Gut microbiome alterations in Alzheimer’s disease: an interview with Giovanni Frisoni

Written by Sharon Salt, Editor

Giovanni Frisoni is a physician and clinical neurologist who is also extremely involved in research. He has been consulting patients for the last 27 years and has been working at the National Center for Alzheimer’s Disease (Brescia, Italy) – the first center entirely devoted to Alzheimer’s research in Italy – for 22 years. Giovanni has been directing the Memory Clinic of the University Hospital of Geneva (Switzerland) for the last 5 years, where he is also a Professor of Clinical Neuroscience.
In this interview, Giovanni speaks to us about his talk on gut microbiome alterations in Alzheimer’s disease (AD) and what impact this research could have for patients in the future. He also provides his opinion on where the field could be in 5–10 years’ time and what his anticipations are.
What is your current research focus and what inspired you to work in this area?

What inspired me is the positive thrust that I have been experiencing throughout the last 25 years. There is a positive dynamic within the AD research field. If you look back at where we started in 1984, when the first clinical criteria for AD was developed, we barely knew what it was. Most experts believed that it was a rare disease of young people.

If you look at where we are at now, after the first neuropsychological assessments for cognitive phenotyping; the development of biomarkers for differential diagnosis and early diagnosis; and the development of a drug with the ability to clear the brain from the toxic substances that we know are causing the disease; the amount of progress that has been done is enormous. This is what motivates me.

In my current research, I have two major areas of interest. The first is my traditional area in imaging biomarkers for differential diagnosis and early diagnosis, which is where a large part of the field is working on because it has a clinical impact. Research on drugs will not have any acute impact on patients yet, but biomarker researcher does have an impact. This is because we are using biomarkers for clinical diagnosis every day, all over Europe, and all over the world. We do CSF studies, high-resolution MRI and molecular PET imaging regularly. So the impact of biomarker research on patient care is huge.

This is where a large part of my motivation comes from – the fact that what I study in research goes straight into practice. When I talk to patients, I use the knowledge that has come to maturity the week before, or the month before, in the lab.

You presented a talk at the Alzheimer’s Association International Conference (22–26 July, IL, USA) on ‘Gut microbiome alterations in AD’ – could you provide an overview about this?

One possible avenue to explain and to prevent the deposition is what occurs in the gut; with the trillions of bacteria that we carry around every day in our stomachs.”

This is my second major area of interest. We have already identified the toxic proteins – the culprits – in familial Alzheimer’s disease and other familial dementias (amyloid, tau, α-synuclein and others). However, we do not know why they deposit in the sporadic cases. One possible avenue to explain and to prevent the deposition is what occurs in the gut; with the trillions of bacteria that we carry around every day in our stomachs. This is the subject of the presentation that I gave at AAIC.

I have a disclaimer to make first – we are in the very early days of microbiota research in neurodegenerative diseases, particularly the Alzheimer’s field. Some of the other neurodegenerative diseases are slightly ahead of us, such as Parkinson’s disease, psychiatric disorders, multiple sclerosis, etc. We are not terribly latecomers but we are latecomers.

In terms of what we found, it’s very basic if you wish. We investigated the profiles of different bacterial genera that we host in our guts. We carried out a very classic case-control study on patients who had AD with brain amyloidosis compared with healthy individuals without cognitive impairment. We collected stool and blood samples and examined the difference in bacterial profiles in the gut, as well as inflammatory markers.

Our results revealed that patients with Alzheimer’s have a proinflammatory state in the blood and proinflammatory bacteria in their gut. What is nice is that Parkinson’s disease, a disease closely related to Alzheimer’s, also has a similar inflammatory state. So, why do some patients develop Alzheimer’s and others develop Parkinson’s? This is what we do not know. We don’t know this because the biochemical pathways in the gut and in the blood are largely unknown. This is an area that we will study in the coming months and years.

What impact could this research have for patients in the future?

In any line of research, you know where you start from but you don’t know where you will end up.

The problem is that there are approximately 80 species of bad bacteria that we know a lot about but there are also 10,000 species of ancient or good bacteria that we live with everyday, and know nothing about them.”

I think that this area is a promising avenue as it makes a lot of sense. One of my presentation slides at AAIC deconstructed the myth that humans evolved from bacteria over 3.5 billion years ago. This is not true. Bacteria were not just the starting point – they have been living with us all along. Bacteria have been around us and within our bodies. Mitochondria are ancient bacteria and we have mitochondria in almost each and every cell of our body.

I find it unlikely that the only thing the human body has been able to develop, as well as some mammals and fish, is some form of protection from bacteria. This is the traditional knowledge: bacteria are bad and our bodies protect us from them. The problem is that there are approximately 80 species of bad bacteria that we know a lot about but there are also 10,000 species of ancient or good bacteria that we live with every day, and we know nothing about them. But they are necessary for the appropriate functioning or the physiology of the lungs, liver, heart, brain and the whole body. This is an open window and we have to investigate it.

I believe that by studying gut bacteria in Alzheimer’s disease we may come out with something useful for the patients at the end of the road, but of course I cannot be 100% certain.

In your opinion, what are the key hurdles to be overcome in this field?

The first key hurdle is to move from a descriptive taxonomy to a functional one. When we study bacteria, we use the categories that were developed in terms of genera, phyla and species since Lavoisier 250 years ago. They were developed by microbiologists who were studying the bad guys. Consequently, the names that we gave to these bacteria don’t mean anything in terms of function.

Up until now, we are still using these taxonomies. For example, we present findings such as, “There is more Prevotella in AD; less Bifidobacterium in healthy individuals; more Bacillus subtilis in this disease…” and so on. These labels don’t mean anything in functional terms.

How can these hurdles be overcome?

One metabolite is like a single instrument in the orchestra, but we have a whole ensemble of metabolites that we need statistical tools to study. These are currently being developed and are in the making.”

There is technology that is currently being developed out there. The whole field is exploding. Not only are scientists in the Alzheimer’s or Parkinson’s field realizing that bacteria are more relevant than we initially thought, but all fields of medicine have realized that these bacteria might explain many of the diseases that we believe we know nothing about. There are a myriad of techniques that are being developed, such as shotgun metagenomics and many others.

The first thing you want to do is a whole-genome scale of the microbes living with us. Second, we would want a metabolomics scale to find out what droppings, such as lipids and glycolipids, they are producing. Third, you would want to develop a functional metabolomics to see what each of the different metabolites are doing to the human body.

It’s amazing because if we have 100 genera, which translate to around 2000 species of bacteria, then we are in the range of 10,000 or 20,000 metabolic products. Thus, studying each and every one in isolation is impossible. One metabolite is like a single instrument in the orchestra, but we have a whole ensemble of metabolites that we need statistical tools to study. These are currently being developed and are in the making.

More broadly, where do you hope the field will be in 5-10 years’ time?

I anticipate that we will develop preventive drugs and interventions in individuals who are at risk for AD and who do not present with symptoms of the disease.”

With some luck, we may already have some lead on the efficacy of some bacterial species or mixtures of different species in animal models. This is something that scientists are investigating already. If you do not know exactly how the microbiota works, you may think of identifying good bacteria and bad bacteria. If you are skilled at identifying the good ones, then you may transplant them in animal models of AD and see if the mouse does not develop the disease. If the mouse doesn’t develop Alzheimer’s then maybe humans won’t either.

In addition to this, as a clinician, my hope is that in 10 years from now we will not treat patients with memory problems. We will treat patients before they have memory problems. We do this with diseases such as stroke – we treat cholesterol and hypertension with medication beforehand.

I anticipate that we will develop preventive drugs and interventions in individuals who are at high risk for AD and who do not present with symptoms of the disease.

Lastly, if you could give any piece of advice to a new scientist looking to work in the field, what would it be?

My advice would be to try and understand the current molecular biology involving the proteinopathies and analyze how amyloid, tau, and α-synuclein work. This is the basis of knowledge. Once young scientists get a good hold on this, then they need to move beyond that, as the field is moving towards the prevention of the deposition of these toxic proteins.

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Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.