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Research Suggests That Bacteria In The Gut, May Contribute To Multiple Sclerosis

Gut, Gut and Multiple Sclerosis

Researchers at Harvard Medical suggest that bacteria in the gut may influence inflammation and neurodegeneration found in those suffering from Multiple Sclerosis (MS). The team used genome-wide analysis to detect a transcriptional response during central nervous system autoimmunity, and in lesions in MS patients; their findings were published in Nature Medicine on April 9th, 2016.

The Gut and It’s Relationship with the Brain

Within the human body exists an enormous ecosystem known the gut microbiome. This community of organisms consists of over ten trillion bacteria at a time, ranging from 800 to 1,000 different species. There are more of these microorganisms in the gut than there are cells in the body, and they can weigh as much as the liver [1] [2] [6].

These bacteria maintain a mutualistic relationship with the human body. While the gut provides the perfect environment for bacterial growth – warm, moist and dark – the human body relies on their activity to function properly. These bacteria significantly help the body collect energy from food, synthesize vitamins B and K, and metabolize bile acids, other sterols, and xenobiotics [5]. In fact, the gut microbiome provides the host with a wide range of otherwise inaccessible metabolic capabilities [3].

The gut extends its influence all the way to the central nervous system, and more research is accumulating regarding the guts relationship with the brain. Recent studies have even shown that gut health may play a vital role in mental health [4]. An avid interest in gut research has increased over the past years, and the 2016 Gut Microbiome Conference has even labeled it as the “neglected organ.” Now, more than ever, researchers are coming to believe that the gut can be the focus on many treatment approaches for diseases [6] [7].

Multiple Sclerosis

Multiple Sclerosis (MS) is a disease of the central nervous system (CNS) and affects 2.5 million worldwide [14]. The myelin sheath (located along the axon of a neuron) acts as insulation that considerably accelerates the speed of electron impulses, and manages the opening and closing of ion channels. In MS, the myelin is stripped from the axon, reducing the speed of nerve transmission, and disrupts the brain’s ability to communicate with the body. Thus, those affected by MS tend to experience blurred vision, pain, muscle weakness, difficulty with balance and in some extreme cases the inability to walk or complete paralysis [8] [9].

This destruction of myelin, known as demyelination, is the trademark of many neurodegenerative autoimmune diseases. MS causes white blood cells to initiate an inflammatory response during which the myelin is damaged and lesions, patches of inflammation, are formed [8]. Astrocytes, which are star-shaped glial cells located in the brain and spinal cord, are responsible for a large number of maintenance jobs in the central nervous system and have important roles during health and disease [10]. They are the most abundant cell type in the CNS and are involved in controlling inflammation and neurodegeneration [14].

The Microbiome may Influence Multiple Sclerosis

Researchers studied changes in gene expression in the astrocytes of mice after induction of experimental autoimmune encephalomyelitis (EAE, an animal model for MS).  After analysis, they deduced that the genes for Interferon-1 (IFN-1s) were differentially upregulated in astrocytes showing the EAE phenotype.

The group then used a lentivirus to silence the interferon gene with shRNA in this mouse model in order to help determine its function. They found that the EAE response was exacerbated by the silencing of the interferon pathway, implicating that interferon response plays a role in controlling inflammation. They also found that silencing the interferon gene caused an up-regulation of pro-inflammatory genes, further substantiating the theory.

Aryl hydrocarbon receptor (AHR) has been shown to alleviate inflammation and is regulated by small molecules such as tryptophan, an essential amino acid found in turkey. Tryptophan is metabolized into an AHR agonist by microbacteria in the gut.

The group was able to show that IFN-1s were capable of inducing expression of AHR in astrocytes. To test AHR’s effects on inflammation, the team induced EAE in a group of mice, using AHR knockout mice as a control.  After 22 days they began to feed the mice a tryptophan-depleted diet. Results indicated that EAE scores worsened without Tryptophan, and improved when Tryptophan was introduced back into the diet. Mice that had reduced AHR expression were not able to reverse their EAE scores. This implies that tryptophan activated AHR agonists function rely on bacteria in the gut microbiome in order to properly function.

Human Validation

Several genes in the IFN-1 pathway, as well as AHR, were also upregulated in human brain samples with MS lesions. This suggests that IFN-1 signaling promotes AHR upregulation. However, expression of the AHR transcriptional target is impaired in these lesions, which would seem to indicate that the AHR-mediated response to inflammation is malfunctioning in MS patients. Using an AHR response reporter, the group then was able to determine that AHR agonistic activity was significantly decreased in the sera of MS patients. Taken together, this study implies that deficits in AHR agonists — caused by diet, metabolism, and gut microbacteria– could contribute the onset, severity, or general pathogenesis of MS.

Importance

As of now, there is a limited link between the gut and brain inflammation, but how the two are linked is still poorly understood. The team hopes to further this study and examine the possible effects of diet on MS. Findings such as these can help to improve diagnosing and treatment of MS and other autoimmune diseases. The work of these researchers will also encourage others to examine the guts possible influence on other parts of the body, and extend this knowledge to other diseases gut health may be connected with.

Sources:

[1] http://www.sciencedirect.com/science/article/pii/B9780128023044000128
[2] http://www.sciencedirect.com/science/article/pii/S1089326115001130
[3] http://www.sciencedirect.com/science/article/pii/S0016508514003813
[4] http://www.sciencedirect.com/science/article/pii/S0924224416301741
[5] http://www.clinicalnutritionjournal.com/article/S0261-5614(97)80252-X/abstract
[6] Junger, Alejandro. Clean Gut: the breakthrough plan for eliminating the root cause of disease and revolutionizing your health. (2013)[7] http://www.gutmicrobes.org/
[8] http://www.mult-sclerosis.org/howms.html
[9] http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm
[10] http://www.nature.com/nm/journal/v22/n6/full/nm.4106.html
[11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787735/
[12] http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61620-7/abstract 
[14] http://www.mdpi.com/2076-3425/3/3/1109

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    By: Amanda Chernishkin

    Amanda Chernishkin is a graduate student who is pursuing a Masters degree in Kinesiology with a concentration in health promotion. She is interested in preventative disease research, and plans get her P.hD in Nutritional Epidemiology. Amanda has also studied Psychology and Neuroscience, and did research on Alzheimer’s disease her undergraduate senior year. She has an avid interest in public health, and is currently doing research at Georgia College.

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