New research published in Brain investigated the influence of fecal microbiota transplants from Alzheimer’s patients on cognitive function and neurogenesis in rats and human cell cultures [1].
Microbiota-gut-brain axis
There is a growing body of research reporting changes to the composition and metabolites in the microbiomes of Alzheimer’s patients [2]. Studies have also linked the microbiota-gut-brain axis to the origins of neurodegenerative disorders [3].
Previous experiments done on mouse models of Alzheimer’s have suggested connections between gut microbiota and some features of Alzheimer’s, such as endoplasmic reticulum stress [4] and impairment of spatial memory [5].
Transferring gut bacteria from Alzheimer’s patients to healthy rats
The authors of this study asked whether fecal transplants from people with Alzheimer’s disease can induce cognitive and cellular changes in healthy rats. First, the researchers analyzed the plasma from Alzheimer’s patients and healthy controls. Their results indicated that markers of systemic and intestinal inflammation were elevated in Alzheimer’s patients.
Then, the researchers analyzed the gut microbiota composition in a subset of study participants. They observed a higher abundance of pro-inflammatory species in Alzheimer’s patients, while groups of microbes that produce beneficial metabolites were less common. For example, they observed decreased levels of healthy aging-associated microbes that produce the short-chain fatty acid butyrate.
Those alterations correlated with the clinical status of Alzheimer’s patients assessed by the Mini-Mental State Examination (MMSE). Specifically, researchers observed a positive correlation between MMSE score and the abundance of microbes producing short-chain fatty acids. An inverse correlation was observed between the MMSE score and the abundance of disease-associated microbes.
Following the microbiota assessment, the researchers performed fecal transplantation. They acquired fecal samples from people with Alzheimer’s disease and healthy controls and transplanted them to young adult rats whose microbiomes were depleted by antibiotic treatment. An average of 40% of the human gut bacteria became engrafted into these rats.
The researchers evaluated the health of the rats’ intestines following the transplant. Most markers were unaffected: the researchers didn’t observe any differences in fecal and pellet output, caecum weight, body weight composition, food intake, pro-inflammatory cytokine gene expression in colonic tissue, nor the presence of cytokines in systemic circulation.
However, the researchers observed that in the colonized rats, fecal water content and intake were increased and colon length was reduced. Researchers also observed structural changes in the depth of the colonic crypts compared to the control colonized rats and fewer mucus cells in the colon and ileum.
Impaired cognitive abilities and neurogenesis
10 days after the transplantation, the researchers started to perform several behavioral tests on microbiotally colonized rats. Some behaviors seemed unaffected, as the researchers observed no change in locomotor parameters or anxiety-related behavior. The rats also did not form the characteristic Alzheimer’s plaques.
However, differentiating between familiar and novel locations and memory performance was impaired in several tests in rats that received transplants from Alzheimer’s patients. Interestingly, the researchers observed a correlation between the clinical human donor profile and rats’ behavioral readouts.
Those results suggest the role of microbiota in promoting cognitive deficits and impairment of adult hippocampal neurogenesis (AHN)-dependent memory performance. AHN occurs in the adult hippocampus throughout life and is essential for multiple cognitive functions, such as spatial learning or distinguishing between similar events and environments. Many of those functions are impaired in Alzheimer’s disease.
Since the cognitive tests suggested impairment in AHN-dependent memory, the researchers began to test it. They performed their experiments on the dentate gyrus (DG) since it has a role in differentiating highly similar environments, an ability that was impaired in rats harboring human Alzheimer’s microbiota. The researchers observed a reduction in new neuron survival compared to controls. Those rats also had fewer cells expressing markers of cell proliferation and differentiation.
New neurons in the hippocampus of the DG are important in recalling memories. Additionally, proper dendritic sprouting and branching are essential for their function. To test that, the researchers created a 3D reconstruction of cells expressing differentiation markers. They observed that the microbially affected rats had reduced dendritic complexity. Additionally, total dendritic length was reduced in those rats; however, there was no change in the average dendritic length per neuron.
The researchers investigated neurogenesis using embryonic human hippocampal progenitor cells (HPCs). Upon exposing those cells to serum from Alzheimer’s and control patients, they observed that exposure to the Alzheimer patients’ serum led to a reduction in HPCs’ proliferative capacity and neuronal differentiation while altering their morphology. The authors again emphasize that their experimental observations are associated with the Alzheimer’s patients’ clinical phenotype.
The researchers wanted to learn which metabolites might link the gut microbiota with the observed changes in behavior and brain. An analysis of intestinal content and hippocampal tissue discovered a few differences between the metabolites of controls and rats with Alzheimer’s microbiomes.
The authors believe this suggests that cognition and AHN alterations precede amyloid deposition. Those findings corroborate previous findings from post-mortem human brains [6].
In this study, we demonstrate that the transplantation of human gut microbiota from Alzheimer’s patients is sufficient to produce core cognitive symptoms of Alzheimer’s disease coupled with an impairment in AHN, in healthy young adult rats. Moreover, application of human Alzheimer’s disease serum provoked an impairment in AHN in human cells in vitro, supporting AHN as a converging cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer’s disease.
Literature
[1] Grabrucker, S., Marizzoni, M., Silajdžic, E., Lopizzo, N., Mombelli, E., Nicolas, S., Dohm-Hansen, S., Scassellati, C., Moretti, D. V., Rosa, M., Hoffmann, K., Cryan, J. F., O’Leary, O. F., English, J. A., Lavelle, A., O’Neill, C., Thuret, S., Cattaneo, A., & Nolan, Y. M. (2023). Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis. Brain : a journal of neurology, awad303. Advance online publication.
[2] Connell, E., Le Gall, G., Pontifex, M. G., Sami, S., Cryan, J. F., Clarke, G., Müller, M., & Vauzour, D. (2022). Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia. Molecular neurodegeneration, 17(1), 43.
[3] Kowalski, K., & Mulak, A. (2019). Brain-Gut-Microbiota Axis in Alzheimer’s Disease. Journal of neurogastroenterology and motility, 25(1), 48–60.
[4] Wang, F., Gu, Y., Xu, C., Du, K., Zhao, C., Zhao, Y., & Liu, X. (2022). Transplantation of fecal microbiota from APP/PS1 mice and Alzheimer’s disease patients enhanced endoplasmic reticulum stress in the cerebral cortex of wild-type mice. Frontiers in aging neuroscience, 14, 858130.
[5] Kim, N., Jeon, S. H., Ju, I. G., Gee, M. S., Do, J., Oh, M. S., & Lee, J. K. (2021). Transplantation of gut microbiota derived from Alzheimer’s disease mouse model impairs memory function and neurogenesis in C57BL/6 mice. Brain, behavior, and immunity, 98, 357–365.
[6] Moreno-Jiménez, E. P., Flor-García, M., Terreros-Roncal, J., Rábano, A., Cafini, F., Pallas-Bazarra, N., Ávila, J., & Llorens-Martín, M. (2019). Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nature medicine, 25(4), 554–560.
