Slowing down ALS at an early stage thanks to microbiota transplants

Summary: Transplantation of fecal microbiota from healthy individuals may help slow the progression of early ALS by altering a patient’s microbiome and intervening in the inflammatory process.

Source: European Society for Clinical Microbiology and Infectious Diseases

A randomized clinical trial is investigating whether transplantation of fecal microbiota (FMT) from healthy donors into adults with early-stage amyotrophic lateral sclerosis (ALS – one of the most common forms of motor neuron disease) can modulate the immune reaction during inflammatory responses that characterize disease progression and aims to study the relationship between specific intestinal bacteria and their action on cells of the immune system.

Preliminary results from Dr. Alessandra Guarnaccia of IRCCS at Columbus-Gemelli University Hospital, Rome, Italy, and colleagues are presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Copenhagen , in Denmark (April 15-18).

ALS is a devastating disease in which motor neurons in the spinal cord and brain degenerate, causing progressive paralysis, increasing physical disability and ultimately death within an average of two to five years.

ALS is the most common form of motor neurone disease, with an average incidence of 2.8 per 100,000 people in Europe and 1.8 per 100,000 people in North America.

About 5-10% of people with ALS have various genetic causes that can run in families, but 90% have what is called “sporadic” disease because its causes are unknown. It is therefore difficult to find a treatment that will work for all patients with ALS.

Recent findings suggest that oxidative stress (an imbalance between chemical free radicals and antioxidants in the body), damage or death of nerve cells (exotoxicity) and activation of pro-inflammatory pathways are the main triggers of disease.

Given the role of regulatory T cells (Tregs) in regulating or suppressing the immune system, it is thought that increasing or activating their populations in patients with ALS may have therapeutic benefits.

It has been known for some time that changes in the composition of the gut microbiota can be linked to many neurological disorders via the “gut-brain axis”. Indeed, specific populations of the intestinal microbiota (Proteobacteria) interact with the immune system promoting the activation of pro-inflammatory pathways following the loss of the number of Tregs and of the suppressive function.

Moreover, previous mouse models have shown a significant alteration of the gut microbial population in the early stage of ALS, indicating a possible role of the gut microbiota in the development of ALS.

FMT is already used in clinical practice to restore the balance of the intestinal microbiota and to modulate intestinal and systemic immunity in recurrent cases. Clostridioides difficile infectious disease.

The trial randomly assigned 42 ALS patients (aged 18 to 70) who had had symptoms for less than 18 months to either FMT (28 patients) or placebo (14 controls). At the start of the study and 6 months later, researchers will infuse gut microbes from healthy donors into patients in the intervention group, while those in the control group will receive no infusion.

On the day of each procedure, researchers will collect stool, saliva, and blood samples to assess how the transplant affected gut microbiota, immune cells, and inflammatory status, which could shed light on early processes that may lead to the degenerative course of ALS.

Each patient will also undergo three endoscopic procedures to perform intestinal biopsies (at the start of the study and at months 6 and 12).

The primary outcome is a significant change in Treg counts between FMT-treated patients and the control group from baseline to month 6.

FMT has proven to be a safe procedure in these patients, with no adverse events reported to date.

It shows a brain
ALS is a devastating disease in which motor neurons in the spinal cord and brain degenerate, causing progressive paralysis, increasing physical disability and ultimately death within an average of two to five years. Image is in public domain

Preliminary results describing the profile of the gut microbiome of six patients at the start of the study revealed a much higher relative abundance (on average 15%) of proteobacteria – a large group of microbes that have surface proteins that can easily activate immune system. This activation alerts the body to disease and triggers the release of molecules that cause inflammation.

“The unmet need for therapies for ALS is huge, and our work opens up a whole new pathology that we could treat,” says Dr. Guarnaccia. “The hope is that FMT will increase the number of Tregs, shifting the immune system surrounding motor neurons to an anti-inflammatory and neuroprotective status and slowing the progression of ALS.”

The author, Professor Luca Masucci of the Catholic University of the Sacred Heart in Rome, Italy, adds: “With this information, we could potentially propose new treatment approaches by modifying or interfering with these inflammatory pathways. We hope to have all of our data from this trial to analyze in 2024.”

ALS can affect anyone, regardless of racial, ethnic, or socioeconomic background. In general, symptoms usually develop between the ages of 40 and 70, with the average being 55 at the time of diagnosis.

A number of top British athletes have shared their experiences with motor neurone disease in recent years, including rugby league’s Rob Burrow, rugby union’s Doddie Weir and footballer Stephen Darby.

Professor Stephen Hawking also had the disease, but lived 55 years after his diagnosis until his death in 2018 at the age of 76.

About this ALS research news

Author: Simone Bruederli
Source: European Society for Clinical Microbiology and Infectious Diseases
Contact: Simone Brüderli – European Society for Clinical Microbiology and Infectious Diseases
Picture: Image is in public domain

Original research: The results will be presented at ECCMID 2023

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