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  • Gut-Brain Axis

    Interactions between the brain and the gut have been confirmed, showing that the exchange of information between these seemingly distant organs is two-way. The functioning of the gut-brain axis is described on the basis of the operation of three parallel paths: the nervous, immune and endocrine pathways. Additionally, the presence of intestinal dysbiosis predisposes to increased intestinal permeability and is a risk factor for many diseases and inflammation. Trillions of microorganisms inhabiting the digestive tract significantly affect the functioning of other body systems, including the brain and nervous system.

    Two-way information is transmitted directly via the vagus nerve, a part of the autonomic nervous system. There is a nervous system in the gut called the enteral nervous system (ENS), which is also connected to the brain by the vagus nerve. The anatomical paths have been divided into a four-level hierarchy, and the proper organization of the structures exercises control of many intestinal functions.

    Gastrointestinal bacteria are believed to act on the afferent nerves of the enteral nervous system, and the vagus nerve, as a result, may induce an anti-inflammatory response. In addition, intestinal bacteria are able to synthesize neurotransmitters and neuroregulators such as gamma amino acids, butyric acid, 5-hydroxytryptamine, dopamine and short-chain fatty acids, which have a crucial influence on the functioning of the whole organism.

    It has been proven that intestinal microorganisms influence the functioning of the hypothalamic-pituitary-adrenal axis (HPA) and the body’s response to stress. This action is also bi-directional, which means that prolonged exposure to stress and altered HPA axis function can upset the composition of the gut microbiota. Toll-like receptors play a key role in communication between the bacterium and the host. Disturbed composition of the microbiome predisposes to their reduced amount in the body and the generation of a neuroendocrine reaction to the penetrating pathogen.

    There is also an undeniable relationship between the intestinal microbiota and the immune system. For example, it was shown in a study in animal models free from any microorganisms (sterile, germ free, GF mice), which did not show the activity of the immune system. Immune functions resumed after the administration of the microbiota. The aforementioned Toll-like receptors are abundant in the immune system and are responsible for cytokine reactions. Moreover, their presence in neurons has been proven, where bacteria and viruses may modify their abundance and functioning. What is more, the gut microbiota is responsible for maintaining the integrity of the intestinal barrier, regulating inflammation process. Peripherally produced inflammatory factors can increase the permeability of the blood-brain barrier.

    Due to the enormous participation of gut bacteria in the pathways described, the gut-brain axis is turning into the gut microbiota-gut-brain axis and treated as a new, promising field of science.

    Studies on animal models indicate the influence of the intestine and microbiota on the development of psychiatric, gastroenterological, neurodegenerative and immune diseases. Altered microbiota composition and dysbiosis have been linked to a large group of diseases, but in many cases their interactions and causes remain unknown, waiting for well-designed controlled studies.

    FMT contributes to regain intestinal eubiosis and improves cognitive functions in patients with neurological diseases. Hepatic encephalopathy, autism spectrum disorder, multiple sclerosis, Parkinson’s disease, anxiety disorders and depression are the main diseases in which the effectiveness of gut microbiota transplantation is tested, and first animal model studies show promising results.

    Hepatic encephalopathy presents as neuropsychiatric abnormalities in the last stage of cirrhosis. The disease has been linked to altered microbiota composition, including the presence of increased amounts of ammonia-producing pathogenic bacteria. High level of ammonia in the blood is associated with impaired functioning of neurons. Hepatic encephalopathy is currently treated with lactulose supplements and antibiotics that affect the composition of the microbiota. In one randomized controlled trial performed to date, FMT produced significantly better treatment outcomes than standard strategies, and further improved microbiota diversity and cognition in patients.

    The autism spectrum disorder is often associated with ailments from the digestive system. In an open-label study involving 18 children, FMT was proven effective in reducing gastrointestinal discomfort and autistic behavior. Animal model studies have also linked the involvement of the gut microbiota to symptom severity.

    Another interesting case is the transplantation of microbiota from multiple sclerosis (MS) patients into the digestive system of healthy experimental animals that caused symptoms similar to those of MS. Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Among MS patients there is a reduced diversity of bacteria in the gut. Initial studies reported reduced severity of neurological symptoms following FMT and increased disease stability. According to scientists, there is an undeniable relationship between the gut microbiota and neurodegenerative diseases.

    Due to the fact that the presence of intestinal dysbiosis is a risk factor for many diseases, it has also been observed in the course of Parkinson’s disease. As symptoms worsened, there was a decrease in the gut bacteria population, especially Prevotella and butyric acid-producing bacteria. In animal studies where faeces from Parkinson’s disease mice were transplanted into healthy individuals, decreased neurotransmitter secretion and motor impairment were observed. The effectiveness of FMT in people suffering from Parkinson’s disease is currently being tested with the use of Human Biome Institute preparations.

    The altered composition of the microbiota has also been observed in people and animals with Alzheimer’s disease. In studies performed on mice,  scientist used material form individuals with the disorder and the results clearly showed a reduction in neurogenesis in the hippocampus and the secretion of brain-derived neurotrophic factor (BDNF), leading to memory impairment.

    Increasingly detailed research on the gut-brain axis has attracted the attention of psychiatrists. Psychiatric diseases place a significant burden on public and economic health. In addition, the low percentage of response to treatment and frequent relapses prompted the search for alternative therapies. In animal studies, a behavior change was observed in the test group who had performed FMT using material from people with depression. Changes in the gut microbiota may directly affect the activity of the hypothalamic-pituitary-adrenal axis and the activity of monoamine neurotransmitters that are used in treatment, as well as alter the levels of the brain-derived neurotrophic factor involved in the pathogenesis of depression. In addition, stool samples from depressed patients showed a reduced diversity and abundance of gut bacteria compared to healthy subjects. Transplanting microbiota from healthy individuals could benefit and influence the behavior of recipients struggling with psychiatric diseases, but more detailed research in this subject is needed.

     

    References

    Wortelboer K, Nieuwdorp M, Herrema H. Fecal microbiota transplantation beyond Clostridioides difficile infections. EBioMedicine. 2019 Jun;44:716-729. doi: 10.1016/j.ebiom.2019.05.066. Epub 2019 Jun 11. PMID: 31201141; PMCID: PMC6606746.

    Emeran A. Mayer, Karina Nance, and Shelley Chen, The Gut–Brain Axis
    Annual Review of Medicine 2022 73:1, 439-453

    Baldi S, Mundula T, Nannini G, Amedei A. Microbiota shaping – the effects of probiotics, prebiotics, and fecal microbiota transplant on cognitive functions: A systematic review. World J Gastroenterol. 2021 Oct 21;27(39):6715-6732. doi: 10.3748/wjg.v27.i39.6715. PMID: 34754163; PMCID: PMC8554405.

    Wang HX, Wang YP. Gut Microbiota-brain Axis. Chin Med J (Engl). 2016 Oct 5;129(19):2373-80. doi: 10.4103/0366-6999.190667. PMID: 27647198; PMCID: PMC5040025.

    Kim N, Jeon SH, Ju IG, Gee MS, Do J, Oh MS, Lee JK. Transplantation of gut microbiota derived from Alzheimer’s disease mouse model impairs memory function and neurogenesis in C57BL/6 mice. Brain Behav Immun. 2021 Nov;98:357-365. doi: 10.1016/j.bbi.2021.09.002. Epub 2021 Sep 6. PMID: 34500036.

    Du Y, Gao XR, Peng L, Ge JF. Crosstalk between the microbiota-gut-brain axis and depression. Heliyon. 2020 Jun 3;6(6):e04097. doi: 10.1016/j.heliyon.2020.e04097. PMID: 32529075; PMCID: PMC7276434.

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