factors of the microglial sensome, that form a complex that induce microglial activation were indeed reversed by yFMT. Other genes that are linked to cognitive impairment were also restored; notably, Gpr84, which tends to be increased in mouse models of Alzheimer’s disease and Fcgr2b, which is associated to memory impairment. Interestingly, 35 aged hippocampal metabolomes were restored toward pre-aged levels by yFMT. Researchers highlighted that the improved levels of vitamin A, GABA, and N-glycolylneuraminate may be critical findings for the benefits of FMT because they prevent memory deficits, cognitive decline, and neuroinflammation respectively.
Were there noticeable behavioral changes?
In order to test the effects of yFMT in aged mice on hippocampal-related behavior, the mice were had to perform series of tasks and cognitive tests. Mice underwent the Morris water maze which is a widely used to test spatial learning, reference memory, and long-term potentiation in rodents. Fig. 4 shows that the aged mice that received the FMT from the young mice donor paralleled the young mice (yFMT) from the control in path length, mean distance from platform, speed, and latency to the platform. These findings further emphasize the strong bidirectional relationship between the gut and the brain.
Recent Human Application
On August 2021, a case report was published about a 90-year-old woman with Alzheimer’s Disease who underwent FMT from a 27-year-old male donor to see if there would be improvement in cognition. Prior to FMT, her cognitive function was evaluated through Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR) assessment for 30 min by the neurologist. The tests revealed a decline in short-term memory, semantic skills, attention, non-verbal learning, and response inhibition with a score of 20, 16, and 0.5, respectively. She also scored a 23 on the Geriatric Depression Scale (GDS), which is an indication of severely depressive mood. They confirmed that she was not prescribed medications that could hinder her alertness and the results. They performed the same cognitive tests five weeks after FMT; and, they collected her fecal samples three weeks after FMT to observe changes in her gut microbiota composition. Her scores for the MMSE, MoCA, and CDR were 20, 17, and 0.5 respectively and she showed improved mood (GDS 17). Recent studies state that FMT is a safe procedure; however, patient monitoring is necessary post-FMT. The patient did experience some nausea after the first FMT; however, it was improved with anti-emetic medication and did not reoccur even three months after the first FMT.
Final Thoughts
Heterologous FMT, when feces from a donor is transplanted into the recipient, is currently being utilized in clinical practice; however, there is still concerns about the long-term safety. Autologous FMT therapy has been considered the more optimal approach in which the patient’s healthy stool is banked and used in the future to restore the gut microbiota. This therapeutic approach is especially useful for aging population who are more susceptible to infections. There is fundamental evidence that links the gut microbiota and the brain. FMT should be considered a therapeutic approach for the treatment of restoring age-associated cognitive deficits, especially regarding hippocampus-associated decline.