Unhealthy Gut, Unhealthy Brain

By Lynn Nguyen, Physician’s Associate at Neurology Solutions

The gut microbiome refers to the symbiotic, or mutually beneficial, relationship between bacteria, viruses, fungi, and archaea living in the human gut. The flora found in the gut have been differentiated into two distinct categories – opportunistic and beneficial flora. Opportunistic microorganisms cause infection and beneficial microorganisms help us digest food and absorb nutrients. They can also produce chemicals that ward off harmful bacteria, fungi, and viruses. An imbalance of the gut flora causes dysbiosis, which leads to an array of gastrointestinal disorders like Crohn’s disease, Colon Cancer, Irritable Bowel Syndrome, and metabolic disorders.

Recent studies have found dysbiosis to be a contributing factor in neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease, and Amyotrophic Lateral Sclerosis. The pathology behind these diseases stems from what is called the microbiota-gut-brain-axis. The gut has an intimate relationship with the central nervous system and communicates through bidirectional pathways involving the sympathetic and parasympathetic nervous system. Because of this communication, the brain is able to regulate gut motility, immunity, permeability, and mucous secretion. Vice versa, the gut is able to communicate with the hypothalamic – pituitary – adrenal axis in the brain, which can be activated in response to emotion or stress, leading to the production of hormones that travel through the bloodstream. These hormones trigger release of other important chemicals to affect intestinal permeability. Microorganisms in the gut can affect the growth and regulation of the immune system and may modulate the immune system CNS communication. Gut bacteria may also be involved in the synthesis of neuroactive molecules and metabolites which may modulate the pathogenesis of various neurodegenerative disorders like Multiple Sclerosis, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Alzheimer’s disease.

Neurodegenerative diseases, affecting our population, have increased in numbers over the last several decades and are expected to continue to climb in the coming decades. According to the National Institute of Environmental Health Sciences, data from 2016 shows that Alzheimer’s disease was impacting 5.4 million Americans and Parkinson’s disease was impacting 10 million people across the world. In the next 30 years, it is expected that 1 in every 45 Americans and 1 in 85 people across the world will be diagnosed with a neurodegenerative disorder. These numbers are staggering, which is why it is imperative that we seek to understand the pathogenesis of these diseases, so we can have a chance to treat it.

Alzheimer’s Disease

Alzheimer’s disease, generally known as dementia or cognitive impairment, is the most common neurodegenerative disease and accounts for 80% of dementias. The most prominent feature of Alzheimer’s disease is the gradual decline of cognition. The pathophysiology behind Alzheimer’s disease is characterized by the deposition of Amyloid β (Aβ), followed by the formation of tau proteins, which make up plaques and neurofibrillary tangles. These plaques and neurofibrillary tangles can cause neuroinflammation, which then causes neuronal death. Studies on patients with Alzheimer’s disease have found that patients with amyloid plaques have a lower amount  of eubacterium rectale and Bacillus subtilis and a higher abundance of Escherichia/Shigella in their stools compared to other groups, indicating the role of both amyloid and relevant bacterial accumulation in cognitive impairment.

It has been proposed that intestinal microbiota, such as B. subtilis and E. coli, secrete large amounts of lipopolysaccharides and amyloid proteins, which may directly cross the intestinal barrier or blood-brain barrier damaged by aging or disease and pass through these protective physiological barriers by lipopolysaccharide/amyloid-induced cytokines or other small pro-inflammatory molecules, leading to the development of Alzheimer’s disease. The microbiome of the elderly with Alzheimer’s disease shows a lower proportion of bacteria synthesizing butyrate that contributes to anti-inflammatory activity and immunity regulation, as well as greater abundance of microorganisms that are known to cause pro-inflammatory states. Therefore, a potential therapy of Alzheimer’s disease is to modulate intestinal homeostasis by decreasing inflammatory, and increasing anti-inflammatory, microbial metabolism.

Parkinson’s Disease

Parkinson’s disease is the second most common progressive neurodegenerative disease characterized by motor symptoms such as tremors, postural instability, and slow movement as well as non-motor symptoms like sleep disorder, loss of smell, and gastrointestinal symptoms. Non-motor symptoms can sometimes be seen well before motor symptoms arise, suggesting that non-motor symptoms, like gastrointestinal dysfunction, could be the root cause of the disorder.

These symptoms are caused by the breakdown of dopaminergic neurons in the pars compacta, (part of the substantia nigra, which is found in the midbrain), and the formation of abnormal protein deposits called Lewy bodies. Lewy bodies are made up of a 140 amino-acid protein called α-synuclein, one of the main neuropathological markers of Parkinson’s disease. The tendency of α-synuclein to misfold and act as a template for other α-synuclein molecules allows it to spread from cell to cell. Studies have found α-synuclein aggregates in the gastrointestinal nervous system, specifically in the preganglionic vagal nerves and the submucosal and myenteric plexuses, before being detected in the brain which suggests a gut to brain pathology.

The pathogenesis of Parkinson’s disease may also trigger intestinal inflammation. Metabolites of intestinal microorganisms may trigger an immune response that causes inflammation and even the development of Parkinson’s disease. In studying the gut microbiome, it has been discovered that an abundance of Enterobacteriaceae in the feces of patients with Parkinson’s disease is strongly correlated with the severity of postural instability and gait difficulties.

Although the most commonly recognized symptoms in Parkinson’s disease are seen as neural, the gastrointestinal symptoms of Parkinson’s disease point to the gut as a potential source of disease etiology. Gastrointestinal symptoms such as constipation, pain, and nausea often appear early on in the disease process before other neurological signs arise. The appearance of these symptoms both allows for a potential early diagnosis if they are measured, as well as insight into the early stages of the disease.

Probiotics also show promise in mitigating the molecular pathways of PD pathogenesis. There have been studies showing that a Bacillus subtilis probiotic prevented α-synuclein aggregation and cleared pre-formed aggregates. By stopping α-synuclein aggregation with the use of probiotics, there may be a possibility to mitigate PD progression and even reverse α-synuclein aggregation in tissues. 

Amyotrophic Lateral Sclerosis

ALS is a progressive neurodegenerative disease that is associated with the death of brain and spinal motor neurons, causing an array of motor symptoms, including muscle spasms, twitching, crams, and coordination problems, which can lead to respiratory dysfunction, speech difficulties, and swallowing difficulties. The prominent features of ALS are microglial activation and chronic neuroinflammation.  A clinical study of ALS patients found that gastrointestinal symptoms develop prior to neurological symptoms, and examination of feces demonstrated that the diversity of intestinal microbiota is lower in ALS patients than in healthy controls. Another clinical study reported changes in the composition of gut microbiome in ALS patients, including a significant decrease in the Firmicutes/Bacteroidetes ratio along with a decrease in the relative abundance of Anaerostipes, Oscillibacter, and Lachnospiraceae. This suggests that a pro-inflammatory gut microbiome disorder may disrupt the intestinal epithelial barrier, promote an immune/inflammatory response, and alter bowel motility. Some researchers have hypothesized that intestinal barrier dysfunction facilitates the entry of toxins from the intestinal lumen to the blood, causing an increase in circulating lipopolysaccharides and an innate immune response, which plays a vital role in the pathogenesis of ALS. A metabolite of the gut microbiome, nicotinamide, improves the motor symptoms and gene expression patterns in ALS mice, and nicotinamide is reduced systemically and in the cerebrospinal fluid of ALS patients.

In conclusion, targeting the microbiota-gut-brain axis in treatment, can potentially prevent and treat neurodegenerative diseases. Research has suggested that the gut microbiome influences a variety of cognitive and behavioral processes and even contributes to the pathogenesis of neurodegenerative diseases. Therapies such as probiotics, antibiotics, fecal microbial implant, and dietary interventions can manipulate gut microbiota, potentially treating and preventing neurodegenerative disease. The ability of the gut-brain axis to influence a number of bodily systems means that dysbiosis can have profound effects, such as impacting the expression of genes related to different neurotransmitters, impairing immune responses, and contributing to inflammation, all of which appear to be linked to mental disorders and brain diseases. Studies have provided evidence that microbiota-gut-brain axis – focused therapies may be beneficial in combating dysbiosis by increasing or manipulating gut microbiota, supporting their use in treating and preventing NDs.

Works Cited

  1. https://www.sciencedirect.com/science/article/abs/pii/S0165572818304545
  2. https://icjs.us/exploring-the-gut-microbiota-hypothesis-of-neurodegenerative-disease-pathogenesis/
  3. https://journals.sagepub.com/doi/10.1177/2515690X20957225
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490573/#:~:text=In%20conclusion%2C%20clear%20relations%20between,eliciting%20autoimmunity%20and%20producing%20metabolites

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