Bacterial neurotoxic metabolites in multiple sclerosis cerebrospinal fluid and plasma

[nerd]

Authors: Achilles Ntranos, Hye-Jin Park, Maureen Wentling, Vladimir Tolstikov, Mario Amatruda, Benjamin Inbar, Seunghee Kim-Schulze, Carol Frazier, Judy Button, Michael A Kiebish,
Fred Lublin, Keith Edwards, Patrizia Casaccia
Published on: December 11, 2021
doi: 10.1093/brain/awab320

Abstract

The identification of intestinal dysbiosis in patients with neurological and psychiatric disorders has highlighted the importance of gut-brain communication and yet, the question regarding the identity of the components responsible for this cross talk remains open. We previously reported that relapsing remitting multiple sclerosis patients (RRMS) treated with dimethyl fumarate have a prominent depletion of the gut microbiota, thereby suggesting that studying the composition of plasma and cerebrospinal fluid (CSF) samples from these patients may help to identify microbially derived metabolites. We used a functional xenogeneic assay consisting of cultured rat neurons exposed to CSF samples collected from multiple sclerosis patients before and after dimethyl fumarate treatment to assess neurotoxicity and then conducted a metabolomic analysis of plasma and CSF samples to identify metabolites with differential abundance. A weighted correlation network analysis, allowed us to identify groups of metabolites, present in plasma and CSF samples, whose abundance correlated with the neurotoxic potential of the CSF. This analysis identified the presence of phenol and indole group metabolites of bacterial origin (e.g. p-cresol-sulfate, indoxyl-sulfate and N-phenylacetylglutamine) as potentially neurotoxic and decreased by treatment. Chronic exposure of cultured neurons to these metabolites impaired their firing rate and induced axonal damage, independent from mitochondrial dysfunction and oxidative stress, thereby identifying a novel pathway of neurotoxicity. Clinical, radiological and cognitive test metrics were also collected in treated patients at follow-up visits. Improved MRI metrics, disability and cognition were only detected in dimethyl fumarate -treated RRMS patients. The levels of the identified metabolites of bacterial origin (p-cresol-sulfate, indoxyl-sulfate and N-phenyl-acetyl-glutamine) were inversely correlated to MRI measurements of cortical volume and directly correlated to the levels of neurofilament light chain, an established biomarker of neurodegeneration. Our data suggest that phenol and indole derivatives from the catabolism of tryptophan and phenylalanine are microbially derived metabolites, which may mediate gut-brain communication and induce neurotoxicity in multiple sclerosis.

 

[Consul]

Seems like a very significant finding. Are there any good arguments that me/cfs cant be the same problem, i.d neurotoxins? E.g it seems like MS can be progressive and i never heard that in me/cfs.

Here is a writeup with researcher commentary
https://www.sciencedaily.com/releases/2021/12/211220190638.htm

 

[nerd]

Seems like a very significant finding. Are there any good arguments that me/cfs cant be the same problem, i.d neurotoxins? E.g it seems like MS can be progressive and i never heard that in me/cfs.

Here is a writeup with researcher commentary
https://www.sciencedaily.com/releases/2021/12/211220190638.htm

I can't say that I see contradictory finding that excludes neurotoxins. Whatever pathology researchers find, it almost always can be traced back to the autonomous nervous system, the brain stem. The brain stem is the susceptible part of the brain that can be exposed to more toxins from the blood or CSF. Structural problems with the spine can enhance the issue.

This doesn't mean that ME and Ms are the same. As far as I can tell, the neurons of MS and ME patients have different abnormalities. But I can only support that with theories and indirect pathology because barely anyone has looked at neurons in ME. As far as I remember, not even Cortene looked at it in affected individuals.

What you would be looking for is an explanation for why MS manifests itself as neurodegenerative and ME doesn't. One could argue that the mechanism that is responsible for the ME symptoms might be neuroprotective and protect the patients from neurodegeneration. Because what presumably happens in ME is that the neurons get overstimulated. If they had issues firing, the overstimulation would compensate for that while also changing the receptor hemostasis and increasing the glial activity baseline, which makes one prone to neurological symptoms upon immune activation.

But we could also look at it from a etiological perspective. The etiological factors and demographics seem to be consistent: Viral infection, presumably genes, overrepresentation of females, lack of Vitamin D. But I can't say that I have looked at the MS etiology in depth, so this is just scratching the surface.

I don't even know how these neurotoxin findings fit into this in the case of MS. Vitamin D and gender might relate to monocyte migration, their transport of toxins at the BBB and the permeability of the BBB. Low Vitamin D might not be part of the etiology but a correlating factor in that more of it is depleted. Viral infection might just be a correlating factor in that viruses reactivate more easily. All of this can be consistent for MS and ME as far as the evidence and models go.

Maybe I'm overlooking something. My knowledge of MS is only superficial.