Alzheimer’s disease gut-brain connection revealed by x-rays

A research team led by CNR Nanotec, Lecce, Italy ─ the Institute of Nanotechnology ─ in collaboration with the European Synchrotron Radiation Facility (ESRF) in Grenoble, France, has discovered how X-ray micro- and nano- tomography can provide clues to the processes linking gut neurons with those in the brain in a process that may trigger Alzheimer’s disease.

Alzheimer’s disease ─ which is the most common form of dementia ─ is a neurodegenerative disorder characterised by alterations to structures in the brain including synaptic loss, chronic inflammation and neuronal cell death.

In recent years, scientists have found evidence that the gut and the brain communicate through the neurons placed in both organs. Dysfunction in this axis has been linked to psychiatric and neurological disorders, including Alzheimer’s.

The gut microbiota ─ the microorganism flora of the intestinal tract ─ plays a key role in human health and influences brain function, cognition and behaviour.

“There are already many studies supporting the assertion that changes to the gut’s composition [of flora] can contribute to Alzheimer’s onset and progression,” said Dr. Alessia Cedola, researcher from the CNR Nanotec and corresponding author for the article.

In particular, dysbiosis, which is the process by which there is a loss of microbial diversity, can lead to the prevalence of dangerous bacteria that produce toxic metabolites which promote inflammation and, consequently, the breakdown of the gut/brain barriers.

“The main hypothesis is that changes trigger the escape of bad bacteria from the gut, entering the circulation, reaching the brain and triggering Alzheimer’s, but evidence is still poor”, adds Cedola. This is the theory being examined behind gut dysbiosis.

Now scientists have discovered that micro- and nano- X-ray phase-contrast tomography (XPCT) is a powerful tool to study structural and morphological alterations in the gut, without tissue manipulation. The team came to the ESRF in Grenoble to scan samples on beamline ID16A.

“Thanks to this technique we can image soft biological tissues with excellent sensitivity in 3D, with minimal sample preparation and without contrast agents,” explained Dr. Peter Cloetens, scientist in charge of ID16A and co-author of the publication.

The data of the experiments, also partially carried out at ‘Soleil’ – France’s national synchrotron facility southwest of Paris in St Aubin – showed the changes in cell abundance and organisation in the tissues, as well as structural alteration in different tissues of mice which were affected by Alzheimer’s.

Specifically, it showed relevant alterations in the villi and crypts of the gut, 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. All these elements, when working correctly, maintain gut health, support digestion and protect the intestinal lining from damage.

“This technique represents a real breakthrough for the thorough analysis of the gut and it could be pivotal in early detection and prognosis of the disease,” said Cedola.

“As a long-time user of the ESRF, I can attest to the incredible opportunities that this facility provides for cutting-edge research, and the nanoimaging beamline, especially with the EBS.

“Coming to the ESRF has been instrumental in advancing our understanding of the gut-brain axis in Alzheimer's disease,” she said.

Together with scientists Dr. Francesca Palermo and Dr. Claudia Balducci, the next steps in this research will be to further exploit the capabilities of XPCT to study how the gut communicates with the central nervous system. The team aims to investigate the enteric nervous system and its role in Alzheimer's disease.

“By gaining a deeper understanding of these processes, we hope to identify new therapeutic targets and develop innovative treatments for this devastating disease. The ESRF will undoubtedly continue to play a crucial role in our research, and we look forward to many more exciting discoveries in the years to come,” concluded Cedola.

For further reading please visit: 10.1126/sciadv.adr8511