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Suolistobakteerit, myeliini ja aivotoiminta (Luettu 11288 kertaa)
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Re: Suolistobakteerit, myeliini ja aivotoiminta
Vastaus #30 - 18.05.2019 - 22:18:21
 
Focus on the gut-brain axis: Multiple sclerosis, the intestinal barrier and the microbiome

https://www.wjgnet.com/1007-9327/full/v24/i37/4217.htm

Much interest has been placed recently on the possible role of the gut microbiome in multiple sclerosis (MS) pathophysiology. Many review articles on this subject have recently been published[1-3], perhaps more than original research articles that actually characterize the gut microbiome in patients with MS. This research is in keeping with the essential role that the gut microbiome has in regulating the development of the immune system[4]. This area of research has also been the subject of recent symposia in international MS conferences[5,6].
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From studies attempting to characterize the composition of the microbiome, it is clear there are some differences in people with MS compared to controls. People with relapsing-remitting MS (RRMS) have an abundance of Anaerostipes, Faecalibacterium, Pseudomonas, Mycoplasma, Haemophilus, Blautia, and Dorea and a relative decrease of Bacteroides, Prevotella, Parabacteroides and Adlercreutzia[14-16]. In pediatric MS, patients have higher levels of members of Desulfovibrionaceae and depletion in Lachnospiraceae and Ruminococcaceae[17,18]. Issues are further complicated by complex analyses at the taxa, phylum and species levels, and a myriad of microbes have been implicated. For example, studies have found a significant depletion in clostridial species[15,19], Butyricimonas[20], Roseburia[21] and an increase in Streptococcus[22], Methanobrevibacter, Akkermansia and Coprococcus[14,20].

However, there are some limitations to these studies. The methods used to analyze the microbiome have been heterogeneous, with most (but not all) studies using a variation of 16S sequencing. There are differences in sample processing, DNA extraction, choice of primers, databases and hyper-variable regions analyzed across studies. Furthermore, close to two thirds of patients with MS have gastrointestinal symptoms such as constipation, dyspepsia and other functional gastrointestinal disorders[23], and many of these have been also associated with an altered gut microbiota[24]. Studies so far have not properly accounted for these symptoms or other relevant variables such as diet. An ongoing International MS Microbiome study aims to define a “core microbiome”[3]. It might shine some light into this complicated field.

Nonetheless, there is mounting experimental evidence that the gut microbiome may play a role in MS pathophysiology and human studies suggest that patients have a different microbiome compared to controls. Of course, the true significance of the results obtained so far is unclear, considering that there has often been a failure to replicate microbiome animal studies in humans. But the next question that comes to mind is whether this can also constitute a relevant therapeutic target. Although this appears to be the case in experimental models, translation to clinical practice may prove challenging.

Modifying the microbiome through medications, possibly antibiotics, could be the simplest method, but several issues arise that question the feasibility of this approach. Targeting specific commensals might prove difficult and requires appropriate identification of these targets. The case of minocycline is an interesting example. Recently shown to delay the occurrence of a second demyelinating event in patients with a clinically isolated syndrome[25], minocycline is an antibiotic known to alter the gut microbiome[26]. Whether this is an additional mechanism of action remains unknown; it is noteworthy that the initial rationale for testing minocycline in early MS is based on its various immune-modifying properties[27]. On the other hand, there is also evidence that MS disease modifying therapies (DMTs) may alter the microbiome directly[26], and indeed, it also appears that a multitude of other medications such as antidepressants, antipsychotics and immune modulators may also do so[28]. Issues such as the generation of resistant strains are also worthy of consideration.

Probiotics are a popular option but there are various issues with their practical implementation. Probiotics do not modify the host microbiome in a robust and persistent manner, although they are purported to be able to influence gut immunity and homeostasis. Despite success in showing a benefit for probiotics in animal models[29,30], there are only a handful of clinical trials in MS. Results have been preliminary, with some modest beneficial trends in clinical variables and some biochemical markers of changes in peripheral immune function[31-33]. However, they have included very small numbers of patients and the duration of these trials have been too short to shed any light onto clinically meaningful outcomes. There are many barriers to be overcome, such as selecting the appropriate formulation, dose and study design. There is also a lesson to be learned from the multiple clinical trials in inflammatory bowel disease (IBD), where despite a wealth of available studies (although heterogeneous in design and quality), the evidence supporting their clinical use is limited to carefully selected subpopulations[34,35].

Fecal microbiota transplantation (FMT) would constitute the optimal strategy to modify the gut microbiome. It has proven to be remarkably effective in managing C. difficile colitis, and isolated case reports describe beneficial effects over MS disease course, through mechanisms that remain unclear[36,37]. A clinical trial of FMT is underway[38], but even before its completion, many questions arise. It is unclear which population should be studied and what characterizes an ideal donor, not to mention the dose, route of administration and dose scheduling (single dose vs multiple doses). Patient with C. diff colitis who undergo FMT have been previously treated with antibiotics such as vancomycin and metronidazole, and presumably, have had some of their microbiota depleted. Would patients with MS require “ablation” of their microbiome before FMT? DMTs have immune modulating properties and they may also directly alter the microbiome[26], so their possible effects on the “engraftment” cannot be underestimated.
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Exciting research suggests that the brain-gut axis, once an almost esoteric concept, might yield novel therapeutic targets in neuroimmunological diseases such as MS (Figure 1). The often-symbiotic roles of the gut microbiome, intestinal barrier and even bile acids in the regulation of neuroimmune responses is beginning to be elucidated. If future pre-clinical and clinical studies confirm the relevance of intestinal barrier dysfunction, bile acid metabolism and the gut microbiome in the pathophysiology of MS, the next step will be to translate these findings into therapeutics. Only well designed clinical trials will answer whether interventions such as FMT, probiotics or barrier protectors yield clinically meaningful results. The time is right to assess whether the gut-brain axis can be transferred from the bench to the bedside.


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Re: Suolistobakteerit, myeliini ja aivotoiminta
Vastaus #31 - 18.05.2019 - 22:22:25
 
Link Between Gut Flora and Multiple Sclerosis Discovered

https://neurosciencenews.com/multiple-sclerosis-gut-flora-10003/

New findings made by the research group of Mireia Sospedra and Roland Martin from the University of Zurich’s Clinical Research Priority Program Multiple Sclerosis now suggest that it is worth broadening the research perspective to gain a better understanding of the pathological processes.

Inflammatory cascade

In the journal Science Translational Medicine, the scientists report that T cells – i.e. the immune cells responsible for pathological processes – react to a protein called GDP-L-fucose synthase. This enzyme is formed in human cells as well as in bacteria frequently found in the gastrointestinal flora of patients suffering from multiple sclerosis. “We believe that the immune cells are activated in the intestine and then migrate to the brain, where they cause an inflammatory cascade when they come across the human variant of their target antigen,” says Mireia Sospedra.

For the genetically defined subgroup of MS patients examined by the researchers, results show that gut microbiota could play a far greater role in the pathogenesis of the disease than previously assumed. Mireia Sospedra hopes that these findings can soon also be translated into therapy; she plans to test the immunoactive components of GDP-L-fucose synthase using an approach that the researchers have been pursuing for several years already.

Re-educating the immune system

“Our clinical approach specifically targets the pathological autoreactive immune cells,” says Sospedra. This approach therefore differs radically from other treatments that are currently available, which throttle the whole immune system. While these treatments often succeed in stopping the progression of the disease, they also weaken the immune system – and can thus cause severe side effects.

The clinical approach of the research group involves drawing blood from MS patients in a clinical trial and then attaching the immunoactive protein fragments onto the surface of red blood cells in a laboratory. When the blood is reintroduced into the bloodstream of patients, the fragments help to “re-educate” their immune system and make it “tolerate” its own brain tissue. This therapeutic approach aims for effective targeted treatment without severe side effects.


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Re: Suolistobakteerit, myeliini ja aivotoiminta
Vastaus #32 - 18.05.2019 - 22:53:43
 
Discovery of long-lived macrophages in the intestine

https://www.sciencedaily.com/releases/2018/08/180830113017.htm

August 30, 2018

Macrophages are specialised immune cells that destroy bacteria and other harmful organisms. KU Leuven scientists, Belgium, have come to the surprising conclusion that some macrophages in the intestines of mice can survive for quite some time. Most importantly, these long-lived macrophages are vital for the survival of the nerve cells of the gastrointestinal tract. This sheds new light on neurodegenerative conditions of the intestine, but also of the brain.

In the immune system macrophages play the role of PacMan: they are white blood cells that clean up foreign substances by engulfing them. Apart from this, macrophages themselves provide vital growth factors and support for different tissues in the body, allowing them to function and develop properly. As such, these specialised immune cells are soldier and nourisher at the same time. Their proper functioning is immensely important in the intestine, as they have to differentiate between harmful bacteria, harmless bacteria and nutritional components.

Scientists assumed that macrophages in the intestine are short-lived and live for about three weeks at most in both mice and humans before being replaced by new cells. A KU Leuven study now shows that this is not entirely true, explains Professor Guy Boeckxstaens. "We've discovered that a small part of the macrophages in mice is long-lived. We marked certain macrophages and found that they still functioned after at least eight months. They can be found in very specific places in the intestine, particularly in close contact with nerve cells and blood vessels."

What is more, the small group of long-lived macrophages play a very important role in the gastrointestinal tract, adds PhD student Sebastiaan De Schepper. "If the long-lived macrophages don't do their job properly, already after a few days the mice suffer from digestive problems. This leads to constipation or even the complete degeneration of the nervous system in the stomach and intestine." The discovery that long-lived macrophages do indeed exist in the intestine and that they are crucial for the normal functioning of the intestine is, therefore, immensely important.

These new insights offer promising opportunities for further research, concludes Boeckxstaens: "Next, we want to study the role of long-lived macrophages in human diseases where nerve cells of the intestine are affected, for instance in obese and diabetic patients with abnormal gastro-intestinal function. Moreover, the results can also be meaningful for brain research. In the brain, we have microglia, similar long-lived macrophages that play an important role in neurological conditions such as Alzheimer's and Parkinson's disease. Scientists currently believe that nerve cells in these patients die off because microglia do not provide sufficient care. Maybe one day research of the intestine can offer us a better understanding of these brain conditions."


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Re: Suolistobakteerit, myeliini ja aivotoiminta
Vastaus #33 - 16.07.2019 - 16:30:41
 
Gut microbes protect against neurologic damage from viral infections

https://www.sciencedaily.com/releases/2019/07/190716081050.htm


July 16, 2019

Gut microbes produce compounds that prime immune cells to destroy harmful viruses in the brain and nervous system, according to a mouse study published today in eLife.

The findings suggest that having a healthy and diverse microbiota is essential for quickly clearing viruses in the nervous system to prevent paralysis and other risks associated with diseases such as multiple sclerosis.


A condition that causes progressive damage to nerve cells, multiple sclerosis has become more common over the past several decades. Viral infections in the brain or spinal cord are thought to trigger this disease. Some scientists believe that changes in the way we eat, increased sanitation or growing antibiotic use may be causing detrimental changes in the helpful bacteria that live within the human body, potentially increasing the risk of multiple sclerosis and other related diseases.

"We wanted to investigate whether gut microbes could alter the immune response to a virus in the central nervous system and whether this affects the amount of damage the virus causes," says one of the lead authors David Garrett Brown, a graduate research assistant in the Department of Pathology at University of Utah Health, Salt Lake City, US.

To do this, Garrett Brown and co-lead author Ray Soto looked at the effect of Mouse Hepatitis Virus, a virus that infects cells in the mouse nervous system and causes multiple-sclerosis type symptoms, on two groups of mice: some with normal gut microbes and some that were bacteria-free. They found that bacteria-free mice had a weak immune response, were unable to eliminate the virus and developed worsening paralysis, while those with normal gut bacteria were better able to fight off the virus.

Mice treated with antibiotics before the onset of disease were unable to defend themselves. They also had fewer immune cells called microglia, which help flag viruses for destruction by other immune cells.

Next, the team identified compounds produced by gut bacteria that might help the microglia. When they administered these helpful compounds to the bacteria-free mice, they saw that the animals were protected from neurologic damage caused by the virus.

"We've shown that gut microbes protect infected mice from paralysis by turning on a specific pathway in central nervous system cells," explains June Round, Associate Professor in the Department of Pathology at University of Utah Health, and a senior author of the study. "This suggests that signals from microbes are essential to quickly clear viruses in the nervous system and prevent damage from multiple sclerosis-like diseases. Our results emphasise the importance of maintaining a diverse community of bacteria in the gut, and that interventions to restore this community after taking antibiotics may be necessary."
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