A study in Italy found that symptoms of Alzheimer’s disease can be transferred to young rats via the gut microbiota of Alzheimer’s patients. Transplanting gut microbiota from feces of Alzheimer’s patients into guts of healthy rats induced cognitive deficits in these rats. The paper was published in the journal Brain.
Alzheimer’s disease is a progressive neurological disorder that leads to the atrophy and death of brain cells, causing a decline in memory and cognitive functions. It is the most common cause of dementia among older adults. Main symptoms are memory loss, confusion, difficulty with language and problem-solving, and changes in personality and behavior.
At the moment, there is no cure for Alzheimer’s disease and treatments only focus on managing symptoms and improving the quality of life of affected individuals. Its exact causes are unknown, although it generally starts in advanced age and various genetic and environmental factors have been linked to its development in younger individuals.
Recently, studies have pointed to associations between gut microbiota properties to the Alzheimer’s disease. They indicated that transplanting gut-microbiota to mice can cause adverse cognitive changes in these mice. This venue of research became particularly important with the recent discovery of the microbiota gut-brain axis. The microbiota-gut-brain axis is a bidirectional communication pathway through which microorganisms living in the gut (the gut microbiota) and the brain can affect each other.
The authors of this study wanted to verify the findings of previous studies and investigate whether the transplantation of gut microbiota from Alzheimer’s patients can cause the development of cognitive deficits in rats. These researchers also wanted to investigate the mechanisms through which this is achieved. They suspected that gut microbiota of Alzheimer’s patients might somehow disrupt adult hippocampal neurogenesis in healthy rats.
Adult hippocampal neurogenesis refers to the capacity of neural stem cells in the hippocampus region of the brain to generate new neurons throughout an individual’s life, including during adulthood. This process is vital for cognitive functions such as spatial learning, distinguishing between similar events and environments, and emotion regulation. The hippocampus’s vulnerability to Alzheimer’s disease may be partly due to its role in these processes.
The study involved 69 Alzheimer’s patients and 64 healthy individuals as controls, all recruited from the IRCCS Centro San Giovanni di Dio Fatebenefratelli in Brescia, Italy. Participants provided blood samples for analysis, and most also contributed stool samples for rat transplantation.
The primary experiments were conducted on male Sprague-Dawley rats, 11 weeks old. After adapting to the laboratory environment, the rats were treated with a potent antibiotic cocktail for 7 days to eliminate their own microbiota (ampicillin (1 g/l), vancomycin (500 mg/l), ciprofloxacin HCL (200 mg/l), and imipenem (250 mg/l)). This treatment destroyed rats’ own microbiota and prepared them to readily accept those transplanted from humans.
Following the depletion of their gut microbiota, the rats were divided into two groups. One group received gut microbiota from human Alzheimer’s patients, while the other group received it from healthy participants. The transplantation was performed by force-feeding the rats a homogenized fecal slurry from human participants through a tube directly inserted into their esophagus (oral gavage) for three days. Behavioral tests were conducted 10 days later to assess the rats’ cognitive functioning.
Additionally, the researchers conducted experiments on undifferentiated human cells from the hippocampus region of the brain, obtained from medically terminated female human fetuses. They treated these cells with serum (the liquid component of blood that remains after coagulation) taken from the two groups of human study participants and observed the effects.
The results indicated that transplantation of gut microbiota from healthy human participants did not affect the recipient rats. However, rats with microbiota from Alzheimer’s patients exhibited impaired recognition of familiar locations and decreased performance in memory-reliant tasks, highlighting the importance of hippocampal neurogenesis in these functions.
Further analyses confirmed that hippocampal neurogenesis was disrupted in rats receiving gut microbiota from Alzheimer’s patients, as these rats produced significantly fewer new neurons compared to the control group.
The experiment with human hippocampal progenitor cells revealed that treatment with serum from Alzheimer’s patients reduced the cells’ proliferation capacity. This reduction varied with the severity of the Alzheimer’s symptoms in the blood donors, with cells maintaining better proliferation capacity when treated with serum from participants with less severe symptoms.
In a press release, study author Yvonne Nolan, a professor at University College Cork, explained: “The memory tests we investigated rely on the growth of new nerve cells in the hippocampus region of the brain. We saw that animals with gut bacteria from people with Alzheimer’s produced fewer new nerve cells and had impaired memory.”
“People with Alzheimer’s are typically diagnosed at or after the onset of cognitive symptoms, which may be too late, at least for current therapeutic approaches. Understanding the role of gut microbes during prodromal — or early stage- dementia, before the potential onset of symptoms may open avenues for new therapy development, or even individualised intervention.”
In their paper, the study authors concluded: “Our results demonstrate that colonization of healthy young adult rats with gut microbiota from Alzheimer’s patients induced behavioral and neurogenic alterations typical of Alzheimer’s disease. We show that the expression of caecal metabolites [substances produced during the fermentation of undigested food by the microbiota in the cecum, part of the large intestine] involved in the neurogenic and cognitive function are altered after FMT [fecal microbiota transplantation] from Alzheimer’s patients, and report a direct and negative impact of serum from Alzheimer’s patients on neurogenesis in vitro.”
“Overall, our findings reveal that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer’s disease. Furthermore, AHN [adult hippocampal neurogenesis] is established as a converging central cellular process for cognitive changes influenced by both systemic circulatory and gut-mediated factors in Alzheimer’s disease.”
The study sheds light on the role of gut microbiota in Alzheimer’s disease. It makes a very valuable contribution to the scientific understanding of this disease and how it can be transmitted. However, it should be noted that the study was conducted on rats with depleted gut microbiota. Effects might not be equal on humans with their gut microbiota intact.
Sandrine Thuret, a professor of neuroscience at King’s College London and one of the study’s senior authors said, “Alzheimer’s is an insidious condition that there is yet no effective treatment for. This study represents an important step forward in our understanding of the disease, confirming that the make-up of our gut microbiota has a causal role in the development of the disease. This collaborative research has laid the groundwork for future research into this area, and my hope is that it will lead to potential advances in therapeutic interventions.”
The paper, ”Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis,” was authored by Stefanie Grabrucker, Moira Marizzoni, Edina Silajdžić, Nicola Lopizzo, Elisa Mombelli, Sarah Nicolas, Sebastian Dohm-Hansen, Catia Scassellati, Davide Vito Moretti, Melissa Rosa, Karina Hoffmann, John F. Cryan, Olivia F. O’Leary, Jane A. English, Aonghus Lavelle, Cora O’Neill, Sandrine Thuret, Annamaria Cattaneo, and Yvonne M. Nolan.
