Thursday, 12 May 2016

Gut bacteria getting astrocytes to save nerves

Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, K├ębir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A, Antel J, Quintana FJ. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016. doi: 10.1038/nm.4106. [Epub ahead of print]

Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-b are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl- 3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation. 
We tend to comment on posts done in Nature and Science Journals but where to start on this one. 

The simple answer is I'm not sure I want to spent the time, getting my head round the science. Living on a few hours sleep for the madcap pleasure of Her Majesties Government, whilst doing a night shift, is not conducive to thinking. So my advice is scout round the internet to see what others are writing about this one. I am not going to do it Justice

This study contains a substantial amount of work and says that astrocytes in the spinal cords of animals with EAE are different from astrocytes in health. Yep I can buy that, you just have to look. Wonder what would be found in astrocytes with chronic disease compared to disease of a few days

They look at the genes that are different between the two and see a response that looks like the cell has been stimulated by a cytokine called and interferon. These are made to limit viral infections but in doing so also stop the proliferative capacity of the host cell infected. They then link this effect to the aryl hydrocarbon receptor (click here to read about it). 

They then do a load of EAE experiments in knockout mice and report that AHR knockout mice do worse and being immunologists they they link every thing to influences of the immune response, cytokines and their transcription factors (factors affecting the production of proteins from the genes). They then argue that the AHR on astocytes controls to modulatory effect of beta interferon. So another new mechanism for beta interferon. 

But they are on a roll and next they argue that dietary tryptophan, an amino acid involved in the  production of nerve transmitters, is metabolised by the gut bacterial into compounds that stimulate AHR and that this can influence inflammation. They can modify the microbes with antibiotics etc,  etc. and I start loosing the will to live as I push away the Zee's and you rush off for that faecal transplant:-)

However, looking at the data I can't but help thinking that we are missing a trick here. The authors show that there is no influence T cell function. But if you look at the EAE data (eg. shown above) it is shown there already and rather than being anything to do with the immune response and driving disease it how astrocytes influence how we cope with the inflammatory response and how it ultimately affects nerve loss. Because, what I see from the EAE graphs is the effect is all about saving and losing nerves

The knockouts get comparable disease but they just don't recover. The actions via the AHR are influencing nerve loss and this is fundementally more interesting that any old imunology- smology stuff. I am sure it points to the astrocyte as being an overlooked character in influencing progressive MS, but if we scientists cannot get over that there is more to progressive MS than immunology, then we may miss a few tricks and may not do the most informative experiments.

Hey Ho Back to work

4 comments:

  1. I just cant wrap my head around fecal transplant. It is used towards some disorders. I suppose there are worse things, like owning a 1962 MGB :)

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  2. Here you go: http://www.gizmag.com/gut-brain-inflammation-link/43274/

    Furthermore: "High tryptophan foods include nuts, seeds, tofu, cheese, red meat, chicken, turkey, fish, oats, beans, lentils, and eggs. The recommended daily intake for tryptophan is 4mg per kilogram of body weight, or 1.8mg per pound."

    MD: Will we see yon on the 18th of June at the MS Research Day?

    Tony Fonda

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  3. Surely something has in this "mush"...

    A good gut microbiota provides the proper absorption of vitamins and minerals, particularly the so-called vitamin D, especially its shape D3 ...

    ReplyDelete
    Replies
    1. Proceeding, seems that vitamin D regulates the activity of the gut microbiota...

      http://www.ncbi.nlm.nih.gov/pubmed/23966330

      Delete

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