Unraveling the Gut-Microbiome-Brain Connection in Parkinson’s Disease

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Parkinson’s Disease (PD) stands as the second most prevalent neurological disorder, affecting 1% of the population aged over 60 in the United States. It is the fastest growing neurological disorder, having increased in prevalence by 61% from 1990 to 2017. Even though this increase is partially related to the increasing age of the US population, part of the increase has been attributed to the dramatically changing environmental and lifestyle factors during the past 75 years and an interaction of these factors with vulnerability genes.

“…while medications can alleviate the symptoms, there is currently no cure for this complex condition.”

Symptoms generally begin with a slight sense of weakness, such as trembling of the hands, but the condition slowly worsens. Initially, symptoms primarily impact movement, including involuntary shaking (tremors), slowed movement, coordination issues, gastrointestinal dysfunction (constipation), and facial expression changes. Day-to-day actions such as walking and eating become taxing, and may reach a point when patient lose all voluntary muscle control. Unfortunately, while medications can alleviate the symptoms, there is currently no cure for this complex condition. PD symptoms progress and increase in severity over time, so monitoring and management is required to maintain one’s quality of life.

“Dopamine, although usually associated with reward and pleasure, also plays a central role in the regulation of voluntary movement…”

One well studied factor in the pathophysiology of PD is the aggregation of a particular group of molecules, the alpha-synuclein proteins, which play an important role in the control of neurotransmitter release. These proteins form “clumps” known as Lewy bodies, primarily affecting a region in the brain, the substantia nigra, which plays a crucial role in movement regulation. The regional accumulation of Lewy bodies leads to the degeneration of dopamine-producing neurons, causing dopamine depletion. Dopamine, although usually associated with reward and pleasure, also plays a central role in the regulation of voluntary movement. Its normal function is transmitting chemical signals between neurons in the brain to coordinate movement, and its deficiency results in motor dysfunction.

In addition to alpha-synuclein aggregation and dopaminergic neuron death, neuroinflammation is implicated in PD progression. This involves immune cell activation and the release of proinflammatory molecules. The precise interactions of neuroinflammation, dopaminergic changes, Lewy body formation in the development of PD remain to be determined. While anti-inflammatory interventions show promise in slowing down disease progression, the precise role of inflammation in PD is and ongoing area of investigation.

“…the gut microbiome–the trillions of microorganisms residing in the gastrointestinal tract–may play an important role in PD pathophysiology…”

As discussed in detail in the book The Mind Gut Immune Connection, several pieces of evidence suggests that the gut microbiome–the trillions of microorganisms residing in the gastrointestinal tract–may play an important role in PD pathophysiology. A meta-analysis across multiple cohort studies suggested that patients with a diagnosis of irritable bowel syndrome have a 46% greater likelihood of developing PD. However, as new onset of constipation secondary to compromised gut motility resulting from Lewy body infiltration of the enteric nervous system can precede the onset of typical PD symptoms by up to 14 years, the association with a symptom-based diagnosis of IBS may be misleading. Further, several clinical studies have shown a correlation between PD status and alterations of the gut microbiome, manifesting in reductions in alpha diversity and shifts in the bacterial taxa abundance in PD patients. These correlations suggest a state of gut dysbiosis in PD, characterized by a decrease in the relative abundance of beneficial microorganisms or an overgrowth of harmful ones. Specifically, investigations into the gut microbiota of PD patients have unveiled a decline in the presence of butyrate-producing bacteria. Butyrate has widespread anti-inflammatory effects and protects intestinal barrier integrity. This PD-associated change in the relative prevalence of certain microbiota has been suggested to contribute to an increased permeability of the intestinal barrier, which permits microbiota-triggered immune reactions in the gut. It remains to be determined if this microbiome changes play a causative role in PD development, or if the PD associated changes in gut motility and transit lead to alterations in the composition of the microbial ecosystem.

“…while several changes in the taxa of the gut microbiota have been found in patients with PD, causation vs correlation has not been determined.”

Furthermore, emerging research suggests that certain microbiota lead to misfolding of alpha-synuclein in the gut, which then makes its way to the brain. Alpha-synuclein is naturally present in the gut, especially given the 150 million nerve cells within the enteric nervous system–the intrinsic nervous system of the GI tract that coordinates digestion, secretion, and nutrient absorption. Rodent models have demonstrated that the introduction of aggregated alpha-synuclein from PD patients into the intestines of mice can lead to its transport to the brain through the vagus nerve. In summary, while several changes in the taxa of the gut microbiota have been found in patients with PD, causation vs correlation has not been determined. Future studies are needed to confirm if changes to bacterial taxa in the intestinal tract may serve as a biomarker for PD diagnosis.

The current management for PD typically involves a combination of medications and lifestyle modifications, with the most common being pharmacological dopaminergic treatment with a drug called L-Dopa. However, individual responses to L-Dopa are highly variable, a phenomenon which has been related to the interference of certain gut microbes with the medication. In addition, L-Dopa effects often gradually diminish, leading to the need for progressively higher doses of this medicine.

“…dietary manipulation may be most effective in delaying the onset of the disease…”

In addition to pharmacological treatment, adjuvant therapies include modulation of the gut microbiome with an anti inflammatory high in fiber, devoid of ultraprocessed food and avoidance of pesticide treated vegetables and fruits. Details and recipes of such a gut and brain friendly diet can be found in the recipe book Interconnected Plates. As PD is a heterogeneous disease composed of subsets of patients with different disease mechanisms, such dietary changes may only be helpful in some patients. Furthermore, dietary manipulation may be most effective in delaying the onset of the disease, ideally starting at the earliest warning signs consisting of new onset constipation and characteristic sleep abnormalities. Once the full blown neurological disease has developed, such adjuvant treatments may be less effective.

Madelaine Leitman Madelaine is an undergraduate student at UCLA, with a major in Computational and Systems Biology. She has a passion for research in gut-microbiota-host interactions and hopes to complete a PhD in this topic.

This article was reviewed and approved by Emeran Mayer, MD