New insights into how the approximately 100 trillion bacteria in our gut also influence cerebral health could lead to new diagnostic and therapeutic approaches to neurological disorders.
Changes in the nature of the gut flora have been linked to a variety of neuropsychiatric disorders, including depression, autism, Alzheimer's disease and multiple sclerosis.
In the last article, we took up a current feature1 in the journal Nature and used the example of Parkinson's disease to show how many perspectives have been added by research in recent years. Bacterial metabolites seem to play an important role in a number of neurodegenerative diseases and this article will therefore deal with another one: ALS (amyotrophic lateral sclerosis).
... says Prof. Eran Elinav, immunologist at the Weizmann Institute of Science in Rehovot, Israel, and head of the "Microbiome and Cancer" department at the German Cancer Research Centre in Heidelberg (Deutsches Krebsforschungszentrum, DKFZ).
He and his team wanted to investigate why ALS progresses quickly in some patients and slowly in others.
They started working with one of the most common murine models and observed more rapid disease progression in mice that had either been kept in germ-free cages from birth and therefore had not developed a gut microbiome, or whose gut bacteria had been killed by antibiotics, than in those with normal gut flora.2
By comparing the bacterial composition between mice with ALS and healthy siblings, they identified several bacterial taxa that appear to be associated with the disease. They painstakingly transplanted these species, one by one, into another group of mice lacking gut bacteria. In this way, they were able to identify two species that worsened ALS symptoms (Ruminococcus torques and Parabacteroides distasonis) and one that ameliorated them (Akkermansia muciniphila, AM).
Why does something that happens in the gut have such a big impact on processes in distant parts of the organism? In the last article, we already explored one important connection through which disturbances from the digestive tract reach the CNS: The vagus nerve. Another pathway is bacterial metabolites, which can reach every cell in the body.
Elinav's research team searched further in this direction and analysed the metabolites produced by the "good" bacterium. One of these was nicotinamide (also known as vitamin B3). Mice predisposed to ALS without gut microbiome accumulated AM-associated nicotinamide in the CNS when given good bacteria (AM). When nicotinamide was administered directly systemically, it migrated into the animals' brains and improved motor symptoms and gene expression profiles in the spinal cord.2
They also compared the microbiomes of ALS patients and their unaffected relatives and here too saw less nicotinamide in the sufferers.
A double-blind, randomised pilot study by another research group reported significant slowing of disease progression and improvements in ALS Functional Rating Scale (ALS-FRS), lung function, muscle strength and skeletal muscle/fat percentage compared to baseline after four months of supplementation, while patients in the placebo cohort deteriorated. However, the sample was small, 32 patients, and vitamin B3 was given in combination with another compound (pterostilbene).3 Elinav's team is therefore planning a separate clinical trial on nicotinamide.
... concludes Elinav, who is convinced that we are only at the beginning.
The microbiome could thus not only have a share in triggering certain pathologies, as outlined in the last post, but it could also influence their course or severity, as in ALS.
In this context, disorders of the gut microbiome can be both a cause and a consequence of diseases. In addition to the neuronal and endocrine signalling pathways already mentioned, these dysbioses influence CNS function via a third pathway: The immune system, which also reacts to the metabolites produced in the gut.
Neurotransmitters, neuromodulators and short-chain fatty acids produced by the intestinal flora reduce the release of proinflammatory cytokines while promoting the development of regulatory T cells and IL-10 secretion. Some of these molecules can also enter the CNS. In neuroinflammatory conditions, the integrity of the blood-brain barrier is disrupted (via mediators such as IL-1, IL-6 and TNFα), leading to neurological complications.4
Meanwhile, scientists are researching other CNS diseases in this regard, including Alzheimer's disease and depression.
Currently, there is still a lack of concrete clinical or large randomised trials. The complexities of microbial interactions with the host and how additive, subtractive or modulatory strategies influence these interactions are also not fully understood. Moreover, microbiome research has been limited to short-term therapies. The question of how the manipulated microbiota establishes itself at the target site, even in the long term and in changing environments, should be further explored, which will also require further developments in experimental methods.4
References:
1. Willyard, C. How gut microbes could drive brain disorders. Nature 590, 22-25 (2021).
2. Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474-480 (2019).
3. Rubia, J. E. de la et al. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 20, 115-122 (2019).
4. Editor's Pick: Current Paradigms to Explore the Gut Microbiota Linkage to Neurological Disorders. European Medical Journal https://www.emjreviews.com/neurology/article/current-paradigms-to-explore-the-gut-microbiota-linkage-to-neurological-disorders/ (2020).