Parkinson’s disease (PD) is a neurodegenerative disorder that affects the movement and coordination of millions of people worldwide. The main cause of PD is the loss of dopamine-producing neurons in the brain, which are responsible for controlling muscle activity and mood. While some genetic factors are known to contribute to PD, most cases are sporadic and have no clear origin. Scientists have been searching for environmental triggers that may influence the onset or progression of PD, such as pesticides, industrial chemicals, and infections. Recently, a new potential factor has emerged: the gut microbiome.
What is the gut microbiome?
The gut microbiome refers to the collection of microorganisms that live in our digestive tract, such as bacteria, fungi, viruses, and archaea. These microbes perform various functions that are essential for our health, such as digesting food, producing vitamins, regulating immunity, and modulating inflammation. The gut microbiome is also connected to the brain through the gut-brain axis, which involves neural, hormonal, and immune pathways. This means that the gut microbiome can influence our mood, cognition, behavior, and even neurological diseases.
How does the gut microbiome differ in PD patients?
Several studies have shown that the gut microbiome of PD patients differs from that of healthy individuals. For example, PD patients tend to have lower diversity and richness of gut microbes, as well as altered abundances of certain bacterial groups1. Some of these changes may be related to the symptoms or treatments of PD, such as constipation, dietary habits, or medication use. However, some studies have suggested that the gut microbiome may also play a causal role in PD by producing or modifying substances that can affect the brain.
What are microbial metabolites?
Microbial metabolites are substances that are produced or transformed by gut microbes during their metabolic processes. Some of these metabolites can be beneficial for our health, such as short-chain fatty acids (SCFAs), which provide energy for intestinal cells and modulate inflammation. However, some microbial metabolites can also be harmful or toxic, such as ammonia, hydrogen sulfide, or indole. These metabolites can enter the bloodstream and reach the brain through various mechanisms, such as crossing the blood-brain barrier or activating receptors on immune cells.
How do microbial metabolites affect PD?
A recent study by researchers from the University of Vienna and the University of Konstanz has discovered a new link between a specific microbial metabolite and PD. The researchers identified a metabolite called 2-methyl-3-phenyl-propanoic acid (MPPA), which is produced by a bacterium called Streptomyces venezuelae. This bacterium is commonly found in soil and plants, but can also colonize the human gut. The researchers found that MPPA can specifically target and destroy dopamine-producing neurons in human cell cultures and in nematodes (worms). Moreover, they showed that MPPA can induce movement difficulties and neuronal patterns similar to those of human PD patients in nematodes.
This finding suggests that MPPA may be one of the environmental factors that can trigger or worsen PD by damaging dopamine neurons. The researchers also speculated that MPPA may interact with other known risk factors for PD, such as pesticides or genetic mutations. For example, MPPA has a similar chemical structure to a pesticide called rotenone, which is known to cause PD-like symptoms in animals and humans. Therefore, MPPA may enhance the toxicity of rotenone or other pesticides by acting synergistically or additively.
Another study by researchers from the University of Luxembourg and the University of Konstanz has revealed another way that microbial metabolites may influence PD. The researchers used personalized metabolic modeling to predict the potential secretion of 129 microbial metabolites by the gut microbiomes of 147 PD patients and 162 healthy controls. They found that nine microbial metabolites had different secretion potentials between PD patients and controls, including increased methionine and cysteinylglycine. These metabolites are involved in various metabolic pathways that are relevant for PD, such as oxidative stress, inflammation, neurotransmission, and bile acid production.
The researchers also found that some microbial metabolites were associated with specific clinical features of PD patients, such as disease stage or non-motor symptoms. For example, they found that pantothenic acid (vitamin B5), which is produced by some gut bacteria, was linked to the presence of anxiety or depression in PD patients. Pantothenic acid is an essential cofactor for several enzymes that are involved in dopamine synthesis and metabolism. Therefore, pantothenic acid may modulate the mood and cognition of PD patients by affecting their dopamine levels.
What are the implications and limitations of these studies?
These studies provide new insights into the possible role of the gut microbiome and its metabolites in PD. They suggest that the gut microbiome may not only reflect the state of PD, but also actively influence its development and progression. They also highlight the potential of using microbial metabolites as biomarkers or therapeutic targets for PD. For example, measuring the levels of MPPA or pantothenic acid in blood or stool samples may help diagnose or monitor PD. Moreover, manipulating the gut microbiome or its metabolites by using probiotics, prebiotics, antibiotics, or dietary interventions may help prevent or treat PD.
However, these studies also have some limitations that need to be addressed in future research. First, these studies are based on observational data and do not prove causality between the gut microbiome and PD. Therefore, more experimental studies are needed to confirm the effects of microbial metabolites on dopamine neurons and PD symptoms in animal models and human trials. Second, these studies are limited by the methods and tools used to analyze the gut microbiome and its metabolites. For example, 16S rRNA gene sequencing can only identify bacterial groups at a coarse level, but not at the species or strain level. Moreover, personalized metabolic modeling can only predict the potential secretion of microbial metabolites, but not their actual levels or activities in the body. Therefore, more advanced techniques are needed to obtain more accurate and comprehensive information about the gut microbiome and its metabolites. Third, these studies are limited by the sample size and diversity of the participants. For example, the participants were mostly from Europe and had typical PD cases, which may not represent the global or heterogeneous population of PD patients. Therefore, more studies are needed to include more participants from different regions and backgrounds, as well as different types of PD cases, such as atypical or genetic forms.
The gut microbiome is a complex and dynamic ecosystem that can influence our health and disease in various ways. Recent studies have suggested that the gut microbiome may play a role in PD by producing or modifying substances that can affect dopamine neurons and PD symptoms. These studies have identified some microbial metabolites that may serve as risk factors or indicators for PD, such as MPPA or pantothenic acid. These studies also open new possibilities for using microbial metabolites as biomarkers or therapeutic targets for PD. However, more research is needed to confirm the causal relationship between the gut microbiome and PD, to improve the methods and tools for analyzing the gut microbiome and its metabolites, and to expand the sample size and diversity of the participants. By doing so, we may be able to better understand and manage this devastating disease.