Bacterial neurotoxic metabolites in multiple sclerosis cerebrospinal fluid and plasma

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.

Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging

“…Sulfidogenic bacteria in the human gut produce hydrogen sulfide; the role of hydrogen sulfide could not only promote NF occurrence but also protect the luminal surface of the colon ( 133 , 212 ). Phenol and indole derivatives in the serum of MS patients were gut-microbiota-generated metabolites, including p-cresol-sulfate, indoxyl-sulfate, and N-phenyl-acetyl-glutamine, which had chronic neurotoxicity to the cultured neurons ( 213 ). In vivo , these bacterial origins were negatively correlated with the patient’s cortical volume and positively correlated with neurofilament light chain ( 213 ).…”

“…Phenol and indole derivatives in the serum of MS patients were gut-microbiota-generated metabolites, including p-cresol-sulfate, indoxyl-sulfate, and N-phenyl-acetyl-glutamine, which had chronic neurotoxicity to the cultured neurons ( 213 ). In vivo , these bacterial origins were negatively correlated with the patient’s cortical volume and positively correlated with neurofilament light chain ( 213 ). Altogether, the gut microbiota not only induces systemic inflammation but also releases neurotoxic metabolites to promote MS.…”

How Microbiota-Derived Metabolites Link the Gut to the Brain during Neuroinflammation

“…Kynurenate, which has neuroprotective action, is also increased in relapse–remitting pwMS compared to controls [ 84 ]. Conversely, decreased levels of kynurenate in the CSF of pwMS are observed [ 85 ]. Interestingly, the quinolinate/kynurenate ratio correlates strongly with EDSS severity and is elevated in PPMS and SPMS [ 84 ].…”

Microbial Metabolites in Multiple Sclerosis: Implications for Pathogenesis and Treatment

“…In this regard, the role of the metabolites produced by the gut microbiota is of increasing interest. It is known that some metabolites, such as p-cresol sulfate, indoxyl sulfate, and n-phenylacetylglutamine have neurotoxic effects ( Ntranos et al, 2021 ), while others have a clear role in normal host physiology, for example, immune modulation, tolerance ( van der Hee and Wells, 2021 ), and in the gut-brain axis ( Dalile et al, 2019 ; O’Riordan et al, 2022 ). Therapies based on the modulation of gut microbiota or even personalized nutrition are now being explored and may be considered promising therapeutic approaches when used either as a monotherapy or in combination with standard treatment.…”