Genes involved in methanogenesis and related methanogenesis pathway enzymes are overrepresented in the gut microbiome of patients with pediatric-onset multiple sclerosis (MS), according to a study in Neurology.

In pediatric-onset multiple sclerosis, the functional potential of the gut microbiome is not understood in part due to a lack of studies that use metagenomic sequencing, according to the researchers. Metagenomic sequencing allows for the assessment of all the genes in the gut microbiome and determine the “abundance of microbial functions,” they stated. The objective of the current study was to assess the functional potential of the gut microbiome in patients with pediatric-onset MS and unaffected control individuals using stool samples.

Researchers compared the gut microbiome’s metabolic pathways, gene functions, and microbial taxonomy in patients with and without pediatric-onset MS with use of metagenomic analysis of stool samples.

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Eligible participants were aged 21 years or younger from 1 of 23 sites in Canada and 1 site in the United States associated with the Canadian Pediatric Demyelinating Disease Network (CPDDS). The participants provided a stool sample between 2015 and 2019 and had not taken antibiotics or corticosteroids within the previous 30 days.

A total of 20 patients with pediatric-onset MS were matched with 20 healthy control individuals according to sex, age, stool consistency, and, when possible, by race. MS patients had a mean age of 16.1 years vs 15.4 years for controls. In both groups, 80% of participants were female, and 11 patients with MS and 9 control individuals self-identified as White.

The patients with pediatric-onset MS did not differ compared with the control individuals regarding richness and diversity of gut microbiome enzymes and proteins (P >.30). Also, no differences were observed for disease-modifying drug exposure (P >.20) between the 2 groups, although differences were found in metabolic pathways, gene annotations, and microbial taxonomy.

Lower relative levels were observed in MS patients for peptidoglycan maturation (meso-diaminopimelate containing), homolactic fermentation, superpathway of pyrimidine ribonucleosides salvage, and glycolysis II (from fructose 6-phosphate), with a log2 fold-change ranging from –0.46 to –0.54 (all P <.046; q >.77).

Among 245 metabolic pathways that were identified, 3 were more prevalent in the MS patients vs the control group and included L-glutamate degradation VIII (to propanoate) and 2 archaeal pathways, methanogenesis from H2 and CO2 and flavin biosynthesis II (odds ratio >9.0, P <.047, q = 1.0).

The gene function annotations that had the largest log2 fold-change in relative abundance between the patients with MS and control individuals were methanogenesis (methane production from Archaea), viral (bacteriophage) genome packaging, archaeal flavin biosynthesis, and enterobactin syntheses (bacterial secreted compound to acquire iron). All were higher in the MS patients, with log2 fold-changes ranging from 1.9 to 4.7 (P values ranged from 0.0031 to 0.030, and q values ranged from 0.81 to 1.0).

Methanogens were more prevalent in patients with MS, including the genus Methanobrevibacter and its species, M. smithii (log2 fold-change = 2.69; P =.0076; q = 1.0).

The researchers noted that their small sample size limited their ability to assess the impact of potentially important cohort characteristics including diet.

“Our findings can be considered as hypotheses-generating, worthy of validation and further investigation, preferably in large longitudinal studies capable of establishing the potential causal relationship of the gut microbiome with MS, and the contribution of other factors, such as dietary patterns,” the researchers concluded.

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Mirza AI, Zhu F, Knox N, et al. Metagenomic analysis of the pediatric-onset multiple sclerosis gut microbiome. Neurology. Published online December 22, 2021. doi:10.1212/WNL.0000000000013245