Aditi Singh ’28
The microbiota-gut-brain axis (GBA) is the complex relationship between the brain and gut, and as more findings emerge, it appears that it could play a substantial role in the treatment of a variety of diseases. Dysbiosis, or atypical gut microbiota composition, has been found to significantly impact diseases for which mitigatory treatments have long been sought, including “neurological disorders (NDs) like anxiety, depression, autism, Parkinson’s disease (PD), and Alzheimer’s disease (AD)” (Ashique). As research continues to unravel the vast array of gut microbiota and their implications, their potential applications to treatments have expanded, encompassing everything from neurodegenerative diseases to mental illness.
The brain and gut communicate through two primary pathways: the vagus nerve and the hypothalamic-pituitary-adrenal axis (HPA). This can be understood through bodily responses to stress. In a stressful situation, the vagus nerve alters gut functions via signals that regulate motility, secretion, and permeability. With the HPA axis, the hypothalamus releases a hormone, activating a pathway resulting in elevated cortisol levels. Because these cortisol levels alter the gut’s environment, they change the composition of microbiota. These communication systems respond to a variety of stimuli—not just stress—enabling us to understand and potentially treat brain-related conditions with microbiota-based solutions. Specifically, when dysbiosis occurs, the gut barrier is disrupted, allowing pro-inflammatory toxins to enter the bloodstream and reach the brain. Such inflammation is characteristic of many neurodegenerative diseases and likely worsens existing symptoms.
Alzheimer’s Disease (AD) is characterized by persistent neurodegeneration and memory loss. At a biological level, patients with AD demonstrate Tau tangles and Amyloid plaques near and around neurons, creating structural and functional problems with brain function. A few different mechanisms have been proposed to explain the relationship between AD and the gut, the first of which relates to microglia. Microglia, or the immune cells of the nervous system, are the primary responders to Amyloid plaques. Under homeostatic conditions, the gut microbiome regulates microglia maturation and activation via short-chain fatty acids. However, patients with AD have significantly reduced gut microbiota diversity, meaning that this amyloid plaque response is weakened and AD symptoms are worsened. Moreover, other research suggests that pathogenic gut microbiota populations like Escherichia and Shigella increase while beneficial bacteria decrease, causing communication to the brain that produces amyloid proteins and lipopolysaccharides, activating immune responses. This occurs concurrently with the activation of the NLSP3 inflammasome. These two processes together worsen AD pathology by substantially exacerbating neuroinflammation. It is possible that replenishing beneficial bacteria and mitigating the presence of Escherichia could improve symptoms detrimental to the quality of life for Alzheimer’s patients.
Similar immune-based inflammation manifests in Multiple Sclerosis (MS), an autoimmune and neurodegenerative disease. Gut dysbiosis in MS is linked to inflammation and activation of encephalitogenic T cells, which result in demyelination and axonal damage. Simultaneously, a decrease in beneficial bacteria amplifies existing inflammation, and transferring microbiota from MS mice to healthy mice induced MS-like symptoms. This suggests that, in the reverse direction, altering gut microbiota concentration could potentially alleviate symptoms in MS patients. In other studies, some patients with MS demonstrated higher levels of E-selectin in the gut, and those patients experienced a more rapid progression of their symptoms. Gut levels of tryptophan are also suspected to alter MS symptoms, particularly since metabolite derivatives of tryptophan are crucial to the efficiency of the intestinal barrier.
The GBA is also suspected to impact various mental illnesses. Disrupted serotonin levels are associated with depression, anxiety, and schizophrenia-related behaviors. Past research conducted by Cocean et al. suggested that probiotics alter tryptophan levels, and by extension, disrupt serotonin levels as well. GABA, the primary inhibitory neurotransmitter in the brain, is also involved in depression. The intake of the Lactobacillus species regulates the activity of the GABA receptor via the vagus nerve, reducing depressive behavior. Considering the myriad side effects associated with most psychiatric medications, the potential to treat depression with microbiota-based medication is revolutionary. The idea of microbiota-based treatments for mental illness is also supported by findings that people with depression have distinctly different microbiota compositions than healthy individuals and that antidepressants impact microbiota composition. A similar potential for treatment seems possible for anxiety, as results have demonstrated that administering Lactococcus lactis, a microbiota subspecies, could potentially alleviate symptoms associated with anxiety and sadness.
Schizophrenia is a disease associated with issues in neural connectivity, relating to regulatory brain development processes such as myelination, synaptic pruning, and the formation of inhibitory neural networks. There are also suspected imbalances in dopamine, norepinephrine, glutamate, GABA, and many other neurotransmitters. A recent study conducted by Ju et al. at Kyung Hee University found that, when comparing gut microbiota populations of healthy and schizophrenic individuals, bacteria producing short-chain fatty acids were less abundant, and there were abnormal levels of glucose and lipid metabolism. Considering that short-chain fatty acids are crucial to maintaining gut health by regulating the intestinal barrier and adjusting immune system activity, this is concerning. One specific bacteria found to be in lower levels in schizophrenic patients was valeric acid, which protects brain cells from damage and regulates cell death. A reduction in this bacterial population likely strengthens the GBA pathways resulting in neuroinflammation and prevents cells damaged from such inflammation from being destroyed, worsening the symptoms of schizophrenia. The potential for probiotic-based mitigation of schizophrenic symptoms seems promisingly high.
For families that have struggled with diseases like Alzheimer’s, MS, and mental illness across generations, this novel research surrounding the gut-brain axis provides an avenue of hope. Through the vagus nerve and hypothalamic-pituitary-adrenal axis, dysbiosis in gut microbiota populations has the ability to alter brain function by impacting the immune system and a variety of neurotransmitters. Considering the vast array of brain-related diseases exhibiting inflammation and altered neurotransmitter levels with no concrete solution, the potential for finding legitimate treatments to mitigate symptoms is optimistic.
Edited by Namitha Alluri ’25
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