Immune cells can predict progression of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease affecting motor neurons in the brain and spinal cord. Patients gradually lose muscular control, often starting with limbs, before progressing to difficulty speaking, swallowing and breathing. Some may experience cognitive impairment, including frontotemporal dementia. Patients often require interventions such as wheelchairs, assistive communication devices, ventilatory support and modified diets. With no cure, ALS eventually leads to paralysis and respiratory failure. “ALS is increasingly recognised as a systemic disease, affecting not only the central nervous system (CNS) but the whole body. Investigating the interplay between the CNS and other physiological aspects may help explain its cause and point to treatments,” says Fang, coordinator of the MegaALS project, which was funded by the European Research Council.
Exploring the gut microbiome and immune response
With changes in energy metabolism and immune response both common in ALS, and associated with disease prognosis, MegaALS hypothesised that these could, at least partially, be attributed to changes in the gut microbiome’s composition and function. To test this, alongside the Karolinska University Hospital ALS clinic, the team first conducted the Stockholm-based ALSrisc Study, comparing energy metabolism, immune responses and gut microbiome markers in ALS patients with a disease-free control group. ALS patients with different disease characteristics (such as age at diagnosis and rate of disease progression) were also compared with each other. The work entailed profiling proteins and various immune biomarkers in blood and cerebrospinal fluid and quantifying the composition and functional status of the gut microbiome. “This study evidenced a change in gut microbiota composition in ALS patients and an association with disease progression, corroborated by our humanised ALS mouse model study,” notes Fang from the Karolinska Institute, the project host. The mouse model study also examined the effectiveness of combining a high-caloric diet, with a faecal microbiota transplant from healthy donors, to prevent and treat ALS. Metabolic and immune responses were evaluated to understand the biological mechanisms involved. “We demonstrated the pivotal role that microbiota play in disease progression in those genetically predisposed. While transplanting faecal microbiota from ALS patients induced a boost in immune response, we saw that a high-fat Western diet can trigger inflammation, worsening the condition,” says Rosa Luisa Potenza, MegaALS researcher from the Italian National Institute of Health (ISS). A significant overall project result was the identification of specific subsets of immune cells as markers of disease progression and patient survival. “Our identification of subsets of immune cells as markers for ALS disease progression, suggests targets for novel therapeutic strategies. This could involve modulating effector T-cell activity or enhancing the role of beneficial cell types, such as regulatory T-cells,” adds immunology researcher Christina Seitz.
Promising avenues for ALS treatments
Although relatively rare, with the underlying causes little understood and no effective treatment available, ALS is becoming an increasing public health challenge, driven partly by an ageing population with incidences projected to reach 376 674 in 2040. The knowledge gained by MegaALS could also benefit other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Meanwhile, the large ALSrisc Study dataset and biobank (including over 500 newly diagnosed ALS patients and a similar control number) is already proving valuable. “I am especially proud of the over 80 % study participation rate and nearly 100 % follow-up rate, strengthening the validity of the findings. As we continue the ALSrisc Study, it will become an international resource,” notes Fang.
Keywords
MegaALS, amyotrophic lateral sclerosis, ALS, neurodegenerative, microbiota, immune cells, gut, microbiome, metabolism, T-cell, Alzheimer’s
