Alzheimer’s disease is a debilitating condition that affects millions of people worldwide, and scientists are still working to understand the underlying causes of this devastating disease. Recent research has suggested that the gut microbiome, which is the community of microorganisms that lives in the human gut, may play a role in the development of Alzheimer’s disease. The gut contains around 500 million neurons which comprise the enteric nervous system. The interaction of the gut with and influence upon the nervous system, and vice versa, is known as the ‘gut-brain-axis’. Much recent evidence suggests that the gut-brain-axis may be implicated in a range of neurological disorders including multiple sclerosis, Parkinson’s disease and dementia. The gut microbiome is composed of trillions of microorganisms, including bacteria, viruses, and fungi, that inhabit the human digestive tract. These microorganisms have a profound impact on human health, and research has shown that they can influence everything from the immune system to the central nervous system. Recently, scientists have begun to explore the link between the microbiome and neurological disorders such as Alzheimer’s disease.
One of the key ways in which the gut microbiome may contribute to Alzheimer’s disease is through the production of amyloid beta, a protein that forms the characteristic plaques that are found in the brains of people with Alzheimer’s disease. Research has shown that certain types of bacteria in the gut can produce amyloid beta, which can then travel to the brain and contribute to the formation of plaques. Additionally, these bacteria may also produce other toxins that can damage the brain and contribute to the development of Alzheimer’s disease. Another way in which the gut microbiome may influence Alzheimer’s disease is through the production of short-chain fatty acids (SCFAs). SCFAs are produced when gut bacteria break down dietary fiber, and they have been shown to have a range of health benefits, including reducing inflammation and improving cognitive function. However, research has also shown that changes in the gut microbiome can lead to a reduction in SCFAs, which may contribute to the development of Alzheimer’s disease.
The role of the gut microbiota in neurodegenerative disease is an emerging research field. Recently, Parkinson’s disease patients showed a different gut microbiota than healthy controls and growing evidence also points to gut microbiota dysbiosis in Alzheimer’s disease (AD) patients and mouse models. A deep characterization of the gut microbiota and metabolites, such as short fatty acids and amino acids, will help in a better understanding of the etiopathology of AD.
A recent study showed that there were alterations in the composition of gut bacteria in patients with Alzheimer’s disease compared to healthy controls. For example, Clostridium and Bifidobacterium species were less abundant in patients with Alzheimer’s, whereas Bacterioides and Gemella were more abundant, to name a couple of examples. Furthermore, cerebrospinal fluid (CSF) markers for Alzheimer’s pathology, such as the levels of amyloid-beta protein, could be correlated with a change in the number of certain bacteria in the gut. For example, a decrease in the number of Bifidobacterium (which is known to be reduced in Alzheimer’s) could directly be correlated with high levels of amyloid-beta-42 (Aβ42) in the CSF of patients with Alzheimer’s. The greater the discrepancy in the levels of gut bacteria, the greater the level of pathological markers in the CSF.
The study of microbiota and, particularly, dysbiosis associated with human diseases is revolutionizing our ideas and modifying the clinical management of many disorders, offering new opportunities to treat patients. Although full development of the individual gut microbiota is achieved within the first 2–3 years of life, with limited fluctuations in its composition during life in healthy individuals, dysbiosis has been documented in several pathological conditions. In particular, gut dysbiosis has been observed in human diseases characterized by gut inflammation such as Celiac Disease, Cystic Fibrosis, Obesity, IBD, diabetes, colon cancer, and more. Although whether cause or consequence of disease onset is still under deep investigation, rebalancing gut microbiota by using prebiotics, probiotics, nutraceuticals or fecal transplants seems to have a positive impact on some disease onset/progression, at least in animal models. Thus, a deep knowledge of gut microbiota modifications associated with specific disorders will help us to better understand the disease and to increase our opportunities to treat patients.
A longitudinal metagenomic and metabolomic analysis of stools samples from a mouse model of AD (3xTgAD), compared to matched WT controls, revealed a dysregulated microbiota and metabolites composition in 6 months-old mice. The authors findings revealed a slight and similar fluctuation of the F/B ratio in both AD and WT groups of mice at weaning and 2 months, while a significant divergence was observed between the groups at 6 months, a time coincident with the progression of the pathology, in this mouse model.
The authors suggest that the intestinal microbiota could influence the onset and/or progression of Alzheimer’s Disease neurodegeneration. In addition, although the most relevant differences in the metabolic profile become evident at six months of age in 3xTgAD mice, SCFA and biodiversity alterations appeared earlier, suggesting that a perturbation of microbiome can occur before the appearance of the main clinical signs of the disease.
While the research on the relationship between Alzheimer’s disease and the microbiome is still in its early stages, the findings so far suggest that there is a strong link between the two. As a result, there is growing interest in the potential of probiotics and other microbiome-based therapies as a way to prevent or treat Alzheimer’s disease. For example, some researchers are exploring the use of prebiotics, which are dietary fibers that promote the growth of beneficial bacteria in the gut, as a way to boost SCFA production and improve cognitive function. Other researchers are investigating the use of fecal transplants, which involve transplanting fecal matter from a healthy individual into the gut of a person with Alzheimer’s disease in order to restore a healthy microbiome.
In conclusion, the gut microbiome appears to play an important role in the development of Alzheimer’s disease, through a variety of mechanisms including the production of amyloid beta, the reduction of SCFAs, and immune dysfunction. While the research is still in its early stages, these findings suggest that therapies aimed at restoring a healthy microbiome may be a promising approach to preventing or treating Alzheimer’s disease.
Favero F, Barberis E, Gagliardi M, Espinoza S, Contu L, Gustincich S, Boccafoschi F, Borsotti C, Lim D, Rubino V, Mignone F, Pasolli E, Manfredi M, Zucchelli S, Corà D, Corazzari M. A Metabologenomic approach reveals alterations in the gut microbiota of a mouse model of Alzheimer’s disease. PLoS One. 2022 ;17(8):e0273036. doi: 10.1371/journal.pone.0273036. PMID: 36001607.