Researchers have explored the connection between the gut and the brain in Alzheimer’s disease, highlighting the impact of gut dysbiosis on the progression of the disease. Using innovative X-ray phase contrast tomography (XPCT), they were able to visualize structural changes in the intestines in 3D in mouse models of Alzheimer’s disease, revealing cellular and inflammatory changes that may influence neurodegeneration.
Alzheimer’s disease (AD) is the most common form of dementia and affects millions of people worldwide. This neurodegenerative condition causes the progressive decline of cognitive functions, such as memory and reasoning, in addition to causing several changes in the brain.
These changes include the loss of connections between neurons (synapses), chronic inflammation and the death of brain cells. Despite many scientific efforts, attempts to develop effective treatments for the disease have not yet been successful.
Therefore, better understanding the mechanisms that lead to Alzheimer’s and finding new therapeutic targets has become a priority in medical research.
In recent years, a new perspective on Alzheimer’s disease has emerged: the relationship between the gut and the brain. This concept is based on the idea that the two organs are connected through different mechanisms, such as hormonal, immune and nervous systems.
This two-way communication is known as the gut-brain axis and has been linked to several psychiatric and neurological diseases, including Alzheimer’s.
The gut is home to a huge community of microorganisms, called gut microbiota, which plays an essential role in digestion, immunity and even in regulating the brain and behavior.
Studies have shown that the composition of the intestinal microbiota is different in people with Alzheimer's and may contribute to the development of the disease.
This imbalance in the microbiota, called dysbiosis, can reduce the diversity of beneficial bacteria and increase the presence of microorganisms that release toxic substances and promote inflammation.
In addition, dysbiosis can compromise the intestinal barrier, facilitating the passage of harmful substances into the bloodstream and, eventually, into the brain. This can trigger inflammatory processes and stimulate the accumulation of β-amyloid (Aβ) plaques, one of the main hallmarks of Alzheimer's disease.
Experimental research has shown that when feces from Alzheimer’s patients are transplanted into healthy mice, the animals begin to exhibit features of the disease, such as memory loss and the accumulation of amyloid plaques in the brain.
These findings reinforce the idea that the gut microbiota may influence the progression of Alzheimer’s disease and suggest that restoring a healthy balance in the gut may be a promising therapeutic strategy.
One of the great advantages of studying the gut is that it is much more accessible than the brain, allowing researchers to look for ways to identify early signs of the disease through tests and biomarkers.
Because gut dysbiosis is a modifiable risk factor, scientists are exploring ways to correct this imbalance through dietary changes, the use of probiotics, prebiotics, and even fecal microbiota transplants to restore a healthier gut environment and potentially reduce the risk or progression of Alzheimer’s disease.
To better understand the intestinal changes associated with Alzheimer's, researchers at the Institute of Nanotechnology – CNR, Italy, have applied a new imaging technique called nano and micro X-ray phase contrast tomography (XPCT).
This innovative method allows the visualization of microscopic structures of intestinal tissue in three dimensions (3D) and with very high resolution, without the need for invasive sections or chemical staining.
XPCT has proven extremely useful for studying neurological diseases because it allows the identification of changes in the composition and organization of cells, in addition to revealing details of the vascular system and other structures involved in the progression of the disease.
Nanotomography of a mouse ileum. White pixels represent low-density tissue, while dark pixels represent high-density tissue. (A) Longitudinal view of the ileum structure at the level of the crypt and muscularis. Circles indicate the approximate position of the morphological details shown in the figure. (B) Bottom of a crypt, where goblet cells are indicated by white arrows, the presence and location of Paneth cells by an asterisk, and telocytes by blue arrows. (C) Neurons of the myenteric plexus (Auerbach). (D) Neurons belonging to the submucosal plexus (Meissner). (E) Longitudinal layer of the muscularis. (F) Blood vessel with enterocytes (red arrow) appearing as black crescent-shaped structures.
The study used this technology to analyze samples from the small intestine of three different mouse models that mimic Alzheimer's disease.
The researchers observed significant structural changes, including modifications in the intestinal villi (structures responsible for nutrient absorption), changes in cellular composition and in the pattern of mucus secretion.
In addition, they identified transformations in specific types of intestinal cells, such as Paneth cells and goblet cells, which play essential roles in protecting the intestinal barrier and regulating the immune system.
These changes suggest that dysbiosis may be directly involved in the inflammation and brain degeneration observed in Alzheimer's.
Nano-XPCT analysis of Paneth and goblet cells. (A) 3D representation of the longitudinal view of a crypt from the SAMR1 mouse. The epithelial layer of the crypt is rendered in green. Paneth cells are colored in yellow and goblet cells in blue. Scale bars, 5 μm. (B) and (C) show 3D renderings and close-ups of nano-XPCT of goblet and Paneth cells, respectively.
One of the great advantages of XPCT is its ability to generate a single three-dimensional image that is equivalent to thousands of conventional histological sections, without the need for specific dyes or markers.
This allows for a more detailed and comprehensive analysis of tissues, facilitating the identification of patterns that could go unnoticed with traditional methods.
For a long time, Alzheimer's was seen as an exclusively brain disease, caused mainly by the accumulation of β-amyloid and the formation of tangles of a protein called tau.
However, the numerous failures of clinical trials aimed at removing these amyloid plaques indicate that the disease is much more complex than previously thought.
This realization has led scientists to search for early biomarkers that can help detect Alzheimer’s disease before the brain is severely damaged. In addition, new evidence suggests that peripheral organs, such as the eyes and gut, may play a role in the progression of the disease.
The relationship between the gut and the brain has been attracting increasing interest, especially due to findings indicating that the gut microbiota can directly influence neurological health.
The main hypothesis is that the balance of the gut microbiota can determine whether an individual is at higher or lower risk of developing Alzheimer's. If this theory is confirmed, strategies such as the use of prebiotics, probiotics and gut microbiota transplantation could be used to prevent or slow the progression of the disease.
In conclusion, the researchers demonstrated that XPCT represents a significant advance in the analysis of the intestine, allowing a detailed mapping of the structural changes associated with Alzheimer's disease.
This method could be fundamental to understanding how gut dysbiosis contributes to Alzheimer's and to developing new strategies for early diagnosis and treatment.
The connection between the gut and the brain could be the key to identifying more effective ways to combat this devastating disease and improve the quality of life of patients in the future.
READ MORE:
Investigating gut alterations in Alzheimer’s disease: In-depth analysis with micro- and nano-3D X-ray phase contrast tomography
FRANCESCA PALERMO, NICOLE MARROCCO, LETIZIA DACOMO, ELENA GRISAFI, VIVIANA MORESI, ALESSIA SANNA, LORENZO MASSIMI, MARIANNA MUSELLA, LAURA MAUGERI, ALESSIA CEDOLA et al.
Science Advances. 31 Jan 2025. Vol 11, Issue 5
DOI: 10.1126/sciadv.adr8511
Abstract:
Alzheimer’s disease (AD), a debilitating neurodegenerative disorder, remains one of the foremost public health challenges affecting more than 30 million people worldwide with the etiology still largely enigmatic. The intricate gut-brain axis, serving as a vital communication network between the gut and the brain, appears to wield influence in the progression of AD. Our study showcases the remarkable precision of x-ray phase-contrast tomography (XPCT) in conducting an advanced three-dimensional examination of gut cellular composition and structure. The exploitation of micro- and nano-XPCT on various AD mouse models unveiled relevant alterations in villi and crypts, cellular transformations in Paneth and goblet cells, along with the detection of telocytes, neurons, erythrocytes, and mucus secretion by goblet cells within the gut cavity. The observed gut structural variations may elucidate the transition from dysbiosis to neurodegeneration and cognitive decline. Leveraging XPCT could prove pivotal in early detection and prognosis of the disease.
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