Exploring the Pivotal Role of Gut Dysbiosis in Aging and Parkinson's Disease

Introduction

In recent years, scientists have been working to explore the gut microbiome, a hidden world inside our digestive tract that may hold the key to understanding a multitude of health and disease processes. In the field of Neuroscience, recent research has focused on the potential role that the gut microbiome may play in the development of age-related neurological disorders such as Parkinson's Disease. 

Parkinson's disease is a progressive neurological disorder characterized by tremors, stiffness, and difficulties in movement and coordination, impacting both physical and cognitive functions. Recent research has found that the development of PD may have a surprising connection to the gut microbiome, a complex community of microorganisms living in our digestive tract.  

In this Research Review Article, we will explore how our gut changes with age and how these changes affect the development of diseases like Parkinson's. Additionally, we will uncover compelling strategies that can slow down aging and potentially ease PD's challenges by targeting the gut microbiome. We will discover a way to support our brain health from where we least expect it—our bellies!

What is the Gut Microbiota?

The human gastrointestinal (GI) tract, also known as the digestive tract, is a long tube through which our food passes daily. However, it is not just food; tiny living things called environmental microorganisms also pass through the tract. These include bacteria, eukarya, and archaea. This unique community of microorganisms that colonize our GI tract is known as "gut microbiota."

The gut microbiota and our body share a special relationship. Like you and your favorite pet, the two need each other to be happy and healthy. 

The gut microbiota is vital in stimulating the immune system, breaking down toxic food compounds, synthesizing specific vitamins and amino acids, strengthening gut integrity, and harvesting energy. Additionally, several microorganisms in the microbiota play a crucial role in breaking down stubborn sugars that our bodies cannot digest independently. Think of these bacteria as tiny chefs that cook up something called Short Chain Fatty Acids (SCFAs) from our food. These SCFAs are like special helpers for the cells lining our gut—they are taken in by cells and help enhance their function.

Imagine our gut cells as a team of builders working on a house. SCFAs are like the blueprints that tell the builders how to do their job well. They help the cells grow properly, divide when needed, and even follow the proper instructions from our genes.

Furthermore, SCFAs also protect us from pathogens or harmful microorganisms. It is like having an army of superheroes that protect against the bad guys [1, 7].

With its influence on the cells in our digestive tract, the gut microbiota mediates many critical physiological functions, including properly absorbing and using nutrients for energy. So what happens when the gut microbiota stops functioning correctly? 

Gut Dysbiosis (GD)

Our gut microbiota comprises both 'good' and 'bad' microorganisms. Good microorganisms benefit our body, while bad ones (pathogens) can trigger disease. Typically, there is a balance between good and harmful microorganisms in our gut, keeping our body healthy. But, various factors can change this balance, making our gut vulnerable to disease. This imbalance in the microbial equilibrium is known as gut dysbiosis (GD). Several factors can influence and cause GD:

• Diet: The balance of two bacteria, Firmicutes and Bacteroidetes, play a pivotal role in our body's energy regulation and food processing. A diet high in fat and sugar can alter the balance between these two groups of gut bacteria, particularly by increasing the number of Firmicutes and decreasing the number of Bacteroidetes. Firmicutes are more efficient at breaking down complex sugars and extracting calories from food. This means that when there's an abundance of Firmicutes, more calories from food are extracted and absorbed by the body, contributing to weight gain and potentially obesity. [2]

• Genetic Factors: Studies with twins indicate that genetics shape the types of bacteria in our gut. Identical twins (sharing 100% of genes) tend to have more similar gut microbiomes than fraternal twins (sharing 50% of genes). Therefore, genetic influences may play a role in balancing microorganisms in our gut and gut dysbiosis. [4, 5]

• Substance Consumption: Intake of substances like antibiotics and certain food additives can disturb the balance of gut bacteria. Food additives can, for instance, lead to the overgrowth of a specific bacterial group called Proteobacteria. This overgrowth is associated with inflammatory bowel disease, a condition causing prolonged gut inflammation. [3]

As you can see, our gut microbiota balance is sensitive to internal and external factors. Therefore, dysbiosis in our gut can occur from one or a combination of the above factors.  Dysbiosis can manifest in three potential forms. There can be:

• A loss of good microorganisms.

• An overgrowth of harmful microorganisms.

• An overall loss of microbial diversity.

Generally, Gut Dysbiosis occurs when the delicate balance between good and harmful microorganisms in the gut becomes haywire. Fatty foods, certain antibiotics, and food additives, as well as our genetic makeup, can affect our likelihood of developing GD. GD, if left untreated, can trigger a variety of diseases, including obesity, and can accelerate aging [1].

Gut Dysbiosis and Aging

Aging is a natural process in which our bodies and minds change. As we age, we experience a gradual decline in our mental and physical capacities, increasing our susceptibility to age-related diseases. But besides our bodies and minds, the microorganisms in our GI tract also change as we age.

Earlier in this review, we discussed the essential bacteria that live in our colon and generate SCFAs (short-chain fatty acids). The SCFAs they create enhance the function of cells in our guts and allow for the proper absorption of nutrients from food. While these SCFA-producing bacteria are in strong supply in our youth, their presence decreases with age. This reduction in bacteria reduces the amount of SCFA produced, ultimately leaving GI cells dysfunctional and vulnerable to disease.

One key SCFA that is implicated in aging is butyrate. Butyrate is an SCFA made by gut bacteria that boosts our immunity. Loss of butyrate-producing beneficial bacteria is associated with aging. As the amount of butyrate in our digestive tract decreases, inflammatory messengers rapidly increase. This can then contribute to a process known as inflammaging, where inflammatory markers in the blood are elevated, ultimately leading to an increased risk of chronic illness, disability, and frailty.

Fluctuations in other bacterial populations also accompany aging. In general, there is a decrease in bacteria called Firmicutes and Bifidobacteria and an increase in bacteria called Bacteroidetes and Proteobacteria. These microbial changes can trigger inflammation and reduced immune system function, ultimately adding to aging symptoms.

In addition to a decrease in healthy bacteria, aging is also associated with an increase in disease-causing bacteria. As the cells in our digestive tract receive less essential SCFAs, their function decreases, and their integrity is compromised.

The gut, therefore, becomes more easily invaded by disease-causing bacteria such as Clostridium difficile. Disease-causing bacteria are associated with diarrhea, colitis (or inflammation of the colon), loss of appetite, and stomach pain, which collectively increase mortality risk in aging populations.

Aging is a natural process that affects our bodies and minds in various ways. It changes the microorganisms residing in our gut, including a decrease in beneficial bacteria and an increase in disease-causing bacteria. The reduction in essential bacteria affects the production of SCFAs, including butyrate, leading to inflammation, chronic illness, disability, and frailty. In the following sections, we will explore one of the consequences of gut dysbiosis- neurological disorders, specifically Parkinson's disease [8].

Parkinson's Disease

As scientists continue to explore the gut microbiome, they have found that its dysregulation has consequences beyond gut integrity. The gut microbiome is implicated in various age-related cognitive disorders, including Parkinson's Disease (PD).

PD is a neurological disorder characterized by stiffness, shaking, and coordination impairment. It involves complex biological changes, notably in the brain's frontal cortex, which plays a vital role in decision-making. In the infancy stages of PD, the frontal cortex experiences a mild shrinkage, often leading to difficulties with thinking, planning, decision-making, and memory tasks. The disease might affect a person's ability to multitask, concentrate, or solve problems effectively.

PD also affects the Substantia Nigra pars compacta (SNpc). Think of the SNpc as a control center in your brain responsible for helping your muscles move smoothly. The SNpc is managed by a protein called α-synuclein. In PD, this protein aggregates into clumps, making it challenging for the control center to regulate our movements and maintain balance.

Overall, PD involves structural alterations in both the frontal cortex and SNpc. The frontal cortex incurs a mild shrinkage while the SNpc gets polluted with α-synuclein clumps. Collectively, these changes impede the capacity to regulate movement and maintain balance [7].

How does Gut Dysbiosis Influence Parkinson's Disease?

Our gut microbiota communicates with many body systems, including the nervous system. Think of the nervous system as the body's messaging and control system. It's like a giant communication network that helps you do everything—move, think, feel, and react to the world around you. At the heart of this system are cells called neurons, which act like messengers. They pass information around using electrical signals and chemicals. They are like tiny, super-fast couriers delivering essential messages.

Besides the brain, spinal cord, and nerves, these neurons are also found in our GI tract, where they make up the enteric nervous system (ENS). The ENS's main job is to control and manage the digestive system, helping break down food, absorb nutrients, and handle everything from swallowing to food movement through your intestines.

Interestingly, our gut microbiota is intricately connected to our nervous system. In a healthy body, the gut microbiota sends signals via biological substances like metabolites and hormones to the ENS to fine-tune and support their activity. But when the gut microbiome is dysregulated (GD), the microbiota alters its function, changing the inputs the ENS receives.

As discussed earlier, a key feature of gut dysbiosis is the reduction of SCFA-producing bacteria and, ultimately, SCFAs (short-chain fatty acids). A decrease in SCFAs can cause an increased release of neurotoxins. Neurotoxins are substances that can cause damage to the nervous system and compromise its structure and function. The release of neurotoxins with aging can potentially increase the risk of PD development.

In addition to neurotoxins, changes in the gut microbiota have been associated with the biology of PD. Researchers have found that decreased SCFAs associated with age can lead to cellular dysfunction in the gut. This cellular dysfunction can lead to the build-up of harmful proteins such as α-synuclein. As these proteins build up, they can travel from the gut lining to the brain, where their clumps can disturb the activity of neural cells. The clumping of α-synuclein in the brain is a hallmark sign of Parkinson's Disease.

Beyond the development of PD, the gut microbiota can also play a role in developing and managing its symptoms. In one study, researchers investigated the correlation between butyrate, an essential compound produced by gut bacteria, and postural stability (the body's ability to stay upright and balanced). The study found that lower levels of butyrate correlated with poorer postural stability and greater tendencies toward the 'Parkinsonian gait.', a hallmark symptom of PD, characterized by short, shuffling steps. As discussed earlier, with age, there is a decrease in butyrate-producing bacteria, linking this age-related reduction in healthy bacteria to the development of PD symptoms.

The dynamic interplay between our gut microbiota and the nervous system, particularly the ENS, significantly affects our overall health. When our gut microbiome is dysregulated (gut dysbiosis), the signals that the microbiota release to regulate ENS activity get altered. This results in both the biological mechanisms and symptoms seen with PD. Recognizing these intricate connections may pave the way for targeted interventions and preventive strategies to manage PD better [1, 7].

The Gut Microbiota as a Therapeutic Target for Aging and PD

Supplements

One of the age-related changes in the microbiome involves the loss of a bacteria known as Akkermansia muciniphila. These microbes play a role in producing a protein called mucin, which acts as a protective barrier in our intestines. This barrier is crucial for defending against harmful microorganisms or pathogens. The loss of A. muciniphila can disrupt this barrier, allowing toxic substances to enter and potentially cause inflammation. To counteract this, supplements containing A.muciniphila can help maintain a healthy gut barrier.

In addition to supplements, pharmacological interventions such as acarbose, a drug initially used for blood sugar regulation in type 2 diabetes, are also gaining attention for their role in modulating the gut microbiome. Acarbose has been shown to affect the composition of the gut microbiota, leading to an increase in beneficial bacteria and the production of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in maintaining gut barrier integrity and have anti-inflammatory properties. The influence of acarbose on the gut microbiome presents a promising avenue for enhancing gut health and potentially mitigating age-related decline in gut function.

Further reinforcing the potential of targeting the gut microbiota is a study involving centenarians. In a study focused on individuals over 100 years old (centenarians), researchers created a probiotic combination using bacteria from the gut of these long-lived individuals. Probiotics are beneficial live bacteria that support digestive health. They tested this probiotic combination on rapidly aging mice and found that it had anti-aging effects. The supplementation improved memory and movement functions and reduced inflammation in the brain and gut. This research suggests that targeting the gut microbiota can be a promising approach to addressing age-related dysfunction in the gut [8].

Dietary Interventions

The gut microbiota can also be altered by changing the diet we consume. Caloric restriction (CR) is a dietary plan that reduces the number of calories consumed without missing essential nutrients. In mice, caloric restriction increases specific bacterial populations positively associated with longevity. Apart from CR, avoiding a diet rich in saturated fatty acids (SFA) and low in fiber can also support gut health. High SFA and low fiber diets promote Gut Dysbiosis (GD) and increase the growth of pro-inflammatory bacteria [2].

Saturated Fatty Acids (SFAs) are particularly concerning in the context of cognitive health and neurodegenerative disease. SFAs can promote the build-up of α-synuclein, a protein that, in excess, can clump and block the proper function of cells. This protein can ultimately travel to the brain, destroying vital neurons.

While there is no "perfect diet" to promote a healthy gut microbiome, many dieticians recommend a Mediterranean diet. These diets are rich in fiber and polyunsaturated fats (PUFAs) and can tip the balance in favor of anti-inflammatory bacteria. By keeping inflammation in check, they promote the production of a brain-derived neurotrophic factor (BDNF), a protein that supports the growth and survival of brain cells.

Conclusion

The complex ecosystem within our gut houses both good and harmful bacteria. In our youth, a delicate balance exists between these populations, but this equilibrium tips as we age, giving rise to a condition known as dysbiosis. Dysbiosis can contribute to inflammation, increase infection susceptibility, and expedite aging. One of the most concerning implications of dysbiosis is its correlation with PD. This connection arises from changes in the gut microbiota associated with both the biology and symptoms of the disease.

With its implications throughout our bodily processes, the gut microbiome presents a new frontier for understanding and treating PD, aging, and age-related diseases. Though specific treatments targeting the gut microbiome may still need more research- one thing is known. Our gut has a village of microorganisms that require a delicate balance of conditions to complete their vital functions. Therefore, being vigilant of our dietary choices and using supplements as needed may offer an opportunity to combat Gut Dysbiosis and, ultimately, age-related changes and diseases.